ANBL09P1DOC

Activated:10/04/10 Amendment # 6
Closed: 01/06/16 Version Date: 09/24/14
CHILDREN'S ONCOLOGY GROUP
ANBL09P1
A COG Pilot Study of Intensive Induction Chemotherapy and 131I-MIBG Followed by

Myeloablative Busulfan/Melphalan (Bu/Mel) for Newly Diagnosed High-Risk Neuroblastoma
A Limited Institution Pilot Study
IND sponsor for 131I-MIBG: Jubilant Draximage Inc
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY
OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED
TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH MEANS A
SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO
DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED
BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE
INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE PROCEDURES
IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED
SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON WHO REQUIRES
MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE
NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION.
STUDY CHAIR
Brian Weiss, MD
Cincinnati Children’s Hospital Medical Center
3333 Burnet Avenue, MLC 7013
Cincinnati, OH 45229
Phone: (513) 636-9863
Fax: (513) 636-3549
E-mail: brian.weiss@cchmc.org
For Statistics and Data Center Contact Person see: http://members.childrensoncologygroup.org
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List of participating institutions
NO. NAME OF THE INSTITUTION

1 UCSF Medical School – Parnassus*
2 C.S Mott Children’s Hospital*
3 Children’s Hospital of Philadelphia*
4 Cincinnati Children’s Hospital Medical Center*
5 Dana Farber Cancer Institute*
6 Connecticut Children’s Medical Center
7 Phoenix Children’s Hospital
8 Medical University of South Carolina
9 UT Southwestern Medical Center
10 Children’s Hospital Los Angeles*
11 Children’s Hospital Colorado*
12 Children’s National Medical Center
13 Primary Children’s Hospital
14 University of Chicago*
15 Children’s Hospital of Alabama
16 University of Wisconsin Hospital and Clinics*
17 Duke University Medical Center*
18 Children's Healthcare of Atlanta – Egleston*
19 Midwest Children's Cancer Center
20 Seattle Children's Hospital*
21 Providence Sacred Heart Medical Center and Children's Hospital
22 University of North Carolina at Chapel Hill
23 Cook’s Children’s Hospital* %
* MIBG institution. NOTE: All MIBG Institutions MUST treat at least 3 patients on an
expanded access MIBG protocol before treating a subject enrolled on ANBL09P1 with 131I-
MIBG.
%
Will not enroll at initial diagnosis. Will only serve as an MIBG treatment center.
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TABLE OF CONTENTS
SECTION PAGE
STUDY COMMITTEE 9
ABSTRACT 12
EXPERIMENTAL DESIGN SCHEMA 13
1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 14
1.1 Primary Aim 14
1.2 Secondary Aim 14
1.3 Exploratory Aims 14
2.0 BACKGROUND 14
2.1 Meta-iodobenzylguanidine Therapy 15
2.2 Busulfan/Melphalan Transplant Conditioning for Neuroblastoma 15
131
2.3 Bu/Mel Transplant Following I-MIBG Therapy 16
2.4 Update as of Amendment #4A: 131I-MIBG Dose and Removal of Irinotecan/Vincristine
from MIBG Therapy 17
2.5 Topotecan 18
2.6 Topotecan/Cyclophosphamide-Based Induction Chemotherapy 19
2.7 Timing of Primary Tumor Resection 20
2.8 Radiotherapy as a Component of Local Control 20
2.9 Treatment of Minimal Residual Disease 21
2.10 Feasibility Studies 22
2.11 Correlative Studies 22
2.12 Significance 23
3.0 ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 24
3.1 Study Enrollment 24
3.1.1 Patient Registration 24
3.1.2 IRB Approval 25
3.1.3 Reservation Requirements 25
3.1.4 Enrollment on Biology Study ANBL00B1 25
3.1.5 Study Enrollment on ANBL09P1 26
3.1.6 Timing 26
3.2 Patient Criteria 26
3.2.1 Age 26
3.2.2 Diagnosis 26
3.2.3 Prior Therapy 27
3.2.4 Organ Function Requirements: 27
3.2.5 Exclusion Criteria 28
3.2.6 Regulatory 28
4.0 TREATMENT PROGRAM 29
4.1 Overview and General Guidelines 29
4.1.1 Notification of MIBG Treatment Center 30
4.1.2 Central Line 30
4.1.3 Chemotherapy Dose-Adjustment for Weight 30
4.1.4 Parenteral Chemotherapy Administration Guidelines 30
4.1.5 Concomitant Therapy 30
4.2 Induction Therapy 32
4.2.1 Induction Cycle 1 (Weeks 1-3) 32
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131
4.3 I-MIBG Induction Therapy Block 43
4.3.1 Criteria to Proceed to 131I-MIBG Induction Therapy: 43
4.3.2 131I-MIBG Therapy 43
4.4 Busulfan/Melphalan Consolidation Therapy 48
4.4.1 Criteria to Start Consolidation Therapy 48
4.4.2 Busulfan/Melphalan Auto Transplant Regimen 49
4.4.3 External Beam Radiotherapy 52
4.5 Maintenance Therapy 53
4.5.1 Criteria to Start Maintenance Therapy 53
4.5.2 Maintenance Therapy (Weeks 31-54) 53
5.0 DOSE MODIFICATIONS FOR TOXICITIES 55
5.1 Myelosuppression during Induction 55
5.1.1 Hematopoietic Recovery Criteria 55
5.2 Hematuria during Induction 55
5.3 Renal Toxicity during Induction 56
5.3.1 Cisplatin 56
5.3.2 Cyclophosphamide, Doxorubicin, Vincristine, Topotecan and Etoposide 56
5.4 Cardiac Toxicity during Induction 56
5.4.1 For Change In Ejection/Shortening Fraction 56
5.4.2 For Symptomatic Congestive Heart Failure (CHF) 57
5.4.3 For Dysrhythmia 57
5.4.4 Hypertension 57
5.5 Hepatotoxicity during Cycles 1-5 of Induction 57
5.6 Gastrointestinal Toxicity during Cycles 1-5 of Induction 57
5.6.1 Mucositis 57
5.6.2 Diarrhea 58
5.7 Ototoxicity during Induction 58
5.8 Neurologic Toxicity during Induction 58
5.9 Allergic Reactions 58
5.9.1 Etoposide 58
5.9.2 Cisplatin 58
5.10 Other Toxicities during Induction 58
5.11 Dose Modifications for Isotretinoin Therapy 59
6.0 DRUG INFORMATION 60
6.1 IOBENGUANE I-131 MIBG 60
6.2 BUSULFAN INJECTION 63
6.3 CISPLATIN 65
6.4 CYCLOPHOSPHAMIDE INJECTION 67
6.5 DOXORUBICIN 68
6.6 ETOPOSIDE_IV ONLY 70
6.7 FILGRASTIM 72
6.8 ISOTRETINOIN 73
6.9 MELPHALAN 77
6.10 MESNA IV ONLY 79
6.11 PEGFILGRASTIM 80
6.12 SATURATED SOLUTION POTASSIUM IODIDE (SSKI®) 81
6.13 TOPOTECAN HYDROCHLORIDE 82
6.14 VINCRISTINE SULFATE 84
7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 86
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7.1 Required Clinical, Laboratory and Disease Evaluations 86

7.1.1 Required and Optional Observations for Pre-Treatment and Induction 86
7.1.2 Required and Optional Observations for Consolidation 88
7.1.3 Recommended Timepoints for Busulfan Pharmacokinetic Studies* (See
Section 14.3). 89
7.1.4 Required Observations for Maintenance 89
7.1.5 Required & Recommended Observations for Post-Maintenance Follow-up 90
8.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY
CRITERIA 91
8.1 Off-Protocol Therapy Criteria 91
8.2 Off Study Criteria 92
9.0 STATISTICAL CONSIDERATIONS 92
9.1 Statistical Design 92
9.1.1 Dose Escalation and Determination of MTD 92
9.1.2 Dose Expansion 93
9.2 Patient Accrual and Expected Duration of Trial 94
9.2.1 Accrual 94
9.2.2 Evaluability 97
9.3 Methods of Analysis 97
9.3.1 Primary Endpoints 97
9.3.2 Secondary and Exploratory Endpoints 98
9.3.3 Monitoring Rule for Tolerability at Each Dose Level 99
9.4 Assessment of Study Objectives 100
9.5 Gender and Minority Accrual Estimates 101
10.0 EVALUATION CRITERIA 101
10.1 Common Terminology Criteria for Adverse Events (CTCAE) 101
10.2 Response Criteria for Patients with Solid Tumors 102
10.3 International Staging System72 102
10.4 International Response Criteria72 102
10.4.1 Complete Response (CR)** 102
10.4.2 Very Good Partial Response (VGPR) 102
10.4.3 Partial Response (PR) 102
10.4.4 Mixed Response (MR) 102
10.4.5 No Response (NR) 103
10.4.6 Progressive disease (PD)** 103
11.0 ADVERSE EVENT REPORTING REQUIREMENTS 103
11.1 Purpose 103
11.2 Determination of reporting requirements 103
11.3 Steps to determine if an adverse event is to be reported in an expedited manner 104
11.4 Reporting methods 104
11.5 When to report an event in an expedited manner 105
11.6 Other recipients of adverse event reports 105
11.7 Reporting of Adverse Events for investigational agents 105
11.8 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated
pathway 107
11.9 Routine Adverse Event Reporting and Study-Specific Expedited Adverse Event
Reporting 107
12.0 RECORDS AND REPORTING 108
12.1 Categories of Research Records 108
12.2 CDUS 108
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12.3 Data and Safety Monitoring Committee 108

13.0 SURGICAL GUIDELINES 109
13.1 Surgical Rationale 109
13.2 Pre-Operative Management 109
13.3 Specimen/Sampling Requirements 109
13.4 Operative Management 110
13.4.1 Central Line Placement 110
13.4.2 Diagnostic Surgery 110
13.4.3 Epidural Tumors with Intraspinal Extension 110
13.4.4 Operative Management of Primary Tumors after Chemotherapy 111
13.5 Management of Surgical Complications 111
13.5.1 Intraoperative Complications 111
13.5.2 Post-Operative Complications 111
13.6 Special techniques 112
13.6.1 Nerve Stimulation 112
13.6.2 Ultrasonic Dissector-Aspirators 112
13.6.3 Thoracoscopy 112
13.6.4 Laparoscopy 112
13.6.5 Radiofrequency Ablation, Cryosurgery 112
14.0 PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 113
14.1 Rapid Pathology Review 113
14.1.1 Tracking Center Activity 113
14.1.2 Diagnostic Concordance Study 113
14.1.3 Review Material Required at Diagnosis 113
14.1.4 Review Material at Second Look or Definitive Surgery and/or Relapse 113
14.1.5 Autopsy Review 113
14.1.6 Specimen Shipping 114
14.2 Norepinephrine transporter (hNET) expression tests 114
14.3 Pharmacokinetics for Busulfan Dose Adjustments 115
14.3.1 Busulfan Pharmacokinetics 115
14.3.2 Shipping 115
14.3.3 Guidelines for Adjusting Busulfan Dosing Based on Results of
Pharmacokinetic Studies 116
15.0 SPECIAL STUDIES SPECIMEN REQUIREMENTS 116
15.1 Biologic Requirements 116
16.0 IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 117
16.1 CT Scans 117
16.2 MRI Scans 117
16.3 [18F]–Fluorodeoxyglucose (18FDG)-PET Scintigraphy 117
16.4 MIBG Scintigraphy 119
16.5 Plain Film Radiography 120
16.6 Tumor Measurement 120
16.7 Central Review of MIBG and FDG-PET scans 120
17.0 RADIATION THERAPY GUIDELINES 121
17.0.1 General Guidelines 121
17.0.2 Required Benchmark and Questionnaires 122
17.0.3 Guidelines and Requirements for the Use of IMRT 122
17.0.4 Guidelines and Requirements for the Use of Proton Therapy 122
17.1 Indications for Radiation Therapy 122
17.1.1 Treatment Sites and Doses 122
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17.2 Timing of Radiation Therapy 123

17.3 Emergency Radiation 123
17.4 Equipment and Methods of Delivery and Verification 124
17.4.1 Modality 124
17.4.2 Treatment planning 124
17.4.3 In-room verification of spatial positioning 124
17.4.4 Evaluation and Management of Target and Normal Tissue Motion 124
17.4.5 Calibration 125
17.5 Target Volume Definitions 125
17.5.1 Primary Site 125
17.5.2 Metastatic Sites 127
17.5.3 Peritoneal Cavity 128
17.5.4 Liver 128
17.5.5 Thorax 128
17.5.6 Contralateral Kidney 128
17.6 Target Dose 128
17.6.1 Dose Definition and Specification 128
17.6.2 Prescription Dose and Fractionation 128
17.6.3 Tissue Heterogeneity 129
17.6.4 Dose Uniformity 129
17.6.5 Interruptions and Delays 129
17.7 Treatment Technique 129
17.7.1 Beam Configuration 129
17.7.2 Selection of Proton Beam Arrangements 130
17.7.3 Patient Position 130
17.7.4 Field Shaping 130
17.7.5 Special Consideration for Patient Simulation for Protons 130
17.8 Organs at Risk 130
17.8.1 Normal Tissue Tolerances and Special Site Volume Considerations 131
17.9 Dose Calculations and Reporting 131
17.9.1 Prescribed Dose 131
17.9.2 Prescription Point 131
17.9.3 Normal Tissues Dosimetry 131
17.10 Quality Assurance Documentation 132
17.10.1 Submission of Diagnostic Imaging Data 132
17.10.2 Submission of Radiotherapy Data 132
17.10.4 Metastatic Site(s) Data Submission 133
17.11 Definitions of Deviations in Protocol Performance 134
17.12 Patterns of Failure Evaluation 134
18.0 HEMATOPOIETIC STEM CELL COLLECTION AND TRANSPLANT GUIDELINES 135
18.1 Catheter Use 135
18.2 PBSC Mobilization 135
18.3 PBSC Collection Guidelines 135
18.3.1 Laboratory Studies 135
18.3.2 Apheresis Machine 135
18.3.3 Blood Priming 135
18.3.4 Collection Goals 136
18.4 PBSC Analyses 136
18.5 Cryopreservation of PBSC Products 136
18.6 Autologous Stem Cell Rescue 136
18.6.1 Premedication 136
18.6.2 Thawing of PBSC 136
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18.6.3 Possible Symptoms during Infusion 137

18.6.4 Infusion Dosage/Timing 137
18.6.5 Recommendations for Stem Cell Infusion 137
131
19.0 I-MIBG THERAPY FEASIBILITY ASSESSMENT 137
APPENDIX I: CTEP REGISTRATION PROCEDURES 138
APPENDIX II: RISK ASSESSMENT AND ADDITIONAL BIOLOGICAL STUDIES 139
APPENDIX III: INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM (INSS) 140
APPENDIX IV: TUMOR SIZE MEASUREMENTS BY CROSS-SECTIONAL IMAGING 141
APPENDIX V: NEUROBLASTOMA RESPONSE CRITERIA 142
APPENDIX VI: LIST OF DRUGS THAT INTERFERE WITH MIBG 143
APPENDIX VII: QUALITY CONTROL FOR FREE IODINE IN 131I-MIBG 145
APPENDIX VIII: PATIENT QUESTIONNAIRE FOR MIBG TREATMENT COSTS 146
APPENDIX IX: YOUTH SUMMARIES FOR CHILDREN AND TEENS 148
APPENDIX X: ANATOMICAL REFERENCE DIAGRAM FOR USE IN FDG-PET LESION
SCORING BY INSTITUTIONS 150
APPENDIX XI: POSSIBLE DRUG INTERACTIONS 151
REFERENCES 156
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THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ANBL09P1
STUDY COMMITTEE
STUDY CHAIR STUDY COMMITTEE MEMBERS
Brian Weiss, MD Julie Park, MD
Hematology/Oncology Hematology/Oncology
Cincinnati Children’s Hospital Medical Center Seattle Children’s Hospital
3333 Burnet Ave, MLC 7015 Dept of Hematology/Oncology
Cincinnati, Ohio 45229-3039 M/S MB.8.501, PO Box 5371
Phone: (513) 636-9863 Seattle, WA 98145
Fax: (513) 636-3549 Phone: (206) 987-2106
E-mail: brian.weiss@cchmc.org Fax: (206) 987-3946
E-mail: julie.park@seattlechildrens.org
STUDY VICE CHAIR
Katherine K. Matthay, MD Peter Mattei, MD
Hematology/Oncology Surgery
UCSF Medical Center - Parnassus Children’s Hospital of Philadelphia
Department of Pediatrics General Surgery
505 Parnassus Avenue RM M647 34th Street and Civic Center Blvd
San Francisco, CA 94143-0106 Philadelphia, PA 19104-4399
Phone: (415) 476-3831 Phone: (215) 590-4981
Fax: (415) 502-4372 Fax: (215) 386-4036
E-mail: matthayk@peds.ucsf.edu E-mail: mattei@email.chop.edu
STUDY STATISTICIAN Hiroyuki Shimada, MD

Arlene Naranjo, PhD Pathology
Biostatistics Childrens Hospital of Los Angeles
Childrens’s Oncology Group - Data Center (Gaines) 4650 Sunset Boulevard, MS43
University of Florida – Dept of Biostatistics Los Angeles, CA 90027
6011 NW 1st Place Phone: (323) 361-2377
Gainesville, FL 32607 Fax: (323) 667-1123
Phone: (352) 273-0577 E-mail: hshimada@chla.usc.edu
Fax: (352) 392-8162
E-mail: anaranjo@cog.ufl.edu Jason Anthony Jarzembowski, MD PhD
Pathology
STUDY COMMITTEE MEMBERS Midwest Children's Cancer Center
Barry Shulkin, MD Pathology
Diagnostic Imaging 9000 W. Wisconsin Avenue
St. Jude Children’s Research Hospital Milwaukee, WI 53201
Radiological Sciences Phone: (414) 266-2526
262 Danny Thomas Place MS 220 Fax: (414) 266-2779
Memphis, Tennessee 38105-3678 Email: jjarzemb@mcw.edu
Phone: (901) 595-3347
Fax: (901) 595-3981 Hollie Jackson, MD
E-mail: barry.shulkin@stjude.org Diagnostic Imaging
Children’s Hospital of Los Angeles
Yael Mosse, MD Radiology
Hematology/Oncology 4650 Sunset Blvd., MS81
Childrens Hospital of Philadelphia Los Angeles, CA 90027
Div of Oncology, The Colket Translation Research Bldg. Phone: (323) 361-2411
3501 Civic Center Boulevard, 3056 Fax: (323) 666-4655
Philadelphia, PA 19104 E-mail: hjackson@chla.usc.edu
Phone: (215) 590-0965
Fax: (267) 426-0685
E-mail: mosse@chop.edu
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Roger Giller, MD Gregory Yanik, MD

Hematology/Oncology Hematology/Oncology
Children’s Hospital Colorado C.S. Mott Children’s Hospital
Center for Cancer & Blood Disorders Dept of Peds, BMT Program
13123 E. 16th Ave. B115 5303 CCGC, SPC-5914, 1500 E. Medical Center Drive
Aurora, CO 80045 Ann Arbor, MI 48109-5914
Phone: (720) 777-6892 Phone: (734) 764-8630
Fax: (720) 777-7289 Fax: (734) 936-8788
E-mail: roger.giller@childrenscolorado.org E-mail: gyanik@med.umich.edu
Stephan A. Grupp, MD PhD Judith Villablanca, MD

Stem Cell Transplantation Hematology/Oncology
Children’s Hospital of Philadelphia Children’s Hospital of Los Angeles
Division of Pediatric Oncology Division of Hematology/Oncology
Abramson 902, 3615 Civic Center Blvd. 4650 Sunset Blvd., MS54
Philadelphia, PA 19104 Los Angeles, CA 90027
Phone: (215) 590 -5475 Phone: (323) 361-5654
Fax: (215) 590 -3770 Fax: (323) 660-7128
E-mail: Grupp@email.chop.edu E-mail: jvillablanca@chla.usc.edu
Heidi Russell, MD Laurie Grimme, CCRP

Hematology/Oncology Clinical Research Associate
Baylor College of Medicine Cincinnati Children’s Hospital Medical Center
Cancer Center & Hematology Service Dept of Pediatric Hem-Onc
6621 Fannin St MC 3-3320 3333 Burnet Ave.
Houston, TX 77030-2399 Cincinnati, OH 45229-3039
Phone: (832) 822-4277 Phone: (513) 636-8616
Fax: (832) 825-1503 Fax: (513) 636-5845
E-mail: hvrussel@txch.org E-mail: laurie.grimme@cchmc.org
RADIATION THERAPY STUDY Hsiao-Ming Lu, Ph.D.

COORDINATOR Radiation Oncology
Shannon MacDonald, MD Massachusetts General Hospital Cancer Center
Radiation Oncology Francis H. Burr Proton Therapy Center, Room 112
Massachusetts General Hospital Cancer Center 30 Fruit Street,
Radiation Oncology Boston, MA 02114
100 Blossom Street, Cox 3 Phone: (617) 726-6924
Boston, MA 02114 Fax: (617) 724-9532
Phone: (617) 726-5184 E-mail: hmlu@partners.org
Fax: (617) 726-3603
E-mail: smacdonald@partners.org Sheena Christine Cretella, MSPH
Statistics
Luke Edmond Pater, MD COG Data Center
Radiation Oncology Biostatistics
Cincinnati Children's Hospital Medical Center Univeristy of Florida
3333 Burnet Avenue 6011 NW 1st Place
Cincinnati OH 45229 Gainesville, FL 32607
Phone: (513) 584-0510 Phone: (352) 273-0565
Email: luke.pater@uchealth.com Fax: (352) 392-8162
E-mail: scretella@cog.ufl.edu
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Wendy Fitzgerald, RN MSN PNP-BC RESEARCH COORDINATOR

Nursing Dina C. Willis
Children’s National Medical Center Children's Oncology Group - Data Center (Gaines)
Center for Cancer & Blood Disorders 6011 NW 1st Place
111 Michigan Avenue, N.W. Gainesville FL 32607
Washington, District of Columbia 20010-2970 Phone: (352) 273-0562
Phone: 202 476 -3603 Fax: (352) 392-8162
E-mail: WFitzger@childrensnational.org E-mail: dwillis@cog.ufl.edu
AGENT NSC# IND#

Busulfan 750 Exempt
Cisplatin 119875 Exempt
Cyclophosphamide 26271 Exempt
Doxorubicin 123127 Exempt
Etoposide 141540 Exempt
Filgrastim 614629 Exempt
Iobenguane 131I-MIBG 76,227
Isotretinoin, Accutane 329481 Exempt
Melphalan 008806 Exempt
Mesna 113891 Exempt
Pegfilgrastim 725961 Exempt
Topotecan 609699 Exempt
Vincristine 67574 Exempt
IND sponsor for 131I-MIBG: Jubilant Draximage Inc
SEE SECTIONS 14 & 15 FOR SPECIMEN SHIPPING ADDRESSES
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government,
which will help us protect the privacy of our research subjects. The Certificate protects against the involuntary
release of information about your subjects collected during the course of our covered studies. The researchers
involved in the studies cannot be forced to disclose the identity or any information collected in the study in any
legal proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or
legislative proceedings. However, the subject or the researcher may choose to voluntarily disclose the protected
information under certain circumstances. For example, if the subject or his/her guardian requests the release of
information in writing, the Certificate does not protect against that voluntary disclosure. Furthermore, federal
agencies may review our records under limited circumstances, such as a DHHS request for information for an
audit or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. The Certificate of
Confidentiality will not protect against mandatory disclosure by the researchers of information on suspected
child abuse, reportable communicable diseases, and/or possible threat of harm to self or others.
ABSTRACT
This limited participation pilot study for children with newly diagnosed High-Risk neuroblastoma assesses
the tolerability and feasibility of an Induction regimen containing 5 cycles of multi-agent chemotherapy and
a block of 131I-MIBG followed by a Consolidation regimen of busulfan/melphalan (Bu/Mel) with autologous
stem cell rescue (ASCR) and external beam radiation therapy. Patients will receive Induction chemotherapy,
stem cell harvest, and surgical resection at the enrolling institution followed by 131I-MIBG treatment at one
of the participating MIBG institutions. In order to monitor patient progress closely while allowing for timely
study completion, consecutive patients will be enrolled in the study but the dose of 131I-MIBG therapy will
depend upon toxicities observed in previous patients. Cohorts of patients will be followed for toxicity until
Day 28 after the Bu/Mel ASCR Consolidation before the next cohort of patients is treated at a higher dose of
131
I-MIBG. Cohorts of patients will be treated as per a rolling six design starting at 15 mCi/kg 131I-MIBG,
with escalation to 18 mCi/kg 131I-MIBG if 15 mCi/kg is not the maximally tolerated dose. There will also be
a built in dose de-escalation while observing for the occurrence of dose limiting toxicities through Day 28
after Bu/Mel Consolidation. Specifically, patients may receive 12 mCi/kg 131I-MIBG while awaiting
determination of dose limiting toxicities at 15 mCi/kg 131I-MIBG or may be treated at 15 mCi/kg 131I-MIBG
while awaiting determination of dose limiting toxicities at 18 mCi/kg 131I-MIBG. There will be a maximum
of 18 patients at each dose level. A review of toxicities experienced from MIBG therapy through Bu/Mel
ASCR Consolidation in the entire cohort of 18 patients at each MIBG dose will be assessed and also utilized
to determine the dose of 131I-MIBG to be utilized in future trials. ASCR will be used to ensure prompt
hematologic recovery after 131I-MIBG therapy. After a 10-12 week rest following 131I-MIBG, patients will
receive Consolidation Bu/Mel chemotherapy and stem cell infusion. Following recovery from Bu/Mel
Consolidation chemotherapy, patients who achieve end of Induction primary site complete response (CR)
will receive 21.6 Gy external beam radiation therapy (EBRT) to the primary site (standard dose) while
patients achieving <CR at the primary site will receive an additional boost of 14.4 Gy for a total dose of
36 Gy EBRT delivered to gross residual primary site disease, as per COG ANBL0532. After recovery from
Consolidation radiation therapy, patients will be encouraged to participate in clinical trials of ch14.18
immunotherapy. Patients ineligible for immunotherapy or those who decline participation will remain on
ANBL09P1 for 6 months of Maintenance therapy using isotretinoin alone based on COG A3973. In order to
more completely understand the feasibility of this treatment protocol, an attempt will be made to quantify the
out-of-pocket expenses incurred by participating families. ANBL09P1 will provide pilot feasibility data for a
future randomized study of whether the addition of 131I-MIBG therapy prior to myeloablative chemotherapy
will improve outcome for children with high risk neuroblastoma.
09/24/14 12
EXPERIMENTAL DESIGN SCHEMA
TOPO: Topotecan CR: Complete Response

CPM: Cyclophosphamide VGPR: Very Good Partial Response
CDDP: Cisplatin PR: Partial Response
VP-16: Etoposide SD: Stable Disease
VCR: Vincristine XRT: Radiation Therapy
DOXO: Doxorubicin ASCR: Autologous Stem Cell Rescue
131 131
I-MIBG: I-Meta-iodobenzylguanidine MRD: Minimal Residual Disease
Bu/Mel: Busulfan/melphalan MR: Mixed Response
* Disease Response time points PBSC: Peripheral Blood Stem Cell
@ Consecutive patients will be enrolled but dose of 131I-MIBG therapy will depend upon toxicities
observed in previous patients.
Note: Patients who travel to another institution for MIBG treatment will be asked to fill out a
questionnaire (see Appendix VI) to help quantify the direct costs of travel and stay during the
course of MIBG treatment.
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1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

1.1 Primary Aim
To assess the feasibility of treating High-Risk neuroblastoma patients, age 365 days - 30 years, with a) an
Induction block of meta-iodobenzylguanidine labeled with iodine-131 (131I-MIBG) delivered after multi-agent
chemotherapy, and b) post-Induction Busulfan/Melphalan (Bu/Mel) Consolidation therapy.
1.2 Secondary Aim
1.2.1
To assess the tolerability of treating High-Risk neuroblastoma patients, age 365 days - 30 years, with a) an
Induction block of 131I-MIBG therapy delivered after multi-agent chemotherapy, and b) the tolerability of
receiving post-Induction Bu/Mel Consolidation therapy with ASCR, and local radiation therapy.
1.3 Exploratory Aims

1.3.1
To assess the response rate after a regimen of Induction chemotherapy and 131I-MIBG and after a Consolidation
regimen of Bu/Mel with ASCR and local radiation therapy.
1.3.2
To describe the relationship of tumor norepinephrine transporter (hNET) expression with radioiodinated MIBG
uptake, at diagnosis as well as with tumor response.
1.3.3
To assess the relative reliability of 123I-MIBG and 18
FDG-PET imaging in assessment of tumor activity at
diagnosis and prior to surgical resection.
1.3.4
To compare detectable tumor burden on the pre-surgical resection radioiodinated -MIBG diagnostic scan and the
immediate post-MIBG therapy 131I-MIBG scan.
1.3.5
To test for the relationship of occurrence of sinusoidal obstruction syndrome (SOS) to Bu/Mel or to whole
body radiation dose or delayed radiation clearance due to 131I-MIBG.
1.3.6
To analyze busulfan pharmacokinetics as measured by area under the curve (AUC) and relate exposure to
SOS incidence. In addition, we will relate adjustments in busulfan dosing to SOS incidence.
2.0 BACKGROUND
Neuroblastoma is an embryonic tumor derived from neural crest and is the most common extra-cranial tumor
of childhood. Despite significant advances in delivering dose-intensive and myeloablative therapy with
hematopoietic stem cell support, the survival for patients presenting with metastatic disease remains poor,
with less than 40% long-term survival.1 The emergence of chemotherapy-resistant tumor cells is the major
obstacle to improving initial tumor response and to curing High-Risk neuroblastoma.1-4 A marked escalation
in dose intensity has resulted in improved initial tumor response rates,5-7 although refractory or progressive
disease still occurs in 10-20% of patients.1,3,4,8 Further dose intensification of Induction therapy is limited by
hematopoietic and mucosal toxicity. Thus, novel therapies to eradicate disease are required to improve
09/24/14 14
survival for children with High-Risk neuroblastoma. The addition of new non-cross resistant agents is
necessary to further improve tumor response rates.
2.1 Meta-iodobenzylguanidine Therapy

Meta-iodobenzylguanidine (MIBG), a norepinephrine analog, is concentrated selectively in sympathetic
nervous tissue, and when labeled with iodine-123 (123I), has become an integral component of staging and
response evaluation in neuroblastoma. MIBG labeled with iodine-131 (131I) has demonstrated activity for
targeted therapy of neuroblastoma, both in relapsed and newly diagnosed patients.9-12 As a single-agent in a
Phase 1 dose-escalation study, 131I-MIBG showed a response rate of 37% in children with relapsed
neuroblastoma13,14 and dose-limiting hematologic toxicity was circumvented with ASCR.15,16 A Phase 2
study showed a 36% response rate and another 34% of patients had stable disease after MIBG therapy.14
Additional work has focused on using 131I-MIBG for patients with newly diagnosed disease. European groups
have evaluated the use of therapeutic MIBG in newly diagnosed patients with neuroblastoma in small studies. In
a Dutch study, the administration of 2 cycles of 131I-MIBG to patients with newly diagnosed metastatic disease
resulted in a 66% response rate,17 suggesting a higher rate of response in newly diagnosed patients.131I-MIBG
therapy has also been incorporated into German studies for patients with residual disease after Induction,12,18 and
the feasibility of this approach has been documented.
The NANT consortium has also evaluated 131I-MIBG as a component of Consolidation therapy for patients
with refractory neuroblastoma. In a Phase 1 study, patients received 131I-MIBG,
Carboplatin/Etoposide/Melphalan (CEM) conditioning and autologous stem cell infusion. Twenty-four
patients with primary refractory MIBG-avid neuroblastoma who had not had a prior ASCR were enrolled
into 2 strata, low-glomerular filtration rate (GFR) and normal-GFR.19 Of the 22 evaluable patients, all
engrafted with a median time for neutrophils ≥ 500/µL of 10 days and a median time for platelets ≥ 20,000
of 26 days. Only 1 of the 24 patients enrolled died from toxicity, and 6 of 22 evaluable patients had a CR or
PR while 15 of 22 had a mixed response (MR) or stable disease (SD). A follow-up NANT Phase 2 trial of
131
I-MIBG and CEM/ASCR (N2001-02) enrolled 50 High-Risk neuroblastoma patients who have not
received a prior ASCR. This study confirmed the tolerability of this approach, with final response data
pending at this time.
131
I-MIBG trials performed to date were not designed to detect a difference in response rates among patients
treated with escalating doses of 131I-MIBG. However, in the Phase 1 study, 11 out of 30 patients had
objective responses (PR or CR), and all of those were treated with cumulative doses that exceeded
10 mCi/kg, while no patient at a lower dose responded.13 In a large Phase 2 study in 164 patients, responses
were seen in 37% of patients receiving 18 mCi/kg and 25% of patients receiving 12 mCi/kg.14 In addition, in
a Phase 1 dose escalation trial of No-Carried Added (NCA) 131I-MIBG, 3 of the 4 responses (CR/PR) in the
16 patients were seen in patients who received the highest dose, 18 mCi/kg.20 These data suggest that there
may be therapeutic advantage to delivery of 18 mCi/kg of 131I-MIBG prior to Consolidation. The current
protocol will therefore investigate tolerability of doses up to 18 mCi/kg 131I-MIBG administered prior to
Bu/Mel transplant conditioning regimen.
2.2 Busulfan/Melphalan Transplant Conditioning for Neuroblastoma

Recent COG studies have made use of the Carboplatin, Etoposide, and Melphalan (CEM) preparative regimen
prior to ASCT. However, results from the European SIOP-EN HR NBL-1 randomized Phase 3 study released in
October of 2010 indicate that the use of Busulfan and Melphalan as a preparative regimen is associated with
improved survival in patients with high risk neuroblastoma that is responsive to initial therapy (Ruth Ladenstein,
personal communication). Patients on this study were treated with the Rapid COJEC Induction regimen
consisting of cycles of carboplatin, etoposide, and vincristine, cisplatin and vincristine, and etoposide,
cyclophosphamide, and vincristine given every 10 days. Those with a favorable response (CR or PR at
metastatic sites, consisting of at least a >50% improvement in skeletal MIBG positivity and not more than
09/24/14 15
3 positive but improved bony sites on MIBG scan) after Rapid COJEC or this Induction followed by topotecan,
vincristine, and doxorubicin were eligible for randomization to either CEM or Bu/Mel. A total of 584 patients
were enrolled; 42% went on to ASCT. Three year EFS for those randomized to receive Bu/Mel was 49 +/- 4%
compared to 33 +/- 3% for those randomized to CEM (p< 0.001). Relapse was more common among those
randomized to CEM rather than Bu/Mel (60% vs 48%; p=0.001). OS was likewise higher among those on the
Bu/Mel arm (61% vs 48%).
The Bu/Mel preparative regimen has been used since the mid-1970s, and the toxicities associated with it have
been well described. Rates of sinusoidal obstruction syndrome (SOS) of up to 40% were observed in European
studies when oral busulfan was used; reduced rates (13%) of SOS were observed when busulfan dosing was
changed to IV.21 Among patients treated with Bu/Mel on the SIOP-EN HR NBL-1 study, 13% and 5%
experience Grades 2 and 3 SOS respectively. There were no deaths attributable to SOS during the study. For the
currently proposed study, busulfan will be administered as an IV infusion with dosing being adjusted using AUC
based on required kinetics. Mucositis and diarrhea are expected complications of Bu/Mel therapy, however rates
of severe gastrointestinal toxicity were lower among patients treated with Bu/Mel than among those treated with
CEM in the SIOP-EN trial (Ruth Ladenstein, personal communication). Rates of pulmonary toxicity ≥Grade 3
did not differ between the two arms.
2.3 Bu/Mel Transplant Following 131I-MIBG Therapy

Several pieces of data suggest that the tolerability of Bu/Mel conditioning will not be compromised by the
use of 131I-MIBG therapy prior to the start of conditioning. First, several studies have evaluated the use of
external beam radiotherapy or targeted 131I radionuclides in conjunction with busulfan-based conditioning
regimens. Pagel et al reported on forty-six patients with AML in first remission who received a dose of 131I-
BC8 antibody (a murine IgG1 reactive with all CD45 isoforms combined with 131I) followed by busulfan
(AUC 600-900 ng/mL)/cyclophosphamide (120 mg/kg) and infusion of allogeneic peripheral blood stem
cells.22 The first 4 patients were treated at dose level 1, receiving 105 to 152 mCi (3885-5624 MBq) of 131I,
estimated to deliver 7.2 to 11.2 (average, 9.2) Gy to bone marrow, 14.8 to 23.1 (average, 17.3) Gy to spleen,
and 3.5 Gy to liver. As none of these patients developed Grade 3/4 regimen-related toxicity, the next
42 patients were treated at dose level 2. They received 102 to 298 mCi (3774- 11 026 MBq) of 131I, estimated
to deliver 5.3 to 19.0 (average, 11.3) Gy to bone marrow, 17.5 to 72.3 (average, 29.7) Gy to spleen, and
5.25 Gy to liver. Eighteen (30%) patients reported nausea and 5 (11%) emesis during the first days following
the therapy dose of antibody, each complication presumably resulting from the radioiodine. All patients were
discharged from radiation isolation by the fourth day after radiolabeled antibody treatment. All patients
developed at least Grade 2 mucositis (Bearman scale) after day zero, with onset typically occurring between
Days 1 to 3 after HCT, and which required narcotic therapy. Three (6.5%) of the 46 patients developed
Grade 3/4 regimen-related toxicities. Two patients treated at dose level 2 developed Grade 3 (life-
threatening) mucositis as defined by the occurrence of aspiration pneumonia. A third patient treated at level
2 was recovering from typical Grade 2 mucositis when he developed a severe exacerbation, documented to
be associated with reactivation of herpes simplex virus and was not considered to be Grade 3 regimen-related
toxicity. No patient developed Grade 3 Sinusoidal Obstruction Syndrome (SOS) of the liver. Eight patients
treated at dose level 2 died of the following transplant-related causes: Sepsis (2), Non-infectious pneumonitis
(1), Viral pneumonia (2), Fungal pneumonia (2), and VZV encephalitis (1). The authors concluded that this
therapy was tolerable and feasible.
Similarly, Burke and colleagues treated 31 patients with relapsed/refractory myeloid leukemia (AML) or
advanced myelodysplastic syndrome (MDS) with the radio-labeled murine IgG2a anti-CD33 antibody 131I-
M195 (122-437 mCi) plus busulfan (16 mg/kg) and cyclophosphamide (90–120 mg/kg) followed by infusion
of related-donor bone marrow23 Gamma camera imaging showed targeting of the radioisotope to the bone
marrow, liver, and spleen, with absorbed radiation doses to the marrow of 272–1470 cGy. Beginning at least
4 days after the last dose of radiolabeled antibody, patients received busulfan 16 mg/kg/day orally in four
divided doses daily for 4 days (Days –7 to 4). A total of 28 patients also received cyclophosphamide
09/24/14 16
60 mg/kg/day IV daily for 2 days. On Day 0, all patients received unmodified bone marrow from related
donors. This schedule allowed 4–5 half-lives of the radioimmunoconjugate to elapse from the last treatment
to the infusion of marrow, leaving only minimal isotope present at the time of BMT.
For this study, SOS was defined as hyperbilirubinemia ≥ 2 mg/dL with at least two of the following findings
occurring within 21 days of transplantation: hepatomegaly with right upper quadrant pain, ascites, or weight
gain 45% of baseline. The regimen-related toxicity seen following intensified conditioning with 131I-M195
was similar to that seen with BuCy alone in this patient population. Hepatic toxicity was most common, with
20 of 29 evaluable patients (69%) developing serum bilirubin levels of ≥ 2mg/dL within the first 28 days
after BMT, and 12 patients (41%) developing Grade 3 or 4 hyperbilirubinemia. There was no significant
correlation between the grade of hyperbilirubinemia and the dose of 131I administered or between the grade
of hyperbilirubinemia and the estimated radiation absorbed dose to the liver, which was calculated in eight
patients. In addition, five patients met criteria for SOS. A total of 12 patients (39%) developed interstitial
pneumonia at a median of 56 days after BMT (range 13–314 days). In some patients with interstitial
pneumonia, multiple infectious organisms were identified, while in three patients with interstitial pneumonia,
no causative organism was identified. Other serious infections included bacteremia (10), bacterial meningitis
(1), sepsis syndrome with no causative organism (1), cellulitis (4), Clostridium difficile colitis (5), CMV
colitis (2), acute pyelonephritis (1), and disseminated aspergillosis (1). These studies have utilized a
radiotherapy component closer in time to busulfan administration than is used in the current study and have
nevertheless demonstrated the tolerability of this approach.
Finally, the aforementioned NANT protocols evaluating 131I-MIBG followed two weeks later with CEM
conditioning have demonstrated that 131I-MIBG can be given in close proximity to myeloablative
chemotherapy in this patient population, albeit with a different conditioning regimen.
2.4 Update as of Amendment #4A: 131I-MIBG Dose and Removal of Irinotecan/Vincristine from
MIBG Therapy
Since initial protocol activation, there has been limited experience with 131I-MIBG therapy followed by
Bu/Mel Consolidation in patients with neuroblastoma. French et al at the University of California, San
Francisco (UCSF) have published24 their experience with 8 patients who received 131I-MIBG therapy at
18 mCi/kg (without Irinotecan/Vincristine but with autologous PBSC support) followed 7-9 weeks later by a
Bu/Mel conditioning regimen identical to that used in ANBL09P1. In addition, a ninth patient has since been
treated following the same regimen. Two of the 9 patients developed fatal SOS and died at approximately
Day+50.
Children’s Hospital of Philadelphia has also treated 4 patients following a similar protocol (personal
communication, S Grupp), though one of those patients received 2 doses of 131I-MIBG at 18 mCi/kg before
Bu/Mel conditioning. Two of the 4 patients developed mild SOS, none developed severe SOS and no patient
died from toxicity. In addition, one patient was treated at Cincinnati Children’s Hospital as per the same
protocol with minimal toxicity and no SOS (personal communication).
Finally, the first (and only) 2 patients to complete both 131I-MIBG/Irinotecan/Vincristine and Bu/Mel SCT on
ANBL09P1 developed Grade 4 or Grade 5 toxicity due to SOS that was evident by Day +21. Neither patient
had pre-existing hepatic dysfunction and both patients had total body dosimetry of < 300 cGy.
This cumulative experience comprises a severe SOS rate of 4/16 (25%). For comparison, the European
SIOPEN trial used Bu/Mel conditioning without 131I-MIBG therapy. A severe SOS rate of 5% and a toxic
death rate of 3% have been reported in abstract form by the SIOPEN group.25
A recent European trial has utilized 131I-MIBG at 12 mCi/kg and topotecan given twice (a total of 24 mCi/kg
with approximately 2 weeks between infusions) followed 10-12 weeks later by Bu/Mel conditioning. Results
09/24/14 17
of this study have not yet been published, however data regarding 26 patients analyzed to date indicate that
this therapy has been well tolerated (personal communication, Mark Gaze). In addition, the NANT trial N01-
02 examined 131I-MIBG therapy at 12 mCi/kg followed 2 weeks later by Carboplatin/Etoposide/Melphalan
(CEM) myeloablative chemotherapy in 50 patients with resistant neuroblastoma who had not been
previously transplanted. Six of the 50 (12%) patients developed dose-limiting SOS. There were 2 toxic
deaths on the study, both related to severe SOS; both of those patients had whole body radiation exposures
greater than 300 cGy. The whole body radiation exposure (median) was 162.6 cGy (61-846 cGy) for all
patients and 181 cGy for those with SOS.
In summary, we and others have reported an increased incidence of SOS when giving 131I-MIBG therapy
followed by Bu/Mel conditioning when one or all of following were included: the addition of
radiosensitizing chemotherapy (Irinotecan and vincristine), a relatively short interval between 131I-MIBG
and myeloablative chemotherapy (5-8 weeks) and a higher 131I-MIBG dose (18 mCi/kg). Each of these
ANBL09P1 therapy specific features has been modified in an effort to maximize patient safety. In this
amended protocol, we will no longer include Irinotecan/Vincristine as a radiation sensitizer with 131I-MIBG;
we will give the Bu/Mel conditioning 10-12 weeks after MIBG therapy instead of 5-8 weeks after; and we
will perform a dose escalation of 131I-MIBG starting at 15 mCi/kg. The SIOPEN data suggest tolerability of
131
I-MIBG at 12 mCi/kg given twice prior to Bu/Mel. Therefore, a dose de-escalation to 12 mCi/kg has been
incorporated to further evaluate tolerability of this dose while awaiting assessment of toxicities associated
with the 15 mCi/kg dose. The MIBG dose will ultimately be increased to an 131I-MIBG dose of 18 mCi/kg
assuming that excessive toxicity is not observed at lower dose levels, as prior 131I-MIBG studies suggest a
potential dose response.14,20
2.5 Topotecan
Topotecan, 9-dimethylaminomethyl-10-hydroxycamptothecin, is a semi-synthetic derivative of camptothecin
that inhibits topoisomerase I enzyme, has demonstrated anti-neuroblastoma activity,27,28 potentiates the effect
of other DNA damaging agents, and demonstrates a non-cross resistant mechanism of action.29-31 Anti-tumor
activity demonstrated in xenograft models is maximal following daily x 5 days administration or daily x 5
days x 2 weeks at single day systemic exposure of 52–88 ng*hr/mL which has proven to be feasible in
subsequent clinical trials.32 Patient-derived neuroblastoma cell lines established early in the clinical course
(diagnosis or after Induction therapy) were more likely to be sensitive to topotecan, supporting the
incorporation of topotecan into Induction therapy. In vivo, topotecan is eliminated through hepatic
metabolism and renal excretion. Topotecan penetrates the central nervous system (CNS), a site of recurrence
in neuroblastoma.33,34 Topotecan has a limited toxicity profile notable for dose-limiting myelosuppression
and mild to moderate nausea, vomiting and mucositis, regardless of administration schedule.35-37 Phase 1
trials in pediatric patients have identified a daily maximum tolerated dose (MTD) of 5.5 mg/m2 administered
as a 24-hour infusion,26 2 mg/m2/day administered as a 30-minute infusion for 5 days,32 and 1 mg/m2/day
administered as a continuous 72-hour infusion.37 The 5-day topotecan administration schedule was chosen
for further investigation in pediatric Phase 2 trials, given the neuroblastoma xenograft model correlation of a
more protracted exposure of topotecan with improved anti-tumor activity.32 Anti-neuroblastoma activity has
been demonstrated in both Phase 1 and 2 trials. In a Phase 1 trial, pediatric patients with recurrent tumors
were administered topotecan at dosages of 1.4-2.4 mg/m2/day for 5 days.32 Of 9 patients with neuroblastoma,
PR was demonstrated in 3 patients while SD occurred in 1 patient. A Phase 2 upfront window trial in patients
with newly diagnosed High-Risk neuroblastoma (POG-9341) identified topotecan (2 mg/m2/day for 5 days)
as an active anti-neuroblastoma agent with 38% of patients achieving a complete (n=1) or partial tumor
response (n=11) following 2 cycles of single-agent therapy.4 In a more traditional topotecan single-agent
Phase 2 trial (topotecan 2 mg/m2/day for 5 days) with 37 patients with refractory neuroblastoma enrolled, CR
was achieved in 2 patients, MR in 5 patients, and SD in 8 patients.27 These data are consistent with the anti-
neuroblastoma efficacy of topotecan documented in pre-clinical studies and support the incorporation of
topotecan into upfront therapy for neuroblastoma.
09/24/14 18
2.6 Topotecan/Cyclophosphamide-Based Induction Chemotherapy

Topotecan and cyclophosphamide (T/C) have been safely and successfully combined with proven anti-
neuroblastoma activity greater than that seen with single-agent topotecan.28,29 A Phase 1 trial in pediatric
patients with refractory or recurrent solid tumors demonstrated the topotecan MTD as 0.75 mg/m2/day
administered over 30 minutes daily for 5 days in combination with cyclophosphamide 250 mg/m2/day
administered daily for 5 days.30 Myelosuppression, defined as Grade 4 neutropenia, was the dose-limiting
toxicity (DLT), without additional significant toxicity observed. Anti-tumor activity was further evaluated in
a Phase 2 trial of topotecan 0.75 mg/m2/day x 5 days combined with cyclophosphamide 250 mg/m2/day for 5
days administered to 83 pediatric patients with refractory solid tumors.28 Six of 13 patients with
refractory/recurrent neuroblastoma (5 received prior ASCR, 3 received a prior bone marrow transplant
[BMT]) achieved PR, while 2 patients achieved MR or SD. A randomized Phase 2 trial comparing topotecan
alone to the combination of topotecan/cyclophosphamide in patients with relapsed neuroblastoma showed a
significantly greater response rate and progression-free survival (PFS) in the combination arm.29 To this end,
Children’s Oncology Group (COG) protocol ANBL02P1 examined the feasibility of adding dose-intensive
T/C onto the backbone chemotherapy administered in the COG A3973 study. Escalated doses of
cyclophosphamide (400 mg/m2/day for 5 days) and topotecan (1.2 mg/m2/day) replaced the initial 2 cycles of
A3973 Induction chemotherapy. Thirty-one patients were enrolled onto ANBL02P1 from April 2004
through study closure in December 2005. Toxicity and response data following both topotecan-containing
cycles is available for 25 patients.31 All 25 patients experienced expected Grade 3 or 4 hematologic toxicity
without reaching the defined DLT. No toxic deaths occurred during Induction therapy. Stem cell collection
occurred following Cycle 2 in 23 of the 25 patients. One patient was harvested after Cycle 5 Induction per
physician discretion and 1 patient was removed from protocol therapy prior to stem cell collection. All stem
cell collections were free of tumor contamination, as determined by an immunocytochemical detection assay.
Documented infection occurred in 12.5% of patients during T/C cycles compared to 26% of patients during
subsequent Induction cycles on ANBL02P1 or 30% of patients during the initial 3 cycles of the Memorial
Sloan Kettering Cancer Center (MSKCC) Induction onto A3973. The intended dose intensity of all
chemotherapy agents was maintained in 30 of 31 patients.32 Complete or partial response was achieved in
36% of patients following 2 cycles of T/C. End Induction response rate (CR/very good partial response
[VGPR]/PR) was 76% (19/25) and 2 patients developed progressive disease. These results compare
favorably with the A3973 response rate of 81% (based on response data as of 06/04/07, n = 475). The
response data also compare favorably to the 17 of 44 patients, enrolled in the Societe Francaise d'Oncologie
Pediatrique (SFOP) multi-center trial, who achieved CR at metastatic sites following the MSKCC Induction
regimen.33 This pilot Induction regimen was well tolerated with expected and reversible toxicities. Dose
intensity of standard Induction chemotherapy agents was not limited by the addition of dose-intensive
topotecan. Finally, T/C has become standard of care for chemotherapy Induction of patients with high-risk
neuroblastoma based on the following evidence:
The ANBL02P1 Induction regimen met feasibility and toxicity criteria, and this chemotherapy regimen has
been incorporated into ANBL0532, the upfront Phase 3 clinical trial for treatment of newly diagnosed
patients with High-Risk neuroblastoma. Furthermore, T/C is now part of standard Induction chemotherapy
for patients with High-Risk neuroblastoma based on the following evidence:
1. T/C is a regimen with proven activity in a randomized Phase 2 study34
2. T/C Induction was shown to be effective and yield an excellent PBSC harvest when given
up front in the pilot ANBL02P1 study31
3. T/C showed excellent activity in a Phase 2 window in a POG study of previously untreated
disseminated neuroblastoma4
4. T/C is the standard first 2 cycles of Induction in the completed ANBL0532 trial. (Park,
personal communication and COG progress report).
In the current study, patients receive the first 5 cycles of Induction used in ANBL0532. The sixth cycle of
Induction from ANBL0532 is replaced by a block of 131I-MIBG. This cycle of vincristine / doxorubicin/
09/24/14 19
cyclophosphamide was selected for replacement for several reasons. First, prolonging Induction could be
anticipated to delay Consolidation therapy, perhaps with greater acute toxicity at the time of Consolidation.
Second, a POG study compared the use of cyclophosphamide and doxorubicin to cisplatin and teniposide in
140 patients with metastatic disease.35 There was no clear difference in OS between groups of patients
treated with the two regimens, although the response rate appeared to be higher in patients treated with
cisplatin and teniposide. Third, additional data suggest that 5 cycles of Induction may provide sufficient pre-
Consolidation therapy for most patients. Patients in the POG9340 series of trials who received 5 cycles of
Induction had similar response rates compared to patients who received 7 cycles of Induction.36 Investigators
from Memorial Sloan Kettering Cancer Center compared end-Induction CR/VGPR rates for patients
receiving 5 or 7 cycles of Induction, with rates of approximately 80% for both groups.37 Rates of stable or
progressive disease were also similar between these two groups. Rates of secondary leukemia were lower in
patients receiving 5 rather than 7 cycles of Induction.38 Fourth, although there will be a significant change in
the amount of doxorubicin administered during this study, the proposed change in the number of cycles of
Induction therapy would only reduce cyclophosphamide dose intensity from 688 mg/m2/week in ANBL0532
to 546 mg/m2/week. This cyclophosphamide dose intensity compares favorably to CCG 3891, which had
500 mg/m2/week of cyclophosphamide. In addition, patients receive high-dose alkylator therapy as part of
Consolidation.
2.7 Timing of Primary Tumor Resection

A retrospective analysis of data regarding high-risk neuroblastoma patients enrolled on CCG 3891
demonstrated improved resectability of the primary tumor after initial chemotherapy and revealed a trend
toward improved survival for those patients who underwent gross total resection of primary tumor.39
Complication rates were independent of timing of surgery. Based on these data, resection was delayed until
after Induction Cycle 5 for ANBL0532. However, surgical oncologists have noted that progressive fibrosis
of the tumor occurs in response to treatment, potentially increasing the risk of complications and decreasing
the probability of a complete resection. Ideally, surgery would occur at the time of greatest decrease in tumor
size but prior to onset of significant fibrosis. In a study of 24 pediatric solid tumors (rhabdomyosarcoma,
hepatoblastoma, neuroblastoma), tumor regression was examined using three- dimensional CT
reconstructions. Regression was most rapid during the first 2 cycles of chemotherapy with little change in
volume observed thereafter.40 These data suggest that the optimal timing of surgery may be earlier in
Induction. In the current study, surgery is recommended after recovery from the 4th cycle of Induction.
Surgery may occur later if necessary, but must occur prior to 131I-MIBG therapy.
2.8 Radiotherapy as a Component of Local Control

Local recurrences occur in 17-74% of patients with High-Risk neuroblastoma.41-46 Analysis of CCG 3891
and single institution studies support the use of external beam radiation therapy (EBRT) to enhance local
control. Based upon these data, A3973 utilized 2160 cGy EBRT delivered to the site of primary tumor bed in
all patients following recovery from myeloablative Consolidation chemotherapy. Analyses of CCG 3891, on
which 539 patients with newly diagnosed High-Risk neuroblastoma were enrolled, suggest a dose response
relationship for EBRT administered to the primary disease site.45 For patients who received 10 Gy of EBRT
to the primary site, the addition of 10 Gy of total body irradiation (TBI) and autologous bone marrow
transplant (ABMT) decreased local recurrence compared to Consolidation chemotherapy alone (22% ± 12%
and 52% ± 8%, P = 0.022). Furthermore, none of the 6 patients who received 20 Gy to the primary extra-
abdominal tumor site experienced a primary relapse, whereas local recurrence occurred in 44% of patients
who did not receive EBRT (P = 0.09). Furthermore, in a report of the NB97 trial for patients one year of age
or older with stage 4 neuroblastoma, 13 patients who received 36 Gy of EBRT for local residual disease had
similar outcome (3-year EFS 85 ± 10%, 3-year OS 92 ± 7%) as 74 patients without residual tumor (3-year
EFS 61 ± 6%, 3-year OS 75 ± 6%), while 23 children without EBRT to residual primary had significantly
worse outcome (3-year EFS 25 ± 10%, 3-year OS 51 ± 11%). Separate analysis of 14 patients with isolated
localized residual disease found far better outcome of eight patients with EBRT (3-year EFS 100%, 3-year
OS 100%) compared to six patients without EBRT (3-year EFS 20 ± 18%, 3-year OS 20 ± 18%).47
09/24/14 20
Given the high rates of local recurrence, particularly following an incomplete surgical resection, and the
tolerable toxicity of EBRT evident in multi-institutional trials, patients enrolled onto ANBL09P1 who have
an incomplete surgical resection of the primary tumor will receive 21.6 Gy EBRT to the post-Induction
chemotherapy, pre-operative primary tumor volume and an additional boost of 14.4 Gy EBRT to the gross
residual volume (total dose 36 Gy to gross residual tumor volume). The additional dose of 14.4 Gy to gross
residual disease is unlikely to result in significantly increased toxicities. In CCG 3891, the administration
of EBRT was not associated with enhanced toxicities with the exception of parenteral nutrition
requirement, which occurred in 55% and 44% of patients who did and did not receive EBRT, respectively
(P=0.049).45 Furthermore, 36 Gy is well within normal tissue tolerance for most organs within the field of
radiation. Kidneys and liver will likely prove to be the dose-limiting structures and the same guidelines for
maximal doses to normal structures will be followed, as is standard in all current neuroblastoma protocols.
It should also be noted that the boost for patients with incomplete resections will deliver an additional
14.4 Gy (from 21.6 Gy to 36.0 Gy) only to regions of gross residual disease, a target that generally is
substantially smaller than the original pre-operative tumor volume that receives 21.6 Gy. While the
increased radiation dose in addition to 131I-MIBG therapy is of some concern, the Phase 2 study of 131I-
MIBG as a single agent treated 129 patients with 18 mCi/kg of 131I-MIBG, 9 of whom had previously
received Total Body Irradiation (TBI) as part of their Consolidation preparative regimen. The dose limiting
toxicity of this study was predominantly hematologic.14 After recovery from Consolidation chemotherapy
and stem cell reinfusion, patients who achieve end of Induction primary site complete response (CR) will
receive 21.6 Gy external beam radiation therapy (EBRT) to the primary site (standard dose) while patients
achieving <CR at the primary site will receive an additional boost of 14.4 Gy for a total dose of 36 Gy
EBRT delivered to gross residual primary site disease.
2.9 Treatment of Minimal Residual Disease

The presence of minimal residual disease despite achievement of maximal response to Induction and
Consolidation therapy results in continued risk for neuroblastoma relapse. This was demonstrated in the
CCG-3891 study where the benefit of additional non-cross resistant therapy, isotretinoin administered
following myeloablative Consolidation therapy was observed. Patients with newly diagnosed high-risk
neuroblastoma enrolled in CCG3891 were randomized at Week 34 of therapy (following either
chemotherapy or ABMT Consolidation) to no further therapy versus isotretinoin for six months. Isotretinoin
is a synthetic retinoid derived from the naturally occurring all transretinoic acid by modification of the
terminal carboxyl group. When neuroblastoma cell lines are exposed to all-trans-retinoic acid (trans-RA) or
isotretinoin in vitro, they exhibit decreased proliferation, decreased expression of the MYCN oncogene, and
morphological differentiation.48-51 Growth arrest and differentiation in response to isotretinoin have been
observed in neuroblastoma cell lines initiated from tumors at the time of progression after
chemoradiotherapy,48,49 suggesting that resistance to cytotoxic chemotherapy does not induce resistance to
isotretinoin. Isotretinoin was well tolerated in a pediatric Phase 1 trial using an intermittent administration
schedule of twice daily administration for 14 days followed by 14 days with no therapy.48 Isotretinoin
toxicities are generally mild; consisting primarily of chelitis, dry skin, and hypertriglyceridemia,52 with
hypercalcemia seen at higher doses.53 A significant difference in the three year EFS from the time of this
randomization in the patients receiving isotretinoin (46%) versus those with no further therapy (29%), with p
value of 0.027 in a test of proportions.1 This advantage for EFS was seen in subgroups by prior
randomization, such that the best overall EFS was for patients treated with ABMT with isotretinoin (55%
EFS), second was ABMT without isotretinoin (39%), third was chemotherapy Consolidation with
isotretinoin (32%), and fourth was chemotherapy without isotretinoin (18%).
Despite the use of isotretinoin, greater than 40% of children will develop recurrent neuroblastoma. To further
improve outcome, the efficacy of novel, anti-neuroblastoma targeted immunotherapy to eliminate minial
residual disease has been evaluated. Anti-gangliosidase (GD2) monoclonal antibody ch14.18 has shown
preclinical and early clinical activity against neuroblastoma, which was enhanced when combined with GM-
09/24/14 21
CSF or IL2. COG ANBL0032 was designed to determine if adding ch14.18 + GM-CSF + IL2 to standard
therapy of isotretinoin after intensive multimodality therapy improved outcome for high-risk neuroblastoma
patients. High-risk neuroblastoma patients who responded to Induction therapy and stem cell transplant were
randomized to 6 cycles of isotretinoin (standard therapy) or 6 cycles of isotretinoin with 5 concomitant
cycles of ch14.18 combined with GM-CSF or IL2 in alternating cycles (immunotherapy). An intent-to-treat
randomized comparison (Lan-DeMets interim monitoring, cumulative alpha=0.025) was performed for event
free survival (EFS). A total of 226 eligible patients were evenly randomized to standard or immunotherapy.
Immunotherapy was associated with Grade ≥3 pain, vascular leak syndrome and hypersensitivity reactions in
51%, 23% and 25% of patients, respectively. With 61% of expected events observed, the study met criteria
for early stopping for efficacy. Median follow-up was 2.1 years. Two-year EFS estimates were 66%±5% for
patients randomized to immunotherapy versus 46%±5% for standard therapy (p=0.01). OS was also superior
(p=0.02, unadjusted for interim looks) for immunotherapy: (86%±4%*) versus isotretinoin alone
(75%±5%*). Moreover, for the major subgroup of patients ≥1 year of age with stage 4 disease, EFS was
significantly greater (p= 0.02) for the immunotherapy group (63%±6%*), as compared to isotretinoin alone
(42%±6%*) (*2-year estimates).54
Immunotherapy consisting of ch14.18 with GM-CSF and IL2 significantly improves outcome for high-risk
neuroblastoma patients. Ch14.18 remains under clinical investigation through COG ANBL0032 protocol to
further evaluate efficacy and toxicity. Given the significant improvement in survival from high risk
neuroblastoma following antiGD2 antibody therapy, patients enrolled onto ANBL09P1 should be
encouraged to receive therapy with ch14.18 antibody by participating in actively enrolling clinical trials, or
other mechanisms.. Patients who are not eligible to receive ch14.18 antibody therapy or decline
immunotherapy will remain on ANBL09P1 and receive six months of isotretinoin post ASCR based on the
significant improvement in EFS with isotretinoin documented by CCG3891 trial.
2.10 Feasibility Studies

Financial costs reported for treating childhood cancer do not typically include “hidden” out-of-pocket
expenses for families. It has been estimated that non-medical expenses may account for a 25% or greater
decrease in family income.55 In order to assess the impact of direct non-medical expenses on families who
must travel to a different medical center for 131I-MIBG treatment, expenses will be quantified through direct
measurements.56 The expenses that will be quantified using standard methods include: cost of travel to the
MIBG center, housing while at the MIBG center, and time lost during MIBG treatments.56 Costs of travel
may be covered by charities or third-party payers and the extent of assistance provided will be captured.
Additionally, in order to gauge the feasibility of ANBL09P1 treatment, enrollment will be tracked for High-
Risk neuroblastoma patients from participating institutions onto the neuroblastoma biology study
(ANBL00B1 or its successor) and the Childhood Cancer Research Network (ACCRN07) and will be
compared to enrollment on ANBL09P1.
2.11 Correlative Studies

Therapeutic MIBG doses are approximately 100 times the doses used in diagnostic imaging, and this may
partially account for the gross underestimation of disease burden that can occur with diagnostic MIBG
imaging. Some investigators have found 50% more disease on the immediate post-131I-MIBG therapy images
compared with the pre-therapy MIBG scans.57 The improved tumor detection on post-131I-MIBG therapy
scans may simply be a dose effect, or may reflect altered 131I-MIBG biodistribution with the higher dose.58 In
ANBL09P1, the number of metastases detected on immediate post-131I-MIBG therapy images will be
assessed and compared to the pre-surgical resection radioiodinated-MIBG scans, with particular attention
given to those patients who are CR prior to 131I-MIBG therapy.
Recently, Hawkins et al demonstrated that, in the Ewing Sarcoma family of tumors, PET response is
predictive of outcome.59 All patients had PET imaging performed prior to initiating chemotherapy
(standardized uptake values [SUV]; SUV1) and before local control (SUV2). PET response by SUV2 or
09/24/14 22
SUV2:SUV1 was concordant with histologic response in 68% and 69% of patients, respectively. SUV2 was
associated with outcome (4-year PFS 72% for SUV2 < 2.5 versus 27% for SUV2 ≥ 2.5, P = 0.01 for all
patients; 80% for SUV2 < 2.5 versus 33% for SUV2 ≥ 2.5, P = 0.036 for patients with localized disease).
Matthay et al attempted to correlate early response to chemotherapy by 123I-MIBG scan with the end-
Induction response and with EFS.60 The results showed that patients with a relative MIBG score of ≤ 0.5
after 2 cycles (P = 0.053) or ≤ 0.24 after 4 cycles of chemotherapy (P = 0.045) had an improved EFS. While
PET imaging has been evaluated as an alternative to MIBG imaging in the diagnosis and staging of patients
with neuroblastoma,61-65 it has not been adequately evaluated as a tool to assess response to therapy in our
patient population. In ANBL09P1, patients will be evaluated at diagnosis and before local control by both
radioiodinated-MIBG and 18FDG-PET, and these scan results will be correlated with clinical response.
Further, MIBG is selectively transported by the hNET, which is expressed on approximately 90% of
neuroblastoma cells.60 RT-PCR assays to assess hNET expression are being performed in the laboratory of
Dr C Patrick Reynolds. Uptake of MIBG has been correlated with hNET expression in vitro using
neuroblastoma tumor samples66 and in neuroblastoma cell lines (personal communication, Dr C Patrick
Reynolds). The expression of hNET using RT-PCR on patient tumor samples at diagnosis and at tumor
resection will be measured in ANBL09P1 and the degree of expression correlated with response to MIBG
therapy.
Busulfan Pharmacokinetics
Busulfan is an alkylating agent commonly used in hematopoietic stem cell transplantation. Pharmacokinetic
studies have noted significant inter-patient variability in drug metabolism and clearance of the agent.
Busulfan kinetics may be affected by patient age, weight, hepatic function, concurrent medications, and even
specimen handling, if the samples are not properly processed upon collection. Individualized drug
monitoring MUST be performed (as per institutional guidelines) to ensure that busulfan concentrations are
optimized for patient care. In theory, supra-therapeutic levels may be associated with an increased risk of
end-organ toxicity, including sinusoidal obstructive disease (SOS). Elevated first dose area under the curve
(AUC) values (> 1500 micromole/L/min for q.6 hour dosing, or > 5200 micromole/L/min for q.24 hour
dosing) have been associated with SOS rates in excess of 30%.67,68 In this study, busulfan pharmacokinetics
is required. We will also track whether adjustments to busulfan dosing occur due to pK results, and we will
evaluate the relationship of dose adjustments to incidence of SOS.
Busulfan is a lipophilic drug that concentrates within adipose tissue. Adjusting the dose to account for
obesity has been recommended, typically in those patients > 125% of their ideal body weight. In one report,
32% of obese patients had increased busulfan clearance when compared to non-obese patients.69
2.12 Significance
ANBL09P1 assesses the tolerability, response rate, and feasibility for children newly diagnosed with High-
Risk neuroblastoma in a cooperative group setting of a topotecan-containing Induction therapy regimen
followed by a block of 131I-MIBG with stem cell support followed by Bu/Mel Consolidation, ASCR, local
radiation therapy and MRD therapy with biologic agents. All patients will be assigned to a treatment plan
which utilizes sequential administration of 5 cycles of multi-agent chemotherapy based on ANBL02P1 and
ANBL0532. Following chemotherapy Induction, patients MAY receive an Induction block of 131I-MIBG
with stem cell support followed 10-12 weeks later by Bu/Mel autologous transplant. Groups of up to
6 patients will be treated with 15 mCi/kg 131I-MIBG or 18 mCi/kg 131I-MIBG and toxicities will be closely
monitored. In addition, up to 18 patients will receive 12 mCi/kg 131I-MIBG while toxicities experienced by
the initial patients treated with 15 mCi/kg are being assessed. A maximum of 18 patients may receive 131I-
MIBG at each dose level. All patients who receive 131I-MIBG will also receive mandatory stem cell support
following MIBG therapy and following Bu/Mel myeloablative chemotherapy. After recovery from
myeloablative chemotherapy and stem cell rescue, patients who achieve end of Induction primary site
complete response (CR) will receive 21.6 Gy external beam radiation therapy (EBRT) to the primary site
09/24/14 23
(standard dose) while patients achieving <CR at the primary site will receive an additional boost of 14.4 Gy
for a total dose of 36 Gy EBRT delivered to gross residual primary site disease. Patients will then receive
minimal residual disease treatment based on COG A3973 or ANBL0032.
Patients will be enrolled onto ANBL09P1 at one of 22 institutions, a subgroup of which have capability to
deliver MIBG therapy. In addition, an additional institution will administer MIBG but will not be an
enrolling site. Scheduling of MIBG therapy will be centrally managed and communicated to the enrolling
institution and to the designated MIBG institution. If feasibility and tolerability are confirmed, the next step
will be to compare, in a randomized successor study to ANBL0532, the outcomes of patients treated with a
block of 131I-MIBG therapy preceding Bu/Mel with outcomes of patients treated with Bu/Mel only.
3.0 ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA

3.1 Study Enrollment
3.1.1 Patient Registration
Prior to enrollment on this study, patients must be assigned a COG patient ID number. This number is
obtained via the eRDE system once authorization for the release of protected health information (PHI) has
been obtained. The COG patient ID number is used to identify the patient in all future interactions with
COG. If you have problems with the registration, please refer to the online help.
In order for an institution to maintain COG membership requirements, every newly diagnosed patient needs to
be offered participation in ACCRN07, Protocol for the Enrollment on the Official COG Registry, The Childhood
Cancer Research Network (CCRN).
A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will be
assigned only 1 BPC number per COG Patient ID. For additional information about the labeling of specimens
please refer to the Pathology and/or Biology Guidelines in this protocol.
Please see Appendix I for detailed CTEP Registration Procedures for Investigators and Associates.
A COG-approved transplant center must be identified at the time of study registration. This center may be
changed to another COG-approved transplant center after registration if required due to personal or financial
patient issues. Please note: It is strongly recommended that Consolidation therapy should occur at a
transplant center that has IRB approval for defibrotide administration.
Please note: Once ANBL09P1 has opened at a trial center, appropriate new patients should not be entered
into other COG protocols for newly diagnosed High-Risk neuroblastoma at that site unless ineligible for
ANBL09P1. This study will replace other COG protocols for newly diagnosed High-Risk neuroblastoma at
participating centers during the time-period ANBL09P1 is open. This rule does not apply to Cook’s
Children’s Hospital, which will not enroll patients at initial diagnosis, but will serve as an 131I-MIBG
treatment center.
Patients must have evidence of MIBG avid disease on the diagnostic MIBG scan obtained within
4 weeks prior to study entry or no later than the end of Induction Cycle 1 (see Section 4.2). Patients
enrolled on ANBL09P1 who are found to have MIBG non-avid disease will come off protocol therapy
immediately. It is recommended that these patients receive a standard Induction regimen and single
transplant as per other open COG protocols for newly diagnosed High-Risk neuroblastoma.
09/24/14 24
3.1.2 IRB Approval

Sites must obtain IRB/REB approval for this protocol and submit IRB/REB approval and supporting
documentation to the Cancer Trials Support Unit (CTSU) Regulatory Office before they can be approved to
enroll patients. Allow 3 business days for processing. The submission must include a fax coversheet (or
optional CTSU IRB Transmittal Sheet) and the IRB approval document(s). The CTSU IRB Certification
Form may be submitted in lieu of the signed IRB approval letter. All CTSU forms can be located on the
CTSU web page (https://www.ctsu.org). Any other regulatory documents needed for access to the study
enrollment screens will be listed for the study on the CTSU Member’s Website under the RSS Tab.
IRB/REB approval documents may be faxed (1-215-569-0206), emailed (CTSURegulatory@ctsu.coccg.org)

or mailed to the CTSU Regulatory office.
When a site has a pending patient enrollment within the next 24 hours, this is considered a “Time of Need”
registration. For Time of Need registrations, in addition to marking your submissions as ‘URGENT’ and
faxing the regulatory documents, call the CTSU Regulatory Helpdesk at: 1-866-651-CTSU. For general
(non-regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923.
Study centers can check the status of their registration packets by querying the Regulatory Support System
(RSS) site registration status page of the CTSU members’ web site by entering credentials at
https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically load to RSS.
3.1.3 Reservation Requirements

Investigators should refer to the COG website to determine if the study is currently open for accrual. If the
study is listed as active, investigators should then access the Studies Requiring Reservations page to ensure
that a reservation for the study is available. To access the Studies Requiring Reservations page: 1. log in to
https://members.childrensoncologygroup.org. 2. From the menu bar, click eRDES. The eRDES sub-menu
appears. 3. Click Reservation. The Studies requiring Reservations page appears.
Prior to obtaining informed consent and enrolling a patient, a reservation must be made with the Statistical
and Data Center through the eRDE system.
Reservations may be obtained 24-hours a day through the COG website. Please refer to the Reservation
System eRDES User Guide that can be downloaded from:
https://members.childrensoncologygroup.org/_files/Help/eRDES_ReservationSystem_UserGuide.pdf
3.1.4 Enrollment on Biology Study ANBL00B1

Enrollment on ANBL00B1 is required for all newly diagnosed patients within 21 days of diagnosis. Tissue
procurement is mandatory for biology study registration. For patients with stage 4S disease who are very ill and
in whom an open biopsy to obtain tissue for diagnosis and biologic studies is considered medically
contraindicated, every effort should be made to obtain some tumor tissue by either fine needle aspiration of a
metastatic site of disease and/or sampling of involved bone marrow, so that this tumor sample can be submitted
for MYCN determination. Consent for ANBL00B1 must be obtained at the time of tissue submission and should
be within 1 week of surgery. Needle biopsies are not sufficient for histologic classification. Investigators are
strongly encouraged to obtain adequate tissue (see Sections 13.0, 14.0, and 15.0) via open biopsy techniques. For
patients with Stage 4 disease who are ≥ 547 days of age with unequivocal neuroblasts in the bone marrow, in
whom a diagnostic biopsy is not obtained, a minimum of 2-3 mL of involved bone marrow and a blood
specimen must be sent to the reference lab per the requirements of ANBL00B1 to be eligible for this study
(see ANBL00B1 protocol for specifics).
09/24/14 25
3.1.5 Study Enrollment on ANBL09P1

Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study
enrollment is accomplished by going to the Enrollment application in the RDE system. If you have problems
with enrollment, refer to online help in the Applications area of the COG website.
3.1.6 Timing
Patients must be enrolled onto ANBL00B1 prior to the time of enrollment on ANBL09P1. Once enrolled on
ANBL00B1, biology results will be entered by the NBL reference lab into eRDES when available to be
viewed by the institution. Shortly thereafter, the NBL Tracking Center will perform the Risk Group Analysis
based upon the age, stage, and biology results and results will be sent to the institution. In emergency
situations (or if in the opinion of the treating physician, it is in the patient’s best interest) consent can be
obtained and patient enrolled on ANBL00B1 and enrolled on ANBL09P1 on the same day if patient is
considered “high risk” by virtue of stage and age (see below) prior to submission of biology results in
eRDES by the NBL labs. See Appendix II for Risk Group Analysis (RGA) table. Please note:
• Patients with stage 4 disease who are >547 days old) are considered “High Risk” by virtue of stage
and age.
• Patients ≤ 547 days in age, or those patients with non-Stage 4 disease are only considered “High
Risk” per COG criteria based upon data entered into the eRDE via ANBL00B1. While tracking
center confirmation of risk group assignment is not required prior to consent and enrollment on
ANBL09P1, results of central review of histology or results of MYCN testing through ANBL00B1
are required for documentation of high risk status.
ANBL09P1 enrollment must be done prior to start of protocol therapy (without exception) and the date
protocol therapy is projected to start must be no later than five (5) calendar days after enrollment. Study
enrollment must occur within 4 weeks of diagnosis or after only 1 cycle of chemotherapy on the Low-
/Intermediate-Risk neuroblastoma studies, or within 4 weeks of progression to Stage 4 for INSS Stage 1, 2,
4S. Consent must always be signed before therapy is begun.
3.2 Patient Criteria

Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per
COG policy posted 5/11/01). All clinical and laboratory data required for determining eligibility of a
patient enrolled on this trial must be available in the patient's medical/research record which will serve as
the source document for verification at the time of audit.
3.2.1 Age
Patients must be ≥ 365 days and ≤ 30 years of age at the time of initial diagnosis.
3.2.2 Diagnosis
Patients have a diagnosis of neuroblastoma (ICD-O morphology 9500/3) or ganglioneuroblastoma verified by
histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine
metabolites. Patients with the following disease stages at diagnosis are eligible, if they meet the other specified
criteria.
3.2.2.1
Patients with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following:
a. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals) and
age ≥ 365 days regardless of additional biologic features.
b. Age > 18 months (> 547 days) regardless of biologic features.
09/24/14 26
c. Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features
(MYCN amplification, unfavorable pathology and/or DNA index = 1) or any biologic feature that
is indeterminant/unsatisfactory/unknown.
3.2.2.2
Patients with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following:
a. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), and
age ≥ 365 days, regardless of additional biologic features.
b. Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status.
3.2.2.3
Patients with newly diagnosed INSS Stage 2a/2b with MYCN amplification (> 4-fold increase in MYCN signals
as compared to reference signals) and age ≥ 365 days, regardless of additional biologic features.
3.2.2.4
Patients ≥ 365 days initially diagnosed with: INSS Stage 1, 2, 4S who progressed to a Stage 4 without
interval chemotherapy. These patients must have been enrolled on ANBL00B1. It is to be noted that study
enrollment must occur within 4 weeks of progression to Stage 4 for INSS Stage 1, 2, 4S.
3.2.3 Prior Therapy
Patients must have had no prior systemic therapy except for localized emergency radiation to sites of life-
threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per Low- or
Intermediate-Risk neuroblastoma therapy (P9641, A3961, ANBL0531) prior to determination of MYCN
amplification and histology.
3.2.4 Organ Function Requirements:

3.2.4.1 Adequate renal function defined as:
- Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73m2 or
- A serum creatinine based on age/gender as follows:
Age Maximum Serum
Creatinine (mg/dL)
Male Female
1 to < 2 years 0.6 0.6
2 to < 6 years 0.8 0.8
6 to < 10 years 1 1
10 to < 13 years 1.2 1.2
13 to < 16 years 1.5 1.4
≥ 16 years 1.7 1.4
The threshold creatinine values in this Table were derived from the Schwartz formula for
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data
published by the CDC.
3.2.4.2 Adequate liver function defined as:

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and
- SGOT (AST) or SGPT (ALT) < 10 x ULN for age.
3.2.4.3 Adequate cardiac function defined as:
• Shortening fraction of ≥ 27% by echocardiogram, or

• Ejection fraction of ≥ 50% by radionuclide evaluation.
09/24/14 27
3.2.4.4 Ability to tolerate PBSC collection:

No known contraindication to PBSC collection. Examples of contraindications might be a weight or
size less than the collecting institution finds feasible, or a physical condition that would limit the
ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis
procedure.
3.2.5 Exclusion Criteria
3.2.5.1 Females of childbearing potential must have a negative pregnancy test. Patients of childbearing
potential must agree to use an effective birth control method.
3.2.5.2 Female patients who are lactating must agree to stop breast-feeding.
3.2.5.3 Patients that are 12-18 months of age with INSS Stage 4 and all 3 favorable biologic features (i.e.,
non-amplified MYCN, favorable pathology, and DNA index > 1) are not eligible.
3.2.5.4 Patients are not eligible if they have received local radiation which includes any of the following:
1200 cGy to more than 33% of both kidneys (patient must have at least 1 kidney that has not
exceeded the dose/volume of radiation listed) or 1800 cGy to more than 30% of liver and/or
900 cGy to more than 50% of liver. Emergency local irradiation is allowed prior to study entry,
provided the patient still meets eligibility criteria.
3.2.6 Regulatory
3.2.6.1 All patients and/or their parents or legal guardians must sign a written informed consent.
3.2.6.2 All institutional, FDA, and NCI requirements for human studies must be met.
09/24/14 28
4.0 TREATMENT PROGRAM
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based
on schedules derived from the experimental design or on established standards of care. Minor unavoidable
departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for
surgery) for valid clinical, patient and family logistical, or facility, procedure and/or anesthesia scheduling
issues are acceptable per COG administrative Policy 5.14 (except where explicitly prohibited within the
protocol).
4.1 Overview and General Guidelines

This pilot study assesses the feasibility of administering an Induction regimen of multi-agent chemotherapy
and a block of 131I-MIBG, followed by Consolidation with Bu/Mel chemotherapy and ASCR in children with
newly diagnosed High-Risk neuroblastoma.
The initial chemotherapy Induction regimen will utilize sequential administration of 5 cycles of multi-agent
chemotherapy, based upon previous High-Risk studies ANBL02P1 and ANBL0532. Myeloid growth factors
will be administered with each cycle of Induction chemotherapy to minimize hematologic toxicity.
Filgrastim (G-CSF) must be administered after Cycle 2 in order to allow for PBSC harvest which will occur
after the 2nd cycle. Surgical resection of tumor will occur after the 4th cycle of Induction OR after the 5th
cycle of Induction (if medically necessary). See Section 13.1 and 13.4.4 for details. All patients must have a
minimum stem cell collection to yield 4 x 106 CD34+cells/kg cryopreserved PBSC in 2 aliquots (goal of 10 x
106 CD 34+ cells/kg in at least 3 aliquots) to provide adequate stem cell support following the Induction
MIBG block and Consolidation therapy with Bu/Mel.
The safety of treatment with 131I-MIBG will be evaluated in this trial using a modified Rolling Six design.
While dose limiting toxicity of 15 mCi/kg 131I-MIBG is being determined in up to the first 6 evaluable
patients, subsequent patients will be permitted to receive 131I-MIBG at a dose of 12 mCi/kg. If 15 mCi/kg
131
I-MIBG is determined to be safe, then a dose of 18 mCi/kg 131I-MIBG will be assessed in up to another
6 evaluable patients. While toxicities associated with 18 mCi/kg 131I-MIBG are being evaluated in the cohort
of up to 6 evaluable patients, subsequent patients will receive a dose of 15 mCi/kg. A maximum of
18 patients will be treated on any dose level. It is therefore possible that patients will not be able to receive
131
I-MIBG due to lack of an available MIBG treatment slot (due to maximum patient allotment per dose
level), and will instead come off protocol therapy at completion of Induction chemotherapy. The enrolling
institution and the designated MIBG treating institution will be informed via eRDES email notification and
the Study Chair (or designee) if an MIBG treatment slot is available and the dose of 131I-MIBG assigned by
the time the patient begins Cycle 5. Patients who are unable to receive Induction MIBG and those with
progressive disease after the Induction MIBG block will be taken off protocol therapy. The rest of the
patients will continue on to receive Consolidation with Bu/Mel and ASCR. Following ASCR, patients who
achieve end of Induction primary site complete response (CR) will receive 21.6 Gy external beam radiation
therapy (EBRT) to the original primary site (standard dose) while patients achieving < CR at the primary site
will receive an additional boost of 14.4 Gy for a total dose of 36 Gy EBRT delivered to gross residual
primary site disease (as in ANBL0532).
After recovery from radiation therapy, patients will be encouraged to participate in clinical trials of ch14.18
immunotherapy (ie, ANBL0032). Patients ineligible for immunotherapy or who decline participation will
remain on ANBL09P1 for 6 months of Maintenance therapy using isotretinoin alone based on COG A3973.
09/24/14 29
4.1.1 Notification of MIBG Treatment Center

The desired MIBG treating institution must be specified on the On-study case report form through
eRDE that has to be submitted within 7 days of the patient’s enrollment. Based on this response, the MIBG
center will coordinate with the enrolling institution to confirm the patient’s eligibility for treatment and
assign a tentative treatment date. The institutional physician at the enrolling site must reconfirm the MIBG
treatment date before the start of Cycles 4 and 5. An eRDES email notification and the Study Chair (or
designee) will inform the enrolling institution and the MIBG institution if an MIBG treatment slot is
available and at what dose by the time the patient begins Cycle 5, when possible.
4.1.2 Central Line

All patients will have a double lumen central venous line placed prior to beginning Induction chemotherapy.
A “Y” connector with a controlled rate infusion pump for each arm of the “Y” will be required for
Consolidation therapy.
4.1.3 Chemotherapy Dose-Adjustment for Weight

Chemotherapy doses for all drugs EXCEPT topotecan will be adjusted for patients who weigh ≤ 12 kg. These
patients will have chemotherapy dosed per kg rather than per body surface area (BSA). Dosing will be adjusted
only during cycles when patient’s weight is ≤ 12 kg. Topotecan dosing will be based on BSA regardless of age
or weight.
The 131I-MIBG dose MUST be calculated based on a weight obtained within 7 days prior to the date of 131I-
MIBG administration.
4.1.4 Parenteral Chemotherapy Administration Guidelines

See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for special
precautions and suggestions for patient monitoring during the infusion.
4.1.5 Concomitant Therapy
4.1.5.1
No other cancer chemotherapy or immunomodulating agents (including steroids, except for those listed in
4.1.5.4) will be used.
4.1.5.2
Radiotherapy to localized painful lesions is acceptable, provided at least one measurable lesion is not
irradiated. No irradiated lesion may be used to assess tumor response.
4.1.5.3
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive care are to be
used as necessary.
(https://members.childrensoncologygroup.org/_files/protocol/Standard/SupportiveCareGuidelines.pdf).
4.1.5.4
Other than dexamethasone use as an antiemetic for short periods of time around chemotherapy
administration, corticosteroid therapy is permissible only for treatment of increased intracranial pressure or
spinal cord compression in patients with CNS tumors.
09/24/14 30
4.1.5.5
Clinically significant drug interactions have been reported when using vincristine with strong CYP450 3A4
inhibitors and inducers. Selected strong inhibitors or stimulators of cytochrome P450 3A4 are listed in the
table below and should be avoided during vincristine cycles.
Clinically significant strong CYP3A4 inhibitors and inducers are listed in the table.
Strong inhibitors prohibited 7 days before dosing and during vincristine administration.
azole antifungals (ketoconazole, itraconazole) diltiazem
clarithromycin verapamil
erythromycin
Strong inducers prohibited 12 days before dosing and during vincristine administration.
rifampin phenobarbital
rifabutin phenytoin
rifapentine St. John’s wort
carbamazepine
Enzyme inducing anticonvulsants should be replaced by non-inducing anticonvulsants like gabapentin,

lamotrigine, levetiracetam, or valproic acid. Aprepitant, fluconazole and voriconazole are clinically relevant
moderate CYP3A4 inhibitors that should be avoided, if possible, or used with great caution. Other strong
inducers or inhibitors should be avoided and moderate or inhibitors and inducers should be used with caution
according to the timeline described in the table.
The clinical outcome and significance of CYP450 interactions with cyclophosphamide, doxorubicin and
etoposide are less clear. CYP450 3A4 stimulators or inhibitors should be avoided or used with great caution.
Aprepitant also interacts with CYP3A4 and should be used with caution with etoposide chemotherapy.
Additional inducers or inhibitors of CYP450 enzymes can be found at http://medicine.iupui.edu/flockhart.
4.1.5.6
Concomitant use of phenytoin or fosphenytoin increases clearance of busulfan, which may lead to decreased
serum concentrations of the drug. Phenytoin has been reported to increase busulfan clearance by 15% or
more, possibly by induction of glutathione-S-transferase. Monitoring busulfan plasma concentrations is
REQUIRED for all patients.
Use of acetaminophen in combination with or within 72 hours prior to busulfan therapy may cause a
decrease in busulfan clearance by reducing glutathione concentrations in the blood and tissues. While the
clinical significance of this interaction is not yet known, acetaminophen use should be avoided or minimized
less than 72 hours before the administration of busulfan. Furthermore, acetaminophen use should be avoided
during the administration of busulfan and for 24 hours afterwards.
Itraconazole may reduce the clearance of busulfan by up to 25% in patients receiving oral or IV busulfan
therapy. Administration of itraconazole with IV busulfan may result in a busulfan AUC exceeding 1500 µM
x minute. Therefore, concomitant itraconazole should be avoided. Fluconazole is a safe alternative.
Metronidazole significantly increases busulfan trough level and should be avoided or used with caution.
4.1.5.7
Isotretinoin is contraindicated in patients with parabens allergy as the capsule is preserved with the agent.
Concurrent use of isotretinoin with tetracyclines should be avoided, due to reports of cases of pseudotumor
cerebri with concurrent use. Isotretinoin may increase clearance of carbamazepine and diminish the therapeutic
effect of oral contraceptives. Intake of vitamin A should be limited for the duration of isotretinoin treatment.
09/24/14 31
4.1.5.8
A number of drugs are known or expected to interfere with 131I-MIBG uptake and/or retention. The list of
drugs with their respective recommended time of withdrawal prior to 131I-MIBG is available in Appendix VI.
4.2 Induction Therapy
Patients will receive 5 cycles of chemotherapy followed by 131I-MIBG. Each chemotherapy cycle lasts
21 days (3 weeks). Chemotherapy cycles EXCEPT Cycle 1 may begin when the ANC ≥ 750/µL and
platelets ≥ 75,000/µL after post-chemotherapy nadir. There are no hematologic criteria to begin Cycle 1. See
Section 18.0 for details regarding PBSC harvest that will occur after Induction Cycle 2, and Section 16.0 for
details regarding imaging that will occur prior to surgical resection and at end of Induction. Refer to
Section 13.0 for details regarding surgical resection that will occur after Induction Cycle 4.
Patients who received one cycle of chemotherapy per low or intermediate risk neuroblastoma therapy
(P9641, A3961, ANBL0531) prior to determination of MYCN amplification and histology will receive all
5 cycles of ANBL09P1 Induction chemotherapy plus 131I-MIBG therapy.
Patients must have evidence of MIBG avid disease on the diagnostic MIBG scan obtained within 4 weeks
prior to study entry or no later than the end of Induction Cycle 1. Patients without MIBG avid disease at
diagnosis will come off protocol therapy immediately and are recommended to follow the Induction and
single transplant arm of ANBL0532.
4.2.1 Induction Cycle 1 (Weeks 1-3)
• Begin Cycle 1 therapy regardless of peripheral blood counts.
Cyclophosphamide: IV over 15-30 minutes

Dose: 400 mg/m2/dose. For patients ≤ 12 kg the dose is 13.3 mg/kg/dose
Days 1-5
Suggested hydration: Hydrate at 125 mL/m2/hr with fluid containing at least 0.45% NaCl for 2 hours prior to
and 2 hours after each dose. Achieve urine specific gravity < 1.010 prior to start of cyclophosphamide.
Topotecan: IV over 30 minutes

Dose: 1.2 mg/m2/dose
Days 1-5
Topotecan dosing is based on BSA regardless of age or weight.
Myeloid Growth Factors:

During Induction Cycles 1 and 3-5 (all Induction cycles except Cycle 2 or other cycles in which PBSC
collections are planned), cytokine support need not be limited to G-CSF i.e. pegfilgrastim is also permitted
according to the institution’s standard guidelines. Choice of myeloid growth factor must be recorded
appropriately in the therapy delivery maps. Myeloid growth factors should be started, 24 – 48 hours after the
last dose of chemotherapy. If filgrastim is used, it should be continued until the ANC > 1500/µL.
Discontinue filgrastim support a minimum of 24 hours prior to administration of the next chemotherapy
cycle. If pegfilgrastim is used, the next chemotherapy cycle should start at least 14 days after pegfilgrastim
administration.
09/24/14 32
Page 1 of 1
4.2.1.1 Induction Therapy
Induction chemotherapy consists of five cycles. ____________________________ ____________________________
Cycle 1 is given for Weeks 1-3 Patient name or initials DOB
There are no hematologic criteria to begin Cycle 1. Myeloid growth factors should not be administered for at least 24 hours before the
start of chemotherapy. If pegfilgrastim is used, the next chemotherapy cycle should not start before 14 days from pegfilgrastim
administration. Extensive details are in Section 4.1 (Treatment Overview). This cycle lasts 21 days (3 weeks) and this Therapy Delivery
Map is on one page.
DRUG ROUTE DOSAGE DAYS IMPORTANT OBSERVATIONS
NOTES
Cyclophosphamide IV over 15- 400 mg/m2/dose Days 1-5 See Section 4.2.1 for a. Physical, Ht, Wt
(CPM) 30 minutes or 13.3 mg/kg/dose suggested hydration b. CBC/diff/platelets
if pts ≤ 12 kg guidelines. c. Electrolytes/BUN/Cr/Ca/ Phos/Mg
2 d. ALT/AST/Bilirubin/ Urinalysis
Topotecan IV over 1.2 mg/m /dose Days 1-5 Dosing is based on
e. MIBG scan
(TOPO) 30 minutes BSA regardless of age
f. PET scan (optional)
or weight.
Myeloid growth factor Administration: Begin 24 – 48 hours after completion of See Section 7.1.1 for Pre-Treatment
chemotherapy. If filgrastim is used, continue until post-nadir ANC > 1500/µL. See Section observations.
4.2.1 for specific directions. OBTAIN OTHER STUDIES AS
REQUIRED FOR GOOD PATIENT
CARE
Therapy Delivery Map Ht_________cm Wt_________kg BSA_____________m2
Date Date Week Day CPM TOPO Myeloid growth Studies Comments
Due Given ____mg ____mg factor
_____________
_____mcg
Enter calculated dose above and actual dose administered below
1† 1 ______mg _____mg a-d,e#,f
2 ______mg _____mg
3 ______mg _____mg
4 ______mg _____mg
5 ______mg _____mg
6 _____mcg
7
2 8 b$
9
10
11
12
13
14
3 15 b$
16
17
18
19
20 Record Date of Last dose of Myeloid
Growth Factor ________
21
Begin Cycle 2 (Sec. 4.2.2) on Day 22 or when peripheral counts recover with ANC ≥ 750/µL and platelets
22 ≥ 75,000/µL (whichever occurs later).
OBSERVATION NOTES:
# Recommended to obtain baseline MIBG scan prior to starting therapy. Must be obtained by the end of Induction Cycle 1, at the latest. Repeat MIBG imaging after
Cycle 1 is NOT required if an MIBG scan was obtained prior to or during Cycle 1.
$ Obtain at least weekly (+/- 2 days).
† See Section 4.1.1 for MIBG treatment center notification details.
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE.
09/24/14 33

• Begin Cycle 2 on Day 22 of the prior cycle or as soon thereafter as ANC > 750/µL and platelets
≥ 75,000/µL.
Note: The ANC frequently falls after discontinuing myeloid growth factor support (secondary neutrophil
nadir). If the ANC recovers to > 750/μL after nadir but then falls to < 750/μL after the myeloid growth factor
is stopped, Cycle 2 can be given despite ANC < 750/μL.
Cyclophosphamide: IV over 15-30 minutes

Dose: 400 mg/m2/dose (or if ≤ 12 kg: 13.3 mg/kg/dose)
Days: 1-5
Suggested hydration: Hydrate at 125 mL/m2/hr with fluid containing at least 0.45% NaCl for 2 hours prior to
and 2 hours after each dose. Achieve urine specific gravity < 1.010 prior to start of cyclophosphamide.
Topotecan: IV over 30 minutes

Dose: 1.2 mg/m2/dose
Days: 1-5
Topotecan dosing is based on BSA regardless of age or weight.
Filgrastim: SubQ/IV (SubQ preferred)

Dose: 5 mcg/kg/dose (Recommended starting dose)
Days: Recommend beginning on Day 6 and continue per institutional standard operating procedures (SOP).
In addition, institutional SOPs will be used for mobilization and apheresis. In the absence of institutional
SOPs, please see Section 18.2 for suggested guidelines for mobilization and apheresis.
Note: Filgrastim should be stopped at least 24 hours prior to next chemotherapy cycle. Do not substitute
other colony stimulating factors (e.g: pegfilgrastim or sargramostim).
09/24/14 34
Page 1 of 1
4.2.2.1 Induction Therapy Cycle 2 ____________________________ ____________________________

Induction Chemotherapy consists of five cycles. Patient name or initials DOB
Cycle 2 is given for 3 weeks (Weeks 4-6)
Criteria to start Cycle 2: See Section 4.2.2. Myeloid growth factors should not be administered for at least 24 hours before the start of
chemotherapy. Extensive details are in Section 4.1 (Treatment Overview). This cycle lasts 21 days (3 weeks) and this Therapy Delivery
Map is on one page.
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS
Cyclophosphamide IV over 400 mg/m2/dose Days 1-5 See Section 4.2.2 for suggested a. Physical, Ht, Wt
(CPM) 15- 30 minutes or hydration guidelines. b. CBC/diff/platelets
13.3 mg/kg/dose c. Electrolytes/BUN/Cr/Ca/
if ≤ 12 kg Phos/Mg
d. ALT/AST/Bilirubin/
Urinalysis
Topotecan (TOPO) IV over 1.2 mg/m2/dose Days 1-5 Topotecan dosing will be based on
30 minutes BSA regardless of age or weight.
Filgrastim SubQ (preferred) 5 mcg/kg/dose Daily beg. ^ Recommend beginning on Day 6 and OBTAIN OTHER
(G-CSF) or IV (recommended on Day 6^ continue per institutional standard
Do NOT administer starting dose) operating procedures (SOP).Stop at
STUDIES AS
pegfilgrastim with 10 mcg/kg/dose least 24 hrs prior to next chemotherapy REQUIRED FOR GOOD
this cycle (ending) cycle. In addition, institutional SOPs PATIENT CARE
will be used for mobilization and
apheresis. In the absence of
institutional SOPs, please see Section
18.2 for suggested guidelines for
mobilization and apheresis.
Date Date Week Day CPM TOPO G-CSF ^ Studies Comments
Due Given ____mg ____mg _______mcg (starting)
_______mcg (ending)
4 1 ______mg _____mg a-d
2 ______mg _____mg
3 ______mg _____mg
4 ______mg _____mg
5 ______mg _____mg
6 _____mcg
7
5 8 b$
9
10
11
12
13
14
6 15 b$
16
17
18
19
20 Record Date of Last dose of G-
CSF_____________
21
OBSERVATION NOTES:
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE
GUIDELINES.
09/24/14 35

Begin Cycle 3 on Day 22 of the prior cycle or as soon thereafter as ANC > 750/µL and platelets
≥ 75,000/µL.
CISplatin: IV over 1 hour

Days: 1-4.
Suggested hydration: Hydrate at 3000 mL/m2/day (125 mL/m²/hour) with fluid containing at least 0.45%
NaCl. Hydration fluids may contain supplemental magnesium, calcium, and potassium to decrease acute
electrolyte losses associated with cisplatin. Achieve urine specific gravity ≤ 1.010 prior to start of cisplatin.
Monitor for adequate urine output as per institution guidelines.
Suggested hydration would be D5W ½NS +10 mEq KCl/L + 1-2 grams (8-16 mEq) magnesium sulfate/L at
125 mL/m2/hour. May add calcium gluconate 250 mg/L. CISplatin doses may require use of mannitol to
augment diuresis. Use institution guidelines.
Medication errors have occurred due to confusion between CISplatin (Platinol®) and CARBOplatin
(PARAplatin®).
Etoposide: IV over 1- 2 hours

Dose: 200 mg/m2/dose. For patients ≤ 12 kg, the dose is 6.67 mg/kg/dose
Days: 1-3
Infuse diluted solution (concentration ≤ 0.4 mg/mL) over at least 1-2 hours; slow rate of administration if
hypotension occurs. The use of an in-line filter during the infusion is suggested.

collections are planned), cytokine support need not be limited to G-CSF i.e: pegfilgrastim is also permitted
according to an institution’s standard guidelines. Choice of myeloid growth factor must be recorded
appropriately in the therapy delivery maps. Myeloid growth factors should be administered 24 – 48 hours
after the last dose of chemotherapy. If filgrastim is used, it should be continued until the ANC > 1500/µL.
administration.
09/24/14 36
Page 1 of 1
4.2.3.1 Induction Therapy Cycle 3 (All patients) ____________________________ ____________________________

Induction Chemotherapy consists of five cycles Patient name or initials DOB
Cycle 3 is given for 3 weeks/21 days (Weeks 7-9)
Criteria to start Cycle 3: See Section 4.2.3. Myeloid growth factors should not be administered for at least 24 hours before the start of
chemotherapy. If pegfilgrastim is used, the next chemotherapy cycle should not start before 14 days from pegfilgrastim administration.
Extensive details are in Section 4.1 (Treatment Overview). This cycle lasts 21 days (3 weeks) and this Therapy Delivery Map is on one
page.
CISplatin IV over 50 mg/m2/dose Days See Section 4.2.3 for a. Physical, Ht, Wt
(CDDP) 1 hour or 1-4 suggested hydration b. CBC/diff/platelets
1.67 mg/kg/dose if ≤ 12 kg guidelines. c. Electrolytes/BUN/Cr/Ca/
Phos/Mg
Etoposide IV over 200 mg/m2/dose Days Slow rate of administration d. ALT/AST/Bilirubin/
(ETOP) 1 – 2 hours. (or if ≤ 12 kg: 1-3 if hypotension occurs. The Urinalysis
6.67 mg/kg/dose) use of an in-line filter during
the infusion is suggested. OBTAIN OTHER STUDIES AS
Myeloid growth factor Administration: Begin 24 – 48 hours after completion of chemotherapy. If REQUIRED FOR GOOD
filgrastim is used, continue until post-nadir ANC > 1500/µL. See Section 4.2.3 for specific directions. PATIENT CARE

Date Date Week Day CDDP ETOP Myeloid Studies Comments
Due Given ____mg ____mg Growth Factor
___________
_____mcg

7 1 ______mg _____mg a-d*
2 ______mg _____mg c*
3 ______mg _____mg c*
4 ______mg c*
5 _____mcg
6
7
8 8 b$
9
10
11
12
13
14
9 15 b$
16
17
18
19
21
OBSERVATION GUIDELINES:
* Daily electrolytes during cisplatin administration recommended but not required
GUIDELINES.
09/24/14 37

• Begin Cycle 4 on Day 22 of the prior cycle or as soon thereafter as ANC ≥ 750/µL and platelets
≥ 75,000/µL.
Mesna: IV over 15 - 30 minutes or by continuous infusion.

The total daily mesna dose is equal to 60% of the daily cyclophosphamide dose
Intermittent infusion
Dose: 420 mg/m2/dose (or if ≤ 12 kg: 14 mg/kg/dose) x 3 doses per day
Days: 1 and 2
Administer by short infusion over 15 to 30 minutes. When cyclophosphamide is given over a short time
period (e.g., 1 hour), the initial bolus dose of mesna may be administered 15 minutes before or at the same
time as the cyclophosphamide dose; subsequent doses are given 4 and 8 hours after the start of
cyclophosphamide. When cyclophosphamide is given over a longer duration (e.g., 6 hours), the continuous
infusion approach (below) is preferred.
Continuous infusion (CI)

Dose: 1260 mg/m2/day (or if ≤ 12 kg: 42 mg/kg/day)
Days: 1 and 2
This total daily dose of mesna can also be administered as IV continuous infusion. The continuous infusion
should be started 15-30 minutes before or at the same time as cyclophosphamide and finished no sooner than
8 hours after the end of the cyclophosphamide infusion.
Cyclophosphamide: IV over 1- 6 hours

Dose: 2100 mg/m2/dose (or if ≤ 12 kg: 70 mg/kg/dose)
Days: 1 and 2.
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid hypotonic
solution) or further diluted.
Suggested hydration: Hydrate at 3000 mL/m2/day with fluid containing at least 0.45% NaCl. Achieve urine
specific gravity ≤ 1.010 prior to start of cyclophosphamide. Monitor for adequate urine output as per
institution guidelines. May use diuretics (e.g., furosemide) to increase urine output.
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy.
Dose: Age-based dosing:
Age (mos) Dose
< 12 0.017 mg/kg/dose
≥ 12 (if > 12 kg) 0.67 mg/m2/dose or 0.022 mg/kg/dose [whichever is lower]
(if ≤ 12 kg) 0.022 mg/kg/dose
Note: Total dose may NOT exceed 2 mg in 72 hours or 0.67 mg/day for any patient.
Administer prior to start of DOXOrubicin infusion and then daily for 3 total doses.
Days: 1-3
Special precautions: FOR INTRAVENOUS USE ONLY. The container or the syringe containing
vinCRIStine must be enclosed in an overwrap bearing the statement “Do not remove covering until moment
of injection. For intravenous use only- Fatal if given by other routes.”
09/24/14 38
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine.
VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate liposomal injection, VSLI,
Marqibo®). Use conventional vincristine only; the conventional and liposomal formulations are NOT
interchangeable.
DOXOrubicin: IV over 24 hours

Dose: 25 mg/m2/dose. For patients ≤ 12 kg, the dose administered is 0.83 mg/kg/dose.
Days: 1-3
Continuous infusions require administration through a central venous access. Protect diluted solution from
sun light.
Special precautions: Medication errors have occurred due to confusion between DAUNOrubicin and
DOXOrubicin. DOXOrubicin is available in a liposomal formulation. The conventional and liposomal
formulations are NOT interchangeable.

collections are planned), cytokine support need not be limited to G-CSF i.e: pegfilgrastim is also permitted
appropriately in the therapy delivery maps. Myeloid growth factors should be administered 24 – 48 hours
after the last dose of chemotherapy. If filgrastim is used, it should be continued until the ANC > 1500/µL.
administration.
09/24/14 39
Page 1 of 1
Criteria to start cycle 4: See Section 4.2.4. Myeloid growth factors should not be administered for at least 24 hours before the start of
chemotherapy. If pegfilgrastim is used, the next chemotherapy cycle should not start before 14 days from pegfilgrastim administration. Extensive
details are in Section 4.1 (Treatment Overview). This cycle lasts 21 days (3 weeks) and this Therapy Delivery Map is on one page.
Mesna IV over 15-30 420 mg/m2/dose (or if ≤ 12 kg: Days Start before or with CPM. See a. Physical, Ht, Wt
minutes or by CI 14 mg/kg/dose) x 3 doses per day 1-2 Section 4.2.4. b. CBC/diff/platelets
for 2 days OR c. Electrolytes/BUN/Cr/Ca/
1260mg/m2/day ((or if ≤ 12 kg: Phos/Mg
42 mg/kg/day) by CI on Days 1 d. ALT/AST/Bilirubin/
and 2 Urinalysis,
Cyclophosphamide IV over 1-6 hours 2100 mg/m2/dose (or if ≤ 12 kg: Days See Section 4.2.4 for suggested e. Tumor Imaging, MIBG Scan
(CPM) 70 mg/kg/dose) 1-2 hydration guidelines. f. PET Scan (optional)
VinCRIStine IV push over Age (mos) Dose Days Note: Total dose may NOT
(VCR) 1 minute or < 12 0.017 mg/kg/dose 1-3 exceed 2 mg in 72 hrs or
infusion via ≥ 12 0.67 mg/day for any patient. OBTAIN OTHER STUDIES
minibag as per (if > 12 kg) 0.67 mg/ m2/dose or Administer prior to start of AS REQUIRED FOR
institutional 0.022 mg/kg/dose DOXO infusion and then daily
GOOD PATIENT CARE
policy. [whichever is lower] for 3 total doses.
(if ≤ 12 kg) 0.022 mg/kg/dose
DOXOrubicin IV over 24 hours 25 mg/m2/dose Days Use a central line.
(DOXO) or 1-3
0.83 mg/kg/dose if ≤ 12 kg
Myeloid growth factor Administration: Begin 24 – 48 hours after completion of chemotherapy. If filgrastim is used, continue until post-nadir ANC > 1500/µL.
See Section 4.2.4 for specific directions.
Date Date Week Day CPM Mesna DOXO VCR Myeloid Studies
Due Given ____mg ____mg _____mg _____mg ____mg ____mg Growth Factor
____________
__mcg
10† 1 ______mg _____mg _____mg _____mg ______mg ______mg a-d
2 ______mg _____mg _____mg _____mg ______mg ______mg
3 ______mg ______mg
4
5 _____mcg
6
7
11 8 b$
9
10
11
12
13
14
12 15 b$
16
17
18
19
20
21 (e,f) #
Proceed to surgery after Cycle 4 (see Sec. 13.0 for details). Begin Cycle 5 (Sec. 4.2.5) when peripheral
counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL AND EITHER upon recovery from surgery
22 or Day 22 (whichever occurs later). Record Date of Last dose of Myeloid Growth Factor ________
OBSERVATION NOTES:
# Obtain prior to Surgical resection. † See Section 4.1.1 for MIBG treatment center notification.
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS AND THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINES.
09/24/14 40

• Begin Cycle 5 on Day 22 of the prior cycle or as soon thereafter as ANC ≥ 750/µL and
platelets ≥ 75,000/µL.
Note: The ANC frequently falls after discontinuing myeloid growth factor support (secondary
neutrophil nadir). If the ANC recovers to > 750/μL after nadir but then falls to < 750/μL after
the myeloid growth factor is stopped, Cycle 5 can be given despite ANC < 750/μL.
• If surgery occurred after Cycle 4, begin Cycle 5 when counts recovered as above AND by Day
22 OR as soon as possible following surgery (whichever is later). Therapy should not be
delayed by more than 1 week unless complications arise.
CISplatin: IV over 1 hour

Dose: 50 mg/m2/dose. For patients ≤ 12 kg, the dose is 1.67 mg/kg/dose
Days: 1-4.
Suggested hydration: Hydrate at 3000 mL/m2/day (125 mL/m²/hour) with fluid containing at least 0.45%
NaCl. Hydration fluids may contain supplemental magnesium, calcium, and potassium to decrease acute
electrolyte losses associated with CISplatin. Achieve urine specific gravity ≤ 1.010 prior to start of
CISplatin. Monitor for adequate urine output as per institution guidelines.
Suggested hydration would be D5W ½NS +10 mEq KCl/L + 1-2 grams (8-16 mEq) magnesium sulfate/L
at 125 mL/m2/hour. May add calcium gluconate 250 mg/L.
CISplatin doses may require use of mannitol to augment diuresis. Use institution guidelines.
Medication errors have occurred due to confusion between CISplatin (Platinol®) and CARBOplatin
(PARAplatin®).
Etoposide: IV over 1-2 hours

Days: 1-3
Infuse diluted solution (concentration ≤ 0.4 mg/mL) over at least 1-2 hours; slow rate of administration if
hypotension occurs. The use of an in-line filter during the infusion is suggested.

collections are planned), cytokine support need not be limited to G-CSF i.e: pegfilgrastim is also
permitted according to an institution’s standard guidelines. Choice of myeloid growth factor must be
recorded appropriately in the therapy delivery maps. Myeloid growth factors should be administered 24 –
48 hours after the last dose of chemotherapy. If filgrastim is used, it should be continued until the ANC
> 1500/µL. Discontinue filgrastim support a minimum of 24 hours prior to administration of the next
chemotherapy cycle. If pegfilgrastim is used, the next chemotherapy cycle should start at least 14 days
after pegfilgrastim administration.
09/24/14 41
Page 1 of 1

Criteria to start Cycle 5: See Section 4.2.5. Myeloid growth factors should not be administered for at least 24 hours before the start
of chemotherapy. If pegfilgrastim is used, the next chemotherapy cycle should not start before 14 days from pegfilgrastim
administration. Extensive details are in Section 4.1 (Treatment Overview). This cycle lasts 21 day (3 weeks) and this Therapy
Delivery Map is on one page.
CISplatin IV over 1 hour 50 mg/m2/dose Days 1-4 See Section 4.2.5 for a. Physical, Ht, Wt
(CDDP) or suggested hydration b. CBC/diff/platelets
1.67 mg/kg/dose if guidelines. c. Electrolytes/BUN/Cr/Ca/
≤ 12 kg Phos/Mg
d. ALT/AST/Bilirubin/
Etoposide IV over 200 mg/m2/dose Days 1-3 Slow rate of administration Urinalysis
(ETOP) 1 – 2 hours or: if hypotension occurs. The e. Confirm the MIBG dose
6.67 mg/kg/dose if use of an in-line filter assignment
≤ 12 kg during the infusion is
suggested. OBTAIN OTHER STUDIES
Myeloid growth factor Administration: Begin 24 – 48 hours after completion of chemotherapy. If AS REQUIRED FOR GOOD
filgrastim is used, continue until post-nadir ANC > 1500/µL. See Section 4.2.5 for specific directions. PATIENT CARE
Date Date Week Day CDDP ETOP Myeloid Growth Studies Comments
Due Given ____mg ____mg Factor________
_____mcg
13 † 1 ______mg _____mg a-e*
2 ______mg _____mg c*
3 ______mg _____mg c*
4 ______mg c*
5 _____mcg
6
7
14 8 b$
9
10
11
12
13
14
15 15 b$
16
17
18
19
21
22 Proceed to 131I-MIBG Induction therapy (Section 4.3) after Cycle 5 on Day 22 or when criteria to begin 131I-
MIBG Induction therapy are met (whichever occurs later).

OBSERVATION NOTES:
† See Section 4.1.1 for MIBG treatment center notification details.
* Daily electrolytes during cisplatin administration recommended but not required
GUIDELINES.
09/24/14 42
131
4.3 I-MIBG Induction Therapy Block
Patients will receive an Induction block of MIBG therapy after completion of 5 cycles of chemotherapy
Induction (as explained above) if they meet the eligibility criteria listed in Section 4.3.1 and if data
generated during the conduct of this trial indicate that it is safe to administer MIBG in the context of this
therapy. MIBG therapy will begin no sooner than 3 weeks (and recommended before 6 weeks after start
of Cycle 5 Induction chemotherapy) from the start of Cycle 5 chemotherapy. Total duration of this MIBG
Induction block will be at least 70 days from MIBG administration but will depend on patient recovery
from acute toxicities and ability to meet criteria to start Consolidation therapy as outlined in Section 4.4.1.
4.3.1 Criteria to Proceed to 131I-MIBG Induction Therapy:

• No evidence of progressive disease
• No sooner than 3 weeks after the start of Cycle 5 of Induction chemotherapy
• Minimum frozen PBSC of 4 x 106 CD34+ cells/kg as 2 aliquots. Having a back-up of 2 x 106
CD34+ cells/kg is recommended but not required (see Section 18.0 for collection details)
• Hemoglobin > 10 g/dL (transfusion allowed)
• Platelets ≥ 50,000/µL (transfusion allowed)
• ANC ≥ 500/µL (off myeloid growth factors; e.g. off G-CSF for ≥ 48 hours)
• ALT and AST < 5 x ULN for age
• Total bilirubin ≤ 1.5 x ULN for age
• Renal function that meets criteria in Section 3.2.4.1
• No uncontrolled infection
• Patients must have evidence of MIBG avid disease on the diagnostic MIBG scan obtained within
4 weeks prior to study entry or no later than the end of Cycle 1.
• Both the patient and adult caregivers must be able to cooperate with radiation safety restrictions
during the MIBG therapy period. The patient may receive pharmacologic anxiolysis if needed.
• A treatment slot must be available on one of 3 MIBG dose levels: 12 mCi/kg, 15 mCi/kg, or
18 mCi/kg.
131
4.3.2 I-MIBG Therapy
131
I-MIBG: via either a central or a peripheral IV catheter over 1.5 to 2 hours
Dose: Assigned dose. Patients will receive 12 mCi/kg, 15 mCi/kg, or 18 mCi/kg MIBG (max dose
1000 mCi). The 131I-MIBG dose MUST be calculated based on a weight obtained within 7 days
prior to the date of 131I-MIBG administration.
Day: 1.
Note: Stem cell rescue is required after any dose of 131I-MIBG.
Therapeutic 131I-MIBG will be synthesized by Jubilant Draximage® Canada with specific activity between
15 and 25 mCi/mL. Radiopurity will be initially determined by Jubilant Draximage® prior to shipment to
participating centers. Free radioiodide content must be rechecked at the treating center prior to infusion
using HPLC or Sep-Pac methodology (see Appendix VII).
Jubilant Draximage® therapeutic 131I-MIBG is liquid and ready to infuse with appropriate hydration,
radiation isolation, thyroid blocking with potassium iodide and bladder protection.
Refer to Section 6.1 for details regarding patient preparation and radiation-related precautions.
09/24/14 43
131
See Appendix VI for information about medications that are known or expected to interfere with I-
MIBG uptake and/or retention.
All patients travelling to another institution for MIBG treatment will be required to complete a
questionnaire to help quantify costs relating to travel and stay during the course of the MIBG
treatment. This questionnaire should be submitted before the start of Consolidation. See
Appendix VIII for the questionnaire that is to be submitted after MIBG treatment.
Whole Body Dosimetry

While in radioprotective isolation, whole-body monitoring will be performed using a ceiling-mounted
meter at consistent patient geometry. The person obtaining the measurement should be certain the patient
is centered under the monitor and that the height of the bed has not been changed. If the ceiling mounted
monitor is not functional for any reason, then a slightly decreased number of measurements will be taken
with a handheld ion chamber at 1 meter from the umbilicus with consistent geometry and distance
beginning at the completion of the infusion (Hour 1.5-2) and at Hours 3, 4, 5, 6, 7, 8, then every 8 hr
thereafter (until discharged from radiation isolation). All times are noted from the beginning of the 2-hour
infusion. Considering that the 131I-MIBG is infused from Hour 0 to Hour 2, the whole body measurements
will be taken as follows, and the exact dates and times marked on the data collection form (see COG Web
site for RDE data forms packet). In addition, data should also be collected electronically if possible. All
times are measured from the beginning of the MIBG infusion (Hour 0, Day 1).
Ceiling monitor reading times:
Infusion Hr 0, 1, 2
Day 1 Every 30 minutes of Hours 2-8
Day 1 to 2 Hours 8, 12, 16, 20, 24
Day 3 to 5 Every 8 hours until discharged from radiation isolation
For all patients, whole body readings (collected electronically in an excel document) should be forwarded
to Dr. Brian Weiss (Cincinnati Children’s Hospital) by Day 21 after MIBG infusion of study to allow for
calculation of whole body dosimetry. Paper dosimetry flow sheets are required and must also be
submitted through the COG document imaging system.
Potassium Iodide: PO
Potassium iodide solution will be given in a loading dose of 6 mg/kg 8 to 12 hours prior to initiating the
131
I-MIBG infusion on Day 1 and then given at 1 mg/kg/dose every 4 hrs on Days 1 through 7. On Days 8
to 45, potassium iodide will be given once daily at 1 mg/kg/day.
Myeloid Growth Factor Support

Patients who have received 131I-MIBG who subsequently experience an absolute neutrophil count (ANC)
of < 500/µl before receiving ASCR on Day +13 should NOT receive myeloid growth factors until they
receive ASCR. Myeloid growth factors should be given any time after the ASCR if the ANC < 500/µL.
Cytokine support need not be limited to G-CSF i.e: pegfilgrastim is also permitted according to an
institution’s standard guidelines. Choice of myeloid growth factor must be recorded appropriately in the
therapy delivery maps. If filgrastim is used, it should be continued until the ANC > 1,500/µl. Myeloid
growth factor support may also be given following stem cell infusion according to local stem cell
transplant procedures, regardless of ANC. Discontinue filgrastim support a minimum of 24 hours prior to
start of Consolidation. If pegfilgrastim is used, Consolidation should start at least 14 days after
pegfilgrastim administration.
09/24/14 44
Stem Cell Infusion

For patients receiving 131I-MIBG, peripheral blood stem cells will be infused on Day 13 (± 2 days to
allow for scheduling flexibility) post MIBG. This will most likely occur at the enrolling institution but
could also occur at the MIBG institution, if necessary. Where the DMSO volume in the stem cell
product would exceed the accepted level for infusion within a 24-hour period, stem cell products may be
infused over 2 days to meet this standard. If stem cell infusion occurs sooner (ie, due to an infectious or
bleeding complication) notify the Study Chair. See Section 18 for details.
A minimum of 2 x 106 CD34 + cells/kg must be infused.
09/24/14 45
Page 1 of 2
4.3.2.1a Induction Therapy - 131I-MIBG (Days 0-14) __________________________ __________________________
This course duration will vary from 70 to 84 days depending on when the Consolidation phase begins. Patient name or initials DOB
Criteria to start Induction-MIBG cycle: see Section 4.3.1. Myeloid growth factors should not be administered for at least 48 hours before the administration of I-MIBG. If pegfilgrastim is used, the 131I-MIBG
131
cycle should not start before 14 days from pegfilgrastim administration. Extensive details are in Section 4.1 (Treatment Overview). Patients should begin therapy on Day 22 of the prior cycle or when criteria
to start this cycle (see Sec 4.3.1) have been met (whichever occurs later). This Therapy Delivery Map is on two pages.
131
I-MIBG (131I-Meta- IV over 1.5 to 2 hrs Assigned dose. See Section 4.3.2. Day 1 Free radioiodide content must be rechecked at the treating center a. Whole body exposure reading
iodobenzylguanidine ) prior to infusion using HPLC or Sep-Pac methodology (see b. Physical exam, Ht, Wt
Appendix VII). Refer to Section 6.1 for details regarding c. CBC/diff/platelets
patient preparation and radiation-related precautions. See d.Electrolytes/BUN/Cr/Ca/Phos/Mg/
Appendix VI for information about medications that are known or ALT/AST/Bilirubin
expected to interfere with 131I-MIBG uptake and/or retention. e. T4, TSH
Potassium Iodide PO Loading dose (LD): 6 mg/kg/dose 1 to 45 Give LD 8 to 12 hrs prior to initiating the 131I-MIBG infusion on f. Pregnancy test, urinalysis
(KI) Maintenance dose (MD): 1 mg/kg/dose Day 1; then give MD every 4 hrs on Days 1 to 7; and once daily g. MIBG Scan (see Section 7.1.1 for
on Days 8 to 45. details)
h. MUGA or ECHO, GFR or Creat.
Clearance, Tumor Imaging, MIBG
scan
i. Bilateral BM Asp/Bx
j. Catecholamines (only if elevated at
diagnosis)
OBTAIN OTHER STUDIES AS REQUIRED
FOR GOOD PATIENT CARE
131
Date Due Date Given Wks Day I-MIBG KI Studies Comments
_____mCi LD ____mg MD ___mg
0 (b-f)*
16 1 LD ____mg
_____mCi MD ____mg ____mg ____mg ____mg ____mg
2 MD ____mg ____mg ____mg ____mg ____mg ____mg
3 MD ____mg ____mg ____mg ____mg ____mg ____mg
4 MD ____mg ____mg ____mg ____mg ____mg ____mg
5 MD ____mg ____mg ____mg ____mg ____mg ____mg (a, g)#
6 MD ____mg ____mg ____mg ____mg ____mg ____mg
7 MD ____mg ____mg ____mg ____mg ____mg ____mg
17 8 MD ____mg (b-d)%
9 MD ____mg
10 MD ____mg
11 MD ____mg
12 MD ____mg
13 PBSC infusion on MD ____mg
Day 13 ± 2 days
(See Section 18.6 for
details).
14 MD ____mg
Note: If, myeloid growth factor is given during therapy (see Section 4.3.2 for details), record Name of agent given, Date and Dose of each administration.
* See Section 7.1.1 for details. # Upon release from radiation isolation
% Recommend increasing CBC frequency to twice weekly until count recovery if Grade 4 ANC or Grade 4 platelets, as part of good clinical care.
SEE COG MEMBER WEBSITE FOR SUPPORTIVE CARE.
09/24/14 46
Page 2 of 2
4.3.2.1b Induction Therapy - 131I-MIBG Continued (Days 15-45) ____________________________ ____________________
This course duration will vary from 70 to 84 days depending on when the Consolidation phase begins. Patient name or initials DOB
Criteria to start Induction-MIBG cycle: see Section 4.3.1. Extensive details are in Section 4.1 (Treatment Overview). Patients should begin therapy on Day 22 of the prior cycle or when criteria to start this
cycle (see Sec. 4.3.1) have been met (whichever occurs later). This Therapy Delivery Map is on two pages.
131
I-MIBG (131I-Meta- IV over 1.5 to 2 hrs Assigned dose. See Section 4.3.2. Day 1 Free radioiodide content must be rechecked at the treating center a. Whole body exposure reading
iodobenzylguanidine ) (max dose 1000 mCi) prior to infusion using HPLC or Sep-Pac methodology (see b. Physical exam, Ht, Wt
Appendix VII). Refer to Section 6.1 for details regarding patient c. CBC/diff/platelets
care and radiation-related precautions. See Appendix VI for d. Electrolytes/BUN/Cr/Ca/
information about medications that are known or expected to Phos/Mg/ALT/AST/Bilirubin
interfere with 131I-MIBG uptake and/or retention. e. T4, TSH
f. Pregnancy test, Urinalysis
Potassium Iodide PO Loading dose (LD): 6 mg/kg/dose 1 to 45 Give LD 8 to 12 hrs prior to initiating the 131I-MIBG infusion on g. MIBG Scan (see Section 7.1.1 for
(KI) Maintenance dose (MD): Day 1; then give MD every 4 hrs on Days 1 to 7; and once daily on details)
1 mg/kg/dose Days 8 to 45. h. MUGA or ECHO, GFR or Creat.
Clearance, Tumor Imaging, MIBG
scan
i. Bilateral BM Asp/Bx
diagnosis)
OBTAIN OTHER STUDIES AS
REQUIRED FOR GOOD PATIENT
CARE
Date Due Date Day (Wks) KI Studies Day (Wks) KI Studies Day (Wks) KI Studies Comments
Given LD ____mg MD ___mg LD ____mg MD ___mg LD ____mg MD ___mg

15 (18) MD ____mg (b-d)% 25 (19) MD ____mg
16 (18) MD ____mg 26 (19) MD ____mg 36 (21) MD ____mg (b-d)%
17 (18) MD ____mg 27 (19) MD ____mg 37 (21) MD ____mg
18 (18) MD ____mg 28 (19) MD ____mg 38 (21) MD ____mg
19 (18) MD ____mg 29 (20) MD ____mg (b-d)% 39 (21) MD ____mg
20 (18) MD ____mg 30 (20) MD ____mg 40 (21) MD ____mg
21 (18) MD ____mg 31 (20) MD ____mg 41 (21) MD ____mg
22 (19) MD ____mg (b-d)% 32 (20) MD ____mg 42 (21) MD ____mg
23 (19) MD ____mg 33 (20) MD ____mg 43 (22) MD ____mg
24 (19) MD ____mg 34 (20) MD ____mg 44 (22) MD ____mg
35 (20) MD ____mg 45 (22) MD ____mg (b -j)%*$
Note: If, myeloid growth factor is given during therapy (see Section 4.3.2 for details), record Name of agent given, Date and Dose of each administration.
Proceed to Consolidation (Bu/Mel) no less than 10 weeks and prior to 12 weeks from MIBG infusion.
* These evaluations should be done before the start of therapy. See Section 7.1.1 for details. # Upon release from radiation isolation
% Recommend increasing CBC frequency to twice weekly until count recovery if Grade 4 ANC or Grade 4 platelets, as part of good clinical care.
$ Post Induction evaluation should occur no sooner than 6 weeks post-MIBG therapy and no earlier than 4 weeks pre-Bu/Mel Consolidation.
PLEASE NOTE THAT END OF INDUCTION OBSERVATIONS AND PRIOR TO CONSOLIDATION THERAPY OBSERVATIONS ARE THE SAME AND ARE NOT
TO BE PERFORMED TWICE UNLESS SPECIFIED (see Sections 7.1.1 and 7.1.2 for details).
SEE COG MEMBER WEBSITE FOR SUPPORTIVE CARE.
09/24/14 47
4.4 Busulfan/Melphalan Consolidation Therapy
Consolidation therapy comprised of Bu/Mel therapy is explained in further detail in terms of dose,
schedule and administration in Section 4.4.2. Patients continuing on Consolidation treatment should begin
Consolidation therapy after a minimum of 10 weeks (and preferably no more than 12 weeks) from the
date of 131I-MIBG infusion.
Please note: It is strongly recommended that Consolidation therapy should occur at a transplant
center that has IRB approval for defibrotide administration.
Patients with progressive disease on the end of Induction evaluation (after completion of 131I-MIBG
therapy) are NOT eligible to continue on to the Consolidation phase of protocol therapy. Patients with
mixed response, stable disease or persistent tumor in bone marrow by morphologic evaluation may
remain on protocol therapy as per investigator preference. No restaging will be performed prior to
radiation therapy unless clinically indicated. Other eligibility criteria prior to starting Consolidation have
been listed in Section 4.4.1.
After completion of transplant and recovery from acute toxicity, patients who achieve end of Induction
primary site complete response (CR) will receive 21.6 Gy external beam radiation therapy (EBRT) to the
primary site (standard dose) as well as to MIBG-avid sites seen at pre-Bu/Mel Consolidation (end
Induction) evaluation. For patients achieving <CR at the primary site, an additional boost of 14.4 Gy for a
total dose of 36 Gy EBRT will be delivered to gross residual primary site disease. Extent of surgical
resection will be determined by the patient’s treating physician in conjunction with the responsible
surgeon and radiology colleagues. Post-surgical imaging is not required until after the MIBG Induction
block of therapy. In addition, patients will receive 21.6 Gy EBRT to MIBG-avid metastastic sites seen at
pre-Consolidation (end Induction) evaluation. Local radiation therapy will begin no sooner than
Day +42 following Consolidation ASCR.
See Section 18.0 for details regarding ASCR and Section 17.0 for details regarding radiation therapy.
4.4.1 Criteria to Start Consolidation Therapy

To begin Consolidation therapy, patients must have/be:
• End of Induction disease staging as CR, VGPR, PR, MR, or SD.
• A minimum of 10 weeks from the date of the 131I-MIBG infusion
• Minimum remaining cryopreserved PBSC of 2 x 106 CD34+ cells/kg. In addition, having a back-
up aliquot of 2 - 4 x 106 CD34+ cells/kg is recommended but not required (see Section 18.0 for
collection details)
• Hemoglobin > 10 g/dL (transfusion allowed)
• Platelets ≥ 50,000/µL (transfusion allowed)
• ANC ≥ 500/µL (off myeloid growth factors; e.g. off G-CSF for ≥ 48 hours)
• ALT and AST < 5 x ULN for age
• Total bilirubin ≤ 1.5 x ULN for age
• Shortening fraction ≥ 27% or ejection fraction ≥ 50%, and no clinical congestive heart failure
• No evidence of dyspnea at rest and no requirement for supplemental oxygen
• GFR ≥ 60 mL/min/1.73m2
• No uncontrolled infection
09/24/14 48
4.4.2 Busulfan/Melphalan Auto Transplant Regimen

Day –7 Begin anti-seizure prophylaxis with lorazepam [phenytoin or levetiracetam can
be used as alternatives]: see details below
Day –6 to –3 Busulfan IV q6 hours x 16 doses (see age based dosing below) with
pharmacokinetics (see Section 14.3)
Day –1 Melphalan 140 mg/m2 IV at least 24 hrs after last busulfan dose
Day 0 ASCR a minimum of 24 hours after melphalan infusion (see Section 18.6)
Anti-seizure prophylaxis:
Administered from Days –7 to –2
Seizure prophylaxis is mandatory, but institutional SOPs for choice of agent may be used. The preferred
regimen is lorazepam (0.02-0.05 mg/kg/dose, maximum dose: 2 mg) given 30 minutes prior to each
busulfan dose and then continuing for at least 24 hours after last busulfan dose. Alternative acceptable
regimens include phenytoin or levetiracetam beginning 12 hours prior to busulfan and continue at least
24 hours after completion of busulfan.
The dose of phenytoin is 2.5 mg/kg/dose PO BID (maximum dose: 150 mg).
The dose of levetiracetam is 10 mg/kg/dose PO BID (maximum dose: 1000 mg).
Loading dose and therapeutic monitoring are not required, but for patients with a known seizure disorder,
consider IV dosing with loading and therapeutic monitoring.
Phenytoin interacts with busulfan, causing reduced plasma levels, whereas lorazepam and levetiracetam
do not affect busulfan levels. Thus, it is especially important for busulfan dose adjustments based on 1st
day pharmacokinetics to be made when the drug used is phenytoin.
Busulfan: IV over 2 hours

Note: Once the results of pharmacokinetic studies are known, subsequent doses are based upon those
results.
Dose: Dosing of intravenous busulfan (BusulfexTM) is based on weight and age as follows:
Patients < 10 kg: 0.8 mg/kg/dose as a starting dose every 6 hours x 16 doses
Patients > 10 kg and <4 years old: 1 mg/kg/dose as a starting dose every 6 hours x 16 doses
Patients ≥ 4 years: 0.8 mg/kg/dose as a starting dose every 6 hours x 16 doses
Days: -6 to -3
Busulfan initial dose adjustments should be made for obesity, defined as > 125% of ideal body weight
(IBW). In general, for patients who are > 125% IBW, the following formula should be used for dosing:
Weight for initial busulfan dose = [(Actual body weight – ideal body weight) x 0.25] + ideal body weight.
Busulfan is administered at a final concentration of approximately 0.5 mg/mL in D5W or 0.9% NaCl over
2 hours via central line. Flush line with D5W or 0.9% NaCl before and after busulfan administration. Do
not use polycarbonate syringes or filters.
Busulfan Pharmacokinetic (pK) studies are REQUIRED and are to be performed as per institutional
guidelines. The exposure goal is to achieve an area under the curve (AUC) for busulfan of 900 to
1500 micromole/liter/minute. For further details and time-points of sample collection, please refer to
Section 14.3 and 7.1.3.
09/24/14 49
Melphalan: IV as short infusion to be completed in not more than 30 minutes at a rate not to exceed
10 mg/min.
Administer melphalan 140 mg/m2 AT LEAST 24 hrs after last busulfan dose on Day -1. The final
concentration of the diluted solution should not exceed 2 mg/mL for central line administration or
0.45 mg/mL for peripheral line administration.
Due to limited stability, prepare immediately prior to use and complete administration within 1 hour of
preparation.
ASCR (Day 0, minimum 24 hours after melphalan infusion). Please see Section 18.6 for ASCR details.
Myeloid Growth Factor Support

During Consolidation, myeloid growth factors should be administered per institutional standard operating
procedures (SOPs). Cytokine support need not be limited to G-CSF i.e: pegfilgrastim is also permitted
appropriately in the therapy delivery map.
09/24/14 50
Page 1 of 1
4.4.2.1 Consolidation Therapy – Bu/Mel ____________________________ ____________________________
Busulfan/Melphalan (10 weeks/70 days) Patient name or initials DOB
Criteria to start Consolidation therapy: ANC > 500/µL and platelets > 50,000/µL. Myeloid growth factors should not be administered for at least 48 hours before the
start of chemotherapy. Extensive details are in Section 4.1 (Treatment Overview). Patients should begin therapy on Day -7. This Course lasts 70 days. This Therapy
Delivery Map is on one page.
DRUG ROUTE DOSAGE DAYS IMPORTANT OBSERVATIONS
NOTES
Busulfan IV over Once the results of -6 to -3 Administer at a final a. Physical,Ht, Wt
(BUS) 2 hours pharmacokinetic studies are concentration of b. CBC/diff/platelets
known, subsequent doses are approximately c. Electrolytes/BUN/Cr/Ca/Phos/
based upon those results. 0.5 mg/mL in D5W or Mg/ALT/AST/Total Bilirubin
Patients < 10 kg: 0.9% NaCl via central d. T4, TSH
0.8 mg/kg/dose as a starting dose line. See Section 4.4.2 e. Pregnancy Test
q 6 hours x 16 doses for additional details. f. ECG and MUGA or ECHO, Tumor Imaging
Patients ≥ 10 kg and < 4 years
g. Urinalysis,
old: 1 mg/kg/dose as a starting
dose q 6 hours x 16 doses
h. Bilateral BM Asp/Bx,
Patients ≥ 4 years: i. Catecholamines (only if elevated at diagnosis)
0.8 mg/kg/dose as a starting dose j. Patient Cost Questionnaire
q 6 hours x 16 doses k. Audiogram or BAERs
Melphalan IV as short 140 mg/m2 -1 Start AT LEAST l. MIBG Scan
(MEL) infusion in 24 hrs after last m. GFR or Creat. Clearance
not more busulfan dose. See n. Busulfan PK (Required; AUC goal 900-
than Section 4.4.2 for rate 1500 micromole/liter/minute)
30 minutes OBTAIN OTHER STUDIES AS REQUIRED FOR
of administration.
GOOD PATIENT CARE
ANTI-SEIZURE PROPHYLAXIS (MANDATORY): Agent used for anti-seizure prophylaxis is based on the institutional SOP. Lorazepam is the preferred
agent, while phenytoin and levetiracetam are also acceptable. For details on recommended dosing, administration and schedule, please refer Section 4.4.2
Therapy Delivery Map Ht____________cm Wt_____________kg BSA________________m2
Date Due Date Given Week Day BUS MEL Prophylaxis agent used: Studies Comments
____mg ____mg _______________
_____ mg
Enter calculated dose above and actual dose administered below Note: end of
26 -7 ____mg (a- j, l-m)* Induction and
-6 ____mg ____mg ____mg a, b, c, n& prior to
____mg ____mg Consolidation
-5 ____mg ____mg ____mg studies are the
____mg ____mg same and are not
-4 ____mg ____mg ____mg to be performed
____mg ____mg twice unless
-3 ____mg ____mg ____mg specified (see
____mg ____mg Sections 7.1.1
&7.1.2)
-2 ____mg
-1 ____mg
27 0 ASCR is done within a minimum of 24 hrs after melphalan b@*, c
infusion (See Section 18.6 for more details)
1 to 6
28 7 to 13 b@*, c
29 14 to 20 b@*, c
30 21 to 24 b@*, c
25 to 27
31 28 to 34 b@*, c, l%, m$
32 35 to 41 b@*, c
33 42 # b@*, c
43 to 48
34 49 to 55 b@*, c
35 56 to 59 b@*, c
60 (a-d, f-i, k-m)*
61 to 62
63 Begin Maintenance Therapy (Sec. 4.5) on Day 63 or when criteria to start Maintenance (see Sec. 4.5.1) have been met
(whichever occurs later).
Note: If, myeloid growth factor is given during Consolidation therapy (see Section 4.4.2), record Name of agent given, Date and Dose of each administration
SEE COG MEMBER WEBSITE FOR SUPPORTIVE CARE
* See Section 7.1.2 for details. % Obtain MIBG scan for patients with > 5 MIBG + metastatic sites on pre-Bu/Mel Consolidation 123I -MIBG scan.
$ Obtain radioisotope GFR or Creatinine Clearance if any portion of the kidney(s) will be irradiated
# Local radiation therapy should begin no sooner than Day 42 (see Sec. 17.0 for details).
@ Daily until engraftment and then as needed for clinical care and on Day +60 & See Section 7.1.3 for all recommended time-points for Busulfan PK studies.
09/24/14 51
4.4.3 External Beam Radiotherapy
After completion of Bu/Mel Consolidation and recovery from acute toxicity, patients will undergo
radiation to primary site of disease as well as to MIBG-avid sites seen at pre-Bu/Mel Consolidation (end-
Induction) evaluation. Patients who have a complete surgical resection of the primary tumor will receive
21.6 Gy EBRT to the primary site, while those who have an incomplete surgical resection (residual soft
tissue mass measuring >1 cm3) of the primary tumor will receive 21.6 Gy EBRT to the post-Induction
chemotherapy, pre-operative primary tumor volume and an additional boost of 14.4 Gy EBRT to the
gross residual volume (total dose 36 Gy to gross residual tumor volume). Extent of surgical resection will
be determined by the patient’s treating physician in conjunction with the responsible surgeon and
radiology colleagues. See Section 17.0 for therapy specifics.
Criteria to Start Radiation Therapy: Radiation will be given following Bu/Mel Consolidation and must
not start sooner than 42 days post transplant. Organ toxicity within radiation field should have
resolved. The following additional criteria must be met prior to starting radiation therapy.
1. ANC > 500/µL (off myeloid growth factor support; e.g. off GCSF for ≥ 48 hours).
Platelets >50,000/µL (transfusion allowed). Hemoglobin > 10 g/dL (transfusion allowed).
Please notify study chair before giving back-up PBSC before or following radiation due to
myelosuppression.
2. Mucositis ≤ Grade 2
3. If liver will be in the field:
a) ALT/AST < 5 x ULN for age.
b) Total bilirubin < 1.5 x ULN for age.
c) All abnormalities associated with liver SOS (see Section 9.3.2.2 for definition) must be
resolved to Grade 1.
4. Patient stable on room air AND airway edema < Grade 2 if trachea will be in field.
5 For abdominal radiation fields, diarrhea < Grade 2 AND no uncontrolled infection.
6. If any portion of the kidney(s) will be irradiated, serum creatinine should be < 1.5 x ULN
for age (see normal creatinine for age in Section 3.2.4.1). Creatinine clearance or
radioisotope GFR ≥ 70 mL/min/1.73m2. The patient should not have hematuria. If patient
has two functioning kidneys and >20% of one kidney will be in the field, perform renal
scintigram to assure non-irradiated kidney is functioning well.
7. If bladder is in field, no hematuria is allowed.
09/24/14 52
4.5 Maintenance Therapy
ANBL0032 demonstrated an improvement in EFS and OS for patients who received ch14.18
immunotherapy plus cytokines in addition to isotretinoin. Patients should be encouraged to receive
therapy with ch14.18 antibody by participating in actively enrolling clinical trials, or other mechanisms.
Patients ineligible for immunotherapy or who decline participation will remain on ANBL09P1 for
Maintenance Phase using isotretinoin alone for 6 cycles. Maintenance therapy will last 6 months.
4.5.1 Criteria to Start Maintenance Therapy

Patients must have:
• ALT < 5 X normal for age
• Skin toxicity ≤ Grade 1
• Serum triglycerides < 300 mg/dL
• No hematuria and/or proteinuria on urinalysis
• Serum creatinine < 1.5 x ULN for age (see normal creatinine for age in Section 3.2.4.1).
• For females of childbearing potential: negative pregnancy test and verification of contraception use
4.5.2 Maintenance Therapy (Weeks 31-54)
Isotretinoin: PO
Dose: 160 mg/m2/day divided BID (or if ≤ 12 kg: 5.33 mg/kg/day divided BID). Round up to the nearest
10 mg.
Days: Begin on Day +66
Note: During each cycle, isotretinoin will be given for 14 days followed by 14 days of rest.
Refer to Section 6.8 for details regarding administration, especially for use with young children.
09/24/14 53
Page 1 of 1
4.5.2.1 Maintenance Therapy Cycles 1-6 ____________________________ ____________________________

Each cycle is 28 days (4 weeks)
Patient name or initials DOB
Patients should begin therapy on Day 66 of the prior cycle or when criteria to start Maintenance (see Sec. 4.5.1) have been met (whichever occurs
later). Each cycle is 28 days. The complete Maintenance phase lasts for 168 days (24 weeks). This Therapy Delivery Map is on one page.
Isotretinoin PO 160 mg/m2/day divided Days 1 Round up to the nearest 10 mg. a. Physical, Ht, Wt
(ISOT) BID to 14 b. CBC/diff/platelets
or Refer to Section 6.9 for details c. Electrolytes/BUN/Cr/Ca/Mg/Phos
5.33 mg/kg/day divided regarding administration, especially for d. Triglycerides
BID if ≤ 12 kg use with young children. e. ALT/AST/Bilirubin/Urinalysis
f. ECG and MUGA or ECHO
g. GFR or Creat. Clearance
h. Audiogram or BAERs
i. Tumor Imaging, MIBG Scan
diagnosis)
k. Bilateral BM Asp/Bx
OBTAIN OTHER STUDIES AS
REQUIRED FOR GOOD
PATIENT CARE
Enter cycle number _______ Ht_________cm Wt_________kg BSA_____________m2
Date Date Week Day ISOT Studies
Due Given _____mg _____mg
Enter calculated dose above and actual dose
administered below
31 / 35 / 39 / 43 / 47 / 51 1 _____mg _____mg a-e, (i-j)*
2 _____mg _____mg
3 _____mg _____mg
4 _____mg _____mg
5 _____mg _____mg
6 _____mg _____mg
32 / 36 / 40 / 44 / 48 / 52 7 _____mg _____mg
8 _____mg _____mg
9 _____mg _____mg
10 _____mg _____mg
11 _____mg _____mg
12 _____mg _____mg
13 _____mg _____mg
14 _____mg _____mg
33 / 37 / 41 / 45 / 49 / 53 15 to 20
34 / 38 / 42 / 46 / 50 / 54 21 to 26
27 a-k $
28 See Section 7.1.4 for details about end of
therapy evaluations to be obtained.
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEBSITE FOR SUPPORTIVE CARE.
* Obtain disease evaluations prior to Cycle 4; see Section 7.1.4 for details.
$ At end of Cycle 6 which is the end of therapy.
09/24/14 54
5.0 DOSE MODIFICATIONS FOR TOXICITIES

All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (CTCAE)
version 4.0.
5.1 Myelosuppression during Induction

Dose adjustments will be made based on the neutrophil count and platelet count on Day 29 of each cycle.
Following any cycle, if the ANC < 750/µL and/or platelet count is < 75,000/µL on Day 22, delay next
cycle until recovery occurs or meets criteria to continue based on bone marrow tumor involvement (see
below). If patient recovers to ANC ≥ 750/µL and platelets ≥ 75,000/µL by Day 29, proceed with next
cycle at full dose. If patient has not met hematopoietic recovery criteria on or before Day 29, perform
bone marrow aspirate and biopsy. Proceed based on hematopoietic recovery criteria (see Section 5.1.1).
5.1.1 Hematopoietic Recovery Criteria

If the marrow is positive for tumor at diagnosis or at last evaluation, still contains tumor and is
normocellular or mildly hypocellular with trilinear hematopoiesis, proceed with the next cycle of
chemotherapy without alteration in dose regardless of ANC and platelets. If the marrow has no tumor and
is severely hypocellular without trilinear hematopoiesis, delay the next cycle of therapy until ANC
≥ 750/µL and platelets ≥ 75,000/µL.
• If recovery occurs between Day 30-43 for any cycle of Induction, reduce the doses of all
chemotherapy that caused the myelosuppression except vincristine by 25%.
• If recovery occurs after Day 43 of any cycle, reduce doses of chemotherapy that caused the
myelosuppression by 50%, except for vincristine.
5.2 Hematuria during Induction

For Cycles 1 and 2: If microscopic (> 2 abnormal urinalyses during a cycle of therapy with < Grade 2
hematuria) or gross hematuria occurs after Induction Cycle 1 cyclophosphamide increase hydration to
3000 mL/m2/day and, give mesna (60% of cyclophosphamide dose) with Induction Cycle 2
cyclophosphamide. Mesna administration is as follows: mesna 80 mg/m² (2.7 mg/kg if <12kg) over 15-
30 minutes 15 minutes before or with cyclophosphamide infusion, then mesna 80 mg/m² (2.7 mg/kg if
≤ 12 kg) IV over 15-30 minutes at hours 4 and 8 from start of cyclophosphamide infusion. The total daily
dose (240 mg/m2 or 8 mg/kg if ≤ 12 kg) can also be administered as IV continuous infusion. The
continuous infusion should be started 15-30 minutes before or at the same time as cyclophosphamide and
finished no sooner than 8 hours after the end of the cyclophosphamide infusion. If hematuria resolves
prior to start of Cycle 4 cyclophosphamide, administer cyclophosphamide and mesna in Cycle 4 without
modification.
If Grade 3 or 4 hematuria occurs following a cycle of cyclophosphamide, do not give another cycle of
cyclophosphamide, topotecan (CT) or cyclophosphamide, doxorubicin and vincristine (CDV) until
hematuria resolves to Grade 2 or less. If patient is due to begin next cycle of cyclophosphamide-
containing chemotherapy prior to resolution of hematuria to ≤ Grade 2, substitute cisplatin and etoposide
cycle. Make notation of substitution on data forms. The intent of Induction is to give a total of 2 cycles
each of CT and cisplatin/etoposide and 1 cycle of CDV, therefore if substitution of cisplatin/etoposide is
made for CDV cycle or a CT cycle, make up this missed cyclophosphamide-containing cycle later in
therapy. If gross hematuria from cyclophosphamide recurs, delete cyclophosphamide from subsequent
cycles.
09/24/14 55
5.3 Renal Toxicity during Induction
5.3.1 Cisplatin
No dose reductions in cisplatin will be made for a decrease in the baseline GFR or creatinine clearance as
long as the value remains > 60 mL/min/1.73m². If the serum creatinine increases > 50% during a cycle of
cisplatin-containing chemotherapy, or increased to greater than maximum serum creatinine for age as
listed in table below, omit the remainder of the cisplatin from that cycle.
Age Maximum Serum

Creatinine (mg/dL)
Male Female
1 month to < 6 months 0.4 0.4
6 months to < 1 year 0.5 0.5
1 to < 2 years 0.6 0.6
2 to < 6 years 0.8 0.8
6 to < 10 years 1 1
10 to < 13 years 1.2 1.2
13 to < 16 years 1.5 1.4
≥ 16 years 1.7 1.4
The threshold creatinine values in this Table were derived from the Schwartz formula for
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature
data published by the CDC.
If GFR or creatinine clearance is < 60 mL/min/1.73 m² prior to cisplatin/etoposide cycle, substitute CDV
cycle for cisplatin/etoposide cycle. Make notation of substitution on data forms. The intent of Induction is
to give a total of 5 cycles of therapy with 2 cycles each of CT and cisplatin/etoposide, and 1 cycle of
CDV. Therefore if substitution of CDV cycle is made for cisplatin/etoposide cycle, give the
cisplatin/etoposide cycle later in therapy. If GFR or creatinine clearance remains < 60 mL/min/1.73m²
when patient is due for last cycle of cisplatin, replace this cycle of CE with a cycle of CDV so that patient
receives a total of 5 cycles of chemotherapy. If patient has received 2 cycles of CT and 2 cycles of CDV,
and GFR or creatinine clearance remains < 60 mL/min/1.73m², further cycles of cisplatin therapy will be
omitted. Note replacement therapy and/or omission on data form.
5.3.2 Cyclophosphamide, Doxorubicin, Vincristine, Topotecan and Etoposide

No dose reductions in cyclophosphamide, doxorubicin, vincristine, topotecan or etoposide are necessary
for decrease in creatinine clearance.
5.4 Cardiac Toxicity during Induction
5.4.1 For Change In Ejection/Shortening Fraction

If the cardiac ejection fraction falls below 50% or shortening fraction below 27% and patient is
asymptomatic following a cycle of doxorubicin, repeat the study in 1 week. If the ejection fraction or
shortening fraction remains abnormal 1 week later, proceed as follows:
If cardiac toxicity occurs prior to Cycle 4, substitute cycle of cisplatin/etoposide for CDV. Make notation
of substitution on data forms. The intent of Induction is to give a total of 1 cycle of CDV and 2 cycles of
cisplatin/etoposide, therefore if cisplatin/etoposide cycle is substituted for CDV, give CDV cycle later in
therapy. If cardiac function does not return to normal prior to rescheduled CDV, omit doxorubicin.
09/24/14 56
5.4.2 For Symptomatic Congestive Heart Failure (CHF)

If at any time, the patient develops Grade 3 congestive heart failure, dysrhythmia, or any Grade 4 cardiac
toxicity not related to underlying infection or metabolic abnormality, omit doxorubicin from all
subsequent cycles. If cardiac toxicity resolves to ≤ Grade 2 congestive heart failure or dysrhythmia,
decrease the dose of cyclophosphamide to 50% for the next cycle containing cyclophosphamide. If this
dose of cyclophosphamide is tolerated without > Grade 2 congestive heart failure or dysrhythmia, then
administer full dose of cyclophosphamide in subsequent cycles of chemotherapy.
5.4.3 For Dysrhythmia

If the patient develops Grade 2 cardiac dysrhythmia as defined in the Common Toxicity Criteria, repeat in
1 week. If Grade 2 toxicity resolves to ≤ Grade 1 toxicity, patient may continue on therapy without
chemotherapy dose alterations.
If Grade 2 toxicity occurs prior to Cycle 4, substitute cisplatin/etoposide for CDV cycle until dysrhythmia
resolves. Make a notation of chemotherapy substitution on data form. The intent of Induction is to give a
total of 1 cycle of CDV and 2 cycles of cisplatin/etoposide, therefore if cisplatin/etoposide cycle is
substituted for CDV, give CDV cycle later in therapy. If dysrhythmia symptoms occur prior to
rescheduled CDV, proceed with cyclophosphamide and vincristine, but omit doxorubicin.
5.4.4 Hypertension
Hypertension due to neuroblastoma will NOT be considered reason for removal from protocol therapy or
alteration in chemotherapy doses.
5.5 Hepatotoxicity during Cycles 1-5 of Induction

If direct bilirubin is > 3 mg/dL prior to Cycle 4 chemotherapy, substitute cisplatin/etoposide for CDV cycle.
The intent of Induction is to give a total of 1 cycle of CDV and 2 cycles of cisplatin/etoposide, therefore if
cisplatin/etoposide cycle is substituted for CDV, give CDV cycle later in therapy. If direct bilirubin is
> 3 mg/dL prior to rescheduled CDV chemotherapy, omit doxorubicin and vincristine. If direct bilirubin is
> 1.5 but < 3 (Grade 3 toxicity) prior to Cycle 4 CDV chemotherapy, reduce doxorubicin and vincristine dose
by 50% (vincristine maximum dose is 0.33 mg/dose or 1 mg/72 hours).
5.6 Gastrointestinal Toxicity during Cycles 1-5 of Induction
5.6.1 Mucositis
If patient develops Grade 3 or 4 mucositis that resolves to < Grade 2 by Days 22-29 of next cycle, no dose
adjustments will be made in chemotherapy. If patient develops Grade 3 or 4 mucositis that is NOT
attributable to infectious etiology AND recovery to < Grade 2 occurs between Days 30-43 for any cycle
of Induction, reduce the dose of doxorubicin or etoposide in the next 2 cycles of chemotherapy by 25%. If
subsequent chemotherapy is tolerated without recurrence of Grade 3 or 4 GI toxicity, then resume full
doses of chemotherapy agents in all subsequent cycles of Induction.
If patient develops Grade 3 or 4 mucositis that is NOT attributable to infectious etiology AND recovery to
< Grade 2 occurs after Day 43 of any cycle, reduce dose of doxorubicin or etoposide in the next 2 cycles
of chemotherapy by 50%. If subsequent chemotherapy tolerated without recurrence of Grade 3 or 4 GI
toxicity, then escalate dose by 25% in subsequent cycles of Induction.
If patient develops mucositis that requires intubation for airway management or if patient develops Grade 4
typhlitis or other Grade 4 gastrointestinal toxicity, hold subsequent chemotherapy until toxicity resolved to
< Grade 2. If the toxicity resolves to < Grade 2 by Day 43, proceed with next 2 cycles of chemotherapy but
reduce dose of doxorubicin or etoposide by 25%. If recovery to < Grade 2 occurs after Day 43 of any cycle,
reduce dose of doxorubicin or etoposide in the next 2 cycles of chemotherapy by 50%. If subsequent
09/24/14 57
chemotherapy is tolerated without recurrence of Grade 3 or 4 GI toxicity, then escalate dose by 25% in
subsequent cycles of Induction.
5.6.2 Diarrhea
If patient develops severe diarrhea (Grade 3 or 4) attributable to chemotherapy, and not underlying infection
(ie, C. difficile), that resolves by Days 22-29 of next cycle, no dose adjustments will be made in
chemotherapy. If recovery to < Grade 2 occurs between Days 30-43 for any cycle of Induction, reduce the
dose of doxorubicin or etoposide in next cycle of chemotherapy by 25%. If subsequent chemotherapy is
tolerated without recurrence of Grade 3 or 4 GI toxicity, then resume full doses of chemotherapy agents in all
subsequent cycles of Induction. If recovery to < Grade 2 occurs after Day 43 of any cycle, reduce dose of
doxorubicin or etoposide in the next cycle of chemotherapy by 50%. If subsequent chemotherapy is tolerated
without recurrence of Grade 3 or 4 GI toxicity, then escalate dose by 25% in subsequent cycles of Induction.
5.7 Ototoxicity during Induction

For inner ear/hearing toxicity ≥ Grade 3, decrease cisplatin dose by 50% for subsequent cycles. If loss
extends below 2000 Hz, delete further cisplatin/etoposide cycles and replace this cycle of CE with a cycle
of CDV so that patient receives a total of 5 cycles of chemotherapy. Note replacement therapy on data
form.
5.8 Neurologic Toxicity during Induction

If severe peripheral neuropathy (vocal cord paralysis, inability to walk or perform usual motor functions)
or ileus develops from vincristine, vincristine therapy should be stopped or withheld until the ileus
resolves or the peripheral neuropathy improves. Restart vincristine at 50% of the calculated dose (not to
exceed 0.33 mg/dose or 1mg/72 hours) and escalate by 25% of the calculated dose (not to exceed
0.4 mg/dose or 1.25 mg/72 hours) if tolerated with next course. If neuropathy recurs on escalating dose,
return to previously tolerated dose once neuropathy has improved.
5.9 Allergic Reactions
5.9.1 Etoposide
Etoposide allergic reactions may be managed with pre-medications such as diphenhydramine 1 mg/kg IV
(maximum single dose: 50 mg), ranitidine 1 mg/kg IV (maximum single dose: 50 mg) and hydrocortisone
1-4 mg/kg IV and by slowing the rate of the infusion. For those reactions which are unable to be
controlled with pre-medication and slowing of the rate of etoposide infusion, etoposide phosphate may be
substituted in the same dose and at the same rate. Pre-medication for etoposide phosphate is
recommended.
5.9.2 Cisplatin
Platinum allergic reactions may be managed with pre-medications such as diphenhydramine 1 mg/kg IV
(maximum dose: 50mg), ranitidine 1 mg/kg IV (maximum single dose: 50 mg) and hydrocortisone 1-
4 mg/kg IV.
5.10 Other Toxicities during Induction

For any Grade 3 or 4 toxicity not mentioned above, the treatment should be withheld until patients
recover to ≤ Grade 2 toxicity. For any non-hematologic Grade 3 or 4 organ toxicity attributed to
chemotherapy AND not related to underlying infection or metabolic derangement that is not discussed in
Sections 5.1-5.8, and resolves to < Grade 2 by Day 43, reduce the subsequent dose of that chemotherapy
agent by 25%. For any non-hematologic Grade 3 or 4 toxicity attributed to chemotherapy AND not
related to underlying infection or metabolic derangement that is not discussed in Sections 5.1-5.8 and
resolves to < Grade 2 after Day 43, reduce the subsequent dose of that chemotherapy by 50%.
09/24/14 58
5.11 Dose Modifications for Isotretinoin Therapy
5.11.1
A dose reduction of 25% (to 120 mg/m²/day or 4 mg/kg/day if child weighs ≤ 12 kg) for subsequent
cycles should be made for the occurrence of any Grade 3 or 4 toxicities EXCLUDING: Grade 3 or 4
hematologic, Grade 3 hepatic, Grade 3 nausea, Grade 3 vomiting, or Grade 3 fever. If the same Grade 3 or
4 toxicity recurs at a 25% dose reduction, then decrease dose another 20% (to 100 mg/m²/day or
3.33 mg/kg/day if child weighs ≤ 12 kg). If the same Grade 3 or 4 toxicity recurs after 2 dose reductions
and toxicity cannot be attributed to an alternative etiology, then withhold further therapy.
5.11.2
It has been reported (rarely) that some patients treated with isotretinoin develop new areas of abnormal
uptake on bone scan, likely due to increased bone resorption. If such changes occur during isotretinoin
phase in absence of other evidence of tumor recurrence, do not report as progressive disease.
5.11.3
If criteria (Section 4.5.1) to begin next cycle are not met by the date cycle is due to begin, delay cycle for
1 week. If criteria still not met, hold therapy until criteria are met, and treat at 25% dose reduction
(120 mg/m²/day or 4 mg/kg/day if child weighs ≤ 12 kg). An additional dose reduction to 100 mg/m²/day
(3.33 mg/kg/day if child weighs ≤ 12 kg) should occur if criteria are not met within 1 week after due date
for subsequent cycles.
5.11.4
If serum creatinine increases by > 50% in any cycle of therapy, creatinine clearance or GFR should be
done prior to starting next cycle, and a urinalysis. If creatinine clearance and/or GFR are
< 50 mL/min/1.73 m² reduce isotretinoin by 50%. If serum creatinine continues to increase or GFR
decreased to < 40 mL/min/1.73 m² then withhold further therapy.
5.11.5
If patient develops > Grade 1 hematuria, proteinuria, and/or hypertension during any cycle of therapy,
hold medication until resolves to ≤ Grade 1, then reduce isotretinoin dose by 25%.
5.11.6
For localized cheilitis, apply topical vitamin E to lips for subsequent cycles. If this does not adequately
control symptoms to allow sufficient oral intake, then decrease dose by 25% (120 mg/m²/day or
4 mg/kg/day if child weighs ≤ 12 kg).
5.11.7
If serum triglycerides are > 300 mg/dL when next cycle is due to start, delay starting therapy for 2 weeks.
If still > 300 mg/dL, then start patient on medical therapy for serum triglyceride reduction (consider
cardiology consultation) and begin cycle at previous isotretinoin dosage. If serum triglycerides are
< 300 mg/dL by the time the subsequent cycle is due to start, then continue at the same dosage
isotretinoin. If triglycerides are still > 300 mg/dL after 1 cycle on medical therapy, then reduce
isotretinoin dosage by 25% for subsequent cycles.
09/24/14 59
6.0 DRUG INFORMATION
Please see Appendix XI for drug interactions associated with the drugs used in this study.
6.1 IOBENGUANE I-131 MIBG (03/04/14)

131
(meta-iodobenzylguanidine, Iobenguane sulfate, m-Iodobenzylguanidine sulfate, MIBG, mIBG, I-
mIBG, Iodine-131 iobenguane, Therapeutic 131I MIBG) (Jubilant DraxImage: IND # 76,227)
Source and Pharmacology:

Iobenguane I-131MIBG (131I-MIBG) is a radiopharmaceutical therapeutic agent. Iobenguane is a structural
analogue of the adrenergic neuron blocker guanethidine, and has certain structural similarities to
norepinephrine. In adrenergic nerves, guanidines are believed to share the same transport pathway as
norepinephrine and to accumulate in, and displace norepinephrine from intraneuronal storage granules.
Iobenguane has marked affinity for, and concentration in, the adrenal medulla. The retention of
131
I-MIBG in the adrenal medulla may be a result of its uptake in adrenergic neurons and subsequent
sequestration into chromaffin storage granules. It is this uptake process that allows iobenguane to
concentrate in tissues with rich sympathetic innervations. Also like guanethidine, iobenguane has little or
no inherent pharmacological effect, showing little binding to post-synaptic receptors. 131I-MIBG is
suitable for targeted radiotherapy because its uptake is tissue-specific and a prolonged intracellular
concentration is maintained at tumor sites in contrast to normal tissues. 131I-MIBG has been shown to
concentrate in several neoplasms of neuroectodermal origin. Due to its selective uptake mechanism, when
131
I-MIBG is used at high levels of administered activity, the radionuclidic emissions can result in
localized radiation therapy of tumor tissue. Following intravenous injection, more than 85% of 131I-MIBG
is found in the intracellular component of erythrocytes. Platelets also show 131I-MIBG accumulation. By
1 hour, a mean of 96% of administered 131I-MIBG is lost from the vascular compartment. Uptake of
131
I-MIBG occurs mainly in the liver, and in lesser amounts in the lungs, heart, spleen, urinary bladder
and salivary glands. Although the uptake in normal adrenal glands is very low, hyperplastic adrenals and
tumors such as pheochromocytoma, neuroblastoma, and other tumors with neurosecretory granules have a
relatively higher uptake.
131
I-MIBG undergoes little metabolism; 75-90% is excreted unchanged in the urine. Up to 55% of the
injected radioactivity is recovered from the urine in the first 24 hours, and up to 90% in the first 4 days.
Of the radioactivity recovered, 84-89% was in the form of 131I-MIBG while 2-6% was free 131I-iodide
(indicating a minor degree in vivo deiodonation). In addition, 2-10% was in the form of
131
I-metaiodohippuric acid. A low percentage (14%) of the administered radioactivity is excreted in the
feces, while minute amounts may be detected in the saliva and sweat. Renal clearance is delayed in
patients with renal insufficiency and it appears to parallel the creatinine clearance.
131
I decays with a physical half-life of 8.04 days. The principal photons are 364 keV gamma photons and
606 keV beta photons. The human pharmacokinetics of 131I-MIBG are described by a three-compartment
model. Mean terminal half-life was 37 hours; the volume of distribution, 307 liters/m2; and the area under
the curve, 1.1 MBq•h•ml-1. The total body clearance was 189 mL/min/m2. Tumor half-lives of 3 days
(stage III neuroblastoma) and of 2 to 5 days (stage IV neuroblastoma) have been reported. The mean % of
injected dose in the liver at time 0 is 4.6 %. The mean biological half-life in liver is 27 hours. The mean
radiation dose to the liver is 1.2 rad/mCi.
Numerous pharmacological agents act on the uptake, transport, or secretion of norepinephrine and would
therefore be expected to interact with 131I-MIBG including tricyclic antidepressants, sympathomimetic
amines (ephedrine, pseudoephedrine, phenylpropanolamine, and phenylephrine), reserpine and cocaine.
Alpha and Beta adrenergic blocking agents such as phenoxybenzamine or propranolol do not appear to
reduce the uptake of 131I-MIBG into normal tissue or adrenergic tumors.
09/24/14 60
Toxicity:
Common Occasional Rare
Happens to 21-100 children Happens to 5-20 children out of Happens to < 5 children out of
out of every 100 every 100 every 100
Immediate: Nausea, hypertension or salivary gland pain and swelling Vomiting, hypertensive crisis,
Within 1-2 days of hypotension during infusion, (sialoadenitis) flushing, diaphoresis, metallic
receiving drug dry mouth taste, tingling of arms and face,
tachycardia, chest discomfort,
light headedness, pallor,
abdominal pain, erythematous
rash
Prompt: Bronchiolitis obliterans (L)
Within 2-3 weeks,
prior to next
course
Delayed: Myelosuppression (primarily Infection secondary to Renal dysfunction, prolonged
Any time later thrombocytopenia) myelosuppression, febrile myelosuppression, liver
during therapy, neutropenia, hypothyroidism (in dysfunction, hemorrhage, pleural
excluding the patients with inadequate thyroid effusion, opportunistic
above conditions blockade)(L) infection/pneumonia (e.g.,
Pneumocystis carinii
[Pneumocystis jiroveci]), sepsis
Late: Secondary leukemia, MDS,
Any time after hypergonadotropic
completion of hypogonadism, growth
treatment retardation, adrenal dysfunction
Unknown Fetal and teratogenic toxicities: The use iodine (131I) is contra-indicated, even in diagnostic
Frequency and doses, during pregnancy. It is not known whether 131I-MIBG is distributed into breast milk.
Timing: However, this preparation may be contaminated with free radioiodide, which may be distributed
into breast milk. Radioactive 131I has been reported to be present in breast milk for 2 to 14 days.
(L) Toxicity may also occur later.
Formulation and Stability:

131
I-MIBG is supplied in single-dose glass vials. Each mL contains: 3-Iodobenzylguanidine Sulfate
< 0.83 mg, Niacinamide 16 mg, Sodium Chloride 9 mg, Benzyl Alcohol 9 μL, Sodium Acetate Trihydrate
0.68 mg, Cupric Nitrate (II) < 0.02 mg, Hydrochloric Acid Trace, Sodium Hydroxide Pellets Trace, and
Water for Injection q.s. to 1 mL
Specific activity: Not less than 30 mCi/mg (1110 MBq/mg) MIBG at the calibration date
Radiochemical purity: Not less than 95% of the 131I must be as MIBG
Radiolytic decay: 131I decays by beta emission and associated gamma emission with a physical half-life
of 8.04 days
MIBG Therapeutic 15-25 mCi/mL is supplied in liquid form single-dose in a 30 mL glass vial.
It is shipped frozen and should be stored in the refrigerator at 2°-8°C (36º-46ºF) upon arrival at the site.
The product is stable at 2°-8°C (36º-46º F) for 48 hours with excursions permitted at room temperature.
The drug should not be stored at room temperature.
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol.
131
I-MIBG is a radiopharmaceutical agent and should be received, used and administered only by
authorized persons in designated clinical settings and receipt, storage, use, transfer and disposal are
subject to the regulations and appropriate licenses of the competent authorities.
09/24/14 61
Radiopharmaceuticals should be prepared by the user in a manner that satisfies both radiation safety and
pharmaceutical quality requirements.
The entire dose should be infused over a period of 90 to 120 minutes at a rate of no more than
500 mCi/hour via either a central or a peripheral IV catheter.
Anti-emetics may be given orally prior to the initiation of the 131I-MIBG infusion and as needed
thereafter. Antiemetics that could interfere with MIBG uptake (e.g., phenothiazines) should be avoided.
Patients who have been treated with radioactive medicinal products represent a risk factor for other
personnel because of the external radiation load or because of contamination caused by being splashed by
urine, vomit, etc. Precautionary measures in compliance with national radiation protection regulations are
therefore to be observed. Contamination caused by radioactivity being secreted by the patient is to be
avoided.
RADIATION PROTECTION
All persons involved with direct care of a patient receiving 131I-MIBG should receive radiation safety
instructions prior to their involvement. 131I-MIBG should only be administered in an appropriately
shielded isolation room. Patients should remain in the room until radiation emissions are < 7 mRem/h at a
1 meter distance (or otherwise meet institutional guidelines).
PATIENT PREPARATION
Bladder protection
It is recommended that an indwelling urinary catheter be inserted prior to the 131I-MIBG infusion and
remain in place for the first 72 hours post-MIBG treatment or until the whole body reading is
<7 mRem/hr at a 1 meter distance, whichever happens sooner. If the patient is incontinent, the indwelling
urinary catheter will remain in place until the patient meets institutional discharge criteria. The catheter
will prevent accumulations of large amounts of radioactivity in the bladder. Intravenous fluids will be
administered at 100-125 mL/m2/hour to help maintain urine flow and isotope excretion for at least
72 hours.
Thyroid Protection
To minimize the risk of post-treatment hypothyroidism, patients who are not already hypothyroid will be
given potassium iodide (KI) orally beginning prior to 131I-MIBG and for several weeks after (See
treatment plan). Thyroid blockade, in addition to protocol directed KI, may be used per institutional
standards.
Concomitant medications
Prior to treatment, drugs likely to interfere with the uptake and/or retention of 131I-MIBG should be
withdrawn for a minimum period equal to 5 half-lives of the interfering drug. If alternative medications
are required, patients should be stabilized on these medications prior to receiving 131I-MIBG. A list of
drugs known or expected to interfere with MIBG is in Appendix VI.
Supplier
131
I-MIBG is supplied by Jubilant DraxImage. Information on drug ordering, inventory management and
accountability requirements is available in the MIBG Drug Ordering memorandum and the Pharmacy
Manual posted on the protocol page of the COG website.
Distribution
Jubilant Draximage Therapeutic 131I-MIBG will be provided by Jubilant DraxImage, Montreal,
Canada. MIBG Institution to call 2 weeks prior to infusion to Jubilant DraxImage Customer Service at:
09/24/14 62
Order Department and Customer Service

Phone: 1-888-633-5343; 8am – 5pm Eastern Time
Fax: 1-866-431-4288
Fax: 1-514-694-3865
Email: customerservice@draximage.com
Web: www.draximage.com
Drug ordering details and a list of required forms are provided in the MIBG Drug Ordering memorandum
and the Pharmacy Manual posted on the protocol page of the COG website.
6.2 BUSULFAN INJECTION (06/13/13)

(Busulfex®) NSC #750

Busulfan is a non-cell cycle specific bifunctional alkylating agent. In aqueous media, busulfan hydrolyzes
to release methanesulfonate groups. This produces reactive carbonium ions that interact with cellular thiol
groups and nucleic acids to form DNA cross-links. Busulfan injection is 100% bioavailable by definition of
intravenous administration. The elimination of busulfan appears to be independent of renal function,
presumably reflecting the extensive metabolism of the drug in the liver, since less than 2% of the
administered dose is excreted in the urine unchanged within 24 hours. The drug is metabolized by
enzymatic activity to at least 12 metabolites, among which tetrahydrothiophene, tetrahydrothiophene
12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic
activity. Irreversible binding to plasma proteins (primarily albumin) is approximately 32.4%. Busulfan
has a plasma terminal elimination half-life (t1/2) of about 2.6 hours and demonstrates linear kinetics. It is
rapidly distributed into tissue and crosses the blood-brain and the placental barriers. CSF concentrations are
approximately equal to those in plasma. Itraconazole reduced busulfan clearance by up to 25% in patients
receiving itraconazole compared to patients who did not receive itraconazole. Higher busulfan exposure
due to concomitant itraconazole could lead to toxic plasma levels in some patients. Fluconazole had no
effect on the clearance of busulfan.
09/24/14 63
Toxicities:
Happens to 21-100 children out of Happens to 5-20 children out Happens to < 5 children out of
every 100 of every 100 every 100
Immediate: Nausea, vomiting, fever, electrolyte Weight gain, confusion Seizures (rare with phenytoin
Within 1-2 changes (hypokalemia, prophylaxis), hematemesis,
days of hypomagnesemia, hypocalcemia, hyperuricemia, arrhythmias other
receiving drug hypophosphatemia, and than tachycardia, pleural effusion,
hyponatremia), hyperglycemia, alveolar hemorrhage
dizziness, rash, pruritus, urticaria,
injection site pain and inflammation,
back pain, tachycardia, chest pain,
edema, insomnia, anxiety, depression,
headache, abdominal pain, diarrhea (L)
or constipation, anorexia, rectal
discomfort, dyspnea, epistaxis
Prompt: Myelosuppression, asthenia, Hepatotoxicity, sinusoidal Reduced adrenal function (L),
Within 2-3 immunosuppression (L), mucositis, obstruction syndrome (SOS, esophagitis, radiation recall
weeks hyperbilirubinemia formerly VOD) (L), mild reactions
alopecia (L), arthralgia,
myalgia, hemorrhagic cystitis,
hyperpigmentation (L),
elevated creatinine and BUN
Late: Infertility, testicular atrophy and Secondary malignancy, breast
Any time after azoospermia, amenorrhea, ovarian enlargement, cataracts, idiopathic
completion of failure pulmonary syndrome (cough,
treatment dyspnea, pleural effusion,
infiltrates, and hypoxemia),
bronchopulmonary dysplasia with
interstitial pulmonary fibrosis and
pneumonitis, myocardial fibrosis,
osteonecrosis
Unknown Fetal toxicities and teratogenic effects of busulfan and its solvent have been noted in animals. Toxicities
Frequency include: multiple anomalies and low birth weight. It is unknown whether the drug or its solvent is excreted
and Timing: in breast milk.
(L)Toxicity may also occur later

Each ampoule or vial of busulfan injection contains 60 mg (6 mg/mL) of busulfan, N,N-
dimethylacetamide (DMA) 33% vol/vol and Polyethylene Glycol 400, 67% vol/vol. Store refrigerated at
2°-8°C, (36°-46°F).
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol.
Dilute busulfan injection to a final concentration of approximately 0.5 mg/mL with NS or D5W. The drug
should not be infused with any other drug or IV solution other than NS or D5W. Always add the busulfan
to the diluent, not the diluent to the busulfan injection. Mix thoroughly by inverting several times. Do not
use polycarbonate syringes or filter needles with busulfan injection. Busulfan injection diluted in NS
or D5W is stable at room temperature (25°C) for up to 8 hours but the infusion must be completed within
that time. Busulfan injection diluted in NS is stable at refrigerated conditions 2°-8°C (36°-46°F) for up to
12 hours but the infusion must be completed within that time.
09/24/14 64
Busulfan injection should be administered by IV infusion through a central venous catheter. Patients
receiving busulfan in a conditioning regimen for bone marrow transplant must receive seizure prophylaxis.
If phenytoin is used, it should be given 12 hours prior to the start of busulfan, then daily during busulfan
administration and for 48 hours after completion of busulfan. In dose-finding studies of busulfan where
patients received concomitant busulfan and phenytoin, phenytoin reduced busulfan plasma AUC by
approximately 15%. Use of other anticonvulsants may result in higher busulfan plasma AUCs, and an
increased risk of sinusoidal obstruction syndrome, (SOS, formerly VOD) or seizures. After an initial dose
of busulfan injection, blood levels are monitored with bone marrow transplant patients in order to achieve a
target area-under-the-curve (AUC) plasma concentration.
Supplier: Commercially available from various manufacturers. See package insert for further information.
6.3 CISPLATIN (05/06/11)

(Cis-diamminedichloroplatinum II, CDDP, cis-DDP, Platinol-AQ) NSC #119875

Cisplatin is an inorganic, water-soluble complex containing a central platinum atom, 2 chlorine atoms and
2 ammonia molecules. In aqueous solution, the chloride ions are slowly displaced by water generating a
positively charged aquated complex. This activated complex is then available to react with nucleophilic
sites on DNA, RNA, or protein resulting in the formation of bi-functional covalent links, very similar to
alkylating reactions. The intra-strand cross-links, in particular with guanine and cytosine, change DNA
conformation and inhibit DNA synthesis leading to the cytotoxic and anti-tumor effects of cisplatin.
Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. Cisplatin has a rapid
distribution phase of 25-80 minutes with a slower secondary elimination half-life of 60-70 hours. The
platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins including
albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end
of a three hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin
and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a
minimum half-life of five days or more. Platinum is present in tissues for as long as 180 days after the last
administration. Both cisplatin and platinum are excreted through the kidneys ranging from 10-50%. Fecal
elimination is minimal. Cisplatin’s penetration into the CNS is poor.
09/24/14 65
Toxicity:
Happens to 21-100 children out of Happens to 5-20 children out of Happens to <5 children out of every 100
every 100 every 100
Immediate: Nausea (L), vomiting (L) Metallic taste (L) Anaphylactic reaction ( facial edema,
Within 1-2 wheezing, tachycardia, and
days of
hypotension), phlebitis, extravasation
receiving drug
(rare) but if occurs = local ulceration
(only in concentration > 0.5mg/mL)
Prompt: Anorexia (L), Electrolyte disturbances (L) Vestibular dysfunction, tinnitus (L),
Within 2-3 myelosuppression, (hypocalcemia, natremia, rash, seizure (L), elevated liver function
weeks, prior to
hypomagnesemia (L), high kalemia, & phosphatemia ) tests (L).
the next course
frequency hearing loss (L), peripheral neuropathy
nephrotoxicity (↑ Cr, BUN, (paresthesias in a stocking-
Uric Acid) (L) glove distribution) (L)
Delayed: Hearing loss in the normal Areflexia, loss of proprioception and
Any time later hearing range vibratory sensation, (very rarely loss of
during therapy
motor function) (L), optic neuritis,
papilledema, cerebral blindness, blurred
vision and altered color perception
(improvement or total recovery usually
occurs after discontinuing), chronic renal
failure, deafness
Late: Secondary malignancy
Any time after
completion of
treatment
Unknown Frequency and Timing: Fetal toxicities and teratogenic effects of cisplatin have been noted in animals
and cisplatin can cause fetal harm in humans. Cisplatin is excreted into breast milk.
Formulation and Stability: Available as an aqueous solution containing 1 mg/mL of cisplatin and 9 mg
(1.54 mEq)/mL of sodium chloride in 50 mL, 100 mL and 200 mL multi-dose non-preserved vials. Store at
15° -25°C (68°-77ºF). Do not refrigerate. Protect unopened container from light. The cisplatin remaining
in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under
fluorescent room light. Cisplatin removed from its amber container should be protected from light if not
used within 6 hours.
Guidelines for Administration: See the Treatment and Dose Modifications sections of this protocol.
Cisplatin may be further diluted in dextrose and saline solutions provided the solution contains > 0.3%
sodium chloride. The final infusion solution should contain ≥ 0.2% sodium chloride.
Dextrose/saline/mannitol containing solutions, protected from light, are stable refrigerated or at room
temperature for 24 to 72 hours, however, cisplatin solutions should not be stored in the refrigerator to
avoid precipitation. Cisplatin is incompatible with sodium bicarbonate and alkaline solutions.
Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin should not
be used for preparation or administration. Aluminum reacts with cisplatin causing precipitate formation
and a loss of potency.
Accidental extravasation with solutions that are > 0.5 mg/mL may result in significant tissue toxicity.
Supplier: Commercially available from various manufacturers. See package insert for more detailed
information.
09/24/14 66
6.4 CYCLOPHOSPHAMIDE INJECTION (03/13/13)

(Cytoxan) NSC #26271
Source and Pharmacology: Cyclophosphamide is an alkylating agent related to nitrogen mustard.

Cyclophosphamide is inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9 and
CYP3A4) in the liver to active compounds. The initial product is 4-hydroxycyclophosphamide (4-HC)
which is in equilibrium with aldophosphamide which spontaneously releases acrolein to produce
phosphoramide mustard. Phosphoramide mustard, which is an active bifunctional alkylating species, is 10
times more potent in vitro than is 4-HC and has been shown to produce interstrand DNA cross-link
analogous to those produced by mechlorethamine. Approximately 70% of a dose of cyclophosphamide is
excreted in the urine as the inactive carboxyphosphamide and 5-25% as unchanged drug. The plasma half-
life ranges from 4.1 to 16 hours after IV administration.
Toxicity:
Happens to 21-100 children Happens to 5-20 children Happens to < 5 children out of every 100
out of every 100 out of every 100
Immediate: Anorexia, nausea & vomiting Abdominal discomfort, Transient blurred vision, nasal stuffiness
Within 1-2 days of (acute and delayed) diarrhea with rapid administration, arrhythmias
receiving drug (rapid infusion), skin rash, anaphylaxis,
SIADH
Prompt: Leukopenia, alopecia, Thrombocytopenia, Cardiac toxicity with high dose (acute –
Within 2-3 weeks, immune suppression anemia, hemorrhagic CHF hemorrhagic myocarditis,
prior to the next cystitis (L) myocardial necrosis) (L),
course hyperpigmentation, nail changes, impaired
wound healing, infection secondary to
immune suppression
Delayed: Gonadal dysfunction Amenorrhea1 Gonadal dysfunction : ovarian failure1 (L),
Any time later azoospermia or oligospermia interstitial pneumonitis, pulmonary
during therapy (prolonged or permanent)1 fibrosis2 (L)
(L)
Late: Secondary malignancy (ALL, ANLL,
Any time after AML), bladder carcinoma (long term use
completion of > 2 years), bladder fibrosis
treatment
Unknown Frequency and Timing: Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination
with other antineoplastic agents) have been noted in humans. Toxicities include: chromosomal abnormalities, multiple
anomalies, pancytopenia, and low birth weight. Cyclophosphamide is excreted into breast milk. Cyclophosphamide is
contraindicated during breast feeding because of reported cases of neutropenia in breast fed infants and the potential for
serious adverse effects.
1
Dependent on dose, age, gender and degree of pubertal development at time of treatment
2
Risk increased with pulmonary chest irradiation and higher doses.
Formulation and Stability: Cyclophosphamide for injection is available as powder for injection or
lyophilized powder for injection in 500 mg, 1 g and 2 g vials. The powder for injection contains 82 mg
sodium bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 75 mg
mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is recommended. The product will
withstand brief exposures to temperatures up to 30ºC (86ºF).
09/24/14 67
Cyclophosphamide for Injection:

If the drug will be administered as undiluted drug at the 20 mg/mL concentration, then reconstitute to
20 mg/mL with NS ONLY to avoid a hypotonic solution. If the drug will be further diluted prior to
administration, then first reconstitute with NS, SWFI, or Bacteriostatic Water for Injection (paraben
preserved only) to a concentration of 20 mg/mL. Following reconstitution further dilute in dextrose or saline
containing solutions for IV use.
Supplier: Commercially available from various manufacturers. See package insert for further information
6.5 DOXORUBICIN (05/09/11)

(Adriamycin®) NSC #123127

An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. The cytotoxic effect of
doxorubicin on malignant cells and its toxic effects on various organs are thought to be related to
nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation
inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin
with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of
doxorubicin cytocidal activity. Doxorubicin cellular membrane binding may affect a variety of cellular
functions. Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases, and
dehydrogenases generate highly reactive species including the hydroxyl free radical (OH•). Free radical
formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at
the cellular level. Cells treated with doxorubicin have been shown to manifest the characteristic
morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced
apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic
effects, toxicities, or both.
Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is approximately 5 minutes
suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 48 hours reflects a slow
elimination from tissues. Steady-state distribution volumes exceed 20 to 30 L/kg and are indicative of
extensive drug uptake into tissues. Plasma clearance is in the range of 8 to 20 mL/min/kg and is
predominately by metabolism and biliary excretion. The P450 cytochromes which appear to be involved
with doxorubicin metabolism are CYP2D6 and CYP3A4. Approximately 40% of the dose appears in the
bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same
time period. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about
74 to 76% and is independent of plasma concentration of doxorubicin.
09/24/14 68
Toxicity:
Happens to 21-100 children out Happens to 5-20 children out of Happens to < 5 children out of
of every 100 every 100 every 100
Immediate: Nausea, vomiting, pink or red Hyperuricemia, facial flushing, Diarrhea, anorexia, erythematous
Within 1-2 days of color to urine, sweat, tears, and sclerosis of the vein streaking of the vein (flare
receiving drug saliva reaction), extravasation (rare) but
if occurs = local ulceration,
anaphylaxis, fever, chills,
urticaria, acute arrhythmias
Prompt: Myelosuppression (leukopenia, Mucositis (stomatitis and Radiation recall reactions,
Within 2-3 weeks, prior thrombocytopenia, anemia), esophagitis), hepatotoxicity conjunctivitis and lacrimation
to the next course alopecia
Delayed: Cardiomyopathy1 (CHF occurs Cardiomyopathy1 (CHF occurs in
Any time later during in 5-20% at cumulative doses < 5% at cumulative doses
therapy ≥450 mg/m²) (L) ≤ 400 mg/m²) (L), ulceration and
necrosis of colon,
hyper-pigmentation of nail bed
and dermal crease, onycholysis
Late: Subclinical cardiac dysfunction CHF (on long term follow up in Secondary malignancy (in
Any time after pediatric patients) combination regimens)
completion of treatment
Unknown Frequency Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin have been noted
and Timing: in animal models. Doxorubicin is excreted into breast milk in humans
1
Risk increases with cardiac irradiation, exposure at a young or advanced age.

Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 50 mg¹ vials and
a preservative-free 2 mg/mL solution in 10 mg¹, 20 mg¹, 50 mg¹, 200 mg² vials.
¹: Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF (rapid dissolution formula)
also contains methylparaben, 1 mg per each 10 mg of doxorubicin, to enhance dissolution.
² Multiple dose vial contains lactose, 0.9% NS, HCl to adjust pH to 3.
Aqueous Solution: Store refrigerated 2°-8°C, (36°-46°F). Protect from light. Retain in carton until contents
are used.
Powder for Injection: Store unreconstituted vial at room temperature, 15°-30°C (59°-86°F). Retain in
carton until contents are used. Reconstitute with preservative-free NS to a final concentration of 2 mg/mL.
After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted
solution is stable for 7 days at room temperature and 15 days under refrigeration, 2°-8°C (36°-46°F) when
protected from light. Doxorubicin further diluted in 50 – 1000 mL of NS or D5W is stable for up to 48
hours at room temperature (25°C) when protected from light.
Administer IV through the tubing of rapidly infusing solution of D5W or 0.9% NaCl preferably into a
large vein. Protect the diluted solution from sunlight. To avoid extravasation, the use of a central line is
suggested.
09/24/14 69
6.6 ETOPOSIDE_IV ONLY (03/13/13)

(VePesid®, Etopophos®,VP-16) NSC #141540
Source and Pharmacology: A semisynthetic derivative of podophyllotoxin that forms a complex with
topoisomerase II and DNA which results in single and double strand DNA breaks. Its main effect appears
to be in the S and G2 phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal half-life is 4
to 11 hours. It is primarily excreted in the urine. In children, approximately 55% of the dose is excreted in
the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m² or about
35% of the total body clearance over a dose range of 80 to 600 mg/m². Etoposide, therefore, is cleared by
both renal and non renal processes, i.e., metabolism and biliary excretion. The effect of renal disease on
plasma etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide
elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism
accounts for most of the non renal clearance of etoposide.
The maximum plasma concentration and area under the concentration time curve (AUC) exhibit a high
degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily serum
albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is related to toxicity.
Preliminary data suggests that systemic exposure for unbound etoposide correlates better than total
(bound and unbound) etoposide. There is poor diffusion into the CSF < 5%.
Etoposide phosphate is a water soluble ester of etoposide which is rapidly and completely converted to
etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that etoposide phosphate is
bioequivalent to etoposide when it is administered in molar equivalent doses.
Toxicity:
Happens to 21-100 children Happens to 5-20 children out Happens to < 5 children out of
out of every 100 of every 100 every 100
Immediate: Nausea, vomiting Anorexia Transient hypotension during
Within 1-2 days of infusion; anaphylaxis (chills,
receiving drug fever, tachycardia, dyspnea,
bronchospasm, hypotension)
Prompt: Myelosuppression (anemia, Thrombocytopenia, diarrhea, Peripheral neuropathy, mucositis,

Within 2-3 weeks, leukopenia), alopecia abdominal pain, asthenia, hepatotoxicity, chest pain,
prior to next malaise, rashes and urticaria thrombophlebitis, congestive heart
course failure, Stevens-Johnson
Syndrome, exfoliative dermatitis
Delayed: Dystonia, ovarian failure,
Any time later amenorrhea, anovulatory cycles,
during therapy hypomenorrhea, onycholysis of
nails
Late: Secondary malignancy
Any time after (preleukemic or leukemic
completion of syndromes)
treatment
Unknown Fetal toxicities and teratogenic effects of etoposide have been noted in animals at 1/20th of the
Frequency and human dose. It is unknown whether the drug is excreted in breast milk.
Timing:

Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials (5 mL, 25 mL, or
50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg
09/24/14 70
etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 650 mg
polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. Unopened
vials of etoposide are stable until expiration date on package at controlled room temperature (20˚-25˚C or
68˚-77˚F).
Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized powder in
single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 mg sodium citrate
USP, and 300 mg dextran 40. Etoposide phosphate must be stored under refrigeration (2°-8°C or 36°-
46°F). Unopened vials of etoposide phosphate are stable until the expiration date on the package.
Etoposide:
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions are stable at
room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL; stability is 24 hours at room
temperature with concentrations of 0.4 mg/mL. The time to precipitation is highly unpredictable at
concentrations > 0.4 mg/mL. Use in-line filter during infusion secondary to the risk of precipitate
formation. However, the use of an in-line filter is not mandatory since etoposide precipitation is unlikely
at concentrations of 0.1-0.4 mg/mL. Do not administer etoposide by rapid intravenous injection. Slow
rate of administration if hypotension occurs.
Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags occurred with etoposide
0.4 mg/mL in NS. To avoid leaching, prepare the etoposide solution as close as possible, preferably
within 4 hours, to the time of administration or alternatively as per institutional policy, glass or
polyethylene-lined (non-PVC) containers and polyethylene-lined tubing may be used to minimize
exposure to DEHP.
Etoposide Phosphate:
Reconstitute the 100 mg vial with 5 or l0 mL of Sterile Water for Injection, D5W, NS, Bacteriostatic
Water for Injection with Benzyl Alcohol or Bacteriostatic Sodium Chloride for Injection with Benzyl
Alcohol for a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide equivalent (22.7 mg/mL or
11.4 mg/mL etoposide phosphate), respectively. Use diluents without benzyl alcohol for neonates and
infants < 2 years of age or patients with hypersensitivity to benzyl alcohol.
When reconstituted as directed, etoposide phosphate solutions can be stored in glass or plastic containers
under refrigeration for 7 days. When reconstituted with a diluent containing a bacteriostat, store at controlled
room temperature for up to 48 hours. Following reconstitution with SWFI, D5W, or NS, store at controlled
room temperature for up to 24 hours.
Following reconstitution, etoposide phosphate may be further diluted to a concentration as low as

0.1 mg/mL of etoposide with D5W or NS. The diluted solution can be stored under refrigeration or at
controlled room temperature for 24 hours.
Supplier: Commercially available from various manufacturers. See package insert for more detailed
information.
CANADIAN SITES
Etopophos® (etoposide phosphate) is not commercially available in Canada. Sites may purchase and
import the USA commercial supply from Bristol Laboratories via an International Distributor (Pharma
Exports LLC, phone: 1-412-885-3700, fax: 1-412-885-8022, email: pharexp@aol.com) under the
authority of the protocol’s No Objection Letter (NOL). Drug Accountability Log (DAL) must record Lot
#’s and expiry dates of shipment received and doses dispensed. Sites may use their own DAL as long as it
09/24/14 71
complies with all elements of ICH GCP and Division 5 of the Food and Drugs Act. Each site is
responsible for the procurement (import +/- purchase) of Etoposide Phosphhate (Etopophos). Sites may
import and manage a single clinical trial supply for multiple protocols as long as each protocol has an
NOL and the protocol the patient is registered on is recorded on the DAL.
6.7 FILGRASTIM (05/09/11)

(Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®) NSC #614629
Source and Pharmacology: Filgrastim is a human granulocyte colony-stimulating factor (G-CSF),
produced by recombinant DNA technology. Filgrastim is a 175 amino acid protein with a molecular
weight of 18,800 daltons manufactured by recombinant DNA technology utilizing E coli bacteria into
which has been inserted the human granulocyte colony stimulating factor gene. It differs from the natural
protein in that the N- amino acid is methionine and the protein is not glycosylated. G-CSF is a lineage
specific colony-stimulating factor which regulates the production of neutrophils within the bone marrow
and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation
(including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory
burst, antibody dependent killing, and the increased expression of some functions associated with cell
surface antigens).The elimination half-life is similar for subcutaneous and intravenous administration,
approximately 3.5 hours. The time to peak concentration when administered subcutaneously is 2-8 hours.
Toxicity:
Happens to 21-100 Happens to 5-20 children out Happens to <5 children out of every
children out of every 100 of every 100 100
Immediate: Local irritation at the Allergic reactions (more common
Within 1-2 days of injection site, with IV administration than
receiving drug headache subq):skin (rash, urticaria, facial
edema), respiratory (wheezing,
dyspnea) and cardiovascular
(hypotension, tachycardia), low grade
fever
Prompt: Mild to moderate Increased: alkaline Splenomegaly, splenic rupture, rash
Within 2-3 weeks, prior to medullary bone pain phosphatase, lactate or exacerbation of pre-existing skin
the next course dehydrogenase and uric acid, rashes, sickle cell crises in patients
thrombocytopenia with SCD, excessive leukocytosis,
Sweet’s syndrome (acute febrile
neutrophilic dermatosis)
Delayed: Cutaneous vasculitis, ARDS
Anytime later during
therapy
Late: MDS or AML (confined to patients
Anytime after completion with severe chronic neutropenia and
of treatment long term administration)
Unknown Frequency and Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. Conflicting
Timing: data exist in animal studies and filgrastim is known to pass the placental barrier. It is
unknown whether the drug is excreted in breast milk.
Formulation and Stability: Supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials. It is
also available as prefilled syringes containing 300 mcg/0.5 mL or 480 mcg/0.8 mL. Vials are preservative
free single use vials. Discard unused portions of open vials. Store refrigerated at 2º-8ºC (36º-46ºF). Prior
to injection, filgrastim may be allowed to reach room temperature for a maximum of 24 hours. Avoid
freezing and temperatures > 30ºC.
For IV use, dilute in D5W only to concentrations >15 mcg/mL. At concentrations between 5 and
15 mcg/mL, human serum albumin should be added to make a final albumin concentration of 0.2%
09/24/14 72
(2 mg/mL) in order to minimize the adsorption of filgrastim to plastic infusion containers and equipment.
Dilutions of 5 mcg/mL or less are not recommended. Diluted filgrastim should be stored at 2º-8ºC
(36º-46ºF) and used within 24 hours. Do not shake.
Do not dilute with saline-containing solutions at any time; precipitation will occur.
Guidelines for Administration:

See Treatment, Dose Modifications and Supportive Care sections of the protocol.
Filgrastim should not be administered within 24 hours of (before AND after) chemotherapy.
6.8 ISOTRETINOIN (05/09/11)

(13-cis-retinoic acid, RO-43,780, Accutane®, Amnesteem® Claravis™, Sotret®) NSC#329481
Source and Pharmacology: Isotretinoin is a naturally occurring analogue of Vitamin A. Retinoids are
required for the maintenance of normal cell growth, differentiation, and loss within epithelial tissues.
Various retinoids have been shown to suppress or reverse epithelial carcinogenesis and to prevent the
development of invasive cancers in many animal systems. Retinoids act primarily in the post-carcinogen
phases of promotion and progression, which makes them more useful for chemoprevention. However in
certain malignancies (notably acute promyelocytic leukemia and neuroblastoma), high-doses of retinoids
can have significant anti-tumor activity. The exact mechanism of RA-induced maturation of tumor cells is
not known. The mechanism by which retinoids regulate the growth and differentiation of normal and
malignant cells has not been completely elucidated, but it is thought that these effects result from the
ability of retinoids to modulate the transcriptional regulatory activity of a set of nuclear retinoic acid
receptors (RARs) and retinoid X receptors (RXRs) belonging to the super family of thyroid/steroid
hormone receptors.
Isotretinoin is highly lipophilic and 99.9% bound to plasma protein (almost entirely albumin) and has a half-
life of 10-20 hours. Oral absorption of isotretinoin is enhanced when given with a high fat meal increasing
both the peak plasma concentration and AUC by more than double. Following oral administration of
isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic
acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are
geometric isomers and show reversible inter-conversion. The administration of one isomer will give rise
to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric
isomer 4-oxo-tretinoin. All of these metabolites possess retinoid activity that is in some in vitro models
more than that of the parent isotretinoin. The metabolites of isotretinoin and any conjugates are ultimately
excreted in the feces and urine in relatively equal amounts (total of 65-83%). In a study comparing the
pharmacokinetics of isotretinoin in pediatric and adult patients there were no statistically significant
differences.
09/24/14 73
Toxicity:
Happens to 21-100 Happens to 5-20 children out of Happens to <5 children out of every 100
children out of every 100 every 100
Immediate: Nausea and vomiting Anaphylaxis, bronchospasm
Within 1-2 days of
receiving drug
Prompt: Dry skin (L), dry mucosa Rash (L), conjunctivitis (L), Alopecia, appetite disturbances,
Within 2-3 weeks, (L), epistaxis, cheilitis, headache (L), decrease in high hyperglycemia, hyper- or hypo- skin
prior to the next (L), photosensitivity, density lipoproteins (L), pigmentation, nail changes, eruptive
course elevated ESR, back pain cholesterol elevation L), xanthomas, seizures, dizziness,
(L), arthralgias (L), transaminase elevation (L), pseudotumor-cerebri (papilledema,
triglyceride elevation (L), anemia (L) headache, nausea, vomiting, visual
hypercalcemia (L) disturbances), psychiatric disorders
(depression, aggressive and/or violent
behaviors, suicidal ideation, suicide, dream
disturbances), insomnia, lethargy, malaise,
nervousness, paresthesias, weight loss,
myelosuppression, elevated platelet counts,
agranulocytosis, allergic vasculitis (L),
chest pain, pancreatitis (including very
rarely fatal hemorrhagic pancreatitis),
hearing impairment, inflammatory bowel
disease, visual disturbances (decrease in
night vision, corneal opacities which
resolve on d/c, photophobia, color vision
disturbances, cataracts), edema,
inflammation of the gums, drying of
respiratory tract with voice alteration,
respiratory infections, erythema
multiforme, Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN)
Delayed: Skeletal hyperostosis Osteoporosis, bone fractures or delayed
Any time later healing, premature epiphyseal closure,
during therapy, rhabdomyolysis, abnormal menses, renal
excluding the above disturbances (WBC in urine, proteinuria,
conditions hematuria, renal calculi), calcification of
tendon and ligaments
Unknown Major human fetal abnormalities related to isotretinoin administration in females have been
frequency and documented. There is an increased risk of spontaneous abortion. In addition, premature births have
timing: been reported. Documented external abnormalities include: skull abnormality; ear abnormalities
(including anotia, micropinna, small or absent external auditory canals); eye abnormalities
(including microphthalmia); facial dysmorphia and cleft palate. Documented internal abnormalities
include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation,
hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland
abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the
abnormalities previously noted. Cases of IQ scores less than 85 with or without obvious CNS
abnormalities have also been reported. It is not known whether this drug is excreted in human milk.
Because of the potential for adverse effects, nursing mothers should not receive isotretinoin.
Formulation and Stability: Isotretinoin, a retinoid, is available in 10 mg, 20 mg, 30 mg and 40 mg soft
gelatin capsules for oral administration. Inactive ingredients vary depending on the manufacturer but
capsule formulations may include the following inactive ingredients: beeswax, butylated hydroxyanisole,
edetate disodium, hydrogenated soybean oil flakes, hydrogenated vegetable oil, soybean oil and vitamin
E. Gelatin capsules may contain glycerin and parabens (methyl and propyl), with the following dye
09/24/14 74
systems: iron oxide (red and black) and titanium dioxide; FD&C Red No. 3 or 7, FD&C Blue No. 1 or 2,
FD&C Yellow No. 6 or 10, propylene glycol, and shellac glaze.
Store at controlled room temperature (59°-86°F, 15°-30°C). Protect from light.
Give orally with food (ideally, high fat) or milk to enhance absorption. For children unable to swallow the
capsules whole, the following options may be used:
1. Soften capsule (in warm water) bite, swallow or suck out contents or place softened capsule in fatty
food such as peanut butter and swallow. The method of softening the capsule and withdrawing contents
with an oral syringe is not preferred as it is difficult to remove all of the drug from the capsule.
2. Squeeze out the entire contents of the capsule into a small medicine cup and give with fatty food, such
as peanut butter. (If at all possible have the child suck on the empty capsule in hopes of getting more of
the intended dose)
3. The preferred method is to poke a hole in the capsule to allow the capsule to be chewed and embed the
capsule in a food or candy enjoyed by the child.
Under no circumstances should isotretinoin be removed from the capsules for more than 1 hour prior to
administering to the patient.
Note: Women of childbearing potential should wear gloves when handling isotretinoin capsules.
If the contents are withdrawn from the capsule and mixed with food or milk administer as closely as
possible to mixing to avoid oxidation or conversion by exposure to light to a more toxic and less potent
product.
Isotretinoin is contraindicated in patients with paraben allergies as the capsule is preserved with the agent.
Patients should be warned about enhanced photosensitivity; the use of sunscreen and avoidance of direct
sunlight should be recommended. Patients should limit the intake of vitamin A.
Supplier: Commercially available from various manufacturers. See package insert for further
information.
SITES WITHIN THE UNITED STATES:

Isotretinoin MUST be prescribed under the Committed to Pregnancy Prevention Program (iPLEDGE).
(Physicians must complete a one-time registration with the program in order to be able to prescribe the
drug. Each physician (or their office representative), dispensing pharmacy and patient must be registered
on line @ https://www.ipledgeprogram.com (or call 1-866-495-0654 to begin the registration process.)
UPON REGISTRATION YOU WILL RECEIVE ALL OF THE INFORMATION AND

EDUCATIONAL MATERIALS NECESSARY TO PRESCRIBE ISOTRETINOIN. Because of
isotretinoin’s teratogenicity and to minimize fetal exposure, isotretinoin is approved for marketing only
under a special restricted distribution program approved by the Food and Drug Administration. This
program is called iPLEDGE. Isotretinoin must only be prescribed by prescribers who are registered and
activated with the iPLEDGE program. Isotretinoin must only be dispensed by a pharmacy registered and
activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the
requirements of iPLEDGE. The iPLEDGE program is a computer-based risk management system that
09/24/14 75
uses verifiable, trackable links between prescriber, patient, pharmacy, and wholesaler to control
prescribing, using, dispensing and distribution of isotretinoin.
OVERVIEW: PROGRAM REQUIREMENTS

The iPLEDGE program has specific requirements for prescribers, patients, and pharmacists. One of the
prescriber’s main responsibilities is knowing and educating patients about these requirements. Note: The
FDA has provided the following statement concerning the physician training aspects of the iPLEDGE
site:
“FDA and the sponsors would like the oncology community who uses isotretinoin to enroll in iPLEDGE
and to know that the "I know how to diagnose and treat the various presentations of acne," statement can
be truthfully answered by oncologists who "know how to diagnose and treat" suspected cases by referring
these cases to dermatologists for management. All the sponsors and FDA agree on this interpretation.”
Prescribers are responsible for registering every patient, who meets the program requirements, in the
iPLEDGE program via the automated system. They are responsible for educating patients about the side
effects of isotretinoin and the high risk of birth defects for female patients of childbearing potential while
taking the drug. As part of this process, they are also responsible for counseling patients about the
monthly steps they must follow to receive isotretinoin.
Prescribers can only write a patient’s prescription for isotretinoin once a month, and then only up to a
maximum of a 30-day supply. Patients must plan for monthly appointments to receive their prescriptions.
At each of these appointments, the prescriber must counsel the patient about the iPLEDGE program
requirements and then confirm via the iPLEDGE automated system that this counseling occurred. They
must also enter this information after the first appointment.
There are different program requirements for male patients and female patients who are not of
childbearing potential and for female patients of childbearing potential. The prescriber must
determine if a patient is a female patient of childbearing potential and document that she meets the
specific requirements of the program. These include taking pregnancy tests (processed in a CLIA-certified
laboratory) and using 2 forms of birth control consistently. Both of these requirements must be followed
before, during, and after treatment, but are not necessary for patients the physician determines are not of
childbearing potential. To receive monthly prescriptions, a female patient of childbearing potential must
also answer questions in the iPLEDGE system about the program requirements and pregnancy prevention.
She must also enter the two forms of birth control she is using. In addition to the monthly counseling
information, the prescriber must also enter into the system the patient’s 2 forms of contraception and the
results of the monthly pregnancy test obtained from a CLIA-certified laboratory. This information is the
criteria the system uses to authorize a pharmacy to fill a prescription.
Requirements for Pharmacists

• Isotretinoin can only be obtained from pharmacies registered with and activated in the iPLEDGE program.
• Registered and activated pharmacies can obtain isotretinoin only from wholesalers registered with the iPLEDGE
program.
• The dispensing pharmacist must obtain authorization and a Risk Management Authorization (RMA)
number before filling and dispensing prescriptions.
• Upon receiving authorization, the dispensing pharmacist can fill a prescription for a maximum 30-day supply
of isotretinoin.
• Upon authorization, the iPLEDGE system provides a Risk Management Authorization (RMA) number to the
dispensing pharmacist. The pharmacist should record the RMA number directly on the prescription.
• Upon authorization, the iPLEDGE system provides a “Do Not Dispense to Patient After” date (7 days from
office visit date) to the dispensing pharmacist. The pharmacist should record this date on the prescription bag
sticker.
09/24/14 76
CANADIAN SITES
The iPLEDGE program for pregnancy prevention is not applicable in Canada. Canadian prescribers are
responsible for monitoring and counseling patients (if they are in this age range) regarding birth control
and patient’s caregivers who may handle the agent. Isotretinoin is marketed in Canada with no additional
regulatory requirements.
6.9 MELPHALAN (05/09/11)

(L-phenylalanine mustard, phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran®) NSC #008806

Melphalan, a phenylalanine derivative of nitrogen mustard, is a bifunctional alkylating agent. Melphalan
forms covalent cross-links with DNA or DNA protein complexes thereby resulting in cytotoxic,
mutagenic, and carcinogenic effects. The end result of the alkylation process results in the misreading of
the DNA code and the inhibition of DNA, RNA, and protein synthesis in rapidly proliferating tumor cells.
It is cell cycle non-specific. After IV administration melphalan plasma concentrations decline rapidly in a
bi-exponential manner with distribution phase and terminal elimination phase half-lives of approximately
10 and 75 minutes, respectively. Plasma melphalan levels are highly variable after oral dosing, both with
respect to the time of the first appearance of melphalan in plasma (range approximately 0 to 6 hours) and
to the peak plasma concentration achieved. These results may be due to incomplete intestinal absorption,
a variable "first pass" hepatic metabolism, or to rapid hydrolysis. The oral dose averages 61 % ± 26% of
that following IV administration. The terminal elimination plasma half-life of oral melphalan is
1.5 ± 0.83 hours. The steady-state volume of distribution of melphalan is 0.5 L/kg. The extent of
melphalan binding to plasma proteins ranges from 60-90%. Melphalan is eliminated from plasma
primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. The 24-hour
urinary excretion of parent drug is approximately 10% suggesting that renal clearance is not a major route
of elimination of parent drug. Penetration into CSF is low. Despite the fact that the contribution of renal
elimination to melphalan clearance appears to be low, one pharmacokinetic study suggests dosage may need
to be reduced in patients with renal impairment.
09/24/14 77
Toxicity:
Happens to 21-100 children Happens to 5-20 children Happens to <5 children out of
out of every 100 out of every 100 every 100
Immediate: Anorexia, nausea, vomiting, Anaphylaxis, hypotension,
Within 1-2 days of hyponatremia (high dose) diaphoresis, pruritus
receiving drug atrial fibrillation (high dose),
extravasation (rare) but if occurs
= local ulceration, SIADH,
Seizures
Prompt: Myelosuppression (L), Abnormal liver function tests,
Within 2-3 weeks, prior mucositis, diarrhea, alopecia jaundice, hepatitis
to the next course
Delayed: Amenorrhea, testicular Bone marrow failure, hemolytic
Any time later during suppression anemia, pulmonary fibrosis,
therapy, excluding the interstitial pneumonitis
above conditions
Late: Sterility, primary ovarian Secondary malignancy
Any time after failure
completion of treatment
Unknown Frequency Melphalan was embryolethal and teratogenic in rats following oral (6 to 18 mg/m2/day for
and Timing: 10 days) and intraperitoneal (18 mg/m²) administration. Malformations resulting from
melphalan included alterations of the brain (underdevelopment, deformation, meningocele,
and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the
mandible and tail, as well as hepatocele (exomphaly). It is unknown whether the drug is
excreted in breast milk.
(L) Toxicity may also occur later

Melphalan for Injection is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each single-use vial
contains melphalan hydrochloride equivalent to 50 mg melphalan and 20 mg povidone. Melphalan for
Injection is reconstituted using the sterile diluent provided. Each vial of sterile diluent contains sodium
citrate 0.2 g, propylene glycol 6.0 mL, ethanol (96%) 0.52 mL, and SWFI to a total of 10 mL. Store at
controlled room temperature 15°-30°C (59°-86°F) and protect from light.
• Reconstitute to a concentration of 5 mg/mL by rapidly injecting 10 mL of the supplied diluent

directly into the vial of lyophilized powder using a sterile needle (20-gauge or larger needle
diameter) and syringe. Immediately shake vial vigorously until a clear solution is obtained. Rapid
addition of the diluent followed by immediate vigorous shaking is important for proper
dissolution.
• Immediately dilute the dose to be administered in NS to a final concentration not to exceed
2 mg/mL for IV central line administration or 0.45 mg/mL for peripheral IV administration
• A precipitate forms if the reconstituted solution is stored at 5°C. Do not refrigerate the
reconstituted product.
(The time between reconstitution/dilution and administration of melphalan should be kept to a
minimum because reconstituted and diluted solutions of melphalan are unstable. Over as short a time
as 30 minutes, a citrate derivative of melphalan has been detected in reconstituted material from the
reaction of melphalan with the sterile diluent for melphalan. Upon further dilution with saline, nearly
1% label strength of melphalan hydrolyzes every 10 minutes.)
09/24/14 78
Injection:
Administer by IV infusion through a peripheral or a central line. The infusion must be completed within
60 minutes of product reconstitution.
Supplier: Commercially available. See package insert for further information.

6.10 MESNA IV ONLY (05/09/11)
(sodium 2-mercaptoethane sulfonate, UCB 3983, Mesnex) NSC #113891

Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis induced by
ifosfamide. Mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Mesna disulfide
remains in the intravascular compartment and is rapidly eliminated by the kidneys. In the kidney, the
mesna disulfide is reduced to the free thiol compound, mesna, which reacts chemically with the urotoxic
ifosfamide metabolites (acrolein and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step
in the detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a nonurotoxic 4-
sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic
metabolites. In multiple human xenograft or rodent tumor model studies, mesna in combination with
ifosfamide (at dose ratios of up to 20-fold as single or multiple courses) failed to demonstrate interference
with antitumor efficacy.
After an 800 mg dose the half lives for mesna and dimesna are 0.36 hours and 1.17 hours, respectively.
Approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna
and dimesna, respectively. The majority of the dose recovered was eliminated within 4 hours.
Toxicity1:
Happens to 21-100 children Happens to 5-20 children Happens to <5 children out of every
out of every 100 out of every 100 100
Immediate: Nausea, vomiting, stomach Facial flushing, fever, pain in arms,
Within 1-2 days of pain, fatigue, headache legs, and joints, rash, transient
receiving drug hypotension, tachycardia, dizziness,
anxiety, confusion, periorbital
swelling, anaphylaxis, coughing
Prompt: Diarrhea
Within 2-3 weeks,
prior to the next
course
Unknown Fetal toxicities and teratogenic effects of mesna have not been noted in animals fed 10 times the
Frequency and recommended human doses. There are however no adequate and well-controlled studies in pregnant
Timing: women. It is not known if mesna or dimesna is excreted into human milk.
1
All currently available products in the U.S. are preserved with benzyl alcohol. Benzyl Alcohol has been associated
with death in pre-term infants weighing less than 2500 g and receiving 99-405 mg/kg/day. Benzyl alcohol is
normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid. In
pre-term infants, however, this metabolic pathway may not be well developed. Onset of toxic illness in these infants
occurred between several days and a few weeks of age with a characteristic clinical picture that included metabolic
acidosis progressing to respiratory distress and gasping respirations. Many infants also had central-nervous-system
dysfunction, including convulsions and intracranial hemorrhage; hypotension leading to cardiovascular collapse
was a late finding usually preceding death. [For comparison in the ICE regimen of 3000 mg/m²/day of ifosfamide
and a daily mesna dose of 60% of the ifosfamide dose = to 1800 mg/m²/day; a child would be expected to receive 18
mL/m²/day of mesna (concentration of 100 mg/mL and 10.4 mg/mL of benzyl alcohol) 187.2 mg/m²/day of benzyl
alcohol or 6.24 mg/kg/day].
09/24/14 79

Mesna for injection is available as 100 mg/mL in 10 mL multidose vials which contain 0.25 mg/mL edetate
disodium and sodium hydroxide for pH adjustment. Mesna Injection multidose vials also contain 10.4
mg/mL of benzyl alcohol as a preservative. Store product at controlled room temperature 15°-25°C (68°-
77ºF). Mesna is not light-sensitive, but is oxidized to dimesna when exposed to oxygen. Mesna as benzyl
alcohol-preserved vials may be stored and used for 8 days.
Guidelines for Administration:

See Treatment, Dose Modifications and Supportive Care sections of the protocol.
For IV administration, dilute mesna to 20 mg/mL with dextrose or saline containing solutions. Mesna may
be mixed with ifosfamide or cyclophosphamide. After dilution for administration, mesna is physically and
chemically stable for 24 hours at 25ºC (77ºF). Carefully expel air in syringes prepacked for use to avoid
oxidation to dimesna. Mesna may cause false positive test for urinary ketones.
CANADIAN SITES
Preservative-free Mesna is commercially available in Canada from Baxter Corporation (Urometixan®);
supplied as a 100mg/mL solution which contains edentate disodium and sodium hydroxide for pH
adjustment, 4mL and 10mL single-use ampoules.
6.11 PEGFILGRASTIM (01/30/10)

(pegylated filgrastim, PEG filgrastim, SD/01, Neulasta®) NSC# 725961

Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF (filgrastim). Pegfilgrastim is
produced by covalently binding a 20-kilodalton (kD) monomethoxypolyethylene glycol molecule to the
N-terminal methionyl residue of filgrastim. The molecular weight of pegfilgrastim is 39 kD. G-CSF is a
lineage specific colony-stimulating factor which regulates the production of neutrophils within the bone
marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional
activation (including enhanced phagocytic ability, priming of the cellular metabolism associated with
respiratory burst, antibody dependent killing, and the increased expression of some functions associated
with cell surface antigens).
After subcutaneous injection the elimination half-life of pegfilgrastim ranges from 15 to 80 hours and the
time to peak concentration ranges from 24 to 72 hours. Serum levels are sustained in most patients during
the neutropenic period postchemotherapy, and begin to decline after the start of neutrophil recovery,
consistent with neutrophil-dependent elimination. After subcutaneous administration at 100 mcg/kg in 37
pediatric patients with sarcoma, the terminal elimination half-life was 30.1 (+/- 38.2) hours in patients 0
to 5 years-old, 20.2 (+/- 11.3) hours in patients 6 to 11 years-old, and 21.2 (+/- 16) hours in children 12 to
21 years-old.
09/24/14 80
Toxicity:
Happens to 21-100 Happens to 5-20 children out Happens to < 5 children out of every 100
children out of every 100 of every 100
Immediate: Local irritation at the Low grade fever, allergic reactions
Within 1- injection site (pain, (anaphylaxis, angioedema, or urticaria),
2 days of induration, and local generalized erythem and flushing,
receiving drug erythema), headache
Prompt: Mild to moderate Increased: alkaline Splenomegaly, splenic rupture, sickle cell
Within 2- medullary bone pain phosphatase, lactate crises in patients with sickle cell disease
3 weeks, prior dehydrogenase and uric acid, (SCD), excessive leukocytosis, Sweet's
to the next thrombocytopenia syndrome (acute febrile neutrophilic
course dermatosis)
Delayed: ARDS
Anytime later
during therapy
Unknown Fetal toxicities and teratogenic effects of pegfilgrastim in humans are unknown. Conflicting data exist
frequency and in animal studies. It is unknown whether the drug is excreted in breast milk.
timing:

Supplied as a preservative-free solution containing 6 mg (0.6 mL) of pegfilgrastim (10 mg/mL) in a
single-dose syringe with 27 g, ½ inch needle with an UltraSafe® Needle Guard. The needle cover of the
prefilled syringe contains drug natural rubber (a derivative of latex). Store refrigerated at 2º-8ºC
(36º-46ºF) and in the carton to protect from light. Prior to injection, pegfilgrastim may be allowed to
reach room temperature protected from light for a maximum of 48 hours. Avoid freezing.
Pegfilgrastim should not be administered in the period between 2 weeks before and 24 hours after
chemotherapy. Do not shake. The manufacturer does not recommend use of the 6-milligram (mg) fixed-
dose formulation of pegfilgrastim in infants, children, or adolescents under 45 kilograms.
6.12 SATURATED SOLUTION POTASSIUM IODIDE (SSKI®) (05/10/11)
Source and Pharmacology: Potassium Iodide (KI) is approximately 76.5% iodine. Iodine salts are
involved in the body's synthesis of thyroid hormone; a deficiency will result in hypothyroidism. When
radioactive forms of iodine are administered, the body converts it to iodide and uses it to synthesize
radioactive thyroid hormones. The radioactive hormones will be distributed, metabolized, and excreted in
the same manner as the non-radioactive hormones but will deliver a radiation dose to the tissues
(primarily the thyroid) while they remain in the body. Thyroid uptake of iodide is an active transport
process. When potassium iodide is administered prior to or at the time of exposure to radioisotopes of
iodine, potassium iodide rapidly blocks absorption of radioactive iodine and exposure to the thyroid will
be prevented or greatly reduced. If administered immediately after exposure, potassium iodide will
prevent further accumulation of iodide by the thyroid. Mechanisms of action include saturation of the
iodide transport system of the thyroid, inhibition of intrathyroidal organification of iodide, and dilution of
the isotope atoms with nonradioactive iodine atoms. It also increases the rate of urinary excretion of I-131
iodide atoms and thus decreases whole-body radiation dose. Potassium iodide is readily absorbed in the
intestinal tract. Iodide concentrates in the thyroid gland, salivary glands, gastric mucosa, choroid plexus,
09/24/14 81
placenta, and mammary glands. 85% to 90% of potassium iodide is excreted directly in the urine.
Approximately 10% of an oral dose of potassium iodide is excreted in the sweat, feces, and breast milk.
Toxicity:
Happens to 21-100 Happens to 5-20 children out Happens to < 5 children out of every 100
children out of every of every 100
100
Immediate: Gastrointestinal distress Irregular heartbeat, confusion
Within 1-2 days of (nausea / vomiting / diarrhea / tiredness, fever,
receiving drug stomach pain) hypersensitivity reactions, burning of mouth
/ throat, metallic taste
Prompt: Vasculitis, ioderma, rashes, flare up of
Within 2-3 weeks, adolescent acne
prior to next
course
Delayed: Thyrotoxicosis, hypothyroidism, iodism:
Any time later (with large doses over prolonged periods)
during therapy, skin eruptions, oral burning, coryza, eye
excluding the irritation, eyelid edema, frontal headache,
above conditions pulmonary edema, gastric disturbances, and
inflammation of the tonsils, pharynx, larynx,
and submaxillary and parotid glands
Late: Thyroid adenoma
Any time after
completion of
treatment
Unknown Fetal and teratogenic toxicities: Iodide readily crosses the placenta. Use of potassium iodide during
Frequency and pregnancy has been associated with goiter, hypothyroidism, respiratory problems, enlarged heart,
Timing: compression of the trachea, and death in infants. Iodine (iodide) concentrates in breast milk,
achieving much higher concentrations than in maternal plasma, which could result in significant
infant exposure and possible thyroid dysfunction or goiter.
Formulation and Stability: Saturated Solution of Potassium Iodide USP (SSKI®) contains 1 g potassium
iodide per mL. Store at room temperature 15º-30º C (59º -86º F). Keep tightly closed and protect from
light. When exposed to cold temperatures, crystallization may occur, but on warming and shaking the
crystals will redissolve. If the solution turns a brownish-yellow color, it should be discarded.
Saturated solution of potassium iodide (SSKI®) can be diluted in milk, fruit juice, or water.
Administration with food can decrease gastric irritation.
131
Administer potassium iodide (KI) orally beginning prior to I-MIBG and for several weeks after (see
treatment plan).
6.13 TOPOTECAN HYDROCHLORIDE (06/03/13)

(SKF-104864, Hycamtin®) NSC #609699
Topotecan hydrochloride is a semi-synthetic derivative of camptothecin (an alkaloid derived from the
camptothecin tree which grows widely throughout Asia) and is an anti-tumor drug with topoisomerase I-
inhibitory activity. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand
breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents re-ligation of these single
strand breaks. The cytotoxicity of topotecan is thought to be due to double strand DNA damage produced
09/24/14 82
during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan,
topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double strand breaks.
Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form
that is pharmacologically active. At pH ≤ 4, the lactone is exclusively present, whereas the ring-opened
hydroxy-acid form predominates at physiologic pH. In vitro studies in human liver microsomes indicate
that metabolism of topotecan to an N-demethylated metabolite represents a minor metabolic pathway.
Topotecan exhibits multi-exponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total
exposure (AUC) is approximately dose-proportional. Binding of topotecan to plasma proteins is
about 35%.
In humans, about 30% of the dose is excreted in the urine and renal clearance is an important determinant
of topotecan elimination. In patients with mild renal impairment (Clcr of 40 to 60 mL/min.), topotecan
plasma clearance was decreased to about 67% of the value in patients with normal renal function. In
patients with moderate renal impairment (Clcr of 20 to 39 mL/min.), topotecan plasma clearance was
reduced to about 34% of the value in control patients, with an increase in half-life. Dosage adjustment is
recommended for these patients. Plasma clearance in patients with hepatic impairment (serum bilirubin
levels between 1.7 and 15.0 mg/dL) was decreased to about 67% of the value in patients without hepatic
impairment. Topotecan half-life increased slightly, from 2 hours to 2.5 hours, but these hepatically
impaired patients tolerated the usual recommended topotecan dosage regimen.
Toxicity:
Happens to 21-100 children Happens to 5-20 children out of Happens to < 5 children out
out of every 100 every 100 of every 100
Immediate: Nausea, vomiting, diarrhea Anorexia, headache, asthenia, rash Anaphylaxis, angioedema,
Within 1-2 days of (L), constipation, fever, pain (urticaria, pruritis, bullous chest pain, rigors
receiving drug (abdominal, skeletal, back eruption) (L), asymptomatic
pain) hypotension, dyspnea
Prompt: Myelosuppression, fatigue, Stomatitis/mucositis, increased Elevated bilirubin,
Within 2-3 weeks, febrile neutropenia SGOT (AST)/SGPT paresthesias, myalgia,
prior to next course (ALT)/alkaline phosphatase, arthralgia, intratumoral
sepsis bleeding
Delayed: Alopecia Microscopic hematuria,
Anytime later during increased creatinine,
therapy proteinuria
Unknown Frequency Teratogenic effects of topotecan have been noted in animal models at doses ≤ to those used in
and Timing: humans. It is not known if topotecan is excreted into human breast milk.

Topotecan is available as a lyophilized powder for reconstitution and as a solution concentrate. Each vial
of lyophilized powder contains topotecan hydrochloride equivalent to 4 mg of topotecan as free base.
Inactive ingredients are mannitol 48 mg and tartaric acid 20 mg. Hydrochloric acid and sodium hydroxide
may be used to adjust the pH. Topotecan concentrate solution for injection is supplied as a sterile, non-
pyrogenic, clear, yellow to yellow-green solution at a topotecan free base concentration of 4 mg/4 mL
(1 mg/mL) available in single use vials. Each mL of topotecan injection contains topotecan hydrochloride
equivalent to 1 mg of topotecan as free base, 5 mg tartaric acid, NF and water for injection, USP.
Hydrochloric acid and/or sodium hydroxide may be used for pH adjustment. The pH of the solution is
approximately 2.6 to 3.2; both products must be further diluted prior to administration in a minimum of
50 mL of compatible fluid for infusion. Both types of vials should be protected from light in the original
cartons and stored at controlled room temperature between 20° and 25°C (68° and 77°F).
09/24/14 83
Reconstitute each topotecan 4 mg vial with 4 mL SWFI.to concentration of 1 mg/mL. Further dilute in
50-250 mL D5W or NS. Reconstituted vials of topotecan diluted for infusion are stable at approximately
20°-25°C (68°-77°F) and ambient lighting conditions for 24 hours.
Supplier: Commercially available. See package insert for further information.
6.14 VINCRISTINE SULFATE (08/16/12)

(Oncovin®, VCR, LCR) NSC #67574
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin, disrupting
microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. The initial, middle, and
terminal half-lives are 5 minutes, 2.3 hours, and 85 hours respectively; however, the range of the terminal
half-life in humans is from 19 to 155 hours. The liver is the major excretory organ in humans and
animals; about 80% of an injected dose of vincristine sulfate appears in the feces and 10% to 20% can be
found in the urine. The p450 cytochrome involved with vincristine metabolism is CYP3A4. Within 15 to
30 minutes after injection, over 90% of the drug is distributed from the blood into tissue, where it remains
tightly, but not irreversibly bound. It is excreted in the bile and feces. There is poor CSF penetration.
Toxicity:
Happens to 21-100 children Happens to 5-20 children out of Happens to < 5 children out of
out of every 100 every 100 every 100
Immediate: Jaw pain, headache Extravasation (rare) but if occurs =
Within 1-2 days of local ulceration, shortness of breath,
receiving drug and bronchospasm
Prompt: Alopecia, constipation Weakness, abdominal pain, mild Paralytic ileus, ptosis, diplopia, night
Within 2-3 weeks, prior brief myelosuppression blindness, hoarseness, vocal cord
to the next course (leukopenia, thrombocytopenia, paralysis, SIADH, seizure, defective
anemia) sweating
Delayed: Loss of deep tendon reflexes Peripheral paresthesias including Difficulty walking or inability to
Any time later during numbness, tingling and pain; walk; sinusoidal obstruction
therapy clumsiness; wrist drop, foot syndrome (SOS, formerly VOD) (in
drop, abnormal gait combination); blindness, optic
atrophy; urinary tract disorders
(including bladder atony, dysuria,
polyuria, nocturia, and urinary
retention); autonomic neuropathy
with postural hypotension; 8th cranial
nerve damage with dizziness,
nystagmus, vertigo and hearing loss
Unknown Frequency Fetal toxicities and teratogenic effects of vincristine (either alone or in combination with other
and Timing: antineoplastic agents) have been noted in humans. The toxicities include: chromosome
abnormalities, malformation, pancytopenia, and low birth weight. It is unknown whether the drug
is excreted in breast milk.

Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine sulfate 1 mg
(1.08 µmol), mannitol 100 mg, SWFI; acetic acid and sodium acetate are added for pH control. The pH of
vincristine sulfate injection, USP ranges from 3.5 to 5.5. This product is a sterile, preservative free
solution. Store refrigerated at 2˚-8˚C or 36˚-46˚F. Protect from light and retain in carton until time of use.
Do not mix with any IV solutions other than those containing dextrose or saline.
09/24/14 84
Guidelines for Administration: See Treatment and Dose Modifications sections of protocol.
The World Health Organization, the Institute of Safe Medicine Practices (United States) and the Safety
and Quality Council (Australia) all support the use of minibag rather than syringe for the infusion of
vincristine. The delivery of vincristine via either IV slow push or minibag is acceptable for COG
protocols. Vincristine should NOT be delivered to the patient at the same time with any medications
intended for central nervous system administration. Vincristine is fatal if given intrathecally.
Injection of vincristine sulfate should be accomplished as per institutional policy. Vincristine sulfate must
be administered via an intact, free-flowing intravenous needle or catheter. Care should be taken to ensure
that the needle or catheter is securely within the vein to avoid extravasation during administration. The
solution may be injected either directly into a vein or into the tubing of a running intravenous infusion.
Special precautions: FOR INTRAVENOUS USE ONLY.

The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the
statement: “Do not remove covering until moment of injection. For intravenous use only - Fatal if given
by other routes.”
Supplier:
Commercially available from various manufacturers. See package insert for more detailed information.
09/24/14 85
7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED

Timing of protocol therapy administration, response assessment studies, and surgical interventions
are based on schedules derived from the experimental design or on established standards of care.
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or
facility, procedure and/or anesthesia scheduling issues are acceptable per COG administrative
Policy 5.14 (except where explicitly prohibited within the protocol).
Pre-treatment studies must be performed within 2 weeks (4 weeks in case of scans) prior to starting
protocol therapy unless otherwise noted below.
7.1 Required Clinical, Laboratory and Disease Evaluations

7.1.1 Required and Optional Observations for Pre-Treatment and Induction
Observation Pre- Prior to Prior to After Pre- Post- End of At
Treatment Each Cycle Surgery Surgery MIBG MIBG MIBG Relapse
Therapy Therapy Induction17
Physical Exam, Ht, Wt X X X X16 X
1
CBC with Diff, Platelets X X X X1 X
Electrolytes, BUN, Cr, Ca,
X X2 X X16 X
Phos, Mg
ALT, AST, Bilirubin X X X X16 X
Urinalysis X X X X
T4, TSH X X
ECG and MUGA or ECHO X X
GFR or Creatinine Clearance4 X X
Audiogram or BAERs X
Tumor Imaging5 X X X X
MIBG Scan 6 X X7 X14 X X
18
FDG-PET Scan8, 13 X X
Catecholamines (VMA, HVA) X X9 X
Pregnancy Test 10 X X X
Bilateral BM Asp/Bx X X X11
Whole Body Exposure
X15
Reading
hNET tests12 X X
Patient Cost Questionnaire3 X
1 Obtain at least weekly (+/- 2 days) during Induction and post MIBG therapy. Post-MIBG therapy, recommend increasing
CBC frequency to twice weekly until count recovery if Grade 4 ANC or Grade 4 platelets, as part of good clinical care.
2 Recommend obtain daily during cisplatin administration.
3 Patients who travel to another institution for MIBG treatment only: A questionnaire will be completed by the patient and/or
the patient’s parent(s) or legal guardian(s) to detail expenditures incurred in obtaining MIBG therapy (see Section 19.0 and
Appendix VIII). Questionnaire should be submitted before beginning Consolidation.
4 Calculated creatinine clearance can be used for pre-treatment evaluation. Plasma method of GFR calculation preferred at
end induction. If a urine creatinine clearance is performed at end of Induction/prior to Consolidation and the result is < 100
mL/min/1.73m2, the test must be repeated and a GFR performed using the plasma method ONLY.
5 Tumor imaging: CT/MRI as needed for optimum visualization of all areas of bulk tumor (primary and metastases). CT/MRI
required prior to surgical resection.
6 For further details on baseline 123I-MIBG scan, see Section 16.4. Attempt to obtain MIBG scan prior to starting therapy.
Must be obtained by the end of Induction Cycle 1, at the latest.
7 The pre-surgical MIBG scan is required
18FDG-PET Scan is optional depending on whether or not the patient has consented for them. See Section 16.3 for details.
8
9 Repeat catecholamine levels if elevated at diagnosis.
10 Perform for all females of childbearing age.
09/24/14 86
11 Send bone marrow and if biopsy performed, send sample of fresh and snap frozen tumor. Ship per ANBL00B1guidelines.
Label “Relapse” specimen.
12 Specimens for the hNET test are OPTIONAL & are collected at diagnosis and after tumor resection (refer to Section 14.2
for details).
13 Lesion #1 (the primary tumor) is required to be reported at each evaluation time point regardless of SUV score. MAKE
EVERY EFFORT TO ACQUIRE FDG IMAGES ON A SINGLE SCANNER FOR A GIVEN PATIENT TO ALLOW FOR
MORE ACCURATE COMPARISON OF SUVs. See Appendix X for more details.
131I-MIBG scan performed without infusion of additional isotope upon release from radiation isolation.
14
15 Whole body dosimetry: see Section 4.3.2
16 Obtain weekly post-MIBG therapy
17 Post Induction evaluation should occur no sooner than 6 weeks post-MIBG therapy and no more than 4 weeks pre-Bu/Mel
Consolidation.
PLEASE NOTE THAT END OF INDUCTION (Section 7.1.1) AND PRIOR TO THERAPY (Section 7.1.2) TESTS REQUIRED ARE
THE SAME AND ARE NOT TO BE PERFORMED TWICE UNLESS SPECIFIED
09/24/14 87
7.1.2 Required and Recommended Observations for Consolidation

Post
During and Post Transplant
Prior to Consolidation At
Day -6 to Day +60
Observation Therapy14 Treatment Relapse
Physical Exam, Ht, Wt X X10 X5
Day -6 then daily until
X X5
CBC with Diff, Platelets engraftment1 and on Day +60
AST, ALT, Total Bilirubin, BUN, Day -6
X X5
Mg, Electrolytes, Cr, Ca, Phos. then weekly
T4, TSH X X5, 15
Pregnancy Test 2 X
Urinalysis X X5
ECG and MUGA or Echo X X5
Day +28 to +42 for
X X5
GFR or Creatinine Clearance11 selected patients9
Audiogram or BAER’s X5
Tumor Imaging4 X X5 X
3 3,5
Catecholamines (VMA/HVA) X X
Day +28 to +42 for
X X5,8 X
MIBG Scan selected patients6
Bilateral BM Asp/Bx X X X7
Busulfan pK12 X
Patient Cost Questionnaire13 X
1 After engraftment, perform as needed for clinical care.
2 Obtain for females 10 years of age and older or post-pubertal.
4 Tumor Imaging: CT/MRI as needed for optimum visualization of all areas of bulk tumor (primary and metastases).
5 Recommended to be performed at Day + 60 post transplant, preferably when the patient is 10 days out after completing local
radiation therapy. If no local radiation therapy is given, then recommended to perform studies at Day +60. In all cases, it is
REQUIRED to be performed before Day 200 post transplant to ensure eligibility onto immunotherapy study.
6 Patients with > 5 MIBG + metastatic sites pre-Bu/Mel Consolidation on 123I -MIBG are required to undergo a 123I-MIBG
scan between Day +28 and Day +42 post transplant. The scan is required to determine external beam XRT to metastatic sites
(see Section 17.4.2).
7 Send bone marrow and if biopsy performed, send sample of fresh and snap frozen tumor. Ship per ANBL00B1 guidelines.
123I-MIBG scan preferred, see Section 16.4 for details.
8
9 GFR must be performed prior to radiation therapy for patients receiving kidney radiation
10 As needed for clinical care, and on Day +60
11 Plasma method of GFR calculation preferred. If creatinine clearance performed prior to Consolidation is
< 100 mL/min/1.73m2, the test must be repeated and a GFR performed using the plasma method ONLY.
12 To be performed as per institutional guidelines. See Sections 7.1.3 and 14.3 for details.
13 Patients who travel to another institution for MIBG treatment only: A questionnaire will be completed by the patient and/or
the patient’s parent(s) or legal guardian(s) to detail expenditures incurred in obtaining MIBG therapy (see Section 19.0 and
Appendix VIII). Questionnaire should be submitted before beginning Consolidation.
14 Pre-Consolidation evaluation should occur no sooner than 6 weeks post-MIBG therapy and no earlier than 4 weeks pre-
Bu/Mel Consolidation.
15 Recommend continuing to follow every 3 months for first year, then yearly.
PLEASE NOTE THAT END OF INDUCTION (Section 7.1.1) AND PRIOR TO THERAPY (Section 7.1.2) TESTS
REQUIRED ARE THE SAME AND ARE NOT TO BE PERFORMED TWICE UNLESS SPECIFIED
NOTE: Submission of Radiotherapy treatment plans in digital format (either Dicom RT or RTOG
format) is mandatory for primary site disease (see Section 17.8).
09/24/14 88
7.1.3 Recommended Timepoints for Busulfan Pharmacokinetic Studies* (See Section 14.3).
Time to draw PK sample
START Time of Busulfan infusion (Hour 0)
2 hours
2 hours 15 minutes (135 minutes)
2 hours 30 minutes (150 minutes)
3 hours
4 hours
5 hours
6 hours
* Tests to be performed as per institutional guidelines, to achieve an area under the curve (AUC) for
busulfan of 900 to 1500 micromole/liter/minute.
7.1.4 Required Observations for Maintenance
Prior to each Before

Observation cycle Cycle #4 End of Therapy At Relapse
Physical Exam, Ht, Wt X X
CBC with Diff, Platelets X X
Electrolytes, BUN, Cr, Ca, Mg, Phos X X
Triglycerides X X
AST, ALT, Bilirubin, Urinalysis X X
ECG and MUGA or ECHO X
GFR or Creatinine Clearance X
Audiogram or BAERs X
Tumor Imaging1 X X X
MIBG2 X X X
Catecholamines (VMA, HVA) X3 X3
Bilateral BM Asp/Bx X X4
1 Tumor Imaging: CT/MRI as needed for optimum visualization of all areas of prior or persistent bulk tumor (primary and
metastases).
123I-MIBG scan preferred, see Section 16.4 for details.
2
4 Send bone marrow and if biopsy performed, send sample of fresh and snap frozen tumor. Ship per ANBL00B1guidelines.
09/24/14 89
7.1.5 Required & Recommended Observations for Post-Maintenance Follow-up

Count time 0 as date of disease evaluation after completion of last cycle of isotretinoin.
Annually
6 9 1 1.5 2 2.5 3 3.5 4 4.5 5 After 5 At
3 Mos
Observation Mos Mos Yr Yr Yrs Yrs Yrs Yrs Yrs Yrs Yrs Years8 Relapse
Physical Exam1 X X X X X X X X X X X X X
Height, Weight X X X X X X X X X
CBC with Diff
X X X X X X X X X X X X X
and platelets1
MUGA or
X5 X
ECHO, ECG
Bilateral BM X6
Tumor Imaging4 X X X X X X X X X X X X X X
MIBG3 X X X X X X X X
Catecholamines2 X X X X X X X X X X X X
TSH, T4 X9 X9 X X X X X X
Pulmonary 7
X
Function tests
1 Perform physical exam and CBC monthly for 1 year after transplant (recommended).
2 Perform if catecholamine levels elevated at diagnosis.
3 Only if positive after completion of isotretinoin therapy. 123I-MIBG scan preferred, see Section 16.4 for details.
4 Perform as scheduled, then as clinically indicated.
5 If abnormal, repeat at 2 Years and as needed. If child is < 5 years when tested as directed, an additional test should be
performed when the child becomes age 5 years.
6 Send bone marrow and if biopsy performed, send sample of fresh and snap frozen tumor. Ship per ANBL00B1
guidelines. Label “Relapse” specimen.
7 Perform PFTs only if child has pulmonary symptoms and if child is ≥ 5 years.
8 Patient’s clinical status will be tracked annually through 10 years after enrollment onto study.
9 Not required, but recommended as part of good clinical care following MIBG therapy.
09/24/14 90
8.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY
CRITERIA
8.1 Off-Protocol Therapy Criteria
8.1.1
a) Patient with progressive disease at end of Cycle 4 Induction therapy OR who develops evidence of
progressive disease at the end of Induction therapy. Patients with mixed response, stable disease or
persistent tumor in bone marrow by morphologic evaluation may remain on protocol therapy as per
investigator preference.
b) Patient who develops any Grade 4 organ toxicity during Induction therapy not related to underlying
infection or metabolic derangement that fails to resolve to < Grade 2 or cannot be controlled with
treatment by 8 weeks from last cycle of Induction therapy EXCEPT:
• Patients who have Grade 4 thrombocytopenia (in the absence of platelet refractoriness) at
Day 70 after MIBG Induction therapy
c) Patients with ejection fraction <50% or shortening fraction <27% that persists past Day 56 after any
cycle of Induction
d) Patient/Parent/guardian refuses further protocol therapy.
e) Unable to obtain adequate stem cell product to support high-dose 131I-MIBG therapy as well as
Bu/Mel transplant.
e) Physician determines it is in patient’s best interest.
f) Development of a 2nd malignancy.
g) Unable to meet clinical criteria to receive 131I-MIBG (as per Section 4.3.1) or Bu/Mel Consolidation
(as per Section 4.4.1).
h) Either the patient or the adult caregivers are unable to cooperate with radiation safety restrictions
during the MIBG therapy period. (The patient may receive pharmacologic anxiolysis if needed.)
i) A treatment slot at one of 3 MIBG dose levels (12 mCi/kg, 15 mCi/kg, or 18 mCi/kg) is NOT
available.
8.1.2
Patients who develop progressive disease (PD) at any time after Bu/Mel Consolidation are off protocol
therapy and may receive alternate therapy.
a) If the patient has PR or SD after Bu/Mel Consolidation (i.e., questionable residual tumor), a biopsy
should be performed to obtain histological diagnosis to determine if there is residual disease. If
active malignant tumor remains, notify Study Chair prior to additional therapy. Surgical removal is
not encouraged unless it would alter therapy. Additional local irradiation should also be considered.
8.1.3
Initiation of non-protocol specified chemotherapy post-Bu/Mel Consolidation and local radiation (e.g.
ANBL0032 or its successor) other than the MRD therapy described in Section 4.5 of this study.
8.1.4
131
Initiation of other non-protocol specified anti-cancer therapy prior to completion of I-MIBG Induction
and Bu/Mel transplant and local radiation.
8.1.5
Treatment Completed Per Protocol.
8.1.6
Patients determined to have MIBG non-avid disease after enrollment.
09/24/14 91
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see below).
Follow-up data will be required unless consent was withdrawn.
8.2 Off Study Criteria

a) Death.
b) Lost to follow-up.
c) Patient enrollment onto another COG study with tumor therapeutic intent.
d) Withdrawal of consent for any further data submission.
e) Tenth anniversary of the date the patient was enrolled on this study.
9.0 STATISTICAL CONSIDERATIONS

9.1 Statistical Design
This is a prospective, single arm, limited institution pilot study to assess feasibility of administering 131I-
MIBG followed by Bu/Mel myeloablative therapy. The study will incorporate a dose-finding component
to determine the maximum tolerated dose (MTD) of 131I-MIBG in cohorts of up to 6 patients. The
tolerability of the regimen at each MIBG dose level will be further assessed in cohorts of up to
18 patients. Patients enrolled on the study before Amendment #4A (N=11) will NOT be used to assess the
tolerability of the therapy. However, these patients may be used to assess the feasibility of the therapy.
9.1.1 Dose Escalation and Determination of MTD

The MTD will be the maximum dose of 131I-MIBG at which fewer than 2 of up to 6 patients in the dose
escalation phase experience a dose-limiting toxicity (DLT) from the beginning of 131I-MIBG therapy to
Day +28 post myeloablative Bu/Mel and autologous stem cell infusion. A DLT is defined as the
occurrence of unacceptable pulmonary toxicity or severe SOS (see Section 9.3.2.2A for definitions).
A modified Rolling Six trial design will be used to efficiently assess toxicity in the initial patients (up to
6 evaluable patients) treated at the 15 and 18 mCi/kg dose levels in the dose escalation phase.70 Two to
6 evaluable patients can be concurrently assigned to a dose level (15 mCi/kg or 18 mCi/kg 131I-MIBG),
with dose level assignment dependent upon (1) the number of patients treated at the current dose level, (2)
the number of patients who have experienced a DLT at a given dose level (as per 9.3.2.2A), and (3) the
number of patients entered but with toxicity data pending at a given dose level. A minimum of 2 patients
evaluable for toxicity (see Section 9.2.2 for definition) will be assigned to each dose level for
determination of the MTD. If participants are inevaluable for toxicity, they are replaced with the next
available participant if escalation or de-escalation rules have not been fulfilled at the time the next
available participant is ready to proceed to 131I-MIBG therapy. Treatment at a particular MIBG dose level
(15 mCi/kg or 18 mCi/kg) is suspended when a cohort of 6 patients has been treated with 131I-MIBG at a
given dose level or when the study endpoints have been met (any dose level). Subjects will be treated
starting at 15 mCi/kg 131I-MIBG, with escalation to 18 mCi/kg 131I-MIBG if 15 mCi/kg is deemed safe.
The following table (9.1.1a) provides the decision rules that will be used to assign a given patient to an
131
I-MIBG dose level for cohorts of patients enrolled in the dose-finding component of the trial:
09/24/14 92
Table 9.1.1a
# Patients Treated # Patients with # Patients without # Patient with
Decision
with 131I-MIBG DLT DLT Data Pending
2 0 or 1 0, 1, or 2 0, 1, or 2 Same dose level
2 2 0 0 De-escalate*
3 0 0, 1, or 2 1, 2, or 3 Same dose level
3 1 0, 1, or 2 0, 1, or 2 Same dose level
3 0 3 0 Escalate**
3 ≥2 0 or 1 0 or 1 De-escalate*
4 0 0, 1, 2, or 3 1, 2, 3, or 4 Same dose level
4 1 0, 1, 2, or 3 0, 1, 2, or 3 Same dose level
4 0 4 0 Escalate**
4 ≥2 0, 1, or 2 0, 1, or 2 De-escalate*
5 0 0, 1, 2, 3, or 4 1, 2, 3, 4, or 5 Same dose level
5 1 0, 1, 2, 3, or 4 0, 1, 2, 3, or 4 Same dose level
5 0 5 0 Escalate**
5 ≥2 0, 1, 2, or 3 0, 1, 2, or 3 De-escalate*
6 0 0, 1, 2, 3, or 4 2, 3, 4, 5, or 6 Suspend
6 1 0, 1, 2, 3, or 4 0, 1, 2, 3, or 4 Suspend
6 0 or 1 5 or 6 0 or 1 Escalate**
6 ≥2 0, 1, 2, 3, or 4 0, 1, 2, 3, or 4 De-escalate*
* If six patients already entered at next lower dose level, the MTD has been defined.
** If final dose level has been reached, the recommended dose has been reached.
If 2 or more of a cohort of up to 6 evaluable patients experience DLT at a given dose level, then the MTD
has been exceeded and dose escalation will be stopped. Patients already treated with 131I-MIBG at that
dose level who have not yet had Consolidation therapy will go off protocol therapy and receive
Consolidation therapy as per their primary oncologist.
Patients treated at any dose of 131I-MIBG will be used to assess the tolerability (Section 9.3.2.2B) and
feasibility (Section 9.3.1) of the therapy.
9.1.2 Dose Expansion

Patient enrollment onto the trial will continue while determination of DLT experienced by the above
cohorts of patients is being assessed.
While determination of DLT data for patients in the dose escalation phase who received 15 mCi/kg 131I-
MIBG are pending (e.g. from the beginning of 131I-MIBG therapy to Day +28 following myeloablative
Bu/Mel ASCR), evaluable subjects due for 131I-MIBG may receive 12 mCi/kg 131I-MIBG and remain on
protocol therapy. Subjects due for 131I-MIBG therapy while awaiting determination of DLT data for
patients in the dose escalation phase who received 18 mCi/kg 131I-MIBG may receive 15 mCi/kg 131I-
MIBG and remain on protocol therapy. There will be a maximum of 18 evaluable patients treated at any
dose level. It is possible that we will reach a maximum of 18 patients at a specific dose level while
awaiting evaluation of toxicity at a higher level. Therefore, some patients may not receive 131I-MIBG
therapy and may instead come off protocol therapy after Cycle 5 of Induction.
Up to 18 evaluable patients will be assigned to treatment at each MIBG dose level to better determine the
tolerability of MIBG followed by Bu/Mel Consolidation. Dose expansion of the 12 mCi/kg and
15 mCi/kg dose levels to 18 evaluable patients will likely occur while awaiting initial dose tolerability
09/24/14 93
assessments of the 15 mCi/kg and 18 mCi/kg dose escalation levels, respectively. If the dose escalation
rules are not exceeded at 18 mCi/kg, then an additional 12 patients will be treated with 18 mCi/kg 131I-
MIBG. If a lower dose is found to be the MTD, that dose level will be expanded to reach a maximum of
18 evaluable patients. A descriptive summary of all toxicities at each dose level will also be analyzed and
reported. Final assessment of tolerability and selection of the dose to bring forward to future clinical trials
will be based upon occurrence of all severe toxicity at each dose level and based upon the monitoring
strategy described in Sections 9.3.2.2A, 9.3.2.2B, and 9.3.3.
9.2 Patient Accrual and Expected Duration of Trial

9.2.1 Accrual
Accrual rate: 3.0 patients/month. Justification: An average of 217 High-Risk patients per year have
enrolled on the ANBL00B1 biology study since 2001. The average enrollment on A3973 over this same
period was 125 patients per year. When the limited institution (6 institutions) front-line High-Risk study
ANBL02P1 was open in competition with A3973, the accrual rate on ANBL02P1 was 19 patients per
year. As long as the 22 institutions now participating in ANBL09P1 do not enroll patients on other high
risk studies, they should accrue 37 evaluable patients per year on ANBL09P1.
Accrual goal: As many as 60 patients will be required to obtain 54 evaluable patients for DLT and
tolerability: 12 evaluable patients on the dose escalation and an additional 42 evaluable patients on the
expansion portion of the study, respectively. During the dose escalation portion of the study up to
12 (6+6) evaluable patients will receive one of two doses of 131I-MIBG being evaluated (15 and
18 mCi/kg). In addition, up to 30 evaluable patients (18 + 12) could receive MIBG at a lower dose level
while awaiting the assessment of DLT: 18 patients will be treated at 12 mCi/kg (all of whom will be
treated while the 15 mCi/kg dose level is being evaluated for toxicity) and 12 at 15 mCi/kg (treated while
the 18 mCi/kg dose level is being evaluated for toxicity and 15 mCi/kg has already been deemed safe). As
a conservative estimate, up to 6 patients may receive Induction therapy but not 131I-MIBG due to
suspension of the MIBG phase of therapy (reaching the maximum 18 patients at any dose level) while
patients are evaluated for toxicity. Should dose escalation up to 18 mCi/kg be tolerable then an additional
12 evaluable patients will be required to complete the expansion phase of the protocol.
09/24/14 94
Based upon A3973 and ANBL0532 data, 10% of patients with newly diagnosed high-risk neuroblastoma
diagnosed at participating institutions are expected to have MIBG non-avid disease and would not be
eligible for continuing to Cycle 2 of Induction on this protocol. An additional 25% of patients who meet
initial eligibility criteria for the study will not meet eligibility criteria (due to disease response, organ
function, etc) to receive MIBG therapy and/or Bu/Mel Consolidation. Therefore, the total expected
accrual is a minimum of 100 patients. This total number includes the 11 patients that enrolled prior to
Amendment #4A. Data regarding these patients cannot be used to evaluate the tolerability aim because
the therapy they received is different from therapy administered to patients enrolled after Amendment
#4A. However accrual may continue up to 105 patients to ensure that data from a sufficient number of
fully evaluable patients are available. Although the total planned accrual is a much higher accrual than
originally anticipated for this pilot study, key safety data required for planning of a randomized trial of
MIBG in high risk patients will be generated.
09/24/14 95
The following institutions have agreed to participate:
MIBG Institutions: Potential annual accrual of 40 patients

Average annual high risk
Institution ANBL00B1 enrollment*
Cincinnati Children’s Hospital Medical Center 1.8
UCSF Medical Center - Parnassus 1.4
Children’s Hospital of Philadelphia 7.7
C.S. Mott Children’s Hospital 2.7
Dana-Farber Cancer Institute 4.4
University of Wisconsin Hospital and Clinics 1.3
Seattle Children's Hospital 3.5
Duke University Medical Center 1.5
Children’s Hospital Los Angeles 5.0
The Children’s Hospital, Denver 2.8
Children's Healthcare of Atlanta - Egleston 6.6
University of Chicago 1.5
*2001-2011
NOTE: All MIBG Institutions MUST treat at least 3 patients on an expanded access MIBG
protocol before treating a subject enrolled on ANBL09P1 with 131I-MIBG.
Note: Cook’s Children’s Hospital will not enroll patients at initial diagnosis but will be able to administer
MIBG therapy to patients enrolled at other centers.
Non-MIBG Institutions: Potential annual accrual of 19 patients

Average annual high risk
Institution ANBL00B1 enrollment*
Phoenix Children’s Hospital 1.7
Medical University of South Carolina 1.6
Children’s National Medical Center 2.8
UT Southwestern Medical Center 2.3
Primary Children’s Hospital 2.6
Children’s Hospital of Alabama 2.4
Connecticut Children’s Medical Center 0.7
Midwest Children's Cancer Center 2.2
Providence Sacred Heart Medical Center and Children's Hospital 1.3
University of North Carolina at Chapel Hill 1.5
*2001-2011
Accrual duration: At a rate of 37 evaluable patients per year, assuming that the 15 and 18 mCi/kg dose
levels are both explored, 18-20 months will be required for the dose escalation portion of the study.
Another 4 months will be required to enroll and assess tolerability in the 12 additional evaluable patients
for the dose expansion portion of the study. This estimate is based on a conservative accrual duration of
2 months for the cohort of 6 patients at each of the MIBG dose levels (3 patients per month), and an
additional 9 months to evaluate all patients for toxicity at each dose level. However, prior to amending the
protocol, study accrual had to be halted to assess a stopping rule; this temporary closure added an
additional 9 months to the study duration. Therefore, the total study duration will be about 3 years.
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9.2.2 Evaluability
Patients will be evaluable for toxicity at their prescribed dose level during the dose escalation portion of
the study (see Section 9.1.1) if they receive a dose of MIBG that is within 10% of their prescribed dose
level. Patients who receive < 90% or more than 110% of their prescribed dose level or go off protocol
therapy before the completion of therapy for reasons other than toxicity will be replaced during the dose
escalation portion of the study, although their toxicities will be reported. Patients who receive < 90% of
their prescribed dose level will be included in the tolerability monitoring rule (Section 9.3.3) at one dose
level below their prescribed dose level. Patients who receive more than 110% of their prescribed dose
level will go off protocol therapy and not be included in the tolerability monitoring rule.
Patients will be evaluable for the tolerability monitoring rule (Section 9.3.3) at their prescribed dose level
during the dose expansion portion of the study (Section 9.1.2) if they receive a dose of MIBG that is
within 10% of their prescribed dose level. Patients who receive < 90% or more than 110% of their
prescribed dose level or go off protocol therapy before the completion of therapy for reasons other than
toxicity in the dose expansion portion of the study will not be replaced. Patients who receive < 90% of
their prescribed dose level will be included in the tolerability monitoring rule at one dose level below
their prescribed dose level. Patients who receive more than 110% of their prescribed dose level will go off
protocol therapy and not be included in the tolerability monitoring rule.
MIBG avid patients who complete Cycles 1-5 of Induction chemotherapy and meet criteria to receive 131I-
MIBG therapy (Section 4.3.1) will be evaluable for the feasibility of administering MIBG. MIBG avid
patients who complete Cycles 1-5 of Induction chemotherapy and 131I-MIBG therapy and meet criteria to
receive Bu/Mel Consolidation therapy (Section 4.4.1) will be evaluable for the feasibility of administering
MIBG and Bu/Mel Consolidation therapy.
Patients who receive 131I-MIBG therapy will be evaluable for End-Induction response. Patients who
receive Bu/Mel Consolidation and external beam radiation (after receiving 131I-MIBG therapy at any
dose) will be evaluable for response to and tolerability of the entire regimen.
9.3 Methods of Analysis
9.3.1 Primary Endpoints
Feasibility rate will be calculated as both the feasibility of receiving 131I-MIBG therapy and the feasibility
of receiving 131I-MIBG and then Bu/Mel.
MIBG Feasibility rate: the proportion of MIBG avid patients assigned an MIBG dose level at Cycle 5
Induction who are able to be treated with 131I-MIBG. This proportion will be calculated as the number of
MIBG avid patients who receive 131I-MIBG divided by the number of patients evaluable for the feasibility
of MIBG endpoint (those who meet criteria described in Section 4.3.1). The definition of receiving 131I-
MIBG is receiving 131I-MIBG infusion.
MIBG and Bu/Mel Feasibility rate: the proportion of MIBG avid patients assigned an MIBG dose level at
Cycle 5 Induction who are able to be treated with 131I-MIBG and then Bu/Mel. This proportion will be
calculated as the number of MIBG avid patients who receive 131I-MIBG and Bu/Mel divided by the
number of patients evaluable for the feasibility of MIBG and Bu/Mel Consolidation endpoint (see
Sections 4.3.1 and 4.4.1). The definition of receiving Bu/Mel conditioning is receiving the first dose of
planned busulfan on Day -6 of conditioning.
In addition, the following endpoints will be considered in the assessment of feasibility:
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• The percentage of average per capita income encompassed by the total of travel + housing
+ lost wages;
• The proportion of eligible High-Risk patients accrued to the study; and
• The 1-year EFS rate.
The patient/caregiver survey in Appendix VIII will provide the information about travel for each patient
travelling to the MIBG Center. A cost of travel for each person will be determined using the standard
mileage reimbursement rates available from the United States General Services Administration
(www.gsa.gov). Additionally, standard federal per diem rates (www.gsa.gov) will be utilized for families
who stay in a hotel. Lost wages will be calculated for up to a maximum of 2 adults. This will be
accomplished by multiplying the standard federal wage rates by the number of days at the MIBG center
for those adult caregivers who are employed. For those adults who are on medical leave of absence or
unemployed, the figure will be multiplied by a factor of 0.5. In order to determine if the ‘out-of-pocket’
costs are less than 10% of yearly income, expenditures will be totaled and compared to the average per
capita income, assuming 52-weeks with a 40-hour work week (2,088 hours/year – this measurement also
accounts for lost vacation time).56 In addition, we will collect data on those people other than the patient
and 2 adult caregivers who travel to the MIBG center, though these expenditures will not be counted as
part of the total expenditures.
All MIBG avid patients treated with MIBG will be used for the feasibility assessment based on the 1-year
EFS rate. Time to event will be calculated as the time from enrollment to the first occurrence of relapse,
progression, secondary malignancy or death, or to the time of last contact if no event occurred. A 95%
confidence interval will be calculated for the 1-year EFS rate. We will perform a comparison of the 1-year
EFS rate on this study versus a hypothesized model of the standard (the 1-year EFS rate observed on
A3973 assuming an exponential distribution of failure) using the methodology of Woolson.71 For a
conservative power calculation, we will assume that the proportion of patients who are event-free at 1-
year follows a binomial distribution. In a one-sided test of proportions for a decrease of 20% in the 1-year
EFS rate (as compared to that observed on A3973), 54 patients (18 patients at each of the 3 MIBG dose
levels) will be sufficient in order to provide > 85% power in a 0.05 level test. This large of a decrease in
the 1-year EFS rate would be considered a “disaster”, and the treatment approach would be considered
not feasible if the 1-year EFS rate was statistically significantly lower than that observed on A3973.
9.3.2 Secondary and Exploratory Endpoints
9.3.2.1
Response rate: The proportion of evaluable patients who attain a response ≥ PR at the end of 131I-MIBG +
Bu/Mel therapy and local XRT. This will be calculated two ways, all MIBG dose levels combined and
separately for each MIBG dose level. Secondarily, response rates will also be calculated at the completion
of MIBG Induction therapy for MIBG-avid patients, all MIBG dose levels combined as well as separately
for each MIBG dose level. Response will be determined using the International Response Criteria defined
in Section 10.4. Response at the end of Cycle 4 (pre-surgical resection) will be used for the reliability
comparison of PET SUV score and MIBG score.
9.3.2.2
Only those toxicities assigned by the treating physician as possibly, probably or definitely attributed to
131
I-MIBG, Busulfan, Melphalan, or some combination of the three will be considered in the definition of
Dose Limiting Toxicites (see Section 9.3.2.2A) or Determination of Tolerability (see Section 9.3.2.2B).
9.3.2.2A Dose Limiting Toxicities

During the dose escalation phase of the trial, the following toxicities will be considered unacceptable
(dose limiting) using CTCv.4.0 for toxicity assessment and grading:
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Unacceptable Pulmonary toxicity: CTC Grade 4-5 Pulmonary/Respiratory.
Unacceptable (severe) SOS: The CTC does not include SOS (sinusoidal obstruction syndrome, formerly
known as VOD) as a single toxicity. Therefore, this study will utilize a composite definition of SOS used
in previous studies (NANT N01-02; ANBL0532) to evaluate Consolidation therapy in patients with high-
risk neuroblastoma. Severe SOS is defined as: Serum total bilirubin > 2.0 mg/dL, PLUS at least 2 of the
following findings from the beginning of MIBG to within 28 days of transplantation: hepatomegaly with
right upper quadrant pain, ascites, or weight gain > 5% above baseline PLUS a specific organ failure
listed below:
a. Hepatic encephalopathy (CTC Grade 4 hepatic failure), OR
b. Pulmonary dysfunction: Continuous oxygen support (CTC Grade 3 hypoxia) for > 48 hours,
ventilatory support not clearly attributable to another cause, OR
c. Renal dysfunction: serum creatinine > 3 times the ULN (CTC Grade 3 creatinine), or the
need for dialysis (CTC Grade 4 renal), not clearly attributable to another cause.
Accelerated reporting of treatment data including toxicities is required on this study. Please submit
Reporting Period and toxicity data within 35 days of Bu/Mel ASCR. Toxicity data will be reviewed on a
weekly basis by the study chair and study statistician.
9.3.2.2B Tolerability of treatment with MIBG and Bu/Mel
The following toxicities will be monitored in the entire cohort of 18 patients at assigned dose levels (12,
15 or 18 mCi/kg) and used to assess the tolerability of the regimen. These toxicities include the toxicities
included in the definition of DLT as well as additional toxicities that may impact on the overall
tolerability of this approach.
a) Combined toxic death rate associated with 131I-MIBG and Bu/Mel therapy at each MIBG
dose level
b) Engraftment rate at each MIBG dose level, as defined by:
• ANC ≥ 500 by Day 70 of 131I-MIBG Induction block (in the absence of progressive
marrow involvement with neuroblastoma)
• ANC ≥ 500 by Bu/Mel Consolidation Day 28 post-ASCR (in the absence of
progressive marrow involvement with neuroblastoma)
c) Incidence of Dose Limiting Toxicities as per 9.3.2.2A
d) Incidence of the following toxicities during 131I-MIBG therapy through Day +28 post-
Bu/Mel ASCR at each MIBG dose level:
• Grade 4 renal toxicity
• Grade 4 cardiac toxicity
For a) – d), a patient will be counted as having experienced an unacceptable toxicity for tolerability if at
least 1 of the toxicities above is observed.
9.3.3 Monitoring Rule for Tolerability at Each Dose Level

There may be cause to stop the trial early if the unacceptable toxicity (as defined in Section 9.3.2.2B) rate
appears too high at a single dose level. An average unacceptable toxicity rate of 10% was observed on
COG A3973 (14.2% incidence of severe SOS and CTC Grade 4-5 pulmonary toxicity) and the single
(CEM) transplant arm of ANBL0532 at the time of the Fall 2012 study progress report (11/159 = 7%
incidence). Because Induction chemotherapy is given for several months before patients reach the
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investigational portion of this trial, accrual to the study will not be suspended while the data are
evaluated, however not all patients enrolled will go on to receive MIBG as part of this trial.
If at any time 4 or more patients at any single MIBG dose level who are evaluable for the tolerability of
MIBG endpoint (as per Section 9.2.2) experience a severe toxicity as defined in Section 9.3.2.2B from
start of 131I-MIBG therapy through Day +28 post Bu/Mel ASCR, then conclude that the treatment is not
tolerable at that MIBG dose level. If there are 3 or less patients with severe toxicities at any single MIBG
dose level, then it is reasonable to assume that the dose level is safe enough to warrant further
investigation. For this single-stage rule, with N=18 patients, there is a .90 probability of concluding the
severe toxicity rate is unacceptable when the true rate is 35% and there is a .10 probability of concluding
the severe toxicity rate is unacceptable when the true rate is 10% (i.e., uses a null hypothesis severe
toxicity rate of 10%, 35% under the alternative, and has 90% power with a Type I error rate of 10%). If
the monitoring rule for tolerability is triggered at 12 mCi/kg 131I-MIBG, the study will be referred to
DSMC and the study committee for consideration of dosing and other therapy modifications.
9.4 Assessment of Study Objectives

Objective 1.1 will be assessed by calculating the proportion of evaluable patients who can be treated with
131
I-MIBG and the proportion of evaluable patients who can be treated with 131I-MIBG and then Bu/Mel.
As described in detail in Section 9.3.1, we will also calculate:
• the percentage of average per capita income encompassed by the total of travel + housing +
lost wages;
• the proportion of eligible High-Risk patients accrued to the study; and
• the 1-year EFS rate.
The treatment will be deemed feasible if the upper bound of a 95% confidence interval on the MIBG
feasibility rate and the MIBG and Bu/Mel feasibility rate (as defined in Section 9.3.1) are each not less
than 80% and the 1-year EFS rate is not statistically significantly lower than that of A3973.
Objective 1.2.1 will be assessed as described in Section 9.3.3. The treatment will be deemed tolerable if
the monitoring rule for tolerability is not triggered in at least one of the MIBG dose levels (12, 15 or
18 mCi/kg).
Objective 1.3.1 will be assessed as described in Section 9.3.2.1.
Objective 1.3.2 will be assessed by descriptively comparing the hNET expression level with the semi-
quantitative MIBG uptake at diagnosis using Curie score, and with response. To compare hNET expression
level with response, the median hNET expression level will be calculated for each level of response (CR,
VGPR, PR, etc).
Objective 1.3.3 is focused on assessment of the relative reliability of 123I-MIBG and 18FDG-PET imaging
in assessment of tumor activity for MIBG avid patients at diagnosis and pre-surgical resection (likely
after Cycle 4). A descriptive comparison will be performed of the number of sites of disease and intensity
of uptake for 123I-MIBG versus 18FDG-PET. For patients who have both PET scans done on the same
machine, we will descriptively compare the number of FDG-avid lesions (SUV score ≥ 2.5) and the PET
scores (SUV1 of primary tumor [diagnosis] versus SUV2 of primary tumor [after Cycle 4]). The
cumulative SUV score of (at most) the 10 worst FDG-avid lesions at diagnosis (including the primary
lesion) and after Cycle 4, and changes between them, will be correlated with response at Day 60 post-
transplant, using the Wilcoxon rank-sum test to compare responders (CR/PR) versus non-responders
(NR/PD). Similarly, we will descriptively compare the MIBG scores at diagnosis and pre-surgical
resection. We will test for the association of MIBG score prior to surgical resection versus response to
therapy (responders versus non-responders) with the Wilcoxon rank-sum test.
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Objective 1.3.4 will be assessed by comparison of detectable tumor burden on the pre-surgical resection
radioiodinated-MIBG diagnostic scan and the immediate post-MIBG therapy 131I-MIBG scan using the
MIBG score for MIBG avid patients.
Objective 1.3.5 will be assessed by collecting data on targeted organ toxicity that may be related to
exposure to 131I-MIBG or Bu/Mel. Specifically, we will collect data on the development of SOS
(sinusoidal obstruction syndrome, formerly known as VOD and defined in Section 9.3.2.2A) for MIBG
avid patients and explore its relationship to whole body radiation dose due to 131I-MIBG with a logistic
regression model. The incidence of severe SOS in patients on this study will also be compared to the
incidence of severe SOS in ANBL0532 and the incidence described with Bu/Mel on the HR-NBL-1
SIOPEN trial.
Objective 1.3.6 will be assessed by relating busulfan pharmacokinetics as measured by area under the
curve (AUC) and will be performed on patients undergoing Consolidation chemotherapy, to the
occurrence of SOS with a logistic regression model. In addition, we will determine whether patients’
busulfan doses are adjusted in accordance with pK results, and whether that dose is increased or
decreased. We will relate these data to the occurrence of SOS.
9.5 Gender and Minority Accrual Estimates

The gender and minority distribution of the study population is expected to be:
Accrual Targets
Sex/Gender
Ethnic Category
Females Males Total
Hispanic or Latino 4 4 8
Not Hispanic or Latino 41 56 97
Ethnic Category: Total of all subjects 45 60 105
Racial Category
American Indian or Alaskan Native 0 0 0

Asian 2 2 4
Black or African American 4 11 15
Native Hawaiian or other Pacific Islander 0 0 0
White 39 47 86
Racial Category: Total of all subjects 45 60 105
This distribution was derived from ANBL00B1.
10.0 EVALUATION CRITERIA

10.1 Common Terminology Criteria for Adverse Events (CTCAE)
The description and grading scales found in the NCI Common Terminology Criteria for Adverse Events
(CTCAE) version 4.0 will be utilized for AE reporting. A copy of the CTCAE version 4.0 can be
downloaded from the CTEP website at
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). All appropriate treatment
areas should have access to a copy of the CTCAE version 4.0. Additionally, toxicities are to be reported
on the appropriate data collection forms.
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10.2 Response Criteria for Patients with Solid Tumors

This study will use the International Neuroblastoma Staging System (INSS) Response Evaluation
Criteria. This will allow direct comparison with legacy COG studies as well as Phase 3 trials performed
abroad.
10.3 International Staging System72
Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease;
representative ipsilateral lymph nodes negative microscopically (nodes attached to and removed with the
primary tumor may be positive).
Stage 2A: Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph
nodes negative for tumor microscopically.
Stage 2B: Localized tumor with or without complete gross excision; with ipsilateral nonadherent lymph
nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.
Stage 3: Unresectable unilateral tumor infiltrating across the midline with or without regional lymph node
involvement; or, localized unilateral tumor with contralateral regional lymph node involvement; or,
midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The
midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must
infiltrate to or beyond the opposite side of the vertebral column.
Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin
and/or other organs (except as defined for Stage 4S).
Stage 4S: Localized primary tumor (as defined for Stage 1 or 2A or 2B), with dissemination limited to
liver, skin, and/or bone marrow (limited to infants < 1 year of age). Marrow involvement should be
< 10% of total nucleated cells identified as malignant on bone marrow biopsy or on marrow aspirate.
MIBG scan (if performed) should be negative in the marrow.
10.4 International Response Criteria72
Measurable tumor is defined as the product of the longest x widest perpendicular diameter. The third
dimension is added when possible. Elevated catecholamine metabolite levels and tumor cell invasion of
bone marrow also is considered measurable tumor. See Appendix V.
10.4.1 Complete Response (CR)**
No evidence of primary tumor, no evidence of metastases (chest, abdomen, liver, bone, bone marrow,
nodes, etc.), and HVA/VMA normal.
10.4.2 Very Good Partial Response (VGPR)
Greater than 90% reduction of primary tumor; no metastatic tumor (as above except bone); no new bone
lesions, all pre-existing lesions improved on bone scan; HVA/VMA normal.
10.4.3 Partial Response (PR)
Fifty to 90% reduction of primary tumor; 50% or greater reduction in measurable sites of metastases; 0-1
bone marrow samples with tumor; number of positive bone sites decreased by > 50%.
10.4.4 Mixed Response (MR)
Greater than 50% reduction of any measurable lesion (primary or metastases) with, < 50% reduction in
any other site; no new lesions; <25% increase in any existing lesion (exclude bone marrow evaluation).
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10.4.5 No Response (NR)

No new lesions; <50% reduction but <25% increase in any existing lesion (exclude bone marrow
evaluation).
10.4.6 Progressive disease (PD)**
Any new lesion or increase of a measurable lesion by >25%; previous negative marrow positive for
tumor.
** MIBG scan must be negative for patient to be classified as having a complete response. New site of
disease documented by MIBG scan qualifies patient as having progressive disease.
11.0 ADVERSE EVENT REPORTING REQUIREMENTS

11.1 Purpose
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using
similar agents. Certain adverse events must be reported in an expedited manner to allow for timelier
monitoring of patient safety and care. The following sections provide information about expedited
reporting.
11.2 Determination of reporting requirements

Reporting requirements may include the following considerations: 1) whether the patient has received an
investigational or commercial agent; 2) the characteristics of the adverse event including the grade
(severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) of
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or
prolongation of hospitalization was associated with the event.
An investigational agent is a protocol drug administered under an Investigational New Drug Application
(IND). In some instances, the investigational agent may be available commercially, but is actually being
tested for indications not included in the approved package label.
Commercial agents are those agents not provided under an IND but obtained instead from a commercial
source. The NCI, rather than a commercial distributor, may on some occasions distribute commercial
agents for a trial.
When a study includes both investigational and commercial agents, the following rules apply.
• Concurrent administration: When an investigational agent is used in combination with a
commercial agent, the combination is considered to be investigational and expedited
reporting of adverse events would follow the guidelines for investigational agents.
• Sequential administration: When a study includes an investigational agent and a
commercial agent on the same study arm, but the commercial agent is given for a period of
time prior to starting the investigational agent, expedited reporting of adverse events which
occur prior to starting the investigational agent would follow the guidelines for commercial
agents. Once therapy with the investigational agent is initiated, all expedited reporting of
adverse events follow the investigational agent reporting guidelines.
Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (eg, treatment with
investigational agent/intervention, radiation or chemotherapy). A metastasis of the initial neoplasm is not
considered a secondary malignancy.
All secondary malignancies that occur following treatment need to be reported via CTEP-AERS. Three
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options are available to describe the event:

• Leukemia secondary to oncology chemotherapy
• Myelodysplastic syndrome
• Treatment related secondary malignancy
11.3 Steps to determine if an adverse event is to be reported in an expedited manner

Step 1: Identify the type of event using the NCI Common Terminology Criteria
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events
(CTCAE) version 4.0 will be utilized for AE reporting and are located on the CTEP website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate treatment
areas should have access to a copy of the CTCAE.
Step 2: Grade the event using the NCI CTCAE.

Step 3: Determine the attribution of adverse event in relation to the protocol therapy. Attribution categories
are: Unrelated, Unlikely, Possible, Probable, and Definite.
Step 4: Determine the prior experience of the adverse event.
For investigational agents that are not commercially available and are being studied under a
company’s IND or an investigator held IND, expected AEs are usually based on the
Investigator’s Brochure.
Guidance on expectedness of the agent is provided in the Drug Information Section of this protocol.
Step 5: Review Tables A and/or B in this section to determine if:
• there are any protocol-specific requirements for expedited reporting of specific adverse
events that require special monitoring; and/or
• there are any protocol-specific exceptions to the reporting requirements.
Step 6: Determine if the protocol treatment given prior to the adverse event included an investigational
agent, a commercial agent, or a combination of investigational and commercial agents.
Note: If the patient received at least one dose of investigational agent, follow the guidelines in Table A.
If no investigational agent was administered, follow the guidelines in Table B.
11.4 Reporting methods

• The reporting methods described below are specific for clinical trials evaluating agents for which
the IND is held by COG, an investigator, or a pharmaceutical company. It is important to note
that these procedures differ slightly from those used for reporting AEs for clinical trials for which
CTEP holds the IND.
• Use the NCI’s CTEP Adverse Event Reporting System (CTEP-AERS). The NCI’s guidelines for
CTEP-AERS can be found at http://ctep.cancer.gov.
An CTEP-AERS report must be submitted by the following method:
Electronically submit the report via the CTEP-AERS Web-based application located at
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm.
• Fax or email supporting documentation for AEs related to investigational agents to:
COG (fax # 626-303-1768; email: COGAERS@childrensoncologygroup.org; Attention: COG
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AERS Coordinator).
• DO NOT send the supporting documentation for AEs related to commercial agents to the
NCI. Fax this material to COG (fax # 626-303-1768; attention: COG AE Coordinator).
ALWAYS include the ticket number on all faxed documents.
• Use the NCI protocol number and the protocol-specific patient ID provided during trial
registration on all reports.
11.5 When to report an event in an expedited manner

• Some adverse events require notification within 24 hours (refer to Table A) via e-mail to the
COG AE Coordinator.
• Submit the report within 5 calendar days of learning of the event.
11.6 Other recipients of adverse event reports
COG will forward reports and supporting documentation to the Study Chair, to the drug company (for
industry sponsored trials) and to the FDA (when COG holds the IND).
Adverse events determined to be reportable must also be reported according to the local policy and
procedures to the Institutional Review Board responsible for oversight of the patient.
11.7 Reporting of Adverse Events for investigational agents

Reporting requirements are provided in Table A. The investigational agent used in this study is 131I-
Metaiodobenzylguanidine (Jubilant Draximage® Therapeutic 131I-MIBG), IND # 76,227, Jubilant
Draximage®, Canada.
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Table A
CTEP-AERS Expedited Reporting Requirements for Adverse Events That Occur Within 30 Days1
of the Last Dose of the Investigational Agent
Grades Grades
Grade 1 Grade 2 Grade 2 Grade 3 Grade 3 4 & 52 43 & 52
Unexpected Expected
Unexpected Unex-
with without with without Unex-
and pected Expected Hospitali- Hospitali- Expected
Hospitali- Hospitali- pected
Expected
zation zation zation zation
5 5 5 5
Unrelated Not Not Not Not Not
Calendar Calendar Calendar Calendar
Unlikely Required Required Required Required Required
Days Days Days Days
Possible 5 5 5 5 24-Hour; 5
Not Not Not
Probable Calendar Calendar Calendar Calendar 5 Calendar Calendar
Required Required Required
Definite Days Days Days Days Days Days
1
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after
the last dose of treatment with an agent under a CTEP IND or non-CTEP IND require reporting as
follows:
CTEP-AERS 24-hour notification (via CTEP-AERS for CTEP IND agents; via e-mail to COG AE
Coordinator for agents in Non-CTEP IND studies) followed by complete report within 5 calendar days for:
• Grade 4 and Grade 5 unexpected events
CTEP-AERS 5 calendar day report:
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization (see exceptions
below
• Grade 5 expected events
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease,
a full report is required as outlined in the table.
3 Please see exceptions below under section entitled “Additional Instructions or Exceptions.”
March 2005
Note: All deaths on study require timely reporting to COG via RDE regardless of causality.
Attribution to treatment or other cause must be provided.
• Expedited AE reporting timelines defined:

 “24 hours; 5 calendar days” – The investigator must initially report the AE via e-
mail to COG AE Coordinator within 24 hours of learning of the event followed by
a complete CTEP-AERS report within 5 calendar days of the initial 24-hour report.
 “5 calendar days” - A complete CTEP-AERS report on the AE must be submitted
within 5 calendar days of the investigator learning of the event.
• Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization

(or prolongation of existing hospitalization) must be reported regardless of attribution and
designation as expected or unexpected with the exception of any events identified as
protocol-specific expedited adverse event reporting exclusions.
• Any event that results in persistent or significant disabilities/incapacities, congenital

anomalies, or birth defects must be reported via CTEP-AERS if the event occurs
following treatment with an agent under a CTEP IND.
• Use the NCI protocol number and the protocol-specific patient ID provided during trial
registration on all reports.
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• Protocol specific reporting of AEs, in addition to the CTEP-AERS requirements, are to

be entered in the COG remote data entry system.
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements:
• Any death that occurs more than 30 days after the last dose of treatment on this study
which can be attributed (possibly, probably, or definitely) to the investigational agent (131I-
MIBG) or to the combination of 131I-MIBG and Bu/Mel and is not due to cancer
recurrence/progression must be reported via CTEP-AERS per the timelines outlined in the
table above.
• Grades 1-4 myelosuppression do not require expedited reporting.

131
NOTE: Also see Section 11.9 for expedited reporting of adverse events via CRFs following I-
MIBG and Bu/Mel ASCR therapy
11.8 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway
The following are expedited reporting requirements for adverse events experienced by patients on study
who have not received any doses of an investigational agent on this study.
Commercial reporting requirements are provided in Table B.
COG requires the CTEP-AERS report to be submitted within 5 calendar days of learning of the event.
Table B
Reporting requirements for adverse events experienced by patients on study who have NOT
received any doses of an investigational agent on this study.
CTEP-AERS Reporting Requirements for Adverse Events That Occur During Therapy With a
Commercial Agent or Within 30 Days1
Attribution Grade 4 Grade 5
Unexpected Expected
Unrelated or Unlikely CTEP-AERS
Possible, Probable, CTEP-AERS CTEP-AERS
Definite
1
This includes all deaths within 30 days of the last dose of treatment with a
commercial agent, regardless of attribution. Any death that occurs more than 30
days after the last dose of treatment with a commercial agent which can be
attributed (possibly, probably, or definitely) to the agent and is not due to cancer
recurrence must be reported via CTEP-AERS.
11.9 Routine Adverse Event Reporting and Study-Specific Expedited Adverse Event Reporting
Note: The guidelines below are for routine reporting of study specific adverse events on the COG case
report forms and do not affect the requirements for CTEP-AERS reporting.
The NCI defines both routine and expedited AE reporting. Routine reporting is accomplished via the
Adverse Event (AE) Case Report Form (CRF) within the study database. For this study, routine reporting
will include all CTEP-AERS reportable events AND Grade 3 and higher non-hematologic Adverse
Events with the exception of the following adverse events that will be collected irrespective of the grade:
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• Grade 1 and higher blood bilirubin if associated with SOS (Sinusoidal obstruction syndrome,
formerly known as VOD)
• Grade 1 and higher ascites if associated with SOS
PLEASE NOTE: The following toxicities will also be reported via CRFs within 7 days following
Day +28 post Bu/Mel ASCR.
• Grade 4-5 Pulmonary/Respiratory toxicity
• Grade 4-5 renal toxicity
• Grade 4-5 cardiac toxicity
• Severe SOS as defined by:
Serum total bilirubin > 2.0 mg/dL, PLUS at least 2 of the following findings from the
beginning of MIBG to within 28 days of transplantation: hepatomegaly with right upper
quadrant pain, ascites, or weight gain > 5% above baseline PLUS a specific organ failure
listed below:
o Hepatic encephalopathy (CTC Grade 4 hepatic failure), OR
o Pulmonary dysfunction: Continuous oxygen support (CTC Grade 3 hypoxia) for
> 48 hours, ventilatory support not clearly attributable to another cause, OR
o Renal dysfunction: serum creatinine > 3 times the ULN (CTC Grade 3
creatinine), or the need for dialysis (CTC Grade 4 renal), not clearly attributable
to another cause.
12.0 RECORDS AND REPORTING
12.1 Categories of Research Records

Research records for this study can be divided into 3 categories:
1. Non-computerized Information: Pathology Narrative Reports and Surgical Reports. These forms
are submitted through the Document Imaging System in the eRDES.
2. Reference Labs’ required records and IROC Rhode Island (formerly QARC) data. These data
accompany submissions to these centers, which forward their review data electronically to the
COG Research Data Center.
3. Computerized Information Electronically Submitted: All other computerized data will be entered
in the COG Remote Data Entry System with the aid of schedules and worksheets (essentially
paper copies of the RDE screens) as provided in the data form packet.
See separate Data Form Packet which includes submission schedule.
12.2 CDUS
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will
be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and
October 31. This is not a responsibility of institutions participating in this trial.
12.3 Data and Safety Monitoring Committee

To protect the interests of patients and the scientific integrity for all clinical trial research by the
Children’s Oncology Group, the COG Data and Safety Monitoring Committee (DSMC) reviews reports
of interim analyses of study toxicity and outcomes prepared by the study statistician, in conjunction with
the study chair’s report. The DSMC may recommend the study be modified or terminated based on these
analyses.
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Toxicity monitoring is also the responsibility of the study committee and any unexpected frequency of
serious events on the trial is to be brought to the attention of the DSMC. The study statistician is
responsible for the monitoring of the interim results and is expected to request DSMC review of any
protocol issues s/he feels require special review. Any COG member may bring specific study concerns to
the attention of the DSMC.
The DSMC approves major study modifications proposed by the study committee prior to implementation
(eg, termination, dropping an arm based on toxicity results or other trials reported, increasing target
sample size). The DSMC determines whether and to whom outcome results may be released prior to the
release of study results at the time specified in the protocol document.
13.0 SURGICAL GUIDELINES
Timing of protocol therapy administration, response assessment studies, and surgical interventions are
based on schedules derived from the experimental design or on established standards of care. Minor
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations
(and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure
and/or anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where
explicitly prohibited within the protocol).
13.1 Surgical Rationale

The overall surgical goal in High-Risk patients with neuroblastoma is the most complete tumor
resection with as much preservation of full organ and neurologic function as possible. In addition,
the surgeon is responsible for the preservation and delivery of an adequate surgical specimen to the
appropriate laboratory for crucial biologic analyses; including determination of MYCN amplification,
ploidy, and molecular genetic analyses. Titanium clips should be placed around sites of residual disease.
Surgical resection of soft tissue disease will occur during Induction therapy. Residual persistent mass
after initial chemotherapy is common, and in previous analyses is not correlated with patient outcome.
All patients will undergo attempt at complete surgical resection of primary tumor following Cycle 4 (or
Cycle 5, if medically necessary) of Induction chemotherapy.
13.2 Pre-Operative Management

Adequate pre-operative imaging of the primary tumor and sites of regional spread is done by either CT,
MRI, or a combination of the modalities. Sites of distant metastases should be evaluated by a combination
of clinical and bone marrow assessment as well as 18FDG-PET, and MIBG scans. When dealing with
paraspinal or epidural lesions, pre-operative neurosurgical consultation is recommended and a baseline
neurologic assessment carried out. The planned operation should be discussed with the attending pediatric
oncologist and at tumor board, and the goals of the surgery should be clearly understood by all involved
services pre-operatively.
13.3 Specimen/Sampling Requirements
In all patients, the primary purpose of the initial surgical procedure is to obtain enough tissue to establish
the diagnosis, determine stage, and secure enough properly preserved tumor for biological studies. All
patients must be enrolled onto ANBL00B1 to be eligible to participate in ANBL09P1. Refer to
ANBL00B1 for complete details of specimen requirements.
An adequate biopsy to determine the diagnosis and assess biological variables like histopathologic
classification, MYCN amplification and ploidy is required. Usually more than 1 cubic centimeter of viable
tissue is needed for all these assays. Needle biopsies are not sufficient for histologic classification. The
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surgeon should remember that a significant portion of the tumor may be necrotic. Frozen section
examination of a small amount of tissue will verify that viable neuroblastoma is being biopsied.
Placement of the specimen in formalin should be avoided. Rather, the pathologist should be alerted and
the specimen rapidly transferred from the operating room fresh and sterile. The surgeon should verify
with the pathologist that viable tissue was sent and is being processed for COG biological studies and
histopathology. Since it is hoped to extract RNA from these specimens, rapid freezing of some of the
tissue is required.
For patients with Stage 4S disease who are very ill and in whom an open biopsy to obtain tissue for
diagnosis and biologic studies is considered medically contraindicated, every effort should be made to
obtain some tumor tissue by fine needle aspiration of a metastatic site for at minimum the determination
of MYCN status.
13.4 Operative Management

13.4.1 Central Line Placement
Patients will require central venous access both for treatment and apheresis. It is usually feasible and
efficient to place a vascular access device and obtain a bone marrow aspirate and biopsy during the same
anesthetic. The appropriate catheter should be placed from initiation of therapy.
Medcomp or similar catheters are specifically designed as tunneled, permanent apheresis catheters. It may
not be possible to draw at a sufficient rate from a non-apheresis catheter that is smaller than 10Fr. If a
smaller double lumen must be placed, or if it is not possible to draw at a sufficient rate (2 mL/kg/min)
then it may be necessary to place an additional 8-10 Fr single lumen catheter for the apheresis. If a
second, single-lumen line is needed, it is best to place it electively PRIOR to starting the mobilization
cycle of chemotherapy (i.e., Cycle 2 Induction chemotherapy).
13.4.2 Diagnostic Surgery
The great majority of High-Risk patients will undergo initial diagnostic biopsy without resection. Biopsy
of the primary tumor or an accessible metastatic site is acceptable. The surgeon should try to obtain at
least 1 cm3 of viable tumor tissue, if feasible, according to the surgeon’s judgment. Complete excision of
the primary tumor can occasionally be performed if the tumor is easily resectable without a lengthy
procedure or extensive dissection. However, a resection should not be undertaken if it might result in
significant delay in the initiation of chemotherapy or great morbidity. In some institutions the diagnosis is
established by finding neuroblastoma in bone marrow specimens in conjunction with elevated urinary
catecholamines.
13.4.3 Epidural Tumors with Intraspinal Extension
When the tumor approaches the spinal canal on imaging (see Section 16.2), a detailed examination must
assess neurological function.
Laminectomy should not be performed in patients who are neurologically asymptomatic. Patients with
symptomatic spinal cord compression secondary to epidural extension of neuroblastoma through a neural
foramina may require laminectomy, or osteoplastic laminotomy at diagnosis to prevent permanent paralysis.
However, treatment with chemotherapy alone or chemotherapy and radiation therapy will frequently be
sufficient to rapidly reverse symptoms of cord compression. Therapeutic decisions in neuroblastoma patients
with spinal cord compression should be made with the multidisciplinary involvement of the attending
pediatric oncologist, general pediatric surgeon, and pediatric neurosurgeon.
If neurologic deterioration occurs during chemotherapy, neurosurgical evaluation should be sought and
operative decompression strongly considered. Appropriate to the degree of neurological impairment, the
treating physicians may decide that operative neurosurgical decompression is indicated under these
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circumstances. If feasible, the neurosurgeon should perform an osteoplastic laminotomy, with secure
replacement of the laminae after decompression has been accomplished. Operative details will be
recorded in the RDE.
13.4.4 Operative Management of Primary Tumors after Chemotherapy
The majority of patients will undergo resection of the primary tumor after initial Induction chemotherapy.
Surgical resection should be performed when the ANC > 500/µL and the patient is medically stable after
Cycle 4 of Induction. This is to allow maximal tumor reduction by chemotherapy prior to resection and to
reduce vascularity. Surgical resection may be performed later in Induction, if necessary, but MUST occur
prior to Consolidation. Surgical scheduling SHOULD AVOID DELAYS OF MORE THAN 6 WEEKS
BETWEEN CHEMOTHERAPY CYCLES, OR BETWEEN CHEMOTHERAPY AND MIBG
THERAPY IF SURGERY IS PERFORMED AFTER CYCLE 5 OF INDUCTION. IN ADDITION, A
MINIMUM OF 2 WEEKS BETWEEN SURGERY AND MIBG THERAPY IS RECOMMENDED.
The goal of delayed surgery is gross total resection of residual tumor in the primary site as well as tumor in
areas of regional dissemination (usually lymph nodes). Resection with microscopically negative margins may
not be feasible because of proximity to major vascular structures and the spine. Instead, the surgeon should
concentrate on removing, as completely as possible, all gross disease. It is acceptable, and often necessary, to
incise the tumor and remove it in a segmental fashion. Titanium clips should be used to mark all areas of
residual disease. All attempts should be made to preserve organs, especially the kidney. Rarely, nephrectomy
may be necessary for complete tumor removal but this should only be planned if the involved kidney has
greatly diminished function. If pre-operatively a nephrectomy is being considered, then a differential
GFR should be obtained to determine what the renal function will be in the remaining kidney. The
COG Surgical Committee strongly recommends kidney preservation when feasible.
It is vital that the operating surgeon dictate a detailed operative note, which should include: the completeness
of resection, areas of residual disease, estimated blood loss, and any operative complication such as
identification of injury to adjacent structures, removal of normal organs, renal injury, and vascular injury.
Surgical resection of residual disease following Bu/Mel + ASCR is not encouraged, unless it would alter
therapy.
13.5 Management of Surgical Complications
13.5.1 Intraoperative Complications
Intraoperative complications are site-dependent. Major hemorrhage from either venous or arterial
structures is always possible with these infiltrative tumors. The principles of vascular surgery, including
proximal and distal control, pertain. Appropriate intraoperative vascular consultation should be sought if
necessary. Crucial vessels like the carotid, subclavian, hepatic, superior mesenteric or renal arteries
should be repaired and flow restored even if bypass grafting is required. Nerve injuries may also be
incurred and should be primarily repaired using magnification.
13.5.2 Post-Operative Complications
This topic is too broad for simple discussion. Generally, large neuroblastoma resections result in
significant third space losses and require vigorous fluid replacement. Because of this fluid requirement,
patients may require significant periods of post-operative ventilation. The need for post-operative
monitoring in an intensive care environment should be anticipated. Acute and long-term complications
and duration of complications will be prospectively monitored, including chylous leak (thoracic and
abdominal); secretory non-infectious diarrhea; bowel obstruction due to post-surgical adhesions; and
renal dysfunction due to vascular injury.
Pulmonary Complications
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Resection of large abdominal neuroblastoma may result in significant third space losses and require
vigorous fluid replacement intraoperatively and postoperatively. Because of this fluid requirement
patients may require significant periods of post-operative ventilation. The need for post-operative
monitoring in an intensive care environment should be anticipated. Pneumonias or other pulmonary
complications related to ICU and postoperative course (including intubation >7 days) should be reported.
Bowel Obstruction
Small bowel obstruction may occur for many reasons, including injury, exposure, or blunt trauma during
the resection, postoperative intussusception, formation of adhesions, or related to radiation injury.
Obstruction may occur in the early postoperative period, or may occur months to years later.
Chylous Leak
Extensive dissection of the retroperitoneum or mediastinum may result in either frank disruption of
chylous channels, or interruption causing intraluminal lymphatic hypertension and leak.
Renal Injury/Atrophy
Renal injury may manifest in many forms, related to the nature of the injury or insult. While nephrectomy
is strongly discouraged, extensive perirenal dissection and kidney sparing surgery may still result in
vascular occlusion, infarction, traumatic compression, or other injury mechanisms sufficient to cause long
term dysfunction or atrophy. Additionally, radiation therapy may lead to kidney damage, again with the
long term finding of atrophy.
Diarrhea
Extensive sympathetic denervation associated with aggressive retroperitoneal dissection may result in
increased frequency of stooling or diarrhea.
13.6 Special techniques
13.6.1 Nerve Stimulation
Nerve stimulation can be useful in detecting motor nerves in the brachial or lumbo-sacral plexus. This
requires cooperation from the anesthesiologist as muscle relaxation must be allowed to wear off. Nerve
stimulation should always be used when dissection along the pelvic sidewall or in the neck or thoracic
inlet.
13.6.2 Ultrasonic Dissector-Aspirators
Some authors have described the use of ultrasonic dissectors (CUSA) to debulk the interior of large
tumors allowing an easier capsular dissection. The technique is useful for friable tumors but not those that
are stroma rich. The surgeon should try to perform a generous incisional biopsy prior to ultrasonic
dissection as it is difficult to capture the tumor specimen after it has been aspirated into the device.
13.6.3 Thoracoscopy
Video-assisted thoracoscopy can be used to remove small posterior mediastinal or thoracic inlet tumors
provided there is no vascular encasement. One-lung ventilation is recommended.
13.6.4 Laparoscopy
Laparoscopic resection of small adrenal or pelvic primaries can be done. Extensive tumors or those with
significant vascular encasement, or locoregional nodal spread can be more completely resected using
standard open approaches.
13.6.5 Radiofrequency Ablation, Cryosurgery

These techniques have significant drawbacks when applied to lesions in proximity to major vascular
structures and should be avoided when treating neuroblastoma.
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14.0 PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS

14.1 Rapid Pathology Review
A rapid review of histology (under COG ANBL00B1) is required to determine eligibility of patients for
this study. See ANBL00B1 for complete details on specimen requirements. Recently, as part of the
international cooperative effort to develop a complete set of International Neuroblastoma Risk Groups,
the International Neuroblastoma Pathology Committee devised a morphologic classification of
neuroblastoma tumors that is modeled on the one proposed by Shimada and colleagues.73,74 In
ANBL00B1, tumor sections will be centrally reviewed, and classified as favorable or unfavorable
according to the criteria described by the International Neuroblastoma Pathology Committee (INPC).
As per ANBL00B1, representative slides MUST be sent to the COG Biopathology Center via Federal
Express for overnight delivery. The slides will then be forwarded to Dr Hiroyuki Shimada, who will
determine the histologic classification (INPC) and will notify the Neuroblastoma Biology Reference
Laboratory. The Tracking Center will then determine protocol assignment (Low-, Intermediate-, and
High-Risk) and will notify the treating institution of the results via eRDES email notification.
14.1.1 Tracking Center Activity
Institutions will first enroll patients on ANBL00B1 once the patient’s age, stage of disease, and diagnosis
have been determined. The COG Statistical Office will notify the Tracking Center with the enrollment
information. Results of MYCN and ploidy status will be sent to the Tracking Center and to the treating
institution by the Neuroblastoma Biology Reference Laboratory as soon as the results are available. The
Tracking Center will immediately notify Dr Shimada in the event that a patient’s stage, age, MYCN, and
ploidy status mandate immediate review of histology for risk-grouping and treatment assignment.
14.1.2 Diagnostic Concordance Study
In order to perform a concordance study between local institution and central review determination of the
INPC classification, the Neuroblastoma Pathology Checklist is REQUIRED to be completed by the
institutional pathologist when tumor tissue is obtained at diagnosis.
14.1.3 Review Material Required at Diagnosis

Review materials are submitted through ANBL00B1. Do not submit separate pathology review materials
for each protocol. Please refer to ANBL00B1 for submission details.
14.1.4 Review Material at Second Look or Definitive Surgery and/or Relapse
Pathology materials must be submitted through ANBL00B1 at the time of second look surgery, whether
this procedure is a biopsy, partial resection, or complete resection, and/also at the time of relapse. Please
refer to ANBL00B1 for specimen requirements.
14.1.5 Autopsy Review

If autopsy permission is obtained, please send the following material:
a. 2 H&E sections of each major organ or paraffin blocks
b. 2 H&E and 6 unstained slides of residual tumor, both primary and metastatic, or send paraffin
blocks.
c. Copy of the autopsy report.
d. COG Neuroblastoma Biology Data Sheet and Shipping Form
Label the autopsy materials with the COG Patient ID number and the Surgical Pathology ID (SPID) and
block numbers from the corresponding pathology report. Ship to the Biopathology Center by regular mail
or using your institution’s courier account.
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14.1.6 Specimen Shipping

Submit materials to:
COG Biopathology Center
Nationwide Children’s Hospital
700 Children’s Drive, Room WA 1340
Columbus, OH 43205
Phone: (614) 722-2865
Fax: (614) 722-2897
Email: BPCParaffinTeam@nationwidechildrens.org
Study Pathologist of record:

Hiroyuki Shimada, M.D.
Department of Pathology
Children’s Hospital Los Angeles
4650 Sunset Blvd
Los Angeles, CA 90027
Phone: (323) 361-2377
Fax: (323) 361-8005.
Email: hshimada@chla.usc.edu
14.2 Norepinephrine transporter (hNET) expression tests
The degree of hNET expression is correlated to MIBG uptake. Therefore, the hNET test is done to
analyse the subject’s response to MIBG therapy. This test is optional depending on whether or not the
patient has signed an informed consent for them.
Specimen Timing:
The hNET expression test is done using RT-PCR on patient tumor samples collected at diagnosis and
tumor resection.
Specimen Collection:
Obtain between 200mg and 1g of frozen tissue that has to be wrapped in aluminium foil and placed in a
specimen bag. Store at -20º C or preferably at -70ºC until shipped on dry ice.
Label all specimens with the BPC number, COG patient ID, specimen type, collection date and time.
Shipping Instructions:
All specimens should be shipped via Federal Express PRIORITY OVERNIGHT. Please see the link
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf for details. Arrange
for Federal Express pick-up through your usual institutional procedure, but stress that pickup is at your
institutional address. If specimens are sent on a Friday, be sure to indicate Saturday delivery on the air-
bill.
The samples have to be sent with the specimen transmittal form available in the COG website at:
https://members.childrensoncologygroup.org/prot/generic.asp.
Advanced notice of incoming samples is kindly requested by email or phone PRIOR TO SHIPMENT,
especially if shipment of material may arrive on a weekend or holiday. Emailing of the tracking
information is especially helpful. If shipment of material may arrive on a weekend (i.e. when
shipping is done on a Friday) or holiday, advance arrangements must be made with the laboratory
(as the university does not accept weekend samples so you will be given an alternate shipping address).
Contact: Tito Woodburn, Lab phone: 806-743-2707; Email: TITO.WOODBURN@TTUHSC.EDU. If it
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is impossible to contact the lab prior to shipping, it is required that the tracking number and carrier
information for the shipment be emailed to the laboratory when shipping the specimen.
All specimens must be sent directly to:

C Patrick Reynolds, MD PhD
Cancer Center Core Labs STOP 9450
Texas Tech University Health Sciences Center-Amarillo,
School of Medicine Cancer Center
3601 4th Street
Lubbock, Texas- 79430-6450
Phone: 806 743-1558

Fax: 806 743-2691
Email: PATRICK.REYNOLDS@TTUHSC.EDU
Lab phone: 806-743-2707
Contact in lab: Tito Woodburn
Email: TITO.WOODBURN@TTUHSC.EDU
14.3 Pharmacokinetics for Busulfan Dose Adjustments

14.3.1 Busulfan Pharmacokinetics
Pharmacokinetics should be performed as per institutional guidelines, to achieve an area under the curve
(AUC) for busulfan of 900 to 1500 micromole/liter/minute. Note that busulfan levels may be reported as
AUC or steady state concentration (Css: ng/mL); the target in this study requires that results be reported
as AUC (note Css levels typically run lower).
Busulfex concentrations will be determined in plasma by collecting blood into a green top sodium heparin
tube. Samples should not be drawn from the lumen used to infuse busulfan. Samples are recommended to
be collected at the end of the 2 hour infusion, 135 minutes after start of infusion, 150 minutes after start of
infusion, and 3, 4, 5, and 6 hours after the start of the first infusion. See table in Section 7.1.3.
In case infusion runs more or less than two hours, draw one sample immediately when infusion ends.
Then, draw the next two samples 15 min apart and continue to draw 3, 4, 5, and 6 hours samples by
counting from beginning of the infusion.
Institutional pharmacokinetic studies are acceptable only if they are performed in CLIA certified
laboratory. If pharmacokinetics cannot be performed at a local laboratory, samples can be shipped to the
Seattle Cancer Care Alliance (address below) or other regional laboratories experienced in this assay.
Results are usually available in time for adjusting doses 7 through 16. Brief instructions are as follows:
Collect 1-3 mL of blood into sodium heparin tubes (green top) according to the schedule above. Place
labeled samples immediately on wet ice and refrigerate. Centrifuge samples as soon as possible at 4oC.
Separate plasma from RBCs. Store plasma at –20°C. Plasma tubes must be labeled with the patient’s
name, medical records number, and the date and actual clock time that the sample was drawn. Include the
Busulfex Pharmacokinetics requisition form with shipment.
Sample requisition form, collection schedule, and instructions can also be found at:
http://www.seattlecca.org/busulfan-lab-samples.cfm
14.3.2 Shipping
Samples must be shipped on a minimum of 3 kg of dry ice the day they were drawn using an urgent
overnight carrier. Please include IV Busulfex PK requisition form with sample shipment.
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Send samples to:

Pharmacokinetics Laboratory
Seattle Cancer Care Alliance
Room G7-405
825 Eastlake Ave. East
Seattle, WA 98109
Tel: (206) 288-7389
Fax: (206) 288-7397
Email: pklab@seattlecca.org
Note: Notify the lab staff of sample shipment at least 48 hours prior to arrival. Samples can be
received Monday through Friday, or on Saturdays with at least 3 days advance notice. Coordinate
the taking of samples so that delivery will occur Monday through Saturday and there will be time
for a possible dose adjustment. Please provide the lab with a tracking number for the package at
the phone or email listed above.
Provide fax and phone numbers for the attending physician so that results can be reported in time
for targeted dose adjustment.
14.3.3 Guidelines for Adjusting Busulfan Dosing Based on Results of Pharmacokinetic Studies
Once the results of the area under the curve (AUC) analysis of the busulfan dose are available, subsequent
doses will be adjusted to achieve an overall exposure target AUC of 900-1500 micromole/liter/minute.
The amount by which the dose is increased or decreased should be decided by the patient’s attending
physician in conjunction with the institutional toxicology laboratory director, or the Seattle Cancer Care
Alliance Pharmacokinetics Laboratory (see above).
In cases where the pharmacokinetics are performed locally, a second AUC analysis may be performed
after administration of the first modified dose, and further dose adjustments made accordingly.
15.0 SPECIAL STUDIES SPECIMEN REQUIREMENTS

15.1 Biologic Requirements
Patients must be enrolled on ANBL00B1 prior to the time of enrollment on ANBL09P1. Enrollment on
ANBL00B1 is required for all newly diagnosed patients within 21 days of diagnosis for all patients, with
the exception of infants with Stage 4S neuroblastoma who are too ill to undergo a diagnostic biopsy
procedure. Tissue procurement is mandatory for biology study registration. Consent for ANBL00B1 must
be obtained at the time of tissue submission and should be within 1 week of surgery. Needle biopsies are
not sufficient for histologic classification. Investigators are strongly encouraged to obtain adequate tissue
(see Sections 13.0 and 14.0) via open biopsy techniques. See protocol ANBL00B1 for details on the type
of specimen to be obtained, how the specimen should be prepared, when the specimen should be shipped
and the appropriate contact information.
ANBL00B1 enrollment allows tumor tissue and blood samples obtained at the time of diagnosis to be
tested for the determination of INPC histologic classification, MYCN copy number and tumor cell ploidy.
These results are used in real time to determine risk categorization and treatment assignment, especially
for patients age 12-18 months with Stage 4 disease or Stage 3 disease. Residual tissues may be used for
additional research testing and/or banking if informed consent for these options is indicated on the
patient’s ANBL00B1 consent document.
Study enrollment on ANBL09P1 must be within 28 days of diagnosis, with confirmed biology status for
initial risk group assignment.
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16.0 IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING

Timing of protocol therapy administration, response assessment studies, and surgical interventions are
based on schedules derived from the experimental design or on established standards of care. Minor
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up
to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or
anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where explicitly
prohibited within the protocol).
Note: the guidelines below are recommendations only and are not intended to replace institutional
guidelines.
CT/MRI will be utilized for optimum visualization of all areas of bulk tumor (primary and metastases).
CT/MRI is required: pre-treatment, prior to surgical resection, Pre-Consolidation, post Consolidation
treatment, prior to Cycle #4 of Maintenance, at end of therapy, and at relapse. During follow-up, CT/MRI
is required at the following timepoints after completion of the last cycle of isotretinoin treatment: 3, 6,
and 9 months; 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 years; and then annually after 5 years through 10 years
following enrollment onto the study.
16.1 CT Scans
Axial imaging of the site of the primary tumor will be performed using low-dose technique according to
the ALARA concept.75 The studies will be performed using current-generation single or multi-detector
systems. CT slice thickness should be 5 mm or less. Imaging will be performed during the administration
of intravenous contrast, generally at 2 mL/kg. The use of oral contrast will be determined by the
individual radiologist performing the study, but may be helpful in abdominal imaging. Images will be
reconstructed in soft tissue and edge-enhanced bone/lung and liver algorithms. Coronal and sagittal
multiplanar reconstructions may be helpful.
16.2 MRI Scans
Typically MRI will be performed on 1.5 T MRI units. Axial and at least 1 additional plane (coronal or
sagittal) of the primary tumor will be performed using at least 2 pulse sequences (T1, T2, STIR, FLAIR,
in/out phase, post contrast). The use of intravenous gadolinium (0.2 mL/kg) will be determined by the
radiologist performing the study. Slice thickness will be determined by patient size, and region covered,
but should be less than 7 mm. The smallest appropriate coil should be used. Measurements should be
made using the same axial sequence best showing the tumor in follow-up for comparisons.
MRI is superior to CT in characterizing epidural tumor extension or leptomeningeal disease, and is the
preferred imaging modality in such cases (neck, chest, nonadrenal retroperitoneum) with spinal cord or
canal encroachment.76 It may also be useful in evaluating an MIBG-avid focus detected in the skeleton or
soft tissues.
The lack of ionizing radiation also makes MRI attractive for younger children, but this must be balanced
with the need for sedation in these patients. With the exceptions noted above, the choice of MRI or CT
will be left to the referring pediatric radiologist.
16.3 [18F]–Fluorodeoxyglucose (18FDG)-PET Scintigraphy

18
FDG-PET scan is optional depending on whether or not the patient has signed an informed consent for
them. This scan is strongly recommended as it is done for diagnostic and response evaluation purposes. It
can be done at the following time-points: within 4 weeks prior to study entry (this scan will take place
subsequent to any other therapy the patient has received pre-treatment) and prior to surgical resection
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(after Cycle 4 of Induction chemotherapy). It is recommended that the PET scan be performed following
count recovery if possible in order to minimize the likelihood that augmented marrow signal is related to
colony stimulating factor effect/marrow recovery. Standardized uptake values (SUV) will be collected
from the primary lesion at each time point. The SUV from (at most) 9 other FDG-avid lesions (in
addition to the primary lesion) will be collected at each of the two time-points mentioned above. For the
purposes of the study, a PET-avid lesion will be defined as a lesion with an SUV >= 2.5. However,
Lesion #1 (the primary tumor) is required to be reported at each evaluation time point regardless
of SUV score. These values will be recorded in the RDE system as a possible predictor of response. See
Appendix X for details.
FDG-PET may be performed prior to initiation of chemotherapy. Exceptional circumstances may require
emergent therapy and therapy should not be delayed in these cases. The patient should be fasted for at
least 4 hours prior to injection of FDG. Plasma glucose should be checked and, if the patient is
substantially hyperglycemic, the study should be rescheduled when adequate glucose control has been
established
FDG is administered intravenously at a dose of 0.125-0.200 mCi/kg, with a minimum total dose of
2.0 mCi and maximum total dose of 12.0 mCi. Good hydration is required as the primary route of FDG
excretion is renal. The patient should drink water or receive intravenous fluids after injection to promote
urinary FDG excretion. After injection, the patient is kept at rest for 45-60 minutes and imaging is then
performed. The patient should void his/her bladder immediately prior to imaging.
The body should be imaged at minimum from the top of the ears to the proximal thigh, just below the
pubis. Scans should proceed upward from the pelvis to diminish the effects of accumulation of activity in
the bladder. If there is suspicion of involvement in the lower extremities, skull or skull contents, the
volume that is imaged may be expanded. The 511 keV-annihilation photons, produced by interaction of
positrons with electrons, are imaged.
Because of the short physical half-life of 1.8 hours and the high photon energy of 511 keV, FDG
imaging may follow MIBG (either I-123 or I-131) or a MUGA study on the same day, or FDG
imaging may be performed on the day preceding any of these studies.
Imaging with a dedicated PET/CT camera is greatly preferred, but imaging with a standalone PET
scanner is acceptable. The scan time per table position for the PET emission scan is typically 5 minutes.
The scan time per table position for the transmission scan, done with rotating rod sources, is typically 2-4
minutes.
The FDG-PET study is processed for display by an iterative reconstruction algorithm. FDG activity
should be corrected for attenuation, scatter, and radioactive decay. Attenuation correction is necessary, as
apparent uptake will otherwise vary with depth of the lesion in the body and the nature of surrounding
tissues. The procedure used for attenuation correction should be recorded. The level of tumor uptake is
assessed subjectively by visual inspection and semi-quantitatively by determination of SUV. Uptake time,
glucose levels, and partial volume effects influence both methods. The SUV method is also dependent on
body weight and correction of SUV by normalizing for body surface area (BSA) reduces this dependency
on body weight. Small lesions may have underestimated SUV’s due to partial volume averaging effects.
To calculate the SUV, a region of interest (ROI) should be carefully drawn around the area of elevated
FDG uptake in the lesion to minimize partial volume effects. The SUV should be calculated as
SUVBSA=ROI activity concentration (nCi/cc) X BSA / injected activity (nCi). The BSA is calculated from
body mass (kg) and height (cm) using an appropriate algorithm. The SUVBSA for each measured lesion
should be recorded and the technique for assessing SUVBSA should be consistent on follow-up studies.
SUV measurements are directly available on almost all PET/CT display programs using simple ROIs
PET may be performed in combination with CT on dual modality PET/CT scanners. Typically a low-
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dose, non-contrast-enhanced CT is performed for attenuation correction from the neck through the pelvis
with the patient breathing shallow, followed by emission imaging at 5 minutes per bed position. A
contrast-enhanced CT may also be used for attenuation correction. 2D acquisitions are recommended for
certain earlier PET/CT devices, but it is likely that most acquisitions in the future will be 3D. Data are
reconstructed as described above.
PLEASE MAKE EVERY EFFORT TO AQUIRE FDG IMAGES ON A SINGLE SCANNER FOR A GIVEN
PATIENT TO ALLOW FOR MORE ACCURATE COMPARISON OF SUVs.
16.4 MIBG Scintigraphy

All patients will undergo a diagnostic quality 123I–MIBG scan within 4 weeks prior to study entry or no
later than the end of Cycle 1. Preferably, this scan will take place before therapy is initiated, but if a
MIBG diagnostic scan is not readily available, the scan must be obtained no later than the end of Cycle 1.
This scan is for diagnostic and response evaluation purposes. Patients whose tumor is MIBG non-avid
will come off protocol therapy immediately. For patients with an MIBG avid tumor, MIBG scan is also
required: prior to surgical resection, prior to the start of Bu/Mel Consolidation, between Day +28 and
Day +42 of Consolidation for patients with > 5 MIBG positive metastatic sites at start of Bu/Mel
Consolidation (required to determine subsequent RT guidelines for metastatic sites), post Consolidation
treatment, prior to Cycle #4 of Maintenance, at end of therapy, and at relapse. During follow-up, MIBG
scan is required at the following timepoints after completion of the last cycle of isotretinoin treatment:
3 and 6 months; 1, 1.5, 2, 2.5, and 3 years. In addition, an 131I-MIBG scan will be obtained at release of
radiation isolation, which is not addressed in this section. MIBG scans will be assigned a Curie (MIBG)
score by central reviewers as described in Section 16.7.
123
I-MIBG studies have significantly less risk to the thyroid gland compared to 131I-MIBG.77 A typical
dose of 123I-MIBG is 5.7 MBq/kg (maximum 400MBq). Planar and, as appropriate, SPECT imaging will
be performed.
The MIBG scan guidelines are given below.78
Patient Preparation
Potassium Iodide administration to reduce thyroidal accumulation of free radioiodine.
Usually potassium iodide drops (13% KI; 100 mg iodide/ml) are administered daily beginning 30
minutes prior to radionuclide injection, and continuing on a BID schedule for 3 days following 123I-
MIBG and for 7 days following administration of 131I-MIBG. Dose is by weight; 1.2 mg iodine/kg (4
mg/drop).
Ask about any exposure to potential interfering agents (see Appendix VI)
Normal Scintigraphic Findings
Normal in vivo distribution of 131I-MIBG includes the salivary glands, nasopharynx, heart, liver, spleen
and bladder. Depending on the level of thyroid blockade, faint uptake of free radioiodine may be seen in
the thyroid.
The same structures are seen with 123I-MIBG in addition to bowel activity, the lungs, normal adrenal
medullae and supraclavicular muscle uptake. Other areas of uptake are considered abnormal until proven
otherwise.
MIBG Scintigraphy Procedures

131
I-MIBG
Dose: 0.5 –1.0 mCi / 1.7 m2 body surface area (approximately 7µCi / kg to 15 µCi / kg).
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Scintigraphy: Performed 1-2 and occasionally 3-4 days after administration of 131I-MIBG. Conjugate
views of head, neck, chest, abdomen and pelvis are acquired for 100,000 counts or 20 minutes, whichever
comes first. Anterior views of the extremities are adequate. Alternatively a low-speed, whole-body scan
could be used. A large field of view, dual-head gamma camera with high energy collimators is preferred.
Physiologic MIBG uptake loses activity so that normal anatomy is less recognizable at later imaging times,
however, tumors often become more evident over time due to the reduction in surrounding background.
Digital data should be stored in addition to analog images to allow for computer enhancement and adjustment
of background.
Simultaneous dual-isotope acquisition or subtraction studies after MIBG imaging after administration of
other agents (i.e., 99mTc-MDP) is possible.
123
I-MIBG
Dose: 10 mCi / 1.7m2 body surface area (approximately 150 µCi / kg; maximum 10 mCi).
Scintigraphy: Performed to obtain both planar and tomographic images. For planar imaging, anterior and
posterior spot views from the top of the head to the proximal lower extremities are obtained for
10 minutes at approximately 24 hours after injection and may be done 48 hours after injection. Anterior
views of the distal lower extremities are sufficient. A large field of view dual-head gamma camera with
low-energy or medium-energy collimators is preferred.
SPECT imaging with 123I-MIBG is performed 24 hours after injection using a single or multiheaded
camera with low-energy collimator. The camera is rotated through 360°, 120 projections at 25 seconds
per stop. Data are reconstructed cutoff frequency of 0.2-0.5.
Tumor Dosimetry
For all patients, a scintigraphic MIBG imaging study, comparable to that from a diagnostic 131I-
MIBG, will be made on the patient at the time of release from radiation isolation. Patients will not
receive any MIBG injection for this scan.
16.5 Plain Film Radiography

This will be performed as needed using ALARA technique. If gonadal shielding does not interfere with
diagnostic accuracy, it should be utilized. Breast shielding should also be utilized in scoliosis screening
unless clinically there is a reason why it should be omitted.
16.6 Tumor Measurement
Tumors will be measured according to the COG Radiology Group guidelines. Diameter of a “measurable
mass” must be at least twice the reconstructed slice thickness. Target lesions at baseline must be greater
than 1 cm. When multiple or metastatic masses are present, all masses will be described, and up to
5 target masses will be measured using the same method in subsequent follow-ups.
Measurement of each mass (see Appendix VII) will consist of the maximal perpendicular diameters (x
and y dimensions) on the slice showing the largest surface area. The length (z axis) will then be
determined by either (a) the difference in table position of the first and last slices showing the tumor plus
1 slice thickness or (b) the product of [slice thickness + gap] times the number of slices showing the
tumor minus 1 gap distance. According to the elliptical model, the lesion volume is then calculated as 0.5
x [length x width x height].
16.7 Central Review of MIBG and FDG-PET scans

Central review of MIBG and PET scans for the exploratory objectives in this study will be performed by
the Imaging Specialists on the Study Committee.
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Submit the MIBG scans with corresponding reports at the following time points:
• Within 4 weeks prior to study entry and no later than the end of Induction Cycle 1
• Prior to surgical resection
• Post MIBG therapy
Submit FDG-PET scans, if done, with corresponding reports at the following time points:
• Pre-treatment
• Prior to surgical resection
Submission of Diagnostic Imaging data in digital format is required. Digital files must be in DICOM
format. These files can be submitted via sFTP. Information to obtain an sFTP account and submission
instructions can be found at www.QARC.org. Follow the link labeled digital data. Alternatively, if sFTP
is not feasible, the imaging may be burned to a CD and mailed to IROC Rhode Island (formerly QARC).
Multiple studies for the same patient may be submitted on one CD; however, please submit only one
patient per CD. Sites using Dicommunicator@QARC.org may submit imaging via that application.
Contact IROC Rhode Island with questions or for additional information.
Please submit the MIBG studies (and FDG-PET studies, if done) with their corresponding reports to:
Imaging and Radiation Oncology Core, Rhode Island
Building B, Suite 201,
640 George Washington Highway
Lincoln, RI 02865-4207
Phone: 401-753-7600
Fax: 401-753-7601
17.0 RADIATION THERAPY GUIDELINES
Timing of protocol therapy administration, response assessment studies, and surgical interventions
are based on schedules derived from the experimental design or on established standards of care.
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or
facility, procedure and/or anesthesia scheduling issues are acceptable per COG administrative
Policy 5.14 (except where explicitly prohibited within the protocol).
Radiation therapy (RT) for patients on COG protocols can only be delivered at approved RT
facilities (per COG administrative policy 3.9).
17.0.1 General Guidelines
The radiation therapy guidelines for this study were developed specifically for patients with high-risk
neuroblastoma. The objective of radiation therapy is to improve disease free and overall survival while
preserving uninvolved organ function. Three-dimensional conformal radiation therapy (3D-CRT),
intensity-modulated radiation therapy (IMRT), or proton therapy are required for patients treated on this
protocol to minimize the risk of late-term normal tissue complications.
Radiation therapy will be delivered following 5 cycles of induction chemotherapy, an 131I-MIBG

Induction therapy block, and intensified consolidative therapy consisting of busulfan/melphalan (Bu/Mel
Consolidation) and autologous stem cell rescue. Radiation will be given to the primary tumor site,
involved nodal disease and metastatic sites noted on pre-Bu/Mel Consolidation imaging, unless these sites
involve entire large bony structures such as skull or pelvis. The primary site will be irradiated to a total
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dose of 2160 cGy even if a macroscopically complete resection was achieved. An additional boost of
1440 cGy will be delivered to gross residual disease as defined in GTV2 Section 17.5.1. Extent of
surgical resection will be determined by the treating physicians in conjunction with the responsible
surgeon and diagnostic imaging colleagues. Post-surgical imaging is not required until after the MIBG
Induction block of therapy.
17.0.2 Required Benchmark and Questionnaires

3D-CRT, IMRT and proton therapy will be the allowed methods for this study. Patients may not receive
intraoperative radiation therapy on this protocol. Centers participating in this protocol using 3D-CRT are
required to complete the 3D benchmark; those using IMRT must complete the IMRT questionnaire and
benchmark or irradiate the Radiological Physics Center (RPC) head and neck phantom; those using
protons must complete the proton benchmark and questionnaire and receive approval for the use of proton
therapy in clinical trials from RPC. Benchmark materials and questionnaires may be obtained from the
Imaging and Radiation Oncology Core, Rhode Island (IROC Rhode Island (formerly QARC),
www.qarc.org) and must be submitted before patients on this protocol can be evaluated. Contact the RPC
(http://rpc.mdanderson.org/rpc) for information regarding their IMRT phantoms.
17.0.3 Guidelines and Requirements for the Use of IMRT

Investigators using IMRT will be required to comply with the guidelines developed for the use of IMRT
in National Cancer Institute sponsored (NCI) cooperative group trials. These guidelines shall be available
through www.qarc.org. These guidelines require that the protocol explicitly state their requirements and
methods for localization and immobilization; the use of volumetric imaging; target and organ motion
management; nomenclature, definitions and rationale for targets and organs at risk; target volume
coverage and normal tissue dose constraints; effects of heterogeneity in tissues; and quality assurance.
17.0.4 Guidelines and Requirements for the Use of Proton Therapy

Proton therapy may be used on this protocol. Investigators using proton therapy must comply with the
NCI proton therapy guidelines available through www.qarc.org. Both passively scattered and uniform
scanned beams may be used. The RPC must review and credential the specific beam line delivery
parameters. Dose will be reported in Gy (RBE), Gray Radiobiological Equivalent (where 1 Gy (RBE) =
proton dose Gy x RBE [radiobiological effective dose], RBE = 1.1). Radiation doses shall be prescribed
using protocol specified definitions for gross (GTV) and clinical (CTV) target volumes. For set-up
uncertainties and target motion, additional margin, compensator smearing, width of modulation will be
added on a per beam basis. The proton institution is required to participate in on-site and remote review
according to COG guidelines.
17.1 Indications for Radiation Therapy

17.1.1 Treatment Sites and Doses
All patients will be irradiated and volumetric targeting for radiation therapy planning should be priority.
Table 17.1.1
Site Dose
Primary tumor site and initially involved lymph nodes 2160 cGy
according to imaging criteria or documented by surgery
Primary tumor site gross residual disease 3600 cGy (cumulative dose including boost)
Metastatic disease present after Induction chemotherapy 2160 cGy
and prior to Bu/Mel Consolidation
Life or organ-threatening disease Document and report to Study Coordinator
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Table 17.1.2
Treatment Site(s) Methods to anatomically confine CTV
Intra-Abdominal: adrenal and paraspinal ganglia Adjust CTV to avoid kidneys, liver, vertebral bodies.
primary sites, involved nodal and metastatic When vertebral bodies need to be treated the entire
disease width of the vertebral body should be included in the
CTV
Cervico-Thoracic: Adjust CTV to avoid uninvolved heart, lung and
vertebral bodies
Pelvic: Adjust CTV to avoid bowel, bladder, and uninvolved
bone
Head and Neck: Adjust CTV to avoid uninvolved critical structures
and bone
17.2 Timing of Radiation Therapy

Radiation will be given after recovery from Bu/Mel transplant. Treatment volumes will be based on post-
Induction imaging (MIBG, CT and/or MRI) and operative reports. Organ toxicity within the radiation
field should have resolved. Radiation therapy must not start sooner than Day +42 following ASCR of
the Bu/Mel transplant.
17.2.1 Criteria to Start Radiation Therapy

The criteria in the table should match criteria to start Consolidation therapy in Section 4.4.
Table 17.2.1
Organ System Criteria to Start Radiation Therapy
Hematologic Absolute neutrophil count > 500/µL (off G-CSF for ≥ 48 hours)
Platelets ≥ 50,000/µL (transfusion allowed)
Hemoglobin > 10 g/dL (transfusion allowed)
Mucous Membranes < Grade 2
Liver Irradiation (Any) ALT and AST < 5 x ULN for age
Total bilirubin < 1.5 x normal for age
No evidence of SOS (sinusoidal obstruction syndrome, formerly
known as VOD)
Tracheal Irradiation (Any) Patient stable on room air
< Grade 2 airway edema.
Abdominal Irradiation (Any) No uncontrolled infection
Diarrhea, if present, must be < CTCAE Grade 2
Kidney Irradiation* Serum creatinine < 1.5 X ULN (see Table in Section 3.2.4.1)
Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2
No hematuria
Bladder Irradiation No hematuria
*Renal scintigraphy is required only for patients with two functioning kidneys when > 20% of one kidney will be irradiated. This requirement is
to assure that the non-irradiated kidney has normal function according to institutional criteria.
17.3 Emergency Radiation

Patients are allowed to have received emergent radiation at diagnosis to sites of life-threatening or function-
threatening disease. This must be reported to the study coordinator at the time of registration on study and
will not be considered as part of the planned treatment course to be delivered at a later time provided normal
tissue dose constraints are met. Prior radiation therapy dose constraints are included as part of protocol
eligibility criteria.
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17.4 Equipment and Methods of Delivery and Verification

17.4.1 Modality
Equipment Photons (any energy) IMRT (4-10MV) Protons

Linear Accelerator X X
Proton Beam X
IMRT or proton therapy is not permitted on this study for patients with thoracic tumors when any of the
treatment beams traverse normal lung parenchyma. To avoid treatment delays resulting from unplanned
equipment unavailability, photon therapy may be administered instead of proton therapy.
17.4.2 Treatment planning

CT (volumetric) based planning is required to optimize dose to the PTV while protecting normal tissues.
Organs at risk within the irradiated volume should be contoured including those required. A DVH is
necessary to determine target coverage and evaluate dose to normal tissues. CT section thickness should
be ≤ 3mm.
17.4.3 In-room verification of spatial positioning

17.4.3.1
Portal imaging is the most common system used to verify patient position, in particular when the target
volume is believed to possess a fixed spatial relationship with visualized bony anatomy. If volumetric
imaging is not available, orthogonal paired (AP and lateral) portal images (MV or kV) are required to
verify that the isocenter is in correct alignment relative to the patient position. Beamline imaging of the
treatment port should be performed when feasible.
17.4.3.2
Volumetric imaging is allowed in this study. This includes in-room kV or MV cone beam or conventional
CT imaging. Please be able to submit representative axial images showing the isocenter and the correct
alignment in relationship to the patients’ position. For CT tomography where isocenters are not used, a
printout of the isodoses overlaid on the fused CT images can be printed to demonstrate in room
verification.
17.4.4 Evaluation and Management of Target and Normal Tissue Motion
17.4.4.1 Considering motion of target and normal tissue volumes is important. The internal target volume
(ITV) is defined as the CTV surrounded by the internal margin (IM) component of the PTV and is meant
to account for potential motion of the CTV. The planning organ at risk volume (PRV) includes the OR
surrounded by a margin to compensate for physiologic change in the organ. Limited clinical data exist to
define the IM component of the PTV or the PRV margin. Evaluation of target and normal tissue motion is
required for patients treated with proton therapy and suggested for patients treated with IMRT.
The following guidelines suggest a framework for achieving improved immobilization and targeting:
• If general anesthesia is used for simulation, this should be continued through therapy.
• For most cases, CT simulation supine, in neutral position, with arms over head and with
adequate upper torso wing-board and/or vac-lock support out of the plane of treatment
ports to prevent brachial plexopathy should be used.
• For adrenal cases, elevating the lower extremities with behind the knee blocks can flatten
the lower spine against the treatment table to enhance immobilization and attempt to
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make most of the superior/inferior respiratory motion conform to a plane close to parallel
with the treatment table. (This would not be considered useful for pelvic extension or
mediastinal extension.)
• Two axial planes should be marked to enhance setup uncertainty, even if CBCT is used to
verify positioning. Markers approximating the anterior superior iliac spine and xiphoid
process are suggested.
17.4.4.2
A description of the method used and evidence of the remaining tumor motion (eg, observed motion
during fluoroscopy, motion of surrogate markers using camera systems, or analysis of 4D CT or 4D MRI)
should be submitted on the Motion Management Reporting Form with the Quality Assurance
documentation materials.
17.4.5 Calibration
All therapy units used for this protocol shall have their calibrations verified by the RPC.
17.5 Target Volume Definitions

International Commission on Radiation Units and Measurements (ICRU) Reports 50, 62 and 78
(www.icru.org) define prescription methods and nomenclature that will be utilized for this study. Using
the ICRU terminology, the gross tumor volume (GTV) is anatomically defined, the clinical target volume
(CTV) is anatomically confined and the planning target volume (PTV) is comprised of two margins
meant to account for physiologic changes in the CTV (IM=internal margin) and set-up uncertainty
(SM=set-up margin). ICRU-62 conventions should also be considered by the treating radiation oncologist
where organs at risk and target volume motion may compromise either preservation of normal tissue
tolerances or target volume coverage, respectively.
17.5.1 Primary Site
Gross Tumor Volume 1 (GTV1)
• The GTV1 is the volume of tissue containing the highest concentration of residual tumor cells.
• The GTV1 includes disease defined by CT, MR and MIBG imaging PRIOR to surgery.
• The GTV1 includes disease (tumor and lymph nodes) identified intra-operatively.
• The GTV1 is corrected volumetrically after surgical resection but not at the point of attachment.
• The GTV1 does NOT include the extent of disease PRIOR to chemotherapy.
• The GTV1 does NOT include uninvolved draining lymph node regions.
Special Circumstances (GTV1)
• If the primary tumor was grossly resected at diagnosis, GTV1 will be based on the initial
diagnostic tumor volume.
• In cases where there is discrepancy between imaging studies or intraoperative findings, the larger
volume will define GTV1.
• When the primary tumor expands into a body cavity such as the lung or displaces a normal
structure such as the liver without infiltration, if following surgical resection the normal structure
now occupies the space previously occupied by tumor, normal tissue volume should not be
included within GTV1.
Gross Tumor Volume 2 (GTV2)
• The GTV2 is defined as the volume of residual tumor measuring >1cm3 AFTER Induction
chemotherapy, surgery and 131I-MIBG therapy.
• The GTV2 includes disease defined by CT, MR or MIBG imaging.
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Special Circumstances (GTV2)

• GTV2 will NOT be altered even when there is a complete response after Bu/Mel consolidative
chemotherapy.
Clinical Target Volume 1 (CTV1)

• The CTV is defined as the volume of tissue containing subclinical microscopic disease:
• The CTV1 margin should be an expansion of the GTV1 to encompass microscopic disease.
• The CTV1 for this protocol is the GTV1 with an anatomically confined margin of 1.5 cm.
• The CTV1 should be tailored at tissue interfaces where invasion/infiltration is not likely.
Clinical Target Volume 2 (CTV2)

• The CTV is defined as the volume of tissue containing subclinical microscopic disease
surrounding the post-surgical residual tumor (GTV2).
• The CTV2 margin should be an expansion of the GTV2 to encompass microscopic disease.
• The CTV2 for this protocol is the GTV2 with an anatomically confined margin of 1.0 cm.
• The CTV2 should be tailored at tissue interfaces where invasion/infiltration is not likely.
Planning Target Volume (PTV1)

• The PTV1 is a geometric concept and includes a margin surrounding the CTV1.
• The PTV1 should account for physiologic change or motion in the CTV1 and set-up uncertainty.
• The PTV1 is defined as the CTV1 with a geometric margin of 0.5-1.0 cm.
• The PTV1 may vary depending on immobilization and patient cooperation, 0.5 cm is the
minimum extent of the margin surrounding CTV1 to form PTV1.
• The PTV1 margin does not have to be uniform in all dimensions; especially if it compromises
normal tissue volumes or if directional target or normal tissue motion is assessed and understood.
Planning Target Volume (PTV2)

• The PTV2 is a geometric concept and includes a margin surrounding the CTV2.
• The PTV2 should account for physiologic change or motion in the CTV2 and set-up uncertainty.
• The PTV2 is defined as the CTV2 with a geometric margin of 0.5-1.0 cm.
• The PTV2 may vary depending on immobilization and patient cooperation, 0.5 cm is the
minimum extent of the margin surrounding CTV2 to form PTV2.
• The PTV2 margin does not have to be uniform in all dimensions; especially if it compromises
normal tissue volumes or if directional target or normal tissue motion is assessed and understood.
Target Volume Definitions for Proton Therapy:

• GTV is the same for protons and photons.
• CTV is the same for protons and photons.
• PTV will be uniquely defined for proton therapy.
When passive scattering or uniform scanning methods are used, the boost planning target volume (PTV)
for proton therapy will include a margin which is added to the CTV in 3-dimensions. The margin should
be consistent with the motion control and setup accuracy for the particular type of treatment at the treating
proton center. The PTV will be used for dose reporting and not specifically for treatment planning.
The goal of treatment planning will be CTV coverage at 100% directly with specific measures taken for
each specific uncertainty. Specific adjustments will be made to (1) aperture margin definitions, (2)
smearing of compensator, (3) range of the individual beams (depth of penetration), and (4) modulation
width of the SOBP. The following parameters must be explicitly reported for each beam: range,
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modulation, smearing radius of the compensator, set-up margin (SM) and PTV margin. The specifics of
dose reporting for the proton PTV and recommendations regarding the PTV margin are discussed below.
For dose reporting purposes, a PTV volume with a lateral margin of 0.5 cm to 1 cm may be used. The
distal expansion for the PTV should be based on the distal range uncertainty for each beam. A standard
expansion will not be used to determine the distal range for the individual proton beams given the unique
nature of the range uncertainty in a patient. In principle, the beam range could be determined by adding a
distal margin to the CTV and this margin will be determined per beam based on the distal aspect of the
CTV and additional margin(s) meant to account for range uncertainties due to the uncertainties in CT
based range calculations as well as those caused indirectly by the SM and IM components of the PTV
which are understood for this group of patients and which may affect the proton distal range.
Symbolically, this can be expressed as,

Proton Distal Target Margin = CTV + Range Calculation Uncertainty + Set-up Margin + Internal Margin
Where,
• CTV = the distal aspect of the CTV
• Range Calculation Uncertainty = generally 3.5% of the water-equivalent range of the CTV at max
depth
o > 1mm
• Set-up Margin = set-up, mechanical and dosimetric uncertainties
o Protons are relatively unaffected by set-up uncertainty in axis of beam
o Uncertainty in hardware and software – no assigned value available
• Internal margin = compensates for all variations in site, size and shape of the tissues contained in
or adjacent to the CTV
o > 1mm
The proton distal range may be adjusted at the discretion of the treating radiation oncologist based on
normal tissue dose concerns. No existing treatment planning system is capable of producing such a beam
specific CTV expansion incorporating the various effects listed above. The common practice is simply
adding the range calculation uncertainty component explicitly. For the other components, the technique of
compensator smearing is used with the smearing radius consistent with SM and IM.
Accounting for Motion of Target and Normal Tissue Volumes

• A margin of 0.5 cm should be added to any organ at risk to form the PRV.
• For a CTV susceptible to physiologic motion, a margin of 0.5 cm should be added to the CTV
prior to PTV margin expansion or a PTV margin of 1.0 cm should be chosen.
17.5.2 Metastatic Sites

17.5.2.1 Criteria for Treatment of Metastases
While the primary site is always irradiated, radiation is only given to those metastatic sites with persistent
active disease demonstrated at the time of evaluation prior to Bu/Mel Consolidation (NOT the immediate
post-MIBG therapy 131I-MIBG scan). Sites that are negative on imaging prior to Bu/Mel Consolidation
will NOT be irradiated, even if they had enhanced uptake on MIBG at diagnosis. If greater than 50% of
the bone marrow would be irradiated using these criteria, treatment fields should be discussed or reviewed
with the study coordinator prior to simulating the patient for radiation therapy.
17.5.2.2 Patients with > 5 MIBG positive metastatic sites prior to Bu/Mel Consolidation
If the patient had > 5 persistently positive MIBG metastatic sites identified prior to Bu/Mel
Consolidation, the scan should be repeated between Day +28 and Day +42 after stem cell rescue. Only
sites remaining MIBG positive will then be irradiated. If there are still > 5 MIBG positive sites, notify the
study coordinator or chair.
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In patients with > 5 MIBG positive lesions prior to transplant, consideration should be given to reserving
a portion of the collected peripheral blood stem cell product to use as boost after radiation if leukocyte
counts fall and fail to recover approximately 2 weeks after radiation is completed. THE STUDY CHAIR
OR VICE CHAIR MUST BE NOTIFIED BEFORE REINFUSING PERIPHERAL BLOOD STEM
CELLS IN THIS MANNER AND PRIOR TO KEEPING AN ALIQUOT OF PURGED PERIPHERAL
BLOOD STEM CELLS ON HOLD.
The planning target volume for metastatic sites is the area of residual tumor defined on MIBG, CT, or MR
scan with a 2 cm margin. In cases where there is a discrepancy in volume between the scans, the larger
volume will be irradiated. For osseous metastases, the margin need not extend more than 2 cm outside the
bone or across a joint space.
17.5.3 Peritoneal Cavity

When the entire peritoneal cavity must be irradiated, the CTV includes the entire peritoneal cavity and
extends from the diaphragm to the bottom of the obturator foramina. Dose tolerances should be respected
by shielding the liver and kidneys at 1800 cGy and 1440 cGy, respectively. It is expected that these
organs will receive additional dose once shielded from the primary beams.
17.5.4 Liver
The liver dose should be minimized to reduce the risk of sinusoidal obstruction syndrome (formerly
known as veno-occlusive disease).
17.5.5 Thorax
When a major portion of both lungs must be treated because of a large intrathoracic tumor volume,
suitably shaped portals shall be used to minimize the irradiated lung volume.
17.5.6 Contralateral Kidney

The kidney dose should be minimized to reduce the risk of chronic renal failure.
17.6 Target Dose
17.6.1 Dose Definition and Specification

Photon dose is to be specified in centigray (cGy)-to-muscle. For proton beam, the absorbed dose is specified
in Gy (RBE), which is the same as ICRU 78 DRBE using a standard RBE of 1.10 with respect to water. All
proton doses shall be expressed as Relative Biological Effectiveness (RBE)-weighted absorbed dose, DRBE
(this quantity is equivalent to Cobalt-Gray-Equivalent (CGE)) employing a standard RBE of 1.1 with
respect to 60Co. The unit of RBE-weighted dose is gray (Gy(RBE)).
17.6.2 Prescription Dose and Fractionation

The daily dose should be 180 cGy for the primary and metastatic sites. Sites of metastatic disease should
be irradiated concurrently with the primary site.
Table 17.6.2
Nominal Dose by Site Dose/fraction Number of Fractions
Primary Site (PTV1) 2160 cGy 180 cGy 12
Residual Primary Tumor after
180 cGy 8
Induction/Surgery (PTV2) 3600 cGy
Metastatic Site(s) 2160 cGy 180 cGy 12
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17.6.3 Tissue Heterogeneity

All dose calculations shall take into account the effects of tissue heterogeneities.
17.6.4 Dose Uniformity
17.6.4.1 For photons, at least 95% of the protocol-specified dose should encompass 100% of the PTV, no
more than 10% of the PTV should receive greater than 110% of the prescription dose as evaluated by
DVH. Wedges, compensators, and other methods of generating more uniform dose distributions are
encouraged.
17.6.4.2
For proton therapy, treatment planning does not specifically use a PTV. All uncertainties are taken into
account explicitly to create a robust plan that provides full dose coverage of the CTV. For passive
scattering and uniform scanning, the aperture margin must include the appropriate beam penumbra for the
selected beam energy, and setup and internal margins (SM and IM). These margins depend on the patient
setup techniques used at the treating proton center. The aperture margin may be expanded further if a
cold spot occurs near the edge of CTV due to insufficient lateral scatter. The smearing radius for the
range compensator must be equal to the setup and internal margins (SM and IM). The beam range should
be equal to the maximum water equivalent depth of the CTV plus a range margin. The main part of the
range margin comes from uncertainty in CT accuracy and the conversion of the Hounsfield units to proton
stopping power ratios. Most proton centers are expected to use 3.5% of the maximum water-equivalent
depth of the CTV and then add another millimeter to account for uncertainties in beam range calibration
and compensator fabrication. Additional range margin should be applied if internal motion could increase
the water equivalent depth of the CTV. The modulation width should be increased consistently to ensure
proximal coverage of the target volume. The beam range may be adjusted at the discretion of the treating
radiation oncologist based on normal tissue dose concerns. As noted above, a PTV should be created by a
uniform expansion from CTV for reporting purposes. The expansion margin should be consistent with
SM and IM and is typically 0.5-1.0 cm for a static target volume when daily imaging is performed. With
the planning guidelines provided herein, no more than 10% of PTV should receive greater than 110% of
the protocol dose as evaluated by DVH. In most cases, at least 95% of the protocol-specified dose should
encompass 100% of the PTV. A potential exception is when the range margin is smaller than the PTV
expansion. As a result, the beam may not penetrate deep enough to sufficiently cover the distal portion of
the PTV. This may occur for shallow target volumes where the maximum depth of the CTV is small and
the range margin is small. Such incomplete coverage of the PTV will not constitute a planning deviation
because the plan should be sufficiently robust to cover the CTV with the protocol specified dose
accounting for all uncertainties.
17.6.5 Interruptions and Delays

There will be no planned rests or breaks from treatment, and once radiation therapy has been initiated,
treatment will not be interrupted except for severe hematologic toxicity defined as ANC < 300/µL or
platelets less than 40,000/µL during the course of treatment. Under these circumstances, radiation therapy
shall be delayed until the counts have recovered. Blood product support should be instituted according to
institutional/protocol guidelines. The reason for any interruptions greater than 3 treatment days should be
recorded in the patient’s treatment chart and submitted with the QA documentation. There should be no
modifications in dose fractionation due to age or field size.
17.7 Treatment Technique
17.7.1 Beam Configuration

Every attempt should be made to minimize the dose to critical normal tissue volumes without
compromising coverage of the target volume. If significant volumes of vertebral bodies are contained
09/24/14 129
within the treated volume, the dose should be distributed homogeneously to the vertebral bodies to avoid
growth asymmetry.
17.7.2 Selection of Proton Beam Arrangements

The use of posterior or posterior oblique fields is strongly recommended as the majority of these tumors
are posterior in location (adrenal or paraspinal) and it is advisable to avoid uncertainties introduced by
tissue heterogeneity and organ motion. Any treatment plan including anterior, anterior oblique or lateral
fields should be discussed with the radiation oncology protocol coordinators prior to treatment delivery.
The use of a 4D CT is recommended for proton planning to evaluate for target volume and organ motion.
Gating may be used during treatment.
17.7.3 Patient Position

Reproducible setups are critical and the use of immobilization devices is strongly encouraged. Use of
anesthesia is encouraged if necessary for proper positioning.
17.7.4 Field Shaping

Field shaping for photons will be done with either customized cerrobend blocking or multileaf
collimation. Field shaping for protons will be done with either customized brass apertures, proton-specific
multileaf collimation, or through scanning.
17.7.5 Special Consideration for Patient Simulation for Protons

Patient set-up and immobilization will be determined prior to obtaining the planning CT scan. CT
planning is required for proton therapy because the relative stopping power based on Hounsfield units
must be defined. The type of immobilization will be determined by the anatomic location of the site to be
treated. Most patients will be immobilized in the supine position for reproducibility and ease of anesthesia
administration. The majority of neuroblastomas are located posterior (adrenal or para-spinal). Posterior-
anterior or posterior oblique fields typically allow for improved normal tissue sparing and minimize
uncertainties due to organ motion and tissue heterogeneity introduced by organ motion or filling (i.e.
lung, bowel). Posterior field arrangements are strongly recommended and this should be taken into
consideration at the time of simulation. 4-D CT is recommended to evaluate target volume and organ
motion.
17.8 Organs at Risk

Planning should be done to minimize dose to normal tissue volumes including those described in the table
below. No attempt should be made to spare these structures when they intersect or are adjacent to the
target volumes. To avoid exceeding the suggested dose constraints, the dose coverage may be adjusted
provided the guidelines of the protocol are observed.
Following the recommendations of ICRU 62, a margin matching the PTV margin shall be added around
each of these structures to compensate for geometric uncertainties. The volume, which includes this
margin, is called the Planning Organ at Risk Volume (PRV). The dose to each PRV should not exceed
those outlined in this section. Any change in clinical condition or anatomy should be monitored carefully
and with repeat imaging when indicated.
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17.8.1 Normal Tissue Tolerances and Special Site Volume Considerations
Table 17.8.1
Organ Dose Limit (Gy)
Contralateral Kidney-whole (100% of the kidney receives < 1440 cGy) 1440 cGy
Ipsilateral Kidney-whole (100% of the kidney receives < 1800 cGy) 1800 cGy
Liver-whole (100% of the liver receives < 1800 cGy) 1800 cGy
Liver-partial (50%) (50% of the liver receives <2340 cGy) 2340 cGy
Lung-whole 1200 cGy
Lung (when PTV occupies > ½ bilateral lung volume) 1500 cGy
Lung (when PTV occupies < ½ bilateral lung volume) 1800 cGy
17.9 Dose Calculations and Reporting

Centers participating in this protocol must complete the appropriate benchmarks outlined in Section 17.0.
17.9.1 Prescribed Dose

The dose prescription and fractionation shall be reported on the RT1/IMRT/Proton Dosimetry Summary
Forms. If IMRT is used, the monitor units generated by the IMRT planning system must be independently
checked prior to the first treatment. Measurements in a QA phantom can suffice for a check as long as the
patient plan can be directly applied to a phantom geometry.
17.9.2 Prescription Point

The total dose shall be calculated and reported on the RT-2 Radiotherapy Total Dose Record. If 3DCRT,
IMRT or proton therapy is used dose should be prescribed to an isodose surface that encompasses the
PTV and allows the dose uniformity requirements to be satisfied.
17.9.3 Normal Tissues Dosimetry

The dose to the critical organs indicated should be calculated whenever they are included in the radiation
field. For patients treated with volume-based techniques, the appropriate dose-volume histograms should
be submitted. If IMRT is used, a DVH must be submitted for a category of tissue called “unspecified
tissue,” which is defined as tissue contained within the skin, but which is not otherwise identified by
containment within any other structure.
Required normal tissue DVH data according to primary site of treatment
Table 17.9.3
Treatment Area Required DVH
Neck Thyroid
Spinal Cord
Chest Right Lung
Left Lung
Heart
Spinal Cord
Abdomen Liver
Right Kidney
Left Kidney
Spinal Cord
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17.10 Quality Assurance Documentation
Key Points
• No on-treatment review will be required for this study
• Within 1 week of the completion of radiotherapy
o Submit data for the primary site only (see checklist)
o Primary site data submission must be in digital format
o Diagnostic imaging data must be in digital format
• Only the RT-2 form and a copy of the treatment chart need to be submitted for metastatic sites
17.10.1 Submission of Diagnostic Imaging Data

Copies of the diagnostic imaging and operative reports used to determine the primary treatment volume
(CT, MRI, and/or MIBG scans performed prior to surgical resection and post- MIBG Induction therapy)
with corresponding reports should be submitted. Instructions for digital diagnostic submissions may be
found on the IROC Rhode Island (formerly QARC) website - www.qarc.org, under Digital Data,
Diagnostic.
17.10.2 Submission of Radiotherapy Data

Digital Submission:
Submission of treatment plans in digital format (either DICOM RT or RTOG format) is required. Digital
data must include CT scans, structures, plan, and dose files. Submission may be by either sFTP or CD.
Instructions for data submission are on the IROC Rhode Island (formerly QARC) web site at
www.qarc.org under "Digital Data." Any items on the list below that are not part of the digital submission
may be included with the transmission of the digital RT data via sFTP or submitted separately. Screen
captures are preferred to hard copy for items that are not part of the digital plan.
17.10.3 Primary Site Data Submission

Treatment Planning System Output:
• RT treatment plans including CT, structures, dose, and plan files. These items are included
in the digital plan.
• Dose volume histograms (DVH) for the composite treatment plan for all target volumes and
required organs at risk. When using IMRT, a DVH shall be submitted for a category of
tissue called “unspecified tissue.” This is defined as tissue contained within the skin, but
which is not otherwise identified by containment within any other structure. DVHs are
included in the digital plan.
• Digitally reconstructed radiographs (DRR) for each treatment field. Please include two sets,
one with and one without overlays of the target volumes and organs at risk. When using
IMRT, orthogonal setup images are sufficient.
• Treatment planning system summary report that includes the monitor unit calculations,
beam parameters, calculation algorithm, and volume of interest dose statistics.
Supportive Data
• Radiotherapy record (treatment chart) including prescription and daily and cumulative
doses to all required areas and organs at risk.
• Documentation of an independent check of the calculated dose when IMRT is used.
• If the recommended doses to the organs at risk are exceeded, an explanation should be
included for review by the IROC Rhode Island (formerly QARC) and the radiation
oncology.
09/24/14 132
• Proton therapy: smearing radius of the compensator, set-up margin (SM) and PTV margin for
each treatment beam and a description of the rationale for the PTV margins.
Forms
• RT1/IMRT Dosimetry Summary Form
• RT-2 Radiotherapy Total Dose Record form
• Motion management reporting form, if applicable
• Proton Dosimetry Summary Form (if applicable).
17.10.4 Metastatic Site(s) Data Submission

Hard copy data submission (required unless otherwise not available)
• The RT-2 Radiotherapy Total Dose Record form.
• Copy of the patient radiotherapy record including prescription and daily and cumulative
doses to all targeted volumes and critical organs.
These data should be forwarded to:

IROC Rhode Island (formerly QARC)
640 George Washington Highway, Suite 201
Phone: 401-753-7600
Fax: 401-753-7601
Questions regarding the dose calculations or documentation should be directed to:
COG Protocol Dosimetrist
Quality Assurance Review Center
640 George Washington Highway, Suite 201
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17.11 Definitions of Deviations in Protocol Performance

In the following table, the GTV, CTV and PTV descriptions and evaluations will applied and scored
separately for the primary and boost (when applicable) phases of treatment.
DEVIATION
Minor Major
Prescription Dose
Difference in prescribed or computed Difference in prescribed or computed
dose is 6-10% of protocol specified dose is > 10% of protocol specified
dose dose
Dose Uniformity
>10% PTV received > 110% 90% isodose covers < 100% of CTV
of the prescription dose
or
95% isodose covers < 100% of CTV
Volume
CTV or PTV margins are less than the GTV does not encompass MR-visible
protocol specified margins in the residual tumor
absence of anatomic barriers to tumor
invasion (CTV) or without written
justification (PTV)
Organs at Risk
OAR deviations will be assessed at OAR deviations will be assessed at
the time of final review. the time of final review.
Timing
Radiation therapy started BEFORE
Day +42 after Bu/Mel Consolidation
17.12 Patterns of Failure Evaluation

The patterns of failure for patients with neuroblastoma may be described as local, marginal or distant and
may be based on multi-modality imaging. Local failure is defined as progression of known residual tumor
or the appearance of tumor at known prior sites of disease that were at some point without evidence of
disease within the targeted volumes. Distant failure is defined as the appearance of tumor at sites outside
of the target volumes. Marginal failure is defined as progression of disease within or outside of the target
volume margins. There is no uniform method to define marginal failure which is usually assessed by
DVH. Determining the patterns of failure will require an assessment of tumor recurrence with respect to
targeting and dosimetry. There is no universally accepted analytical method to assess pattern of failure.
For this study, the pattern of failure will be assessed qualitatively and quantitatively by registering the
best imaging modality data obtained at the time of failure to the dosimetry from the original treatment
plan.
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18.0 HEMATOPOIETIC STEM CELL COLLECTION AND TRANSPLANT GUIDELINES

All transplants performed on COG trials must occur at FACT-accredited SCT programs with the
exception of adolescents/adults being treated on COG trials who are referred to an adult transplant
facility. See the COG Administrative Policy 3.3 regarding the agreement requirements for these cases.
18.1 Catheter Use

PBSC may be collected using a large bore double lumen central venous catheter that will allow the 1-
2 mL/kg/min flow rates required for apheresis. Many institutions use temporary or tunneled apheresis
catheters (such as the 8 Fr Medcomp catheter) in neuroblastoma patients. Femoral line placement is generally
not required.
18.2 PBSC Mobilization
Institutional standard operating procedures (SOPs) will be used for mobilization and pheresis.
In the absence of institutional SOPs, the following suggested guidelines could be used:
Patients should begin G-CSF starting one day after completing a cycle of chemotherapy. They should
continue on G-CSF 5 mcg/kg/day while recovering from the cycle of chemotherapy until the post-nadir
ANC > 500-1000/µL, at which point it is recommended to increase the dose of G-CSF to at least 10
mcg/kg/day per institutional policies.
Institutions which time collections using circulating CD34 cell counts will generally begin when the
count is ≥ 10-20 cells/µL. Otherwise, the timing of collection is often within 1-3 days of increasing the G-
CSF dose, when WBC is > 2000 (usually Day 14 from start of chemotherapy), although rapid
hematopoietic recovery as indicated by a significant left shift and/or a rapidly rising WBC count, may
provide an opportunity for earlier collection. It is critical that G-CSF be given daily until PBSC collection
is complete. If post-WBC is > 60,000, decrease G-CSF dose to 5 mcg/kg/day.
If patients are off G-CSF prior to planned PBSC harvest, they should receive G-CSF 10-16 mcg/kg/day
for 3 days prior to the first day of scheduled PBSC harvest (per institutional policies), harvest on Day 4 of
G-CSF treatment, and continue daily G-CSF until PBSC collections are completed. If post-WBC is
> 60,000, decrease G-CSF dose to 5 mcg/kg/day.
TIMING: PBSC mobilization is strongly recommended following Cycle 2 REGARDLESS of disease

status in the marrow. Documentation of clearance of tumor cells from the bone marrow is NOT
REQUIRED, because the rate of ICC positivity is <1% even in the setting of marrow disease.
However, if the patient’s medical condition prohibits safe apheresis, it is appropriate to delay PBSC
mobilization and harvest after subsequent Induction therapy.
18.3 PBSC Collection Guidelines

18.3.1 Laboratory Studies
For patients < 25 kg, a type and cross for poor red blood cells (PRBC) should be performed one day prior to
procedure to avoid apheresis delays.
18.3.2 Apheresis Machine
The Cobe Spectra or the Fenwal CS 3000+ is recommended because the continuous flow centrifugation
devices are better tolerated than discontinuous flow machines. Institutional SOPs will be used.
18.3.3 Blood Priming
For patients less than 25 kg, priming of the apheresis machine with IRRADIATED, leukocyte-PRBC may
be required.
09/24/14 135
18.3.4 Collection Goals

It is recommended that large volume apheresis be performed on all patients for each collection. During
each leukopheresis procedure, the typical target volume of whole blood processed will be approximately
480 mL/kg (6 blood volumes).
Optimal collection goal (total for all collections) is 10 x 106 CD 34+ cells/kg for PBSC. The minimum
collection is 4 x 106 CD 34+ cells/kg divided in 2 aliquots of at least 2 x 106 CD 34+ cells/kg per aliquot.
The targeted number of cells can usually be obtained in 1-3 collection days. Optimum goal collection
should be stored as a minimum of 3 aliquots of cells:
• 2-4x106 CD34+ cells/kg for PBSC support following 131I-MIBG
• 2-4x106 CD34+ cells/kg for PBSC support following Bu/Mel conditioning
• 2-4x106 CD34+ cells/kg as a backup for delayed engraftment, or for potential subsequent use.
Because of the advantages of collecting these backup cells during this pheresis episode (as
opposed to later in the patient’s clinical course79 it is recommended that these this additional
aliquot of PBSC be collected, even if this requires an additional day of apheresis.
CD34+ cell counts should be done at local institution for each daily collection as per institutional SOP.
18.4 PBSC Analyses
The following studies are recommended for each PBSC collection:
1) Culture for bacterial and fungal contamination,
2) Nucleated cell count and differential,
3) CD34+ cell enumeration
18.5 Cryopreservation of PBSC Products

Each aliquot (as detailed above) should be processed and cryopreserved on the day of collection as per
Institutional SOPs. These SOPs include the use of 7.5-10% dimethyl sulfoxide final concentration in the
cryopreservation medium, use of a monitored, controlled-rate freezer, and storage in liquid nitrogen with
appropriate monitoring. The goal is to have 3 separate aliquots cryopreserved in separate bags – 1 for
each ASCR procedure and 1 for a potential backup.
18.6 Autologous Stem Cell Rescue
Institutional SOPs may be followed. However, the PBSC product should NEVER be irradiated prior
to infusion.
18.6.1 Premedication
DMSO may cause a histamine-like reaction when infused into the patient. Therefore, premedication with
Benadryl and Tylenol is recommended.
18.6.2 Thawing of PBSC

PBSC are thawed in a 37°C water bath. Only 1 bag of PBSC should be thawed at a time – when the
infusion of 1 bag is completed, the next bag should be thawed.
Thawed PBSC should be infused as rapidly as tolerated through a central venous catheter. The unit may
be infused by gravity, or the cells may be drawn up into a syringe and pushed by trained personnel.
Microaggregate filters and leukodepletion filters MUST NOT be used for infusion of PBSC. If a thawed
unit appears clumpy or stringy and these particles cannot be dispersed with gentle kneading, the PBSC
product could be infused through a standard 170 micron blood filter.
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18.6.3 Possible Symptoms during Infusion

Precipitating Factor Possible Symptoms
hemolyzed red cells fever, chills, hemoglobinuria
cellular clumps and debris chest pain, hypoxia, hypertension
cold 10% DMSO nausea, headache
microbial contamination fever, chills, hypotension
plasma proteins urticaria
18.6.4 Infusion Dosage/Timing

For patients receiving 131I-MIBG, stem cells will be infused on Day 13 (± 2 days to allow for scheduling
flexibility) of the 131I-MIBG block of Induction therapy.
All patients will have stem cells infused on Day 0 of Consolidation (Section 4.4).
Where the DMSO volume in the stem cell product would exceed accepted level for infusion within a
24 hour period, stem cell products may be infused over 2 days to meet this standard. A minimum of
2 x 106 viable CD34+ cells/kg must be available for each of the two required ASCRs. Having a back-up
of 2-4 x 106 viable CD34+ cells/kg is recommended, but not required.
18.6.5 Recommendations for Stem Cell Infusion
a. Institutional SOPs may be followed
b. Discontinue all other IV fluids as possible during stem cell infusion to avoid volume overload.
c. The stem cells will be infused intravenously on Day 13 of MIBG and on Day 0 of Consolidation
within 1 hour of thawing.
d. Consider antiemetics prior to ASCR to limit DMSO-induced nausea and vomiting.
e. Hydrate for 12 hours post stem cell infusion at 125 mL/m²/hr.
131
19.0 I-MIBG THERAPY FEASIBILITY ASSESSMENT
Enrollment will be tracked for High-Risk neuroblastoma patients from participating institutions onto the
neuroblastoma biology study (ANBL00B1 or its successor) and the Childhood Cancer Research Network
(ACCRN07) and will be compared to enrollment on ANBL09P1.
A questionnaire for patients and their families who travel to another institution for MIBG treatment will
be completed before beginning Consolidation by either the MIBG treating center or the enrolling center
(see Appendix VIII). The questionnaire is required to help quantify the costs for travel and stay during the
course of MIBG treatment ONLY (i.e. do not include costs incurred as part of Induction therapy or
ASCR). CRAs of Institutions will be responsible to enter the information from the questionnaire to the
reporting period form (which is part of the eRDE forms packet in the COG Web site).
09/24/14 137
APPENDIX I: CTEP REGISTRATION PROCEDURES
CTEP Investigator Registration Procedures

Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy
require all investigators participating in any NCI-sponsored clinical trial to register and to renew
their registration annually.
Registration requires the submission of:
• a completed Statement of Investigator Form (FDA Form 1572) with an original signature
• a current Curriculum Vitae (CV)
• a completed and signed Supplemental Investigator Data Form (IDF)
• a completed Financial Disclosure Form (FDF) with an original signature
Fillable PDF forms and additional information can be found on the CTEP website at
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>. For questions,
please contact the CTEP Investigator Registration Help Desk by email at
<pmbregpend@ctep.nci.nih.gov>.
CTEP Associate Registration Procedures / CTEP-IAM Account
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM)
application is a web-based application intended for use by both Investigators (i.e., all physicians
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in
the conduct of NCI-sponsored clinical trials).
Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account.
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP
Investigator Registration Procedures above for information on registering with CTEP as an
Investigator, which must be completed before a CTEP-IAM account can be requested.)
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials
Support Unit) websites and applications, including the CTSU members’ website.
Additional information can be found on the CTEP website at

<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For questions, please contact
the CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>.
09/24/14 138
APPENDIX II: Risk Assessment and Additional Biological Studies
The criteria currently used in ANBL00B1 by the COG to assign risk-group are shown below:
INPC Risk Group

Stage Age MYCN Ploidy Histology Other
1 any any any any Low
resection >50%, Low

2A/2B any not amp any any asymptomatic
resection > 50%, Intermediate
2A/2B any not amp any any symptomatic
2A/2B any not amp any any resection <50% Intermediate
2A/2B any not amp any any biopsy only Intermediate
2A/2B any amp any any any degree of resection High
3 <547d not amp any any Intermediate

3 >547d not amp any Fav Intermediate
3 any amp any any High
3 >547d not amp any Unfav High
4 <365d amp any any High

4 <365d not amp any any Intermediate
4 365-<547d amp any any High
4 365-<547d any DI=1 any High
4 365-<547d any any Unfav High
4 365-<547d not amp DI>1 Fav Intermediate
4 >547d any any any High
4S <365d not amp DI>1 Fav asymptomatic Low

4S <365d not amp DI=1 any asymp or symp Intermediate
4S <365d missing missing missing too sick for biopsy Intermediate
4S <365d not amp any any symptomatic Intermediate
4S <365d not amp any Unfav asymp or symp Intermediate
4S <365d amp any any asymp or symp High
NOTE: THE TERM “ANY” DOES NOT IMPLY THAT THE DATA ARE NOT IMPORTANT.
EVEN THOUGH CERTAIN VARIABLES MAY NOT INFLUENCE CURRENT RISK
ASSIGNMENT WITHIN CERTAIN PATIENT SUBSETS, THESE DATA ARE BEING USED TO
ASSIGN TREATMENT DURATION (INTERMEDIATE-RISK PATIENTS) AND/OR TO
ATTEMPT REFINEMENT OF THE RISK CLASSIFICATION SYSTEM. EVERY ATTEMPT
SHOULD BE MADE TO OBTAIN ALL BIOLOGICAL DATA WHENEVER POSSIBLE.
09/24/14 139
APPENDIX III: INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM (INSS)
Stage 1
Localized tumor with complete gross excision, with or without microscopic residual disease;
representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and
removed with the primary tumor may be positive).
Stage 2A
Localized tumor with incomplete gross resection; representative ipsilateral non-adherent lymph
nodes negative for tumor microscopically.
Stage 2B
Localized tumor with or without complete gross excision, with ipsilateral non-adherent lymph
nodes positive for tumor; enlarged contralateral lymph nodes must be negative microscopically.
Stage 3
Unresectable unilateral tumor infiltrating across the midline2, with or without regional lymph
node involvement; or localized unilateral tumor with contralateral regional lymph node
involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph
node involvement.
Stage 4
Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin,
and/or other organs (except as defined for Stage 4S).
Stage 4S
Localized primary tumor (as defined for Stage 1, 2A or 2B) with dissemination limited to skin,
liver, and/or bone marrow3 (limited to infants <1 year of age).
1. Multifocal primary tumors (e.g., bilateral adrenal primary tumors) should be staged according to
the greatest extent of disease, as defined above, and followed by a subscript “M” (e.g., 3M).
2. The midline is defined as the vertebral column. Tumors originating on one side and crossing the
midline must infiltrate to or beyond the opposite side of the vertebral column.
3. Marrow involvement in Stage 4S should be minimal, i.e., less than 10% of total nucleated cells
identified as malignant on bone marrow biopsy or marrow aspirate. More extensive marrow
involvement would be considered to be Stage 4. The MIBG scan (if performed) should be
negative in the marrow.
4. Proven malignant effusion within the thoracic cavity if it is bilateral or the abdominal cavity
upstages the patient to INSS 3
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APPENDIX IV: TUMOR SIZE MEASUREMENTS BY CROSS-SECTIONAL IMAGING
RELATIONSHIP BETWEEN CHANGE IN SINGLE DIAMETER (RECIST), PRODUCT OF

TWO DIAMETERS (WHO), AND THREE PERPENDICULAR DIAMETERS (“VOLUME”)
Target lesions at baseline must measure greater than 1 cm; if these target lesions decrease in size to below
1 cm, care should be taken in measuring and inadvertently progressing a patient due to minimal changes
in measurement from a nadir value below 1 cm, which may be within measurement error. When multiple
primary or metastatic masses are present, all masses will be described. However, up to 5 target masses
should be measured, using the same method in subsequent follow ups.
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APPENDIX V: NEUROBLASTOMA RESPONSE CRITERIA
(International Recommendations)6
SITE TEST COMPLETE VERY GOOD PARTIAL RESPONSE MIXED STABLE PROGRESSIVE
RESPONSE PARTIAL RESPONSE DISEASE DISEASE
RESPONSE
Primary 3 dimensional CT or no tumor >90% reduction in 50-90% reduction in 3-
MRI imaging (determine 3-dimensional dimensional tumor
volume from product of tumor volume volume
three dimensions
physical exam and/or
surgical measurement)
Metastases Bone marrow1 (aspirate no tumor no tumor no or only one sample 50-90% no new any new lesion;
x 2 and biopsy x 2) with tumor2 reduction of lesions; increase of any
any measurable <25% measurable
Bone x-rays and lesion (primary increase in
lesion by >25%;
scintigraphy (Tc and/or no lesions all lesions all lesions improved; no or metastases); any lesion;
MIBG) improved; no new new lesions4 no new lesions; exclude previous negative
lesions3 <25% increase bone bone marrow
Liver imaging 50-90% reduction in any existing marrow positive
(ultrasound, CT, or no tumor lesions, exclude evaluation
MRI) no tumor bone marrow
evaluation
Chest x-ray, chest CT 50-90% reduction
scans no tumor
if x-ray abnormal no tumor
Physical exam5 50-90% reduction

no tumor
no tumor
Tumor Urine catecholamine Normal normal or both both decreased 50-90%
marker metabolites (HVA & decreased >90%
VMA)
Response must be evaluated before and after surgery for the primary site. If complete response, very good partial response, or partial response is
achieved surgically, indicate such when reporting the response.
The total response can be no better than the worst response in any subcategory (e.g., if primary = complete response, metastases = partial
response, and, tumor marker = very good partial response, the total response = partial response).
1) Immunocytology results are not used to determine response.
2) One sample may be positive only if there is a reduction in the number of sites originally positive for tumor at diagnosis.
99
3) Tc bone scan may show residual abnormalities but the MIBG scan (if performed) must be negative.
99
4) Tc bone scan and/or MIBG scan (if performed) must show improvement, but residual abnormalities may be present on either scan.
5) Measure palpable lymph nodes in 3 dimensions and calculate tumor volume.
6) Brodeur G et al: JCO 1993; 11:1466-1477
09/24/14 142
APPENDIX VI: LIST OF DRUGS THAT INTERFERE WITH MIBG

A list of drugs known or expected to interfere with MIBG (both diagnostic and therapeutic administration)
with their respective recommended time of withdrawal prior to MIBG exposure is given below.
Known to interfere Expected to interfere Theoretically expected to interfere
Drug Hours Drug Hours Drug Hours
Amitriptyline (1) 48 Benperidol (1) 48 Mianserin (1) 48
Amoxapine (1) 48 Bethanidine (4,3) 48 Oxypertine (1) 24
Butriptyline (1) 48 Bretylium (4,3) 24 Trazadone (4) 48
Clomipramine (1) 24 Chlorpromazine (1) 24 Viloxazine (1) 48
Cocaine (1) 24 Debrisoquine (4,3) 48 Xamoterol (2) 48
Desipramine (1) 24 Dexamphetamine (4) 48
Diltiazem (5,6) 24 Diethylpropion (4) 48
Dothiepine (1) 24 Dobutamine (4) 24
Droxepin (I) 24 Dopamine (4) 24
Ephedrine (1) 24 Droperidol (1) 24
IprindoIe (1) 24 Fenfluramine (4) 48
Isradipine (5,6) 48 Fenoterol (4) 24
Labetalol (1,4) 72 Flupenthixol (1) 48
Lidoflazine (5,6) 48 Fluphenazine (1) 1 month (depot)
lmipramine (1) 24 Guanethidine (4,3) 48
Lofepramine (1) 48 Haloperidol (1) 48
Loxapine (1) 48 Isoprenaline (4) 24
Metaraminol (4) 24 lsoetharine (4) 24
Methoserpidine (4,2) 72 Maprotiline (1) 48
Methylephedrine (4) 24 Mazindol (4) 48
Nicardipine (5,6) 48 Methotrimeprazine (1) 72
Nifedipine (5,6) 24 Methoxamine (4) 24
Nimodipine (5,6) 24 Orciprenaline (4) 24
Noradrenaline (4) 24 Pericyazine (1) 48
Nortriptyline (1) 24 Perphenazine (1) 24
Phenylephedrine (4) 48 Phentermine (4) 48
Phenylpropanolamine (4) 48 Pimozide (1) 72
Protriptyline (1) 24 Pipothiazine (1) 1 month (depot)
Pseudoephedrine (4) 24 Pirbuterol (4) 24
Reserpine (4,2) 72 Prochlorperazine (1) 24
Trimipramine (1) 48 Promazine (1) 24
Verapamil (5,6) 48 Promethazine (1) 24
Reprolterol (4) 24
Rimiterol (4) 24
Salbutamol (4) 24
Terbutaline (4) 24
Thiethylperazine (1) 48
Thioridazine (1) 24
Trifluoperazine (1) 48
Trifluperidol (1) 24
Zuclopenthixol (1) 48
1 month (depot)
Probable mechanism: (1) Inhibition of sodium-dependent uptake system; (2) Inhibition of uptake by active
transport into vesicle; (3) Competition for transport into vesicles; (4) Depiction of content from storage
vesicle; (5) Calcium mediated; (6) Other possible unknown mechanisms. Adapted from Solanki Nucl Med
Comm80
09/24/14 143
In addition to the drugs listed above, the following drugs used in the US are known or expected to
interfere with MIBG. The drugs are included in the table below with their respective recommended time
of withdrawal prior to MIBG.
Known to interfere Expected to interfere Theoretically expected to interfere

Drug Hours Drug Hours Drug Hours
Desipramine (1) 24 Diethylpropion (4) 48 Trazodone (4) 48
Loxapine (1) 48 Droperidol (1) 24
Protriptyline (1) 24 Perphenazine (1) 24
Phentermine (4) 48
Pirbuterol (4) 24
Probable mechanism: (1) Inhibition of sodium-dependent uptake system; (2) Inhibition of uptake by active transport into
vesicle; (3) Competition for transport into vesicles; (4) Depiction of content from storage vesicle; (5) Calcium mediated;
(6) Other possible unknown mechanisms. A complete list is available in the article by Solanki Nucl Med Comm80 and
Jubilant Draximage® Therapeutic 131I MIBG Investigator’s Brochure version 1.1 (1-14-08).
09/24/14 144
APPENDIX VII: QUALITY CONTROL FOR FREE IODINE IN 131I-MIBG
For detection of radiolytic decomposition:
Radiopharmaceutical Jubilant Draximage® Therapeutic 131I-MIBG –15-25mCi/ml
Preparation Receipt of therapeutic 131I-MIBG from Jubilant Draximage

Materials Waters Accell Plus CM Sep-Pac
Ethanol
Sterile water
10 ml test tubes
Instrumentation Capintec well counter

Calculator
Procedure
1. Using a Waters Accell Plus CM SepPac cartridge, wet the sepPac with 5 mL ethanol. The long tip
of the SepPac must be connected to the flushes.
2. Rinse with 5 mL sterile water.
3. Add 1/20 mL MIBG to SepPac. Dilute to around 0.5 uCi.
4. Flush SepPac with 5 mL sterile water into a 10 mL test tube (flush tube).
5. Place cartridge into a second 10 mL test tube (A).
6. Place the cartridge tube into a well counter and record (A), set counter on 131-I.
7. Count both tubes (A and flush) in the well counter, add counts together and record (B), set
counter on 131-I.
8. (A/A+B) x 100 = % tagged. Must be greater than 95% - compare to TLC.
Comments Procedure must be performed within 24 hours of receipt of dose from Jubilant
Draximage®. Results of bound iodine should be greater than 95%. Record results on
worksheet. Notify physicians if there is an aberrant or low result.
All centers administering MIBG therapy must perform an assay for radiolytic decay.
The above is a suggested technique. Other techniques may be used provided they meet
institutional radiopharmaceutical guidelines.
09/24/14 145
APPENDIX VIII: PATIENT QUESTIONNAIRE FOR MIBG TREATMENT COSTS
Questionnaire on MIBG Treatment Costs for Families who Travel for MIBG Therapy
COG Pilot Study of Intensive Induction Chemotherapy with 131I- MIBG
followed by Myeloablative Busulfan/Melphalan (Bu/Mel)
This questionnaire gathers information on the costs for families (not enrolled at an MIBG center) during the time
period of 131I-MIBG treatment. It is to be completed by the patient’s family with the assistance of the social worker
or research team. The CRA at the enrolling institution is responsible for extracting information from this
questionnaire and submitting it via eRDEs.
Date (mm/dd/ccyy): ______________________ COG REG #: __________________________
1. Location of primary treatment:

___Children’s Hospital Los Angeles
___Children’s National Medical Center, D.C.
___ Connecticut Children’s Medical Center
___Medical University of South Carolina
___Phoenix Children’s Hospital
___Primary Children’s Medical Center, Salt Lake City
___The Children’s Hospital, Denver
___University of Alabama, Birmingham
___University of Chicago
___UT Southwestern Medical Center
___ Sacred Heart Children's Hospital
___Midwest Children's Cancer Center
___Children's Healthcare of Atlanta – Egleston
___University of North Carolina at Chapel Hill
2. Location of MIBG treatment: ___C.S. Mott Children’s Hospital `

___Cincinnati Children’s Hospital Medical Center
___Children’s Hospital of Philadelphia
___ Dana Farber Cancer Institute
___UCSF School of Medicine
___ Duke University Medical Center
___Seattle Children's Hospital
___University of Wisconsin Hospital and Clinics
___ Cook’s Children’s Hospital
3. Total number of family members who travelled to MIBG Center (not including patient):
Of the family members who travelled to the MIBG Center:
3a. Number < 18 years of age
3b. Number ≥ 18 years of age
3c. Number employed full time (40 hours):
3d. Number employed part-time (< 40 hours):
3e. Number unemployed (includes children):
3f. Number taking leave of absence specifically to travel to MIBG Center:
09/24/14 146
4. How did the family travel to the MIBG Center? ___Airplane

___Car
___Bus
___Train
___Other, explain:
5. How much did the family pay out of pocket for travel expenses:
___ Nothing – all expenses were covered
___Less than half the costs (< 50%)
___Half or over half the costs (>= 50%)
___Full cost (100%)
___Unknown
___ Other, explain:
6. Where is the family staying while at the MIBG Center?

___Hotel/motel
___Ronald McDonald House
___Private home
___Other, explain:
7. How much did the family pay out of pocket for housing expenses:
___ Nothing – all expenses were covered
___Less than half the costs (< 50%)
___Half or over half the costs (>= 50%)
___Full cost (100%)
___Unknown
___ Other, explain:
8. Did a 3rd party payor (ie: insurance/Medicaid) pay any travel or housing expenses?
___Yes
___No
9. Did charitable organizations pay any travel or housing expenses?

___Yes
___No
9a. If yes, list charitable organizations:
10. Number of days spent at MIBG Center (includes travel days):
11. Filled out by:

Parent /Guardian:____________________________ Date: mm/dd/ccyy:________________________
Name of assistant:____________________________ Date: mm/dd/ccyy:________________________
09/24/14 147
APPENDIX IX: YOUTH SUMMARIES FOR CHILDREN AND TEENS

INFORMATION SHEET REGARDING RESEARCH STUDY
(for children from 7 through 12 years of age)
Combination therapy using drugs, radiation and surgery for newly diagnosed high-risk neuroblastoma
1. We have been talking with you about a type of cancer called neuroblastoma. Neuroblastoma is a
kind of cancer that grows in the nervous system outside of the brain. After doing tests, we have
found that you have high-risk neuroblastoma. You have this type of neuroblastoma that is called
high-risk because your tumor is difficult to treat.
2. We are asking you to take part in a research study because you have high-risk neuroblastoma. A
research study is when doctors use new medicine or a new treatment in people who are sick to try
to find better ways to help them get better. In this study, we are trying to learn more about how to
treat high-risk neuroblastoma. We will do this by giving you medicines, an operation and
X-ray treatments to help kill the cancer. In addition, we may give you a new medicine called
MIBG. Not everyone on this study will be given MIBG therapy.
3. If you take part in this study, you will be given a few different kinds of drugs (medicines) for
12 weeks, followed by an operation. As long as your cancer has not gotten worse, we may then
give you a new drug called MIBG, followed by some more drugs and X-ray treatments. The
entire treatment will take a total time of about one year. We don’t know whether this treatment
plan will help you and if the new drug MIBG will kill your tumor. That is why we are doing this
study.
4. Sometimes good things can happen to people when they are in a research study. These good
things are called “benefits.” We hope that a benefit to you for being part of this study is a better
chance for you to be able to get rid of your cancer. Another possible benefit of taking part in this
study is that you may have lesser side-effects. However, we don’t know for sure if there is any
benefit of being part of this study. We expect that the information learned from this study will
help other patients with high-risk neuroblastoma in the future.
5. Sometimes bad things can happen to people when they are in a research study. These bad things
are called “risks.” The risks to you from this study include having low blood counts, getting
infections, and the chance of getting other cancers. You will be given medicines to help your
blood counts get better after the treatment and to decrease your risk of infections. Other
things may happen to you that we don’t yet know about.
6. Your family can choose for you to be part of this study or not. Your family can also decide for
you to stop being in this study at any time once you start. There may be other treatments for your
illness that your doctor can tell you about. Make sure to ask your doctors any questions that you
have.
7. We are also asking for your permission to collect additional tumor tissue sample from you. We
want to use the extra tumor tissue sample to see if there are ways to tell how the cancer will
respond to treatment. This sample would be taken from you when other standard surgeries are
being done, so there would be no extra procedures. You can still take part in this study even if you
don't allow us to collect these extra samples for research.
09/24/14 148
INFORMATION SHEET REGARDING RESEARCH STUDY

(for teens from 13 through 17 years of age)
Combination therapy using drugs, radiation and surgery for newly diagnosed high-risk neuroblastoma
1. We have been talking with you about a type of cancer called Neuroblastoma. Neuroblastoma is a
kind of cancer that develops in nerve cells outside the brain. After doing tests, we have found that
you have High risk neuroblastoma. This type of neuroblastoma is called high-risk because your
tumor is difficult to treat.
2. We are asking you to take part in a research study because you have high-risk neuroblastoma. A
research study is when doctors work together to try out new ways to help people who are sick. In
this study, we are trying to learn more about how to treat high-risk neuroblastoma. We will do this
by giving you medications (a combination of drugs), an operation, and X-ray beam treatments to
help kill your cancer. In addition, we may give you a new medicine called MIBG that will allow
us to give the X-ray treatment directly to the cancer. Not everyone on this study will receive
MIBG therapy.
3. If you agree to take part in this study, you will be given a drug combination over a period of
12 weeks, followed by surgery. As long as your cancer has not gotten worse, we may then give
you a new drug called MIBG, followed by different drug combinations and radiation therapy. The
entire treatment will take a total time of about one year. We don’t know whether this treatment
plan will help you and if the new drug MIBG will be effective against your tumor. That is why we
are doing this study.
4. Sometimes good things can happen to people when they are in a research study. These good
things are called “benefits.” We hope that a benefit to you for being part of this study is a better
chance for you to be able to get rid of your cancer. Another possible benefit of taking part in this
study is that you may have lesser side-effects. However, we don’t know for sure if there is any
benefit of being part of this study. We expect that the information learned from this study will
benefit other patients in the future.
5. Sometimes bad things can happen to people when they are in a research study. These bad things
are called “risks.” The risks to you from this study involve very low blood counts, possible
infections, bladder damage, and the chance of getting other cancers. You will be given
medicines to help your blood counts recover after the treatment, to prevent infection, and to
reduce bladder damage. You may also suffer from bleeding, severe allergic reactions, other
cancers, or damage to the skin, eyes, heart, kidney and/or liver. If you experience any of
these things, your doctors will be prepared to treat you for them. Other things may happen
to you that we don’t yet know about.
6. Your family can choose for you to be part of this study or not. Your family can also decide for
you to stop being in this study at any time once you start. There may be other treatments for your
illness that your doctor can tell you about. Make sure to ask your doctors any questions that you
have.
7. We are also asking your permission to collect additional tumor tissue sample from you. We want
to use the extra tumor tissue sample to see if there are ways to tell how the cancer will respond to
treatment. This sample would be taken from you when other standard surgeries are being
performed, so there would be no extra procedures. You can still be take part in this study even if
you don't allow us to collect these extra samples for research.
09/24/14 149
APPENDIX X: ANATOMICAL REFERENCE DIAGRAM FOR USE IN FDG-PET LESION

SCORING BY INSTITUTIONS
Institutions will collect the standardized uptake values (SUV) from the primary tumor followed by the 9
most FDG-PET-avid lesions with an SUV >= 2.5 at 2 time points: diagnosis and after Cycle 4 of
Induction (before surgery). Lesion #1 will always refer to the primary tumor and is required to be
reported at each evaluation time point regardless of SUV score. These lesions will be identified
anatomically by using the reference diagram above. The serial #, anatomical reference # and FDG-PET
SUV score will be entered into eRDE [Institutional Lesion Assessment: FDG-PET Scan CRF] for each of
these time points. Refer to protocol Section 16.3.
Lesion Serial Number Description of Lesion FDG-PET SUV

Corresponding to location on Score
anatomical reference diagram >= 2.5*
above
1
Designated for Primary Tumor
2
3
4
5
6
7
8
9
10
*except primary tumor where any SUV is to be recorded.
09/24/14 150
APPENDIX XI: POSSIBLE DRUG INTERACTIONS
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or
their Parents should be encouraged to talk to their doctors before starting any new medications, using
over-the-counter medicines, or herbal supplements and before making a significant change in diet.
Busulfan
Drugs that may interact with busulfan
• Acetaminophen
• Itraconazole
• Metronidazole
• Thioguanine
• Fosphenytoin or phenytoin
Food and supplements that may interact with busulfan**

• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants”
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.
Melphalan
Drugs that may interact with melphalan

o Clozapine, leflunomide, natalizumab, tofacitinib
Food and supplements that may interact with melphalan**

• Echinacea
09/24/14 151
Cisplatin
Drugs that may interact with cisplatin
o Antibiotics like gentamicin or tobramycin

o Anti-seizure medications like fosphenytoin or phenytoin
o Arthritis medications like leflunomide or tofacitinib
• Some chemotherapy (be sure to talk to your doctor about this)
o Other medications like bumetanide, clozapine, furosemide, natalizumab
Food and supplements that may interact with cisplatin**
• Echinacea
Cycophosphamide
Drugs that may interact with cyclophosphamide

• Allopurinol
• Chloramphenicol
• Cyclosporine
• Digoxin
• Etanercept
• Hydrochlorothiazide
• Indomethacin
• Nevirapine
• Pentostatin
• Warfarin
Food and supplements that may interact with cyclophosphamide**

• St. John’s Wort
09/24/14 152
Doxorubicin
Drugs that may interact with doxorubicin

• Some antiepileptics (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, fosphenytoin)
• Some antiretrovirals (stavudine, zidovudine)
• Other agents, such as clozapine, cyclosporine, verapamil, and warfarin
Food and supplements that may interact with doxorubicin**

• Echinacea
• Glucosamine
• Grapefruit, grapefruit juice, Seville oranges, star fruit
Etoposide
Drugs that may interact with etoposide

• Antibiotics
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin
• Antidepressants and antipsychotics
o Aripiprazole, clozapine, nefazodone
• Antifungals
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole
• Arthritis medications
o Leflunomide, tofacitinib
• Anti-rejection medications
o Cyclosporine, tacrolimus
• Antiretrovirals and antivirals
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir,
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir,
tipranavir
• Anti-seizure medications
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone
• Heart medications
o Amiodarone, dronedenarone, verapamil
• Many other drugs, including the following:
o Aprepitant, atovaquone, bosentan, deferasirox, dexamethasone, ivacaftor, lomitapide,
mifepristone, natalizumab, pimozide, sitaxentan
Food and supplements that may interact with etoposide**
09/24/14 153
• Echinacea
• Glucosamine
Isotretinoin
Drugs that may interact with isotretinoin
• Carbamazepine
• Some oral contraceptives
• Some antibiotics, like doxycycline, tetracycline, and tigecycline
Food and supplements that may interact with isotretinoin**

• Vitamin A supplements or multivitamins that contain vitamin A
Topotecan
Drugs that may interact with topotecan

• Antibiotics and antifungals
o Clarithromycin, erythromycin, itraconazole, ketoconazole
o Leflunomide, tofacitinib
o Darunavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir
o Amiodarone, amlodipine, carvedilol, dronedenarone, nicardipine, propranolol, verapamil
o Atorvastatin, clozapine, dipyridamole, ivacaftor, lomitapide, natalizumab
Food and supplements that may interact with topotecan**

• Echinacea
• Grapefruit, grapefruit juice
09/24/14 154
Vincristine
Drugs that may interact with vincristine

• Antibiotics
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin
• Antidepressants and antipsychotics
o Aripiprazole, nefazodone, trazodone
• Antifungals
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole
o Leflunomide, tocilizumab, tofacitinib
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir,
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir,
tenofovir, tipranavir
• Anti-seizure medications
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone
o Amiodarone, digoxin, dronedenarone, propranolol, verapamil
o Aprepitant, deferasirox, ivacaftor, lomitapide, mifepristone, natalizumab, pimozide, warfarin
Food and supplements that may interact with vincristine**

• Echinacea
09/24/14 155
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Activated:10/04/10 Amendment # 6

Closed: 01/06/16 Version Date: 09/24/14

CHILDREN'S ONCOLOGY GROUP

A COG Pilot Study of Intensive Induction Chemotherapy and 131I-MIBG Followed by

A Limited Institution Pilot Study

IND sponsor for 131I-MIBG: Jubilant Draximage Inc

For Statistics and Data Center Contact Person see: http://members.childrensoncologygroup.org

List of participating institutions

NO. NAME OF THE INSTITUTION

4.2.4 Induction Cycle 4 (Weeks 10-12) 38

7.1 Required Clinical, Laboratory and Disease Evaluations 86

12.3 Data and Safety Monitoring Committee 108

17.2 Timing of Radiation Therapy 123

18.6.3 Possible Symptoms during Infusion 137

STUDY STATISTICIAN Hiroyuki Shimada, MD

Roger Giller, MD Gregory Yanik, MD

Stephan A. Grupp, MD PhD Judith Villablanca, MD

Heidi Russell, MD Laurie Grimme, CCRP

RADIATION THERAPY STUDY Hsiao-Ming Lu, Ph.D.

Wendy Fitzgerald, RN MSN PNP-BC RESEARCH COORDINATOR

AGENT NSC# IND#

IND sponsor for 131I-MIBG: Jubilant Draximage Inc

SEE SECTIONS 14 & 15 FOR SPECIMEN SHIPPING ADDRESSES

EXPERIMENTAL DESIGN SCHEMA

TOPO: Topotecan CR: Complete Response

1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

1.3 Exploratory Aims

2.1 Meta-iodobenzylguanidine Therapy

2.2 Busulfan/Melphalan Transplant Conditioning for Neuroblastoma

2.3 Bu/Mel Transplant Following 131I-MIBG Therapy

2.6 Topotecan/Cyclophosphamide-Based Induction Chemotherapy

2.7 Timing of Primary Tumor Resection

2.8 Radiotherapy as a Component of Local Control

2.9 Treatment of Minimal Residual Disease

2.10 Feasibility Studies

2.11 Correlative Studies

3.0 ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA

3.1.2 IRB Approval

IRB/REB approval documents may be faxed (1-215-569-0206), emailed (CTSURegulatory@ctsu.coccg.org)

3.1.3 Reservation Requirements

3.1.4 Enrollment on Biology Study ANBL00B1

3.1.5 Study Enrollment on ANBL09P1

3.2 Patient Criteria

3.2.4 Organ Function Requirements:

3.2.4.2 Adequate liver function defined as:

• Shortening fraction of ≥ 27% by echocardiogram, or

3.2.4.4 Ability to tolerate PBSC collection:

4.0 TREATMENT PROGRAM

4.1 Overview and General Guidelines

4.1.1 Notification of MIBG Treatment Center

4.1.2 Central Line

4.1.3 Chemotherapy Dose-Adjustment for Weight

4.1.4 Parenteral Chemotherapy Administration Guidelines

4.1.5 Concomitant Therapy

Enzyme inducing anticonvulsants should be replaced by non-inducing anticonvulsants like gabapentin,

Additional inducers or inhibitors of CYP450 enzymes can be found at http://medicine.iupui.edu/flockhart.

4.2 Induction Therapy

Cyclophosphamide: IV over 15-30 minutes

Topotecan: IV over 30 minutes

Myeloid Growth Factors:

4.2.2 Induction Cycle 2 (Weeks 4-6)

Cyclophosphamide: IV over 15-30 minutes

Topotecan: IV over 30 minutes

Filgrastim: SubQ/IV (SubQ preferred)

4.2.2.1 Induction Therapy Cycle 2

4.2.3.1 Induction Therapy Cycle 3 (All patients)

Therapy Delivery Map Ht_____cm Wt_kg BSA_________m2

4.2.5.1 Induction Therapy Cycle 5 (All patients)

4.5.2.1 Maintenance Therapy Cycles 1-6