Conditions: Ganglioneuroblastoma Recurrent Neuroblastoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 73
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well irinotecan hydrochloride and temozolomide with temsirolimus or dinutuximab work in treating younger patients with neuroblastoma that has returned or does not respond to treatment. Drugs used in chemotherapy, such as irinotecan hydrochloride and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as dinutuximab, may find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving irinotecan hydrochloride and temozolomide together with temsirolimus or dinutuximab is more effective in treating neuroblastoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To identify whether temsirolimus or ch14.18 (dinutuximab) is the optimal therapeutic agent to consider for further testing in a future Phase III randomized trial for treatment of newly diagnosed high-risk neuroblastoma.

II. To determine the response rate of patients with relapsed, refractory or progressive neuroblastoma following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab) and to compare this with the known response rate of patients treated with irinotecan and temozolomide alone.

EXPLORATORY OBJECTIVES:

I. To compare the response rates (RR) for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan (irinotecan hydrochloride) and temozolomide.

II. To compare the progression free survival (PFS) and overall survival (OS) rates for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan and temozolomide.

III. To compare the toxicities associated with temsirolimus or ch14.18 (dinutuximab) when combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma.

IV. To compare the ability to maintain intended dose intensity of all agents when temsirolimus or ch14.18 (dinutuximab) is combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma.

V. To determine the concordance between tumor responses as defined by standard International Neuroblastoma Response Criteria (INRC) versus response per the revised INRC.

VI. To study the clinical relevance of naturally occurring anti-glycan antibodies in patients receiving ch14.18 (dinutuximab) antibody.

VII. To study the clinical relevance of natural killer (NK) receptor natural cytotoxicity triggering receptor 3 (NKp30) isoforms in patients receiving ch14.18 (dinutuximab) antibody or temsirolimus.

VIII. To study the association between host factors and response to irinotecan, temozolomide and ch14.18 (dinutuximab).

IX. To characterize the tumor immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab).

X. To study the association between changes in the tumor immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) with response following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab).

XI. To study the association between tumor genomic and transcriptomic aberrations as well as levels of circulating ganglioside (GD2) with response to irinotecan, temozolomide and ch14.18 (dinutuximab).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (CLOSED TO ACCRUAL 06/17/2016): Patients receive temozolomide orally (PO) on days 1-5, irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8.

ARM II: Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim subcutaneously (SC) or IV over 2 hours on days 6-12.

In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Arms:
arm 1: CLOSED TO ACCRUAL 06/17/2016 Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. arm 2: Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12.

Interventions: intervention 1: Dinutuximab intervention 2: Irinotecan Hydrochloride intervention 3: Laboratory Biomarker Analysis intervention 4: Sargramostim intervention 5: Temozolomide intervention 6: Temsirolimus
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Optional correlative studies intervention 4: Given SC or IV intervention 5: Given PO intervention 6: Given IV

Protocol document:
Prot_SAP_000.pdf: 
  
 
i 
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, M.S. 
crabtreed@email.chop.edu 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
May 19, 2017 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #6 to protocol ANBL1221, A Phase II Randomized Trial of 
Irinotecan/Temozolomide with Temsirolimus (NSC# 683864, IND# 61010) or Chimeric 14.18 Antibody 
(ch14.18) (NSC# 764038, IND# 4308) in Children with Refractory, Relapsed or Progressive 
Neuroblastoma, for CTEP review. 
 
This amendment is being submitted in response to a Request for Rapid Amendment (RRA) from Dr. 
Jeffrey Moscow, dated May 10, 2017. In this amendment, the revised CAEPR for MoAb 14.18, 
chimeric (Version 2.8, April 10, 2017) has been inserted in the protocol and the associated risk 
information in the informed consent document has been revised accordingly. Revisions to the protocol 
and consent are detailed in the pages below. 
 
The ANBL1221 study team looks forward to approval of this amendment. Please let me know if we 
can offer further information. 
 
 
Sincerely, 
 
 
Jeannette Cassar, Protocol Coordinator (for) 
Rajen Mody, MD, ANBL1221 Study Chair  
Peter Adamson, MD, COG Group Chair 
 


 
ii 
 
 
SUMMARY OF CHANGES: PROTOCOL 
In accordance with the above discussion, the following specific revisions have been made to the protocol. Additions 
are in boldfaced font and deletions in strikethrough font. 
 
# 
Section 
Page(s) 
Change 
1. 
 
Title Page 
1 
Protocol version date and amendment number have been updated. 
2. 
 
Table of Contents 
2-5 
Table of contents has been updated to account for repagination. 
3. 
 
6.1 
44-50 
The revised CAEPR for MoAb 14.18, chimeric (Version 2.8, April 10, 2017) 
has been inserted. The specific changes are as follows: 
 
• 
Added New Risk:  
• 
Also Reported on MoAb 14.18, chimeric Trials But With 
Insufficient Evidence for Attribution: Cardiac disorders - 
Other (gallop on exam); Cardiac disorders - Other (N-
terminal BNP); General disorders and administration site 
conditions - Other (cold and clammy); Syncope  
 
• 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Also Reported on MoAb 14.18, 
chimeric Trials But With Insufficient Evidence for Attribution: 
Hypocalcemia 
• 
Changed to Rare but Serious from Also Reported on MoAb 
14.18, chimeric Trials But With Insufficient Evidence for 
Attribution: Myelitis; Reversible posterior 
leukoencephalopathy syndrome; Sudden death NOS 
 
• 
A typo in the word “a typical” has been corrected to “atypical.” 
 
Minor administrative edits have been made throughout the section, and 
information about investigator brochure availability and useful links and contacts 
have been added. 
 
 
 
 
SUMMARY OF CHANGES: INFORMED CONSENT 
In accordance with the above discussion, the following specific revisions have been made to the consent. Additions are 
in boldfaced font and deletions in strikethrough font. 
 
# 
Section 
Page(s) 
Change 
1. 
 
All 
 
The version date in the footer has been updated.  
2. 
 
Risks of Study 
7 
Updated the section to reflect the current NCI Consent Form Template, 
including the following wording requested in the RRA: 
 
“If you choose to take part in this study, there is a risk that: 
• 
You may lose time at work or home and spend more time in 
the hospital or doctor’s office than usual 
• 
You may be asked sensitive or private questions which you 
normally do not discuss 
 
The MoAb 14.18, chimeric used in this study may affect how different 
parts of your body work such as your liver, kidneys, heart, and blood. 
The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study 
drug(s)/study approach. 


 
iii 
 
 
Here are important points about side effects: 
• 
The study doctors do not know who will or will not have side 
effects. 
• 
Some side effects may go away soon, some may last a long 
time, or some may never go away. 
• 
Some side effects may interfere with your ability to have 
children. 
• 
Some side effects may be serious and may even result in 
death. 
 
Here are important points about how you and the study doctor can make 
side effects less of a problem: 
• 
Tell the study doctor if you notice or feel anything different so 
they can see if you are having a side effect. 
• 
The study doctor may be able to treat some side effects. 
• 
The study doctor may adjust the study drugs to try to reduce 
side effects. 
 
The tables below show the most common and the most serious side 
effects that researchers know about. There might be other side effects 
that researchers do not yet know about. If important new side effects 
are found, the study doctor will discuss these with you.” 
3. 
 
Possible Side 
Effects of MoAb 
14.18, Chimeric 
(dinutuximab) 
8 
Updated the consent risk profile for MoAb 14.18, chimeric to reflect the current 
CAEPR. The specific changes are as follows: 
 
• Increase in Risk Attribution: 
• 
Changed to Rare from Also Reported on MoAb 14.18, 
chimeric Trials But With Insufficient Evidence for Attribution 
(i.e., added to the Risk Profile): Death; Swelling of the spinal 
cord; Brain damage which may cause headache, seizure, 
blindness (also known as Reversible Posterior 
Leukoencephalopathy Syndrome).  
 
• Provided Further Clarification: 
• 
Anemia which may cause tiredness, or may require blood 
transfusion (under Occasional) and Anemia, kidney 
problems which may cause swelling, or may require 
dialysis (under Rare) are now reported as Anemia, kidney 
problems which may cause tiredness, or may require 
blood transfusion or dialysis (under Occasional). 
• 
High blood pressure which may cause headaches, 
dizziness, blurred vision (under Occasional) is now 
reported as High blood pressure which may cause 
dizziness, blurred vision (under Occasional).  
 


ANBL1221 
Version Date: 05/18/2017 
 
Page 1 
 
Activated: 
02/04/13 
Version Date:  
05/18/2017 
Closed: 
 
Amendment: 
#6 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
ANBL1221 
 
 
A Phase II Randomized Trial of Irinotecan/Temozolomide with Temsirolimus (NSC# 683864, 
IND# 61010) or Chimeric 14.18 Antibody (ch14.18) (NSC# 764038, IND# 4308) in Children with 
Refractory, Relapsed or Progressive Neuroblastoma  
 
 
 
A Groupwide Phase II Study 
 
NCI Supplied Agents: Chimeric 14.18 Antibody (ch14.18, dinutuximab) (NSC# 764038, 
IND# 4308)  
 
IND sponsor for ch14.18 (dinutuximab): DCTD, NCI 
 
 
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 
Rajen Mody, MD, MS 
Hematology/Oncology  
C.S. Mott Children’s Hospital 
Div. of Pediatric Hematology/Oncology 
1500 East Medical Center Drive 
D4202 Med Professional Building 
Ann Arbor, MI 48109-5718 
Phone: (734) 232-9335 
Fax: 
(734) 615-0464 
E-mail: rmody@umich.edu 


 
 
 
ANBL1221 
Version Date: 05/18/2017 
 
Page 2 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
6 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Objective 
11 
1.2 
Exploratory Objectives 
11 
2.0 
BACKGROUND 
12 
2.1 
Introduction/Rationale for Development 
12 
2.2 
Rationale for Irinotecan and Temozolomide Chemotherapy Backbone 
12 
2.3 
Rationale for mTOR Inhibition in Pediatric Solid Tumors 
13 
2.3.1 
Pre-Clinical Studies 
13 
2.3.2 
Clinical Experience with Temsirolimus 
14 
2.3.3 
Rationale for closure of Regimen A (Amendment #5) 
15 
2.4 
Rationale for GD2 Directed Therapy 
16 
2.4.1 
Pre-Clinical Studies 
16 
2.4.2 
Clinical Studies using anti-GD2 Antibodies 
16 
2.4.3 
Combination of ch14.18 (dinutuximab) with chemotherapy 
16 
2.4.4 
Use of monoclonal antibodies with chemotherapy in clinical trials in adults 
17 
2.5 
Transition from NCI Manufactured Ch14.18 to UTC Manufactured Ch14.18 
(dinutuximab) 
17 
2.6 
Rationale for Further Study of Regimen B 
18 
2.7 
Additional Studies 
18 
2.7.1 
Rationale for studying naturally occurring anti-glycan antibodies 
18 
2.7.2 
Rationale for NK cell receptor NKp30 isoform 
18 
2.7.3 
Rationale for KIR/KIR-L genotyping 
19 
2.7.4 
Rationale for Fc receptor genotyping 
19 
2.7.5 
Rationale for HACA testing 
19 
2.7.6 
Rationale for immune function studies 
20 
2.7.7 
Rationale for assessment of the tumor microenvironment 
20 
2.7.8 
Rationale for analysis of gene expression studies 
20 
2.7.9 
Rationale for analysis of circulating GD2 levels 
21 
2.7.10 Rationale for tumor exome and transcriptome sequencing 
21 
2.7.11 Revised International Neuroblastoma Response Criteria 
21 
2.8 
Development Plans 
22 
2.8.1 
Importance of trial and impact on future clinical practice 
22 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
22 
3.1 
Study Enrollment 
22 
3.1.1 
Patient Registration 
22 
3.1.2 
IRB Approval 
23 
3.1.3 
Reservation Requirements 
23 
3.1.4 
Study Enrollment 
24 
3.1.5 
Timing 
24 
3.2 
Patient Eligibility Criteria 
24 
3.2.1 
Age 
25 


 
 
 
ANBL1221 
Version Date: 05/18/2017 
 
Page 3 
3.2.2 
Disease Status 
25 
3.2.3 
Performance Level 
25 
3.2.4 
Prior Therapy 
26 
3.2.5 
Concomitant Medications Restrictions 
26 
3.2.6 
Organ Function Requirements 
26 
3.2.7 
Exclusion Criteria 
28 
3.2.8 
Regulatory Requirements 
29 
4.0 
TREATMENT PROGRAM 
30 
4.1 
Overview of Treatment Plan 
30 
4.1.1 
Concomitant Medications and Supportive Care 
30 
4.2 
Patients on Regimen B: Irinotecan/Temozolomide with ch14.18 (dinutuximab) 
31 
4.2.1 
Regimen B: Irinotecan and Temozolomide with ch14.18 (dinutuximab) -           
Cycle 1 
35 
4.2.2 
Regimen B: Irinotecan and Temozolomide with ch14.18 (dinutuximab) -       
Therapy post Cycle 1 
36 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
37 
5.1 
Dose Modifications for Hematologic Toxicity 
37 
5.1.1 
Dose-limiting neutropenia 
37 
5.1.2 
Dose-limiting thrombocytopenia 
37 
5.1.3 
Delayed recovery of platelets and neutrophils 
37 
5.2 
Dose Modifications for Non-hematologic Toxicity 
37 
5.2.1 
Dose modifications for diarrhea 
37 
5.2.2 
Dose modifications for nausea and vomiting 
37 
5.2.3 
Dose modifications for dehydration 
38 
5.2.4 
Dose modifications for elevations in ALT, AST, or GGT 
38 
5.2.5 
ch14.18 (dinutuximab)/GM-CSF specific dose modifications and toxicity 
management recommendations 
38 
5.2.6 
Management of GM-CSF related toxicities 
43 
6.0 
DRUG INFORMATION 
43 
6.1 
CHIMERIC MONOCLONAL ANTIBODY 14.18    (05/12/17) 
43 
6.2 
IRINOTECAN         (05/09/11) 
51 
6.3 
SARGRAMOSTIM        (04/16/14) 
52 
6.4 
TEMOZOLOMIDE        (06/30/14) 
54 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
57 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
57 
7.1.1 
Required and optional studies for all patients 
57 
7.2 
Follow-up 
58 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY      
CRITERIA 
58 
8.1 
Criteria for Removal from Protocol Therapy 
58 
8.2 
Off Study Criteria 
58 
9.0 
STATISTICAL CONSIDERATIONS 
58 
9.1 
Sample Size and Study Duration 
59 
9.2 
Endpoints 
60 
9.2.1 
Primary Endpoint 
60 
9.2.2 
Exploratory Endpoints 
60 
9.3 
Study Design and Interim Monitoring 
61 
9.3.1 
Randomization/Strata 
61 


 
 
 
ANBL1221 
Version Date: 05/18/2017 
 
Page 4 
9.3.2 
Safety Phase 
62 
9.3.3 
Stopping Rule for Tolerability 
62 
9.3.4 
Efficacy Phase 
64 
9.4 
Methods to Address Study Objectives 
65 
9.5 
Gender and Minority Accrual Estimates 
68 
10.0 
EVALUATION CRITERIA 
68 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
68 
10.2 
Response Criteria For Patients with CT/MRI Lesions 
68 
10.2.1 Definition of Measurable (Evaluable) Disease on CT/MRI Scan 
68 
10.2.2 Quantification of Disease Burden 
68 
10.2.3 End-of-Cycle Response 
68 
10.2.4 Overall Best Response Assessment 
69 
10.3 
Response Criteria for Morphologic Bone Marrow Disease 
69 
10.3.1 Bone Marrow Involvement 
69 
10.3.2 Overall Best Response Assessment 
70 
10.4 
Response Criteria for Patients with 123I-MIBG Positive Lesions 
70 
10.4.1 Critera for the Treating Institution 
70 
10.4.2 Critera for Central Review 
70 
10.4.3 Overall Best Response Assessment 
71 
10.5 
Definition of Overall Response for Each Patient 
71 
10.5.1 Complete Response (CR) 
71 
10.5.2 Very Good Partial Response (VGPR) 
71 
10.5.3 Partial Response (PR) 
72 
10.5.4 Progressive Disease (PD) 
72 
10.5.5 Stable disease (SD) 
72 
10.6 
Confirmation of Response Status Determined by MRI, CT, MIBG Scans or FDG-PET 
Scan by Central Review 
73 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
73 
11.1 
Purpose 
73 
11.2 
Determination of Reporting Requirements 
73 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
73 
11.4 
Special Situations for Expedited Reporting 
74 
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
74 
11.4.2 Persistent or Significant Disabilities/Incapacities 
74 
11.4.3 Death 
74 
11.4.4 Secondary Malignancy 
75 
11.4.5 Pregnancy, Fetal Death, and Death Neonatal 
75 
11.5 
Reporting Requirements for Specialized AEs 
76 
11.5.1 Baseline AEs 
76 
11.5.2 Persistent AEs 
76 
11.5.3 Recurrent AEs 
76 
11.6 
Exceptions to Expedited Reporting 
76 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
76 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
76 
11.7 
Reporting Requirements - Investigator Responsibility 
77 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
77 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
79 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
80 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated     
pathway 
80 


 
 
 
ANBL1221 
Version Date: 05/18/2017 
 
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11.12 Routine Adverse Event Reporting 
80 
12.0 
STUDY REPORTING AND MONITORING 
81 
12.1 
CDUS 
81 
12.2 
Data and Safety Monitoring Committee 
81 
12.3 
CRADA/CTA 
81 
13.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
83 
13.1 
Optional Biology Studies: Peripheral Blood 
83 
13.1.1 Prioritization of Blood Samples to be Used for Biology Studies 
83 
13.1.2 Peripheral blood sample collection and schedule 
83 
13.1.3 Sample Processing: Green and Red Top Tubes 
84 
13.1.4 Sample Labeling and Shipping: Green and Red Top Tubes 
84 
13.1.5 Subsequent Processing by Dr. Yu’s Lab 
85 
13.1.6 Sample Processing: PAX Gene Tubes 
85 
13.1.7 Sample Labeling and Shipping: PAXgene Tubes 
85 
13.1.8 Subsequent Processing by Dr. Asgharzadeh’s Lab 
86 
13.2 
Collection of Tumor Tissue and Bone Marrow-derived Tumor Cells 
86 
13.3 
Optional Biology Studies: Tumor Tissue 
86 
13.3.1 Specimen Collection and Labeling 
86 
13.3.2 Specimen Shipment 
86 
14.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
88 
14.1 
Timing of Imaging 
88 
14.2 
Imaging Required for Confirmation of Response Status 
88 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
90 
APPENDIX II:  TEMOZOLOMIDE DOSING (100 MG/M2) NOMOGRAM 
92 
APPENDIX III:  TEMOZOLOMIDE REDUCED (75 MG/M2) DOSING NOMOGRAM 
94 
APPENDIX IV:  RECOMMENDATIONS FOR ADMINISTRATION OF TEMOZOLOMIDE 
95 
APPENDIX V:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
96 
APPENDIX VI:  POSSIBLE DRUG INTERACTIONS 
98 
APPENDIX VII:  RECOMMENDED PROCEDURE FOR PERFORMING MIBG SCANS 
100 
APPENDIX VIII  YOUTH INFORMATION SHEETS 
101 
REFERENCES 
103 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANBL1221 
Version Date: 05/18/2017 
 
Page 6 
 
STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Rajen Mody, MD MS 
Nikki Jane Briegel, BPh PharmD 
Hematology/Oncology 
Pharmacy 
C S Mott Children's Hospital 
Princess Margaret Hospital for Children 
Pediatrics/Hematology - Oncology 
Dept of Pharmacy 
1500 East Medical Center Drive 
GPO Box D184 
D4202 MPB 
Subiaco 
Ann Arbor, MI 48109-5718 
Perth, WA 6001 
Phone: (734) 232-9335 
Australia 
Fax: 
(734) 615-0464 
Phone: (618) 9340-8875 
Email: rmody@med.umich.edu 
Fax: 
(618) 9340-8710 
 
Email: nikki.briegel@health.wa.gov.au 
STUDY VICE CHAIR 
 
Rochelle Bagatell, MD 
Joy Bartholomew, MSN CS FNP  
Hematology/Oncology 
Nursing 
Children's Hospital of Philadelphia 
Children's Mercy Hospitals and Clinics 
Oncology 
Hem/Onc 
CTRB 4022 
2401 Gillham Road 
3501 Civic Center Blvd 
Kansas City, MO 64108 
Philadelphia, PA 19104 
Phone:  (816) 234-3297 
Phone: (267) 426-9737 
Fax:  
(816) 855-1726 
Fax: 
(267) 425-0311 
Email:  joyb@cmh.edu 
Email: bagatellr@email.chop.edu 
 
 
Meredith S. Irwin, MD  
STATISTICIAN 
Hematology/Oncology 
Arlene Naranjo, PhD 
Hospital for Sick Children 
Biostatistics 
Hematology/Oncology 
Children's Oncology Group - Data Center (Gaines) 
555 University Avenue 9th Floor 
UFL -Dept of Biostatistics 
Toronto, ON M5G 1X8 
6011 NW 1st Place 
Canada 
Gainesville FL 32607 
Phone: (416) 813-7654 x302912 
Phone: (352) 273-0577 
Fax: 
(416) 813-5327 
Fax: 
(352) 392-8162 
Email: meredith.irwin@sickkids.ca 
E-mail: anaranjo@cog.ufl.edu 
 
 
Howard Mark Katzenstein, MD  
STUDY COMMITTEE MEMBERS 
Hematology/Oncology 
Wendy B. London, PhD 
Vanderbilt University/Ingram Cancer Center 
Dana Farber/Harvard Cancer Center 
Hematology/Oncology 
Pediatric Hematology/Oncology 
2220 Pierce Avenue, Room 397 PRB 
Pediatric Hematology/Oncology 
Nashville, TN 37232-6310 
Dana 3 
Phone: (615) 936-1762  
450 Brookline Avenue 
Fax: 
(615) 936-1767 
Boston, MA 02215 
Email: howard.katzenstein@vanderbilt.edu 
Phone: (617) 632-4895 
 
Fax: 
(617) 730-0934 
Julia Glade Bender, MD 
Email: Wendy.London@childrens.harvard.edu 
Hematology/Oncology 
 
Columbia University/Herbert Irving Cancer Center 
 
Pediatric Oncology 
 
161 Fort Washington Avenue-IP7 
 
New York, NY 10032 
 
Phone: (212) 305-5808 
 
Fax: 
(212) 305-5848 
 
Email: jg589@cumc.columbia.edu 


 
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STUDY COMMITTEE MEMBERS 
STUDY COMMITTEE MEMBERS 
John M. Maris, MD  
Paul M. Sondel, MD PhD  
Hematology/Oncology 
Hematology/Oncology 
Children's Hospital of Philadelphia 
University of Wisconsin Hospital and Clinics 
The Colket Translation Research Building 
Dept of Pediatric Hem-Onc 
3501 Civic Center Boulevard, 3060 
4159 WIMR Bldg. 
Philadelphia, PA 19104 
111 Highland Ave 
Phone: (215) 590-5244 
Madison, WI 53792 
Fax: 
(267) 426-0685 
Phone: (608) 263-9069 
Email: maris@chop.edu 
Fax: 
(608) 263-4226 
 
Email: pmsondel@wisc.edu 
Julie Ruggieri Park, MD 
 
Hematology/Oncology 
Alice Yu, MD PhD  
Seattle Children's Hospital 
Pediatric Hematology/Oncology 
Dept of Hematology/Oncology 
Rady Children's Hospital  
M/S MB.8.501, PO Box 5371 
University of California, San Diego Medical Center 
Seattle, WA 98145 
200 West Arbor Dr. (8447) 
Phone: (206) 987-2106 
San Diego, CA 92103-8447 
Fax: 
(206) 987-3946 
Phone: (619) 543-2438 
Email: julie.park@seattlechildrens.org 
Fax: 
(619) 543-5413 
 
Email: aliceyu@ucsd.edu 
Joyce Kay Satarino, CCRP 
 
Clinical Research Associates 
Barry Lynn Shulkin, MD 
C S Mott Children's Hospital 
Diagnostic Imaging 
Dept of Ped Hem-Onc 
Saint Jude Children's Research Hospital 
1500 E Medical Ctr Dr 
Radiological Sciences 
D4202 MPB 
262 Danny Thomas Place, MS 220 
Ann Arbor, MI 48109-5718 
Memphis, TN 38105-3678 
Phone: (734) 763-6344 
Phone: (901) 595-3347 
Fax: 
(734) 615-0464 
Fax: 
(901) 595-3981 
Email: jsatarin@med.umich.edu 
Email: barry.shulkin@stjude.org 
 
 
Marguerite T. Parisi, MD 
Dr. Sabah-E-Noor Servaes, MD 
Diagnostic Imaging 
Diagnostic Imaging 
Seattle Children's Hospital 
Children's Hospital of Philadelphia 
Radiology  
Radiology 
M/S MA.7.220 
3rd Floor Main 
PO Box 5371 
34th & Civic Center Blvd 
Seattle WA 98145 
Philadelphia PA  19104 
Phone: (206) 987-2134 
Phone: (267) 425-7135 
Fax: 
(206) 987-2730 
Email: servaes@email.chop.edu 
Email: meg.parisi@seattlechildrens.org 
 
 
Shahab Asgharzadeh, MD 
Collin James McCauley Van Ryn, MS  
Children's Hospital of Los Angeles 
COG Data Center 
Hematology/Oncology 
Biostatistics 
4650 Sunset Blvd. #57 
University of Florida 
Los Angeles CA 90027 
6011 NW 1st Place 
Phone: 323 660-2450 x5101 
Gainesville, FL 32607 
Fax: 
323 664-9455 
Phone:  (352) 273-0571 
Email: shahab@chla.usc.edu 
Fax:  
(352) 392-8162 
 
Email:  cvanryn@cog.ufl.edu 
 
 
 
 
 
 
 


 
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RESEARCH COORDINATOR 
 
Mary Bancroft 
 
Children's Oncology Group 
AGENT 
NSC# 
IND# 
Biostatistics 
ch14.18 (dinutuximab) 
764038 
4308 
6011 NW 1st Place 
GM-CSF 
613795 
Exempt 
Gainsville, FL 32607 
Irinotecan 
616348 
Exempt  
Phone: (352) 273-0555 
Temozolomide 
362856 
Exempt 
Fax: 
(352) 392-8162 
 
E-mail: mbancroft@cog.ufl.edu 
 
 
IND sponsor for ch14.18 (dinutuximab):DCTD, NCI 
 
 
 
SEE SECTION 13.0 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 
Long-term survival rates for children with high-risk neuroblastoma remain poor. In addition, survivors 
experience significant immediate and late toxicities limiting further dose intensification with conventional 
chemotherapy agents. Novel biological therapies are therefore needed. This “Pick the Winner” Phase II 
study is designed to compare the response rates (RR) and progression free survival (PFS) for patients with 
refractory, relapsed or progressive neuroblastoma receiving temsirolimus or ch14.18 (dinutuximab) in 
combination with irinotecan and temozolomide. The irinotecan and temozolomide combination has shown 
activity against relapsed/refractory neuroblastoma. Furthermore, its favorable toxicity profile makes it an 
attractive backbone chemotherapy regimen for assessment of the contribution of novel molecularly targeted 
agents. Neuroblastoma cells have shown sensitivity to mTOR inhibitors both in vitro and in vivo. mTOR 
inhibitors have also been shown to have synergistic or additive effects when combined with several 
conventional chemotherapeutic drugs, including those frequently used in the treatment of neuroblastoma. 
The combination of irinotecan and temozolomide with the mTOR inhibitor temsirolimus is well tolerated 
in children, and this 3-drug regimen will comprise one regimen of this study. The second regimen will 
include irinotecan and temozolomide in combination with the chimeric anti-GD2 antibody ch14.18 
(dinutuximab). The disialoganglioside GD2 is expressed on neuroblastoma cells, but its expression in 
normal human tissues is limited. A randomized Phase III study (COG ANBL0032) compared the event free 
survival of patients with high risk neuroblastoma treated with ch14.18 (dinutuximab) combined with GM-
CSF, interleukin 2 and isotretinoin to that of patients treated with isotretinoin alone as post-consolidation 
therapy. Randomization was stopped early because of superior survival associated with the antibody-
containing regimen. Preclinical studies of anti-GD2 antibodies combined with cytotoxic chemotherapy 
have shown synergistic or additive effects on neuroblastoma cells. These data support evaluation of the 
addition of ch14.18 (dinutuximab) to chemotherapy for children with refractory, relapsed or progressive 
neuroblastoma. The agent selected for further study as a result of this trial will be integrated into frontline 
induction therapy for future patients with high-risk neuroblastoma.   
 
 
 


 
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Disease re-evaluation after Cycle 4 and 6, and every 4 cycles thereafter. May continue therapy up 
to a maximum of 17 cycles in total in the absence of PD or unacceptable toxicity. 
On Study 
Regimen B  
(Irinotecan/Temozolomide/ 
Ch14.18 (dinutuximab)/GM-CSF) 
 
2 cycles of therapy 
 
CR, PR or SD 
 
Continue therapy for up to 
15 additional cycles* 
 
Treatment Complete 
Off Protocol therapy 
 
Disease Evaluation  
 
Off protocol 
therapy 
 
PD 


 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
Specific hypothesis: 
The addition of a molecularly-targeted anti-cancer agent (temsirolimus or ch14.18, dinutuximab) to the 
chemotherapy backbone of irinotecan and temozolomide will be tolerable and will result in improved 
response rates in patients with refractory, relapsed or progressive neuroblastoma. 
 
1.1 
Primary Objective 
1.1.1 
To identify whether temsirolimus or ch14.18 (dinutuximab) is the optimal therapeutic agent to 
consider for further testing in a future Phase III randomized trial for treatment of newly diagnosed 
high-risk neuroblastoma.  
 
1.1.2 
To determine the response rate of patients with relapsed, refractory or progressive neuroblastoma 
following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab) and to compare this 
with the known response rate of patients treated with irinotecan and temozolomide alone. 
 
1.2 
Exploratory Objectives 
1.2.1 
To compare the response rates (RR) for patients receiving temsirolimus or ch14.18 (dinutuximab) 
in combination with irinotecan and temozolomide. 
 
1.2.2 
To compare the progression free survival (PFS) and overall survival (OS) rates for patients 
receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan and 
temozolomide. 
 
1.2.3 
To compare the toxicities associated with temsirolimus or ch14.18 (dinutuximab) when combined 
with irinotecan and temozolomide in patients with refractory, relapsed or progressive 
neuroblastoma. 
 
1.2.4 
To compare the ability to maintain intended dose intensity of all agents when temsirolimus or 
ch14.18 (dinutuximab) is combined with irinotecan and temozolomide in patients with refractory, 
relapsed or progressive neuroblastoma. 
 
1.2.5 
To determine the concordance between tumor responses as defined by standard International 
Neuroblastoma Response Criteria (INRC) versus response per the revised INRC.  
 
1.2.6 
To study the clinical relevance of naturally occurring anti-glycan antibodies in patients receiving 
ch14.18 (dinutuximab) antibody. 
 
1.2.7 
To study the clinical relevance of NK receptor NKp30 isoforms in patients receiving ch14.18 
(dinutuximab) antibody or temsirolimus. 
 
1.2.8 
To study the association between host factors and response to irinotecan, temozolomide and 
ch14.18 (dinutuximab).  
 
1.2.9 
To characterize the tumor immune-microenvironment (gene expression; immune effector cells, 
activities and signaling molecules; immune target expression) following treatment with irinotecan, 
temozolomide and ch14.18 (dinutuximab). 
 


 
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1.2.10 To study the association between changes in the tumor immune-microenvironment (gene 
expression; immune effector cells, activities and signaling molecules; immune target expression) 
with response following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab). 
 
1.2.11 To study the association between tumor genomic and transcriptomic aberrations as well as levels 
of circulating GD2 with response to irinotecan, temozolomide and ch14.18 (dinutuximab). 
 
 
2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
Neuroblastoma remains an important clinical problem, with approximately 50% of patients presenting with 
advanced-stage disease. Despite significant intensification of conventional chemotherapy regimens, the 
long-term survival rates for these children remain less than 40%.1 Significant immediate and late toxicities 
limit further dose intensification with conventional chemotherapy agents.2-4  
 
New therapeutic strategies must build upon our knowledge of neuroblastoma biology by combining 
molecularly targeted agents with conventional chemotherapeutic drugs. The COG ANBL0421 protocol was 
developed to both assess the anti-tumor activity of irinotecan/temozolomide in the setting of refractory or 
relapsed disease and, perhaps more importantly, to provide a backbone on which to integrate rationally 
selected molecularly targeted agents.5 The proposed Phase II ANBL1221 study builds from this strategy. 
The proposed biologic agents, temsirolimus and ch14.18 (dinutuximab), have activity against 
neuroblastoma in pre-clinical models and have demonstrated synergy with conventional cytotoxic 
chemotherapy in these models.6-9 Pediatric dosing and safety data exist for both agents10,11 and there is a 
strong rationale to proceed with the first prospective clinical trial to evaluate the combination of a 
molecularly targeted agent with conventional chemotherapy in the treatment of neuroblastoma. 
 
The primary objective of ANBL1221 is to use a randomized, Phase-II sequential and selection design12-14 
to identify whether temsirolimus or ch14.18 (dinutuximab) warrants further testing in a future upfront 
randomized Phase III clinical trial for treatment of high-risk neuroblastoma. Specifically, ANBL1221 will 
compare the response rate, toxicity, and feasibility of administration of temsirolimus or ch14.18 
(dinutuximab) when combined with a backbone chemotherapy regimen of irinotecan and temozolomide. 
As appropriate for a Phase II selection design trial,14,15 a standard irinotecan and temozolomide only control 
arm will not be included. Rather, the completed COG Phase II trial ANBL0421 will be used as a historical 
comparator for response rates and toxicity of irinotecan and temozolomide.  
 
2.2 
Rationale for Irinotecan and Temozolomide Chemotherapy Backbone 
Relapse following myeloablative therapy for neuroblastoma is almost invariably fatal, and thus no 
“standard” salvage regimen exists. The anti-neuroblastoma activity of irinotecan and temozolomide 
together with its tolerable toxicity profile make it a reasonable backbone chemotherapy regimen with which 
to assess the contribution of novel molecularly targeted agents in refractory/recurrent neuroblastoma. 
Irinotecan is a camptothecin prodrug that is metabolized to the active topoisomerase I poison SN-38. 
Temozolomide is an imidazotetrazine prodrug that undergoes hydrolysis to the active metabolite MTIC, 
which induces cytotoxicity by methylating DNA and generating O6-methylguanine adducts. The 
combination of irinotecan and temozolomide has been shown to be active in vitro and in vivo against 
neuroblastoma.16 
 
A Phase I trial conducted by Wagner and colleagues established the maximum tolerated doses (MTDs) of 
intravenous irinotecan together with oral temozolomide, and objective responses in patients with 
neuroblastoma were observed.17 The COG study ANBL0421 was a multicenter Phase II trial of irinotecan 


 
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plus temozolomide in the setting of refractory or relapsed neuroblastoma.5 A protracted schedule of 
irinotecan (10 mg/m2/dose administered IV for 5 consecutive days given each week for 2 weeks) in 
combination with temozolomide (100 mg/m2/dose) PO for 5 days, was used. Cycles of chemotherapy were 
repeated every 21 days. Fifty-five eligible patients were enrolled, and the objective response rate was 15%. 
Twenty nine patients (53%) had stable disease. The therapy was well tolerated as less than 5% of patients 
experienced ≥ Grade 3 diarrhea. Although 18% of patients with disease measurable by CT/MRI and 35% 
of patients with disease assessable only by MIBG and/or bone marrow aspirate/biopsy experienced ≥ Grade 
3 neutropenia during the first 3 cycles of therapy, less than 10% of all patients developed evidence of 
infection while neutropenic.5 The irinotecan + temozolomide combination is thus a backbone onto which 
newer, biologically based agents may be added for use in the relapse setting or as part of initial therapy.  
 
Two intravenous schedules of irinotecan have been studied in the treatment of refractory pediatric cancers: 
the daily x 5 days schedule and a protracted schedule of daily x 5 days for 2 consecutive weeks. ANBL0421 
made use of the protracted irinotecan schedule based upon xenograft data.18 Recent clinical data suggest 
that a shorter irinotecan administration schedule (daily x 5 for 1 week) maintains anti-tumor activity with 
less burden to the patient. A completed rhabdomyosarcoma study (COG ARST0121) showed no 
statistically significant difference in response rates comparing a daily x 5 schedule of IV irinotecan (50 
mg/m2/dose) to a daily x 5 x 2 week schedule (20 mg/m2/dose).19 The ANBL1221 trial will make use of a 
temozolomide dose of 100 mg/m2/dose PO x 5 days combined with IV irinotecan at a dose of 
50 mg/m2/dose x 5 days.  
 
The other backbone considered for use in this study was topotecan and cyclophosphamide. This 
combination was used in the POG/CCG 9642 study for patients with relapsed/refractory neuroblastoma.20 
For two reasons this regimen was not selected for incorporation into the current trial. First, the 25-30% 
response rate observed in the 9642 trial prompted incorporation of topotecan/cyclophosphamide into a pilot 
study (ANBL02P1) and subsequently into the most recent COG Phase III trial for patients with newly 
diagnosed high-risk neuroblastoma (ANBL0532). Therefore, most patients with high-risk neuroblastoma 
treated at COG centers who develop disease relapse will have received this combination during up-front 
therapy, making its use in the relapse setting sub-optimal. Second, the topotecan/cyclophosphamide 
regimen is associated with considerably higher rates of toxicity than is the irinotecan/temozolomide 
regimen. This is particularly important because the patients enrolled on the current trial will have already 
received the prolonged and intensive multimodality therapy that is presently standard of care for this 
disease. Nineteen percent of the patients treated with topotecan and cyclophosphamide on P9462 developed 
≥ Grade 3 infection, and there was one toxic death. Forty four percent had Grade 3 or 4 neutropenia, and 
60% had Grade 3 or 4 thrombocytopenia. In a study by the NANT consortium for a similar patient 
population, the combination of irinotecan (administered orally) and temozolomide was also tolerated very 
well.21 In this smaller study, only 7% of patients developed Grade 4 neutropenia and Grade 4 
thrombocytopenia, and 6% received blood product transfusions. As on the ANBL0421 study, dose-limiting 
diarrhea was rare. Thus, the combination of irinotecan and temozolomide is attractive for current-era 
patients with relapsed and refractory neuroblastoma both due to its acceptable toxicity profile and because 
previous exposure to this combination is expected to be considerably less frequent than prior exposure to 
topotecan/cyclophosphamide.  
 
2.3 
Rationale for mTOR Inhibition in Pediatric Solid Tumors 
 
2.3.1 
Pre-Clinical Studies 
When activated and associated with appropriate members of a functional complex, mTOR plays an 
important role in regulation of protein synthesis, cell growth, and proliferation.22 Rapamycin and rapamycin 
analogs form complexes with mTOR and FK506-binding protein, leading to inhibition of mTOR signaling. 
The Pediatric Preclinical Testing Program (PPTP) has evaluated the single-agent activity of an mTOR 


 
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inhibitor (rapamycin) using a standardized testing system comprised of over 30 models representing the 
major pediatric solid tumor types.23 Inhibition of cell growth/proliferation following exposure to rapamycin 
was variable across the cell lines tested in vitro. Objective responses to rapamycin were seen in 4 of 36 in 
vivo solid tumor models. Growth inhibition following administration of rapamycin was seen in a 
neuroblastoma model, though an objective response was not observed in the PPTP experiments.23 Other 
investigators have also shown that neuroblastoma cells are sensitive to mTOR inhibitors both in vitro and 
in vivo.6 
 
mTOR inhibitors have been shown to have synergistic or additive effects when combined with several 
conventional chemotherapeutic drugs, including those frequently used in the treatment of pediatric 
malignancies.24,25 Rapamycin has been shown to have synergistic antiproliferative effects in vitro when 
combined with carboplatin, and additive effects were observed when rapamycin was combined with 
doxorubicin.24 In vivo, treatment with rapamycin in combination with doxorubicin resulted in greater 
inhibition of angiogenesis and tumor growth than did exposure to either agent administered alone.25 
Similarly, Teachey and colleagues have shown that the combination of methotrexate and the mTOR 
inhibitor temsirolimus resulted in long term disease control in a xenograft model of human acute leukemia 
while each agent alone provided only short term disease control.26 Rapamycin has also been shown to 
reverse resistance to topotecan and mitoxantrone in a breast cancer model.27 Furthermore, rapamycin has 
been shown to sensitize tumors to irinotecan in xenograft models of colon cancer. Marked decreases in 
tumor volume were observed following exposure to irinotecan + rapamycin.28 Residual masses evaluated 
following exposure to the combination were found to have extensive necrosis and fibrosis.28 Taken together, 
these data suggest that the combination of an mTOR inhibitor with chemotherapy, including irinotecan, 
may be a promising strategy for treatment of solid tumors. 
 
2.3.2 
Clinical Experience with Temsirolimus 
 
2.3.2.1 Adult Studies with Temsirolimus: 
In a Phase I study of temsirolimus given as a weekly infusion, 24 adults received doses ranging 7.5 to 
220 mg/m2.29 Grade 3 thrombocytopenia was observed in a patient treated at a dose of 34 mg/m2 and in a 
patient treated at a dose of 45 mg/m2. Dose escalation continued without additional dose-limiting toxicity 
up to a dose of 220 mg/m2. Toxicities noted at that dose level included manic-depressive syndrome, 
stomatitis, and asthenia in 2 of 9 patients. The most frequent drug-related toxicities were rashes and 
mucositis or stomatitis. Toxicities were reversible upon discontinuation of treatment.29  
 
A Phase II study of temsirolimus in adults with relapsed or refractory mantle cell lymphoma has been 
conducted.30 Thirty-five patients were treated with this agent at a dose of 250 mg IV weekly. Objective 
responses were seen in 13 of 34 patients (one CR and 12 PR). The median time-to-progression in all patients 
was 6.5 months, and the median duration of response for the responders was 6.9 months. Hematologic 
toxicities were common, and thrombocytopenia was the most frequent cause of dose reductions. The 
thrombocytopenia was brief, however, with resolution typically observed within one week.30  
 
In a multicenter, Phase III trial in patients with poor prognosis renal cell carcinoma, 626 patients were 
randomized to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an 
increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of 
temsirolimus weekly plus 6 million U of interferon alfa three times weekly.31 Patients who received 
temsirolimus alone had longer overall survival and progression-free survival than those who received 
interferon alone or interferon + temsirolimus. Rash, peripheral edema, hyperglycemia, and hyperlipidemia 
were more common in the temsirolimus group; asthenia was more common in the interferon group.31 There 
were fewer patients with serious adverse events in the temsirolimus group than in the interferon group. 
Following an interim analysis of the data from this study, temsirolimus was approved by the FDA for the 
treatment of advanced renal cell carcinoma.31  


 
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Data from studies of temsirolimus as a component of multi-agent therapy are emerging. Concerns regarding 
an increased risk of infection were raised after a patient with glioblastoma multiforme developed fatal 
pneumocystis pneumonia following administration of temsirolimus in combination with temozolomide and 
radiotherapy.32 Antibiotic prophylaxis was subsequently mandated for patients on this trial. Two other 
patients developed fatal gram negative sepsis during the study, and the investigators note that there appeared 
to be an increased risk of opportunistic infections in patients treated with the combination regimen 
compared with the population of patients treated with temsirolimus as a single agent.32  
 
Although administration of weekly temsirolimus in combination with paclitaxel and carboplatin in patients 
with advanced solid tumors was not feasible due to myelosuppression, a regimen including all 3 drugs on 
Day 1 followed by temsirolimus (25 mg) on Day 8 of a 3 week cycle was well-tolerated. Toxicities 
associated with this regimen did not differ substantially from those associated with carboplatin and 
paclitaxel alone.33  
 
2.3.2.2 Pediatric Studies with Temsirolimus: 
A pediatric Phase I study of single agent temsirolimus in patients with recurrent solid tumors has been 
completed.10 Nineteen patients were enrolled on study. Dose limiting toxicities at 150 mg/m2 included 
Grade 4 thrombocytopenia and Grade 3 anorexia. Other Grade 3 or 4 toxicities included leukopenia (17%), 
anemia (11%), neutropenia (22%) and elevated ALT. A dose of 75 mg/m2 weekly IV was recommended 
for study in the Phase II pediatric setting.10 The results of the pediatric Phase II single agent trial of 
temsirolimus have also been published. Among the 19 children with neuroblastoma treated on this study, 
one experienced a partial response while 6 were found to have stable disease. Five of these patients 
experienced stable disease or better for more than 6 months.34  
 
COG ADVL0918 is a Phase I study of irinotecan, temozolomide, and temsirolimus. Irinotecan 
(90 mg/m2/dose) and temozolomide (dose being escalated stepwise from 100 to 150 mg/m2/dose) are both 
given orally on a daily x 5 days schedule. Doses of temsirolimus are delivered intravenously on Days 1 and 
8 of a 3-week cycle. The 3-drug combination was well tolerated when temsirolimus was given at doses up 
to 35 mg/m2/dose. Observed toxicities included neutropenia, thrombocytopenia, lymphopenia, 
nausea/vomiting, mucositis, and elevated transaminases. Following administration of fixed doses of 
irinotecan and temozolomide in combination with 25 mg/m2/dose temsirolimus, 2 patients who had been 
receiving chronic steroids developed dose-limiting hyperlipidemia.  
 
The study was amended to preclude enrollment of children who require chronic steroid administration, and 
dose-limiting lipidemia was not observed at this or subsequent dose levels. The combination of a 
temsirolimus dose of 35 mg/m2/dose in combination with irinotecan (90 mg/m2/dose daily x 5 days) and 
temozolomide (100 mg/m2/dose daily x 5 days) has been shown to be well tolerated, and this dose of 
temsirolimus will be used in this study. 
 
Among 39 evaluable patients with solid tumors treated with these drug doses, 4 have had objective 
responses to protocol therapy. A total of 10 patients with neuroblastoma had been enrolled as of May 2012. 
One of these children experienced a prolonged partial response (14 cycles; confirmed by central review) 
and 2 experienced stable disease for >7 months.35 
 
2.3.3 
Rationale for closure of Regimen A (Amendment #5) 
A total of 18 eligible patients were randomized to ANBL1221 Regimen A during Stage 1 of the activity 
design. The regimen was found to be safe and feasibility was demonstrated, however only 1 objective 
response (PR) was observed. As per Section 9.3.4 of this protocol, if there are 3 or fewer responders on a 
given regimen, this constitutes insufficient evidence of activity for the regimen. For this reason, there will 
be no further enrollments to Regimen A. 


 
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2.4 
Rationale for GD2 Directed Therapy 
 
2.4.1 
Pre-Clinical Studies 
The disialoganglioside GD2 is expressed on neuroblastoma cells, but its expression in normal human tissues 
is restricted to neurons, skin melanocytes and peripheral pain fibers.36-38 Because of this pattern of 
expression, anti-GD2 monoclonal antibodies are an attractive form of targeted immunotherapy for children 
with neuroblastoma. Over the past 3 decades, antibodies directed against GD2 have been studied 
extensively. Early studies were performed using the murine IgG3 monoclonal antibody 3F8.36,37 and murine 
IgG2a,14G2a.39,40 3F8 has been shown to mediate very efficient antitumor antibody dependent cytotoxicity 
(ADCC) in vitro in the presence of GM-CSF.41 However, murine antibody therapy can be accompanied by 
development of a human anti-mouse antibody response (HAMA), which results in the formation of 
neutralizing antibodies. This can be particularly problematic in patients who have not received high dose 
chemotherapy or undergone myeloablative treatment within 90 days preceding murine antibody 
treatment.42 To address this challenge, alternative antibody constructs have been developed. Ch14.18 
(dinutuximab) consists of the variable regions of murine IgG3 b 14.18 and the constant regions of human 
IgG1-κ. Pharmacokinetic and immunological studies have shown that ch14.18 (dinutuximab) has longer 
plasma half life and less immunogenicity when compared to the murine antibody, making it potentially 
more effective.11,43 Preclinical studies performed both in vitro and in vivo indicate that its anti-
neuroblastoma activity involves complement dependent cytotoxicity (CDC) and ADCC when ch 14.18 is 
used alone44 or in combination with GM-CSF.45  
 
2.4.2 
Clinical Studies using anti-GD2 Antibodies 
The murine anti-GD2 antibody 3F8 was tested in a Phase I trial in patients with neuroblastoma, and in a 
Phase II trial of 3F8 in combination with GM-CSF. The 2 agent combination appeared to have efficacy, 
especially in patients with bone marrow disease.46 Phase I and II clinical trials of ch14.18 (dinutuximab) or 
14G2a, alone or combined with cytokines such as GM-CSF or IL2 respectively, also showed signals of 
activity in patients with neuroblastoma.47,48 Subsequent clinical trials have demonstrated a significant 
decrease in risk of relapse and an improvement in survival for patients with high risk neuroblastoma in 
remission after initial multi-modality therapy. An early analysis of results of a German study of ch14.18 
(dinutuximab) therapy alone administered to patients > 1 year of age with Stage 4 neuroblastoma did not 
demonstrate a decrease in recurrence risk compared to no further therapy.49 However, analyses at 9 years 
from therapy revealed a statistically significant improvement in EFS for those patients who received 
ch14.18 (dinutuximab).50 A randomized Phase III study (COG ANBL0032) of ch14.18 (dinutuximab) 
combined with GM-CSF, interleukin 2 and isotretinoin compared with isotretinoin alone as post-
consolidation therapy for patients in remission was stopped early because the EFS of patients treated with 
the antibody containing regimen was clearly superior to that of patients treated with isotretinoin alone.51 
Thus, although few patients with measurable bulk disease experienced objective responses to ch14.18 
(dinutuximab) as a single agent in early phase clinical trials, ch14.18 (dinutuximab) plus cytokine therapy 
is now considered standard post-consolidation care for patients with high-risk neuroblastoma. 
 
The clinical evaluation of various anti-GD2 monoclonal antibodies in children with neuroblastoma has been 
largely focused on treatment of minimal residual disease to date. However, several studies conducted in 
adults with cancer suggest that monoclonal antibodies can be effectively combined with chemotherapy to 
treat patients, including those with measurable disease.52-59  
 
2.4.3 
Combination of ch14.18 (dinutuximab) with chemotherapy 
In the currently proposed study, ch14.18 (dinutuximab) will be given in combination with irinotecan and 
temozolomide in an effort to augment the activity of the antibody in a setting other than that of minimal 
residual disease. Preclinical studies also indicate that anti-GD2 antibodies enhance the effects of 


 
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chemotherapy. This has been shown in a small cell lung cancer (SCLC) cell line60 and in a neuroblastoma 
cell line.61 In the first study with SCLC cell line, the combination of cisplatin (CDDP) with an anti-GD2 
mAb resulted in prominent enhancement of cytotoxicity even in cells with low to moderate GD2 expression. 
The anti-GD2 monoclonal antibody induced weak activation of c-Jun terminal kinase (JNK) in SCLC cells, 
and all anti-cancer drugs also induced its activation to various degrees. When CDDP and an anti-GD2 
antibody were used together, significantly augmented JNK activation was observed with corresponding 
cytotoxic effects, suggesting that synergistic phosphorylation of JNK with 2 reagents induced apoptosis. 
This study suggests that in addition to the ADCC, anti-GD2 antibodies induced direct apoptosis of SCLC 
cells.60 In a later study with a neuroblastoma cell line, the anti-GD2 14G2a antibody was found to have at 
least additive (carboplatin) or synergistic (doxorubicin, topotecan) effects on cell killing.61 These data 
provide compelling reasons to evaluate the addition of an anti-GD2 antibody to chemotherapy outside the 
setting of minimal residual disease for treatment of children with relapsed or refractory neuroblastoma. To 
optimize the effect of the antibody, GM-CSF will also be administered.   
 
2.4.4 
Use of monoclonal antibodies with chemotherapy in clinical trials in adults 
Rituximab, a chimeric monoclonal antibody directed against the B-cell specific antigen CD20, causes 
complement and antibody-dependent cell-mediated toxicity. The combination of rituximab with 
cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was associated with statistically 
significantly higher complete response rates in patients with diffuse large B-cell lymphoma compared to 
CHOP alone. The addition of rituximab to standard chemotherapy was shown to significantly decrease the 
risk of treatment failure and death among patients in this trial.62 Subsequent studies confirmed the 
contribution of rituximab in combination with CHOP in adults with lymphoma, and the long-term benefit 
of this combination has been demonstrated.52  
 
Although the mechanism of action of monoclonal antibodies that interfere with signal transduction within 
tumor cells is somewhat different from that of antibodies that mediate ADCC, the concept of using 
monoclonal antibodies together with chemotherapy is also supported by the trastuzumab and cetuximab 
experiences. Trastuzumab binds to the extracellular domain of the HER-2/neu receptor tyrosine kinase and 
disrupts receptor dimerization.63 This antibody has been successfully combined with chemotherapy 
(doxorubicin and cyclophosphamide) for women with HER-2 positive metastatic breast cancer for more 
than a decade, leading to increased response rate, prolonged progression free and overall survival.53 
Cetuximab is a chimeric antibody that binds to the epidermal growth factor receptor (EGFR) and 
competitively inhibits the binding of ligands including epidermal growth factor (EGF) and transforming 
growth factor alpha. Binding of cetuximab to the EGFR decreases activation of receptor-associated kinases 
and inhibits cell growth and proliferation.64 This agent is approved for use in combination with irinotecan 
in patients with EGFR-expressing metastatic colorectal cancer refractory to irinotecan-based therapy.65  
 
2.5 
Transition from NCI Manufactured Ch14.18 to UTC Manufactured Ch14.18 (dinutuximab)  
The investigational agent, chimeric monoclonal anti-GD2, ch14.18, used in ANBL0032 and ANBL1221 
was provided and manufactured by NCI since study activation in October 2001 and February 2013, 
respectively. 
 
As of January 21, 2014, the ch14.18, dinutuximab (NSC 764038) distributed by the NCI is manufactured 
by United therapeutics, Inc. The ch14.18 (NSC 623408) manufactured by the NCI is no longer being 
utilized in NCI sponsored protocols. The NCI has continued to distribute the agent through the 
Pharmaceutical Management Branch, under the same IND. However, the dosing calculation was adjusted 
in order to reflect the change from a theoretical extinction coefficient used by the NCI to a calculated 
extinction coefficient used by United Therapeutics. This adjustment was necessary in order to ensure the 
delivery of the same amount of ch14.18 (dinutuximab) as for those patients treated prior to Jan 21, 2014. 
 


 
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2.6 
Rationale for Further Study of Regimen B 
A total of 17 patients were randomized to Regimen B therapy. Sixteen of these received treatment while 
one declined therapy following randomization. During a safety phase in which 6 patients were treated, one 
patient experienced unacceptable toxicity as defined in Section 9.3.3. This patient experienced Grade 4 
hypoxia and required mechanical ventilation for more than 24 hours. Of the 16 patients treated with 
Regimen B therapy, 11 patients required dose modifications. Among these patients, five required 
temozolomide dose modifications. In one patient the dose was modified due to a formulation issue, and in 
one the temozolomide dose was modified due to emesis. In 3 patients temozolomide dosing was modified 
due to hematologic toxicity (neutropenia and thrombocytopenia), mostly during later cycles, however all 
patients continued protocol therapy uninterrupted. An additional six patients required dinutuximab dose 
modifications, including one patient with protocol-defined unacceptable toxicity, and one with Grade 4 
bronchospasm. In both cases protocol therapy was discontinued. The remaining four patients required 
dinutuximab dose modifications due to pain (two), infection (one) and hypotension (one). However these 
patients all continued therapy without toxicity that required additional dose modification. After review of 
the cases in which doses were modified, the study committee and the data safety monitoring committee 
determined that no changes in drug dosing as described in Section 4 are required. However, to further assess 
the feasibility of delivering this regimen, evaluation of toxicity in additional patients is needed. 
 
Response to therapy was also assessed. Analysis of data available as of January 15, 2016 shows that among 
the 17 patients assigned to Regimen B, nine had objective responses (5 CR, 4 PR). Responses were observed 
in patients with both relapsed/progressive disease (5/10; 3 PR, 2 CR) and refractory (4/7; 3 CR, 1 PR) 
disease. Among Regimen B responders, prior frontline therapy included high dose chemotherapy with stem 
cell rescue in 5 and anti-GD2 therapy in 3 patients. The protocol-defined minimum number of responses 
required to deem Regimen B worthy of additional study was exceeded during Stage 1. However, the 
confidence intervals around the 53% response rate for Regimen B are wide (95% CI: 0.31, 0.74). In 
addition, the small number of patients treated with Regimen B therapy precludes subgroup analyses that 
are important for application of the findings to the overall population of patients with neuroblastoma. To 
allow further study of feasibility and to more accurately estimate the response rate to this therapy, additional 
patients will be assigned to Regimen B to permit accrual of a total of 50 eligible patients.  
 
2.7 
Additional Studies 
2.7.1 
Rationale for studying naturally occurring anti-glycan antibodies 
Administration of ch14.18 (dinutuximab) is often associated with allergic reactions, which may occur even 
during the first infusion. Natural occurring antibodies to non-human glycans, galactose alpha-1,3-galactose 
(alpha-gal) and Neu5Gc, are present in all humans.66 Ch14.18 (dinutuximab), which is produced in rodent 
cells, contains alpha-gal and Neu5Gc. Levels of anti-alpha-gal have been correlated with allergic reactions 
to cetuximab (Erbitux), a chimeric antibody against the EGF receptor that is extensively modified with 
these glycans.67 Thus, it is possible that the presence and/or levels of antibodies to these non-human glycans 
may correlate with allergic reactions to ch14.18 (dinutuximab), and the levels of anti-glycan antibodies may 
increase after serial courses of immunotherapy. The presence and/or level of antibodies to non-human 
glycans may affect the blood levels of ch14.18 (dinutuximab) and ultimately impact response to therapy.   
 
2.7.2 
Rationale for NK cell receptor NKp30 isoform 
The natural killer (NK) cell receptor NKp30 is selectively expressed by all human NK-cells and plays an 
important role in triggering NK-mediated cytotoxicity. NKp30 is also involved in the cross-talk between 
NK and dendritic cells. The three NKp30 splice variants68 have been shown to be of prognostic significance 
in gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with 
NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct 
patterns of transcription of functionally different NKp30 isoforms. In individuals with GIST, predominant 
expression of the immunosuppressive NKp30c isoform (compared to the immunostimulatory NKp30a and 


 
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NKp30b isoforms) was associated with reduced survival, decreased NKp30-dependent tumor necrosis 
factor-α (TNF-α), IL10 and CD107a release, and defective secretions of interferon-γ (IFN-γ) and 
interleukin-12 (IL-12) in the NK-DC cross-talk that could be restored by blocking of IL-10.69 In a recent 
French study, an association between high levels of the immunosuppressive Nkp30c-isoform and worse 
prognosis (PFS p-value= 0.01) of patients with high risk neuroblastoma has been reported. No impact of 
the Nkp30a-isoform was noted.70 Treatment of glioblastoma patients with temsirolimus, temozolomide and 
radiation suppressed helper and cytotoxic T cells, B cells, and natural killer cells but increased numbers of 
regulatory T cells. These cells recovered to baseline levels during adjuvant temozolomide.71 Since NK 
cytotoxicity plays a major role in tumor immunity in general, and in anti-GD2-mediated tumor cell kill in 
particular, the impact of NKp30 isoforms including the NKp30c-isoform may be more pronounced in 
patients receiving either ch14.18 (dinutuximab) or temsirolimus therapy. 
 
2.7.3 
Rationale for KIR/KIR-L genotyping 
Killer-Immunoglobulin-like Receptors (KIR) recognize specific HLA molecules, regulate function of 
human NK cells and control their self-tolerance. The interactions between KIR on donor NK cells and KIR 
ligands (KIR-L) on recipient tissues influence anti-tumor efficacy of allogeneic hematopoietic stem cell 
transplantation, and influence the antitumor effects of autologous transplantation. Since the genes encoding 
KIR and KIR-L are inherited independently, it is possible for an individual to be KIR-receptor ligand 
mismatched with oneself. In a COG phase II study of 38 relapsed/refractory neuroblastoma receiving 
humanized anti-GD2 linked to IL2, 7 of 24 mismatched patients experienced either complete response or 
improvement of their disease after immunocytokine therapy, while there was no response or comparable 
improvement of disease in 14 patients who were matched (p = 0.03)72. These data suggest that patients with 
KIR receptor-ligand mismatch may be associated with better clinical response to immunotherapy with an 
anti-GD2 antibody. KIR and KIR ligand genotyping will therefore be performed as part of this trial. 
 
2.7.4 
Rationale for Fc receptor genotyping 
In general, the anti-tumor activities of unconjugated monoclonal antibodies require the contribution of 
either complement or Fcγ receptor (FcγR)-expressing effector cells in order to achieve tumor cell killing. 
However, because most tumor cells, including neuroblastoma, express increased amounts of complement-
inhibiting proteins that protect the cells against lysis by complement, antibody-dependent cell cytotoxicity 
(ADCC) is considered the key antitumor mechanism of therapeutic antibodies in vivo. Most natural killer 
(NK) cells, certain subpopulations of T lymphocytes, as well as monocytes and granulocytes are capable of 
mediating ADCC against antibody-coated targets via their expression of FcγR for IgG. The FcγR genes 
display polymorphisms that greatly influence the affinity of IgG for the Fcγ receptor. NK cells bearing the 
FcγRIIIa-158V/V allele mediate ADCC more effectively than those with F/F allele. Similarly, for FcγRIIA, 
the high-affinity H allele at 131 results in greater affinity of FcγRIIa for IgG, whereas the low-affinity R 
allele correlates with decreased binding. Fc receptor polymorphisms have been reported to influence the 
response of lymphoma to rituximab (anti-CD20)73,74. More recently the FcγRIIc molecules have also been 
shown to influence ADCC; polymorphisms at this locus can influence expression vs. lack of expression 
(function vs. lack of function) of this FcγRIIc.  Recently, it has been shown that an algorithm incorporating 
polymorphism data for FcγRIIa, FcγRIIIa and FcγRIIc is associated with clinical benefit in an 
immunotherapy trial for adults with renal cell carcinoma.75 Because dinutuximab is very effective in 
mediating ADCC, its efficacy in neuroblastoma may be associated with Fc receptor genotype. The 
association between Fc receptor genotype and response to irinotecan/temozolimide/dinutuximab therapy 
will be examined. 
 
2.7.5 
Rationale for HACA testing 
Analysis of samples from a Phase 1 trial of a humanized anti-GD2 antibody (hu14.18K322A) conducted at 
St. Jude Children’s Research Hospital76 has shown that sera obtained prior to therapy from 9 of 38 patients 
contained Pre-existing Anti-Therapeutic Antibodies (PATA) that reacted against the anti-GD2 antibody 


 
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although there subjects had no prior exposure to any monoclonal antibody. Initial analyses of the 
immunologic reactivity pattern of the sera from these 9 PATA+ patients revealed that these PATA are not 
anti-idiotypic antibodies against the therapeutic hu14.18K322A mAb. Unexpectedly, these PATA bound 
to other human IgG1 mAbs (rituximab, trastuzumab), pooled human IgG (Gammagard), and also to the 
anti-GD2 chimeric antibody dinutuximab. However, they did not bind to the parental mouse anti-GD2 mAb 
(14.G2a). The presence of PATA may be linked to patient outcome. Of the 38 initially evaluable patients, 
only 4 were known to be in remission or without progression 2.5 years following treatment. All 4 of these 
patients were among the 9 found to to PATA positive (p= 0.002). (Paul Sondel, personal communication) 
This preliminary observation requires further study, however it suggests that these PATA recognize a 
shared IgG1 epitope (also known as an antibody-allotype)77 that is found on most human IgG1 antibodies, 
but is “foreign” to the 9 PATA+ patients who may have been immunized via exposure to allo-IgG1 in prior 
transfusions). PATA/anti-alloantibodies may potentially augment the efficacy of tumor reactive therapeutic 
antibodies and may represent some of the antibody reactivity identified in prior “human anti-chimeric 
antibody (HACA)” assays. An understanding of the role of PATA/anti-allotype biology may aid in the 
selection of patients for GD2 directed immunotherapy. The association between results of testing for the 
presence HACA, anti-idiotype and PATA/anti-allotype antibody (not directed against the dinutuximab 
idiotype) with response to study therapy will be examined.  
 
2.7.6 
Rationale for immune function studies 
Understanding the state of the immune effector cells may be crucial to the design of future passive 
immunotherapies for cancer. Specifically, the number of NK and NK-T cells, T cell subsets and expression 
of NK activation and inhibitory receptors present in patient blood may have an association with clinical 
responses to immunotherapies, including dinutuximab.  In addition, cytokine levels may be important in 
understanding responses to immunotherapy for children with neuroblastoma. Cytokines released by cancer 
cells or by cells of the tumor microenvironment have a multitude of effects that can either promote tumor 
cell growth or can potentiate the effect of immunotherapy.78 In addition, proinflammatory cytokines have 
been linked to neuropathic pain. Therefore the association between serum cytokine levels (IL1, IL6, TNF-
alpha, IFN-gamma, etc) with toxicity and response to therapy merit evaluation.  
 
2.7.7 
Rationale for assessment of the tumor microenvironment 
Tumor-infiltrating leukocytes (TILs) can act as critical participants in tumor progression, and the presence 
of tumor-associated macrophages (TAMs) has been associated with poor prognosis in many adult cancers. 
In neuroblastoma, expression levels of genes related to M2 polarization of macrophages may be prognostic 
in patients with high-risk disease.79 The importance of inflammatory pathways in neuroblastoma 
progression reinforces the concept that the tumor microenvironment may be important in resistance to 
therapies including immunotherapies in neuroblastomas and other pediatric malignancies.80,81 In this study, 
the association between levels of infiltrating TILs (including TAMs) in tumor samples with response and 
outcome following dinutuximab and irinotecan/temozolomide will be examined. In addition, because 
immune checkpoint proteins CD274 (PDL1) and CD276 (B7H3) affect the activity of T and NK cells,82-84 
expression of these proteins in tumor samples will also be evaluated. Finally, expression of GD2 itself will 
also be assessed in tumor samples. 
 
2.7.8 
Rationale for analysis of gene expression studies   
Expression of immune response related genes may be predictive of ADCC and anti-tumor effect in patients 
treated with dinutuximab and irinotecan/temozolomide. RNA samples obtained prior to and following 
therapy and samples collected after administration of dinutuximab/irinotecan/temozolomide will be used 
for analysis of expression of a panel of genes related to immune function (including cell surface receptors, 
proteases, cytokines and cytokine receptors, cell cycle and protein kinases, etc) and for more global analysis 
via RNASeq. Gene expression studies will also include assessment of tumor burden in the circulating blood 
using the NB5 assay. This assay quantifies expression of CHGA, DCX, DDC, PHOX2B, and TH with a 
sensitivity of one tumor cell among 106 normal blood mononuclear cells.  The results of this assay can be 


 
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used to correlate expression of immune related genes to tumor burden levels. 
 
2.7.9 
Rationale for analysis of circulating GD2 levels 
The ganglioside composition of neuroblastoma cells was studied decades ago,85 yet much remains to be 
learned regarding the relationship between the presence of gangliosides on neuroblastoma cells (particularly 
GD2) and response to anti-GD2 based therapy. Because serial tumor sampling is not possible in young 
children receiving neuroblastoma therapy, methods for detection of GD2 shed from the surface of 
neuroblastoma cells have been developed. A high performance liquid chromatography (HPLC)/tandem 
mass spectrometry (MS/MS) assay for enhanced detection of GD2 in plasma and serum has recently been 
validated (A. Desai, personal communication). The level of GD2 detectable at baseline may be predictive 
of response to the combination of irinotecan, temozolomide and dinutuximab. Alternatively, changes in 
levels of GD2 following treatment with this combination may be more informative.  
 
2.7.10 Rationale for tumor exome and transcriptome sequencing 
Next generation sequencing studies have demonstrated that recurring genomic aberrations may have both 
prognostic and therapeutic significance in neuroblastoma.86 Recurrent molecular aberrations in tumor may 
provide critical insights into the basis for the differential response to irinotecan, temozolomide and 
dinutuximab. Available tumor samples collected for clinical purposes will be analyzed by deep exome 
sequencing and by transcriptome sequencing. To facilitate the analysis, results will be interpreted in the 
context of results from exome sequencing of DNA derived from peripheral blood. The number of patients 
to be studied in the proposed expanded cohort to be enrolled on this study is small, however findings from 
these sequencing studies together with results from studies described in the preceeding paragraphs may be 
critical in identifying future patients most likely to benefit from the combination of irinotecan, 
temozolimide and dinutuximab.  
 
2.7.11 Revised International Neuroblastoma Response Criteria 
The International Neuroblastoma (NB) Response Criteria (INRC) provide a common basis for comparisons 
of response across clinical trials conducted throughout the world. While these criteria have proven to be 
extremely helpful over time, they were last updated in 1993. Since that time, it has become apparent that 
the current INRC guidelines suffer from significant limitations, particularly with respect to definitions of 
response at metastatic sites (bone and bone marrow). The INRC provide limited guidance for incorporation 
of now-standard imaging modalities (123I-MIBG imaging), and they provide no guidance for incorporation 
of FDG-PET. Furthermore, the criteria that were applicable in the early to mid-1990s do not address modern 
techniques for quantification of marrow disease. A National Cancer Institute-sponsored international 
meeting was held in 2012 to develop updated consensus guidelines for assessment of response in patients 
with neuroblastoma. Data obtained from COG, New Agents for Neuroblastoma Therapy (NANT), Society 
of Paediatric Oncology European Neuroblastoma Network (SIOP-EN) and Gesellschaft für Pädiatrische 
Onkologie und Hämatologie (GPOH) contemporary clinical trials were analyzed. Individual response 
components of a revised INRC will include primary tumor dimensions using anatomic imaging, and 
metastatic disease assessment using 123I-MIBG imaging. For patients with MIBG non-avid disease, FDG-
PET will be used for metastatic imaging. Furthermore, in addition to bone marrow morphologic assessment, 
immunocytochemistry will be used to assess the burden of neuroblastoma in the marrow. An updated 
version of the INRC (including definitions of complete response, partial response, stable disease, and 
progressive disease) is expected to be finalized by the end of 2012. Until that time, for patients on the 
current trial, data regarding each component of response (cross sectional imaging, functional imaging, 
marrow assessment) in the revised INRC will be collected to permit subsequent comparisons of response 
using the older and newer criteria. 
 


 
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2.8 
Development Plans 
The agent shown to be the most promising during this selection design study will be integrated into frontline 
therapy for patients with high-risk neuroblastoma in 1 of 2 ways. One option would be to integrate the entire 
cassette of irinotecan, temozolomide and the “winner” from this trial as salvage therapy for the treatment 
of patients with disease that is refractory to initial induction therapy. Recent analyses of end-induction 
MIBG scans for patients enrolled on COG A3973 indicate that 3 year event free survival for patients with 
Curie scores >5 following multi-agent chemotherapy was less than 10%.87 Integration of a novel therapeutic 
cassette containing cytotoxics with either temsirolimus or ch14.18 (dinutuximab) may improve disease 
response for these patients prior to proceeding to myeloablative consolidation therapy.  
 
Alternatively, the agent identified as the “winner” during this trial could be integrated into induction therapy 
for all patients with high-risk disease. While the 3-year EFS in patients with end-induction Curie scores > 5 
is extremely poor, survival even among patients with better end-induction Curie scores (≤ 5) is still less 
than 50%87 and 20% of patients will experience disease progression during induction therapy. Thus, there 
is considerable room for improvement among all patients with high-risk neuroblastoma. Toxicity data 
generated during the current trial will inform decision-making regarding the best approach to integrating 
the “winner” into upfront therapy. Given the known toxicity of high-risk neuroblastoma chemotherapy 
induction, a small pilot trial would need to be undertaken to ensure tolerability of combining the “winner” 
with induction therapy. 
 
2.8.1 
Importance of trial and impact on future clinical practice 
Survival of patients with relapsed high-risk neuroblastoma remains poor despite multi-modality therapy. 
Moreover, despite improvement in overall survival for high-risk neuroblastoma, an unacceptable 
percentage of patients experience early disease progression or have disease that is refractory to current 
induction therapy. It is therefore critical to integrate agents that target specific biologic pathways critical to 
neuroblastoma survival. Temsirolimus and ch14.18 (dinutuximab) have shown activity against 
neuroblastoma in both in vitro and in vivo animal models, and have been shown to be safe and tolerable in 
pediatric Phase I trials. This will be the first attempt to move molecularly targeted agents in combination 
with chemotherapy into front-line therapy in this important pediatric disease. We expect that at least one of 
these agents will move forward to a randomized Phase III trial as part of induction therapy for high-risk 
neuroblastoma. Alternatively, one of these agents could be used in a regimen for patients refractory to initial 
induction therapy. Furthermore, this trial design will serve as a model for testing of molecularly targeted 
agents for integration into neuroblastoma therapy. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
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 COG Registry 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.   
 
A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will be 
assigned only one 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, and Cancer 
Trials Support Unit (CTSU) Registration Procedures including: how to download site registration documents; 


 
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requirements for site registration, submission of regulatory documents and how to check your site’s registration 
status. 
 
3.1.2 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB approval and supporting 
documentation to theCTSU 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), 
E-mailed (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. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are 
not required to submit separate IRB approval documentation to the CTSU Regulatory Office for 
initial, continuing or amendment review. This information will be provided to the CTSU Regulatory 
Office from the CIRB at the time the site’s Signatory Institution accepts the CIRB approval. The Signatory 
site may be contacted by the CTSU Regulatory Office or asked to complete information verifying the 
participating institutions on the study. Other site registration requirements (i.e., laboratory certifications, 
protocol-specific training certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Reservation Requirements 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in conjunction with 
the Registration system on Oncology Patient Enrollment Network (OPEN). Prior to discussing protocol 
entry with the patient, all site staff must use the CTSU OPEN Slot Reservation System to insure that a slot 
on the protocol is available to the patient. Once a slot- reservation confirmation is obtained, site staff may 
then proceed to enroll patients to this study.  
 
CRAs/Site Investigators should refer to the COG website to determine if the study is currently open for 
accrual. If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and password.  
2) In order to make a reservation, the patient must have an OPEN patient number. Click on the ‘Slot 
Reservation’ tab to create an OPEN patient number, under ‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the COG Patient ID, and 
choose the required stratum (if applicable) in order to obtain a reservation. 
 


 
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Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under the ‘Help’ tab in OPEN for 
detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_QuickReference_SiteUser
Guide_102612.pdf&ftype=PDF 
 
Prior to obtaining informed consent and enrolling a patient, a reservation must be made following the steps 
above. Reservations may be obtained 24 hours a day through the OPEN system. 
 
3.1.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). OPEN is a 
web-based registration system available on a 24/7 basis. To access OPEN, the site user must have an active 
CTEP-IAM account (check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on 
either the lead protocol organization (LPO) or participating organization roster. 
 
All site staff will use OPEN. It is integrated with the CTSU Enterprise System for regulatory and roster 
data and, upon enrollment, initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website at 
https://www.ctsu.org. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of registration and treatment 
information. Please print this confirmation for your records. 
 
Further instructional information is provided on the CTSU members' web site OPEN tab or within the 
OPEN URL (https://open.ctsu.org). For any additional questions contact the CTSU Help Desk at 1-888-
823-5923 or ctsucontact@westat.com. 
 
3.1.5 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is projected to start must be 
no later than five (5) calendar days after the date of study enrollment. Patients who are started on protocol 
therapy on a Phase II study prior to study enrollment will be considered ineligible.  
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated in the eligibility section below. 
 
3.2 
Patient Eligibility 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.  
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy. Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility. If a post-enrollment lab value is outside 


 
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the limits of eligibility, or laboratory values are >7 days old, then the following laboratory evaluations 
must be re-checked within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT 
(SGPT) and serum creatinine. If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies and bone 
marrow examination must be obtained within 3 weeks prior to enrollment (repeat if necessary). 
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
3.2.1 
Age 
Patients of all ages are eligible for this study. 
 
3.2.2 
Disease Status 
 
3.2.2.1 Histologic Diagnosis: 
Patients must have had histologic verification of neuroblastoma or ganglioneuroblastoma or demonstration 
of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (ie, > 2 x ULN), at the 
time of initial diagnosis. 
 
3.2.2.2 Active Disease:  
For the purposes of this study, aggressive multidrug chemotherapy is defined as chemotherapy including 2 
or more agents that must include an alkylating agent and a platinum-containing compound. Patients must 
have ONE of the following:  
1) First episode of recurrent disease following completion of aggressive multi-drug frontline 
therapy.  
2) First episode of progressive disease during aggressive multi-drug frontline therapy.  
3) Primary resistant/refractory disease (less than partial response by INRC) detected at the 
conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according 
to a high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1, 
etc.).  
 
3.2.2.3 Documentation of Disease:  
Patients must have at least ONE of the following: 
1) Measurable tumor on MRI, CT scan obtained within 3 weeks prior to study entry. Measurable 
is defined as ≥ 10 mm in at least one dimension on spiral/helical CT that is MIBG avid or 
demonstrates increased FDG uptake on PET scan.  
2) MIBG scan obtained within 3 weeks prior to study entry with positive uptake at a minimum of 
one site. This site must represent disease recurrence after completion of therapy, progressive 
disease on therapy, or refractory disease during induction.  
3) Patients with resistant/refractory soft tissue disease that is not MIBG avid or does not 
demonstrate increased FDG uptake on PET scan must undergo biopsy to document the 
presence of viable neuroblastoma. Biopsy is not required for patients who have new site of soft 
tissue disease (radiographic evidence of disease progression) regardless of whether progression 
occurs while receiving therapy or after completion of therapy. 
 
Note: Patients with elevated catecholamines (ie, > 2 x ULN) only or bone marrow disease only are 
NOT eligible for this study. 
 
3.2.3 
Performance Level 


 
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Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2. Use Karnofsky for 
patients 
> 16 years 
of 
age 
and 
Lansky 
for 
patients 
 16 years 
of 
age. 
See 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for 
Protocols. 
 
3.2.4 
Prior Therapy 
3.2.4.1 
Patients must have received frontline therapy (including surgery, chemotherapy, autologous SCT +/- 
MIBG, immunotherapy, radiotherapy, and retinoids) but may NOT have received second line chemotherapy 
for resistant/refractory, relapsed disease or progressive disease. 
 
3.2.4.2 Myelosuppressive chemotherapy: At least 14 days must have elapsed since completion of 
myelosuppressive therapy. 
 
3.2.4.3 Biologic (anti-neoplastic agent): At least 7 days must have elapsed since the completion of therapy 
with a non-myelosuppressive biologic agent or retinoid.  
 
3.2.4.4 XRT: No interim time prior to study entry is required following prior RT for non-target lesions. 
However, patients must not have received radiation for a minimum of 4 weeks prior to study entry at the 
site of any lesion that will be identified as a target lesion to measure tumor response. Lesions that have been 
previously radiated cannot be used as target lesions unless there is radiographic evidence of progression at 
the site following radiation or a biopsy done following radiation shows viable neuroblastoma. Palliative 
radiation is allowed to sites that will not be used to measure response during this study. 
 
3.2.4.5 Stem Cell Transplants (SCT): Patients are eligible ≥ 6 weeks after autologous stem cell transplants 
or stem cell infusions as long as hematologic and other eligibility criteria have been met.  
 
3.2.4.6 131I-MIBG therapy: Patients are eligible ≥ 6 weeks after therapeutic 131I-MIBG provided that all 
other eligibility criteria are met. 
 
3.2.4.7 Study specific limitations on prior therapy: Subjects who have previously received anti-GD2 
monoclonal antibodies for biologic therapy or for tumor imaging are eligible unless they have had 
progressive disease while receiving prior anti-GD2 therapy. Subjects who have received autologous marrow 
infusions or autologous stem cell infusions that were purged using monoclonal antibody linked to beads, 
but no other form of anti-GD2 monoclonal antibody, are eligible. 
 
3.2.5 
Concomitant Medications Restrictions  
(Please see Section 4.1.1 for the concomitant therapy restrictions for patients during treatment.) 
 
 
- 
Patients must not have received long-acting myeloid growth factors (eg, Neulasta) within 
14 days of entry on this study. Seven days must have elapsed since administration of a short-
acting myeloid growth factor. 
 
3.2.6 
Organ Function Requirements 
 
3.2.6.1 Adequate bone marrow function defined as: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 750/μL 
- 
Platelet count ≥ 75,000/μL (transfusion independent)  
 


 
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Patients known to have bone marrow involvement with neuroblastoma are eligible provided that 
minimum ANC and platelet count criteria are met but are not evaluable for hematological 
toxicity. 
 
3.2.6.2 Adequate renal function defined as:  
- 
Creatinine clearance or estimated radioisotope GFR ≥ 70 mL/min/1.73 m2 or 
- 
A serum creatinine ≤ upper limit of normal (ULN) based on age/gender as follows: 
 
 
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. 
 
3.2.6.3 Adequate liver function defined as: 
- 
Total bilirubin ≤ 1.5 x ULN for age AND  
- 
SGPT (ALT) ≤ 5.0 x ULN for age (≤ 225 U/L). For the purpose of this study, the ULN for 
SGPT is 45 U/L. 
 
3.2.6.4 Adequate central nervous system function defined as: 
- 
Patients with a history of CNS disease must have no clinical or radiological evidence of CNS 
disease at the time of study enrollment 
- 
Patients with seizure disorders may be enrolled if seizures are well controlled on anti-
convulsants 
- 
CNS toxicity ≤ Grade 2 
 
3.2.6.5 Adequate cardiac function defined as:  
- 
Shortening fraction of ≥ 27% by ECHO or  
- 
Ejection fraction ≥ 50% by ECHO or gated radionuclide study 
 
3.2.6.6 Adequate coagulation defined as:  
- 
PT ≤ 1.2 x upper limit of normal. 
 
3.2.6.7 Adequate pulmonary function defined as: 
- 
No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and 
room air pulse oximetry >94% if there is a clinical indication for pulse oximetry. Normal 
pulmonary function tests in patients who are capable of cooperating with testing (including 
DLCO) are required if there is a clinical indication for determination. For patients who do not 
have respiratory symptoms, full PFTs are NOT required. 
 


 
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Important Note: Eligibility criteria listed in Section 3.2 must be met at the time of enrollment AND 
at the start of protocol therapy. If there is a change in the patient’s clinical condition between the 
time of study enrollment and the start of protocol therapy, relevant organ function studies should be 
repeated to determine whether the patient should receive protocol therapy. If there are questions 
regarding a patient with an evolving clinical status, please contact the study chair immediately to 
discuss the changing clinical scenario. 
 
 
3.2.7 
Exclusion Criteria 
 
3.2.7.1 Pregnancy and Breastfeeding 
Men and women of childbearing potential and their partners must agree to use adequate contraception while 
enrolled on this study. Based on the established teratogenic potential of alkylating agents, pregnant women 
will be excluded from this study. Because of potential risks to breastfed infants due to drug metabolites that 
could be excreted in breast milk, female patients who are lactating must agree to stop breastfeeding or will 
otherwise be excluded from this study. Females of childbearing potential must have a negative pregnancy 
test to be eligible for this study. 
 
3.2.7.2 
Patients with elevated catecholamines (ie, > 2 x ULN) only or bone marrow disease only are NOT eligible 
for this study. 
 
3.2.7.3 
Patients must have been off pharmacologic doses of systemic steroids for at least 7 days prior to enrollment. 
Patients who require or are likely to require pharmacologic doses of systemic corticosteroids while 
receiving treatment on this study are ineligible. The only exception is for patients known to require 2 mg/kg 
or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood 
product administration in order to avoid allergic transfusion reactions. The use of conventional doses of 
inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for 
patients with known adrenal insufficiency. 
 
3.2.7.4 
Patients must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, 
valproic acid, or carbamazepine for at least 7 days prior to study enrollment. Patients receiving non-enzyme 
inducing anticonvulsants such as gabapentin or levetiracetam will be eligible. 
 
3.2.7.5 
Patients must not have been diagnosed with myelodysplastic syndrome or with any malignancy other than 
neuroblastoma.  
 
3.2.7.6 
Patients with symptoms of congestive heart failure are not eligible. 
 
3.2.7.7 
Patients must not have ≥ Grade 2 diarrhea  
 
3.2.7.8 
Patients must not have uncontrolled infection. 
 
3.2.7.9 
Patients with a history of Grade 4 allergic reactions to anti-GD2 antibodies or reactions that required 
discontinuation of the anti-GD2 therapy are not eligible.  


 
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3.2.7.10 
Patients with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or 
its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the 
action of study agents or to significantly increase the severity of the toxicities experienced from study 
treatment are not eligible. 
 
3.2.8 
Regulatory Requirements 
 
3.2.8.1 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.8.2 
All institutional, FDA, and NCI requirements for human studies must be met. 
  
 


 
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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 of Treatment Plan 
As of Amendment #5, patients will only be assigned to Regimen B therapy. Patients on Regimen B will 
receive irinotecan/temozolomide/ch14.18 (dinutuximab) followed by sargramostim (GM-CSF). 
 
Treatment cycles will be repeated every 21 days (3 weeks). Tumor response will be assessed after Cycles 2, 
4, 6 and every 4 cycles thereafter until the end of protocol therapy. Patients with CR, PR or SD may continue 
to receive the assigned therapy for a maximum of 17 cycles (approximately 1 year).  
 
Regimens: 
Regimen-B 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Days 6-12 
TEMO 
TEMO 
TEMO 
TEMO 
TEMO 
 
IRIN 
IRIN 
IRIN 
IRIN 
IRIN 
 
ch14.18 
(dinutuximab) 
ch14.18 
(dinutuximab) 
ch14.18 
(dinutuximab) 
ch14.18 
(dinutuximab) 
GMCSF 
TEMO= Temozolomide 100 mg/m2/dose PO daily on Days 1-5; given at least 1 hr prior to 
Irinotecan. For patients whose body surface area is <0.5m2, temozolomide dosing is based on body 
weight in kg (see Appendix II). Subsitution of IV Temozolomide is not permitted. 
 
IRIN = Irinotecan: 50 mg/m2/dose IV daily on Days 1-5. 
ch14.18 (dinutuximab) = ch14.18 (dinutuximab) IV at 17.5 mg/m2/dose on Days 2-5.  
GMCSF = sargramostim 250 mcg/m2/dose SubQ on Days 6-12. 
 
See 
the 
Chemotherapy 
Administration 
Guidelines 
(CAG) 
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. As applicable, also see the 
CAG for suggestions on hydration, or hydrate according to institutional guidelines. 
 
If there is a change in the patient’s clinical condition between the time of study enrollment and the 
start of protocol therapy, relevant organ function studies should be repeated to determine whether 
the patient should receive protocol therapy. If there are questions regarding a patient with an 
evolving clinical status, please contact the study chair immediately to discuss the changing clinical 
scenario. 
 
 
4.1.1 
Concomitant Medications and Supportive Care 
 
4.1.1.1 Diarrhea prophylaxis 
Cefixime (8 mg/kg/day PO once daily) or an available equivalent oral cephalosporin (eg, cefpodoxime 
(VantinTM) 10 mg/kg/day PO divided bid, maximum dose 400 mg/day) should be started 2 days prior to the 


 
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first dose of irinotecan and continued until 3 days after the last dose of irinotecan for a total of 10 days in 
each cycle. 
 
4.1.1.2 Pneumocystis prophylaxis 
Patients must receive pneumocystis prophylaxis during study therapy. 
 
4.1.1.3 Other anti-cancer therapy 
No other systemic anti-cancer therapy will be permitted. Radiotherapy to localized painful lesions is 
acceptable, provided at least one measurable/MIBG evaluable lesion is not irradiated. Lesions irradiated 
during protocol therapy will not be used to assess tumor response. Patients should be evaluated prior to 
radiotherapy with appropriate tumor imaging. If measurable or evaluable progressive disease is documented 
after enrollment then the patient should be taken off protocol therapy. 
 
4.1.1.4 Corticosteroid therapy 
Pharmacologic doses of systemic corticosteroids should be used ONLY for life-threatening conditions (ie, 
life-threatening allergic reactions and anaphylaxis such as bronchospasm, stridor) unresponsive to other 
measures. The use of dexamethasone as an anti-emetic is not permitted. Corticosteroid therapy can be used 
as a premedication for transfusion in patients known to have a history of transfusion reactions or for 
treatment of an unexpected transfusion reaction (hydrocortisone 2 mg/kg or less or an equivalent dose of 
an alternative corticosteroid). The use of steroids during protocol therapy requires clear justification 
and documentation.  
 
4.1.1.5 Other supportive care 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general supportive care are to 
be used as necessary. Note: aprepitant (Emend) should not be used as an anti-emetic. The use of gabapentin 
as an adjunct for patients receiving ch14.18 (dinutuximab) should be considered.  
 
For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for 
Protocols. 
 
 
4.2 
Patients on Regimen B: Irinotecan/Temozolomide with ch14.18 (dinutuximab) 
Each chemotherapy cycle lasts 21 days (3 weeks). Patients will receive up to a maximum of 17 cycles of 
chemotherapy. 
 
A cycle may be repeated every 21 days if the patient has stable disease or better, and has again met 
laboratory parameters as defined in the eligibility section (Section 3.2) except for the following repeat cycle 
modified starting criteria: ALT ≤ 5 x ULN provided that the usual causes of transaminitis such as infections, 
tumor progression, or drug toxicity are excluded by appropriate blood and imaging studies AND the 
transaminitis is stable if not improving. 
 
Drug doses should be adjusted based on the BSA calculated from height and weight obtained within one 
week prior to the beginning of each cycle. 
 
Temozolomide: PO 
Days: 1-5 
Dose: 100 mg/m2/dose for patients ≥ 0.5m2. The maximum dose to be administered is 200 mg. For patients 
whose body surface area is <0.5m2, dosing is based on body weight in kg (see Appendix II). 
 


 
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Absorption is affected by food and therefore, consistency of administration with respect to food is 
suggested. Preferably, administer on an empty stomach (at least 1 hour before or 2 hours after food) to 
decrease nausea and vomiting and improve absorption. The whole dose, even if comprised of several 
capsule sizes, should be taken at one time at approximately the same time each day. Bedtime administration 
may decrease nausea and vomiting. For patients whose body surface area is ≥ 0.5m2, the temozolomide 
dose should be rounded off to the nearest 5 mg (round 2.5 mg down, see Appendix II). For ease of 
swallowing, the capsule content may be mixed with applesauce or juice (see instructions in Appendix IV) 
or an oral suspension may be compounded (see drug monograph in Section 6.5). If emesis occurs within 20 
minutes of taking a dose of temozolomide, then the dose may be repeated once. If emesis occurs after 20 
minutes, the dose should not be repeated.  
 
Administration of PO temozolomide should be documented; missed doses should be noted on the therapy 
delivery map and/or in accordance with institutional policy/procedures. 
 
Special precautions: Temozolomide capsules are available in 6 different strengths. Daily doses are usually 
comprised of multiple capsules of different strengths. To prevent errors, each strength of temozolomide 
capsules must be dispensed in a separate bottle and the total number of each strength of capsules needed 
for the full course must be dispensed at one time. See drug monograph for additional details and examples. 
 
Irinotecan: IV over 90 minutes 
Days: 1-5 
Dose: 50 mg/m2/dose (regardless of BSA) 
Note: Irinotecan should be administered at least 1 hour after the temozolomide has been given.  
Higher incidence of cholinergic symptoms has been reported with more rapid infusion rates. To avoid 
extravasation; the use of a central line is suggested. 
 
ch14.18 (dinutuximab): IV as detailed below 
Days: 2-5 
Dose: 17.5 mg/m2/dose (regardless of BSA). 
 
Sargramostim (GM-CSF): SubQ (preferred) or IV as detailed below 
Days: 6-12 
Dose: 250 mcg/m2/dose (regardless of BSA) 
Detailed administration guidelines for chemotherapy and ch4.18 and GM-CSF (Days 2-5) follow: 
 
• 
At hour 0 patient should receive oral temozolomide. 
• 
At hour 1 patient should start IV irinotecan over 90 minutes and on days patient is receiving ch14.18 
(dinutuximab) infusion (Days 2-5 of each cycle) start IVF bolus of normal saline (≥ 10 mL/kg) 
over one hour. 
• 
At hour 2.5: on days patient is receiving ch14.18 (dinutuximab) infusion (Days 2-5 of each cycle), 
start ch14.18 (dinutuximab) infusion. Each daily dose of ch14.18 (dinutuximab) should be infused 
IV over approximately 10 hours, starting at 0.88 mg/m2/hr x 0.5 hr, then increasing to 
1.75 mg/m2/hr for the remainder of the dose, if tolerated. The infusion duration may be extended 
up to 20 hours for anticipated toxicities (pain, fever, tachycardia, tachypnea, hypotension), not 
responding to other supportive measures, and the duration used should be recorded.  
• 
The maximum infusion time is 20 hours; ch14.18 (dinutuximab) administration must be stopped 
after 20 hours even if the total dose has not been administered. The total dose given in 20 hours 
should be recorded. 
• 
Recommended premedications include: 
o Hydroxyzine (0.5-1 mg/kg; max dose 50 mg) PO or diphenhydramine (0.5-1 mg/kg; max 
dose 50 mg) IV over 10 minutes to start approximately 20 minutes prior to ch14.18 


 
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(dinutuximab) infusion; may be repeated every 6 hours as needed during ch14.18 
(dinutuximab) infusion. Note: intravenous hydroxyzine is NOT recommended. 
o Acetaminophen (10 mg/kg; max dose 650 mg) PO given approximately 20 minutes prior 
to ch14.18 (dinutuximab) infusion; may be repeated every 4-6 hours as needed for fever.  
• 
Recommended pain management: 
o Morphine sulfate loading dose immediately prior to ch14.18 (dinutuximab) administration. 
A dose of 50 mcg/kg is recommended, though this may be adjusted based on a given 
patient’s pain history. 
o Continue with morphine sulfate drip titrated to effect. The recommended dose range for 
the continuous infusion is 20-50 mcg/kg/hr to continue for 2 hours after completion of the 
ch14.18 (dinutuximab) infusion. 
o Other narcotics such as hydromorphone or fentanyl can be used.  
o Gabapentin may be used in conjunction with other pain medications per institutional 
practice. 
o The use of additional pain medications (lidocaine, ketamine) in extenuating circumstances 
should be undertaken in consultation with pediatric pain management specialists. 
▪ 
For example, a lidocaine infusion may be used in conjunction with IV bolus of 
morphine on prn basis. Suggested administration guidelines for a lidocaine 
infusion are shown below: 
• 
Give lidocaine IV bolus at 2 mg/kg in 50 mL NS over 30 min prior to the 
start of ch14.18 (dinutuximab) infusion. 
• 
At the beginning of ch14.18 (dinutuximab) infusion, start IV lidocaine 
infusion at 1 mg/kg/hr and continue until two hours after the completion 
of ch14.18 (dinutuximab) infusion. 
• 
May give morphine IV bolus 25-50 microgram/kg every 2h prn pain. 
• 
Patient should be monitored closely for sedation scale, EKG (rate and 
rhythm), HR, BP, RR, oxygen saturation (pulse oximeter) and pain score. 
If patient develops dizziness, perioral numbness, tinnitus attributable to 
lidocaine, then stop lidocaine infusion. 
• 
Monitoring during ch14.18 (dinutuximab) infusion: 
o Vital signs should be assessed every 15 minutes for the first hour of the infusion, then 
hourly during the remainder of the infusion if stable after the first hour. More frequent 
assessment may be required based on the patient’s clinical condition. Between antibody 
doses, vitals should be assessed every 4 hours.  
o Strict observation of intake and output is required on the days of ch14.18 (dinutuximab) 
administration. 
o Daily physical examination including a careful eye exam for pupillary reflexes and 
extraocular movements. 
o Patients should be weighed daily on the days of ch14.18 (dinutuximab) administration. 
 
• 
Sargramostim (GM-CSF) administration is to begin on Day 6 of each cycle: 
o The standard route of administration is subcutaneous; use of an insuflon catheter is 
permitted. 
o In extenuating circumstances, IV administration over 2 hours is permitted. The reason for 
IV administration of this agent must be documented. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
 


 
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Following completion of Cycle 1, the next cycle starts on Day 22 or when the patient has met the criteria 
for repeat cycles stated above. 
 
The therapy delivery map (TDM) for Cycle 1 is on the next page (Section 4.2.1). The TDMs for therapy 
subsequent to Cycle 1 are provided in Section 4.2.2. 
 
Patients who have stable disease or better following disease re-evaluations may continue on study for a 
total of 17 cycles (approximately 1 year), provided that there are no toxicities that preclude continuation of 
protocol therapy. 
 
 


 
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4.2.1 
Regimen B: Irinotecan and Temozolomide with ch14.18 (dinutuximab) - 
Cycle 1 
Three consecutive weeks (21 days) will constitute one cycle. 
This therapy delivery map relates to Cycle 1of TEMO+IRIN+ch14.18 (dinutuximab). 
 
______________________ 
Patient COG ID number 
_________________ 
DOB 
 
Criteria to start Cycle 1: patient met laboratory parameters as defined in the eligibility section (Section 3.2). 
Each cycle lasts 21 days and this Therapy Delivery Map is on 1 page. Dose calculations should be based on actual BSA 
except where noted for TEMO. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
(See Section 7.1 for 
Baseline studies) 
Temozolomide 
(TEMO) 
PO 
For patients ≥0.5m2: 
100 mg/m2/dose. Round 
off to the nearest 5 mg. 
 
For patients <0.5 m2: 
dose on a per kg basis  
1-5 
Max dose= 200 mg 
Administer at least one hour prior 
to IRIN administration. 
 
See Dosing Table in Appendix II 
and admin. guidelines in Section 
4.2. 
a. History; ht, wt, BSA 
b. Physical exam with vital 
signs 
c. CBC, differential, platelets 
d. Electrolytes and creatinine 
e. ALT, total bilirubin, PO4, 
Mg++ 
f. Optional biology studies 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
Irinotecan 
(IRIN) 
IV over 90 min 
50 mg/m2/dose 
1-5 
Administer at least 1 hour after 
temozolomide, see Section 4.2. 
Ch14.18 
(dinutuximab) 
IND# 4308 
IV over 
10 hours** 
17.5 mg/m2/dose 
2-5 
** Infusion duration may be 
extended to 20 hours maximum, as 
detailed in Section 4.2. 
See Section 4.2 for detailed 
administration guidelines, including 
premedications and monitoring 
during the infusion. 
Sargramostim 
(GM-CSF) 
SubQ 
(preferred) or IV 
over 2 hours 
250 mcg/m2/dose 
6-12 
See Section 4.2 for detailed 
administration guidelines. 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
TEMO 
_______mg 
IRIN 
_______mg 
Ch14.18 
(dinutuximab) 
_______mg 
GM-CSF 
_______mcg 
Studies 
Comments (Include 
any held doses, 
missed doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
_______ mg 
_______ mg 
 
 
a, b, c, d, e, f% 
 
 
2 
_______ mg 
_______ mg 
_______ mg 
 
d 
 
 
3 
_______ mg 
_______ mg 
_______ mg 
 
d 
 
 
4 
_______ mg 
_______ mg 
_______ mg 
 
d 
 
 
5 
_______ mg 
_______ mg 
_______ mg 
 
d, f% 
 
 
6 
 
 
 
_______mcg 
 
 
 
7 
 
 
 
_______mcg 
 
 
 
8 
 
 
 
_______mcg 
b, c#, d, e, f% 
 
 
9 
 
 
 
_______mcg 
 
 
 
10 
 
 
 
_______mcg 
 
 
 
11 
 
 
 
_______mcg 
 
 
 
12 
 
 
 
_______mcg 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
b, c#, d, e, f% 
 
 
 
 
 
 
 
 
 
 
22 
Begin next cycle on Day 22 or when criteria to begin cycle are met (whichever occurs later). See Section 4.2.2. 
# 
If patients have Grade 4 neutropenia, CBCs should be checked at least twice per week until recovery to Grade 3. 
% 
See Section 13.1 for details. 
 
See Section 5.0 for Dose Modifications for Toxicities. For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp. 
  
 


 
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4.2.2 
Regimen B: Irinotecan and Temozolomide with ch14.18 
(dinutuximab) - Therapy post Cycle 1 
This therapy delivery map relates to all cycles of TEMO+IRIN+ ch14.18 
(dinutuximab) subsequent to Cycle 1. Three consecutive weeks (21 days) will 
constitute 1 cycle. 
Use a copy of this page once for each cycle. Please note cycle number below. 
 
__________________________ 
Patient COG ID number 
_________________ 
DOB 
 
Criteria to start each cycle: patient meets laboratory parameters as defined in the eligibility section (Section 3.2) except for the following 
modified criteria: ALT ≤ 5 x ULN provided that the usual causes of transaminitis such as infections, tumor progression, or drug toxicity are 
excluded by appropriate blood and imaging studies AND the transaminitis is stable if not improving. 
Each cycle lasts 21 days and this Therapy Delivery Map is on 1 page. Dose calculations should be based on actual BSA except where 
noted for TEMO. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Temozolomide 
(TEMO) 
PO 
For patients ≥0.5m2: 
100 mg/m2/dose. Round 
off to the nearest 5 mg. 
 
For patients <0.5 m2: dose 
on a per kg basis  
1-5 
Max dose= 200 mg 
Administer at least one hour prior 
to IRIN administration. 
 
See Dosing Table in App. I and 
admin. guidelines in Section 4.2. 
a. History; ht, wt, BSA; physical 
exam with vital signs; 
performance status 
b. CBC, differential, platelets 
c. Electrolytes and creatinine 
d. ALT, total bilirubin, PO4, Mg++, 
albumin 
e. HVA/VMA 
f. Imaging evaluation. See Section 
7.1.1 for details. 
g. Bilateral bone marrow 
aspirates/biopsies 
h. Optional biology studies 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Irinotecan 
(IRIN) 
IV over 90 min 
50 mg/m2/dose 
1-5 
Administer at least 1 hour after 
temozolomide, see Section 4.2. 
Ch14.18  
(dinutuximab) 
IND# 4308 
IV over 
10 hours** 
17.5 mg/m2/dose 
2-5 
** Infusion duration may be extended 
to 20 hours maximum, as detailed in 
Section 4.2. 
See Section 4.2 for detailed admin 
guidelines, including premedications 
and monitoring during the infusion. 
Sargramostim 
(GM-CSF) 
SubQ (preferred) 
or IV over 2 hours 
250 mcg/m2/dose 
6-12 
See Section 4.2 for detailed 
administration guidelines. 
Enter Cycle #: _____ 
 
Ht _________cm 
Wt _________kg 
BSA _________m2
 
Date 
Due 
Date 
Given 
Day 
TEMO 
_______mg 
IRIN 
_______mg 
Ch14.18 
(dinutuximab) 
_______mg 
GM-CSF 
_______mcg 
Studies 
Comments (Include any 
held doses, missed doses, 
or dose mods) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
_______ mg 
_______ mg 
 
 
(a, b*,%, c, d, h$)^ 
 
 
2 
_______ mg 
_______ mg 
_______ mg 
 
c 
 
 
3 
_______ mg 
_______ mg 
_______ mg 
 
c 
 
 
4 
_______ mg 
_______ mg 
_______ mg 
 
c 
 
 
5 
_______ mg 
_______ mg 
_______ mg 
 
c, h$ 
 
 
6 
 
 
 
_______mcg 
 
 
 
7 
 
 
 
_______mcg 
 
 
 
8 
 
 
 
_______mcg 
b*,% , h$ 
 
 
9 
 
 
 
_______mcg 
 
 
 
10 
 
 
 
_______mcg 
 
 
 
11 
 
 
 
_______mcg 
 
 
 
12 
 
 
 
_______mcg 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
b*,% , h$ 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
e#, +, f+,&, g&,@, h$ 
 
 
22 
Begin next cycle on Day 22 or when criteria to begin cycle are met (whichever occurs later). See details above. 
 
^ 
Studies may be obtained within 3 days prior to the start of the cycle. 
* 
If patients have Grade 4 neutropenia, CBCs should be checked at least twice per week until recovery to Grade 3. 
% 
If patients remain on study for > 4 cycles and cytopenias are not observed, CBCs may be obtained at the start of subsequent cycles and as 
clinically indicated. 
# 
Obtain in patients who had elevated catecholamines (ie, > 2 x ULN) at initial diagnosis. 
+ 
End of Cycles 2, 4 and 6, then following every 4th cycle thereafter. 
& 
May be performed within 1 week prior to the start of the next planned cycle of therapy. 
@ 
End of Cycles 2, 4 and 6, then following every 4th cycle thereafter for patients with known marrow involvement. Marrow should be 
evaluated following Cycle 6 for all patients (even if no history of marrow disease).  
$ 
See Section 13.1 for details. 
See Section 5.0 for Dose Modifications for Toxicities. For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp. 
  
 


 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
In addition to dose modifications, this section provides information regarding management of 
toxicities known to be associated with protocol therapy. 
 
In the sections below, when protocol therapy is to be discontinued, all protocol therapy should be 
discontinued. If treating clinicians elect to continue to administer irinotecan and temozolomide, this 
can be done as part of clinical care but will not be considered protocol therapy. 
 
5.1 
Dose Modifications for Hematologic Toxicity 
Patients must meet hematologic criteria for study entry and at the start of each treatment cycle. 
 
5.1.1 
Dose-limiting neutropenia 
Patients who experience neutropenia that causes a delay of ≥ 14 days between treatment cycles in the 
absence of other toxicity requiring dose modification should have the temozolomide dose reduced by 25% 
for subsequent cycles (see dose reduction nomogram in Appendix III). If patient experiences neutropenia 
that causes a delay of ≥ 14 days again after this dose reduction, protocol therapy should be discontinued. 
 
5.1.2 
Dose-limiting thrombocytopenia 
For patients who experience thrombocytopenia that causes a delay of ≥ 14 days between treatment cycles 
with or without other hematologic toxicities, the dose of temozolomide should be reduced by 25% for 
subsequent cycles (see dose reduction nomogram in Appendix III). If patient experiences thrombocytopenia 
that causes a delay of ≥ 14 days again after this dose reduction, protocol therapy should be discontinued.  
 
5.1.3 
Delayed recovery of platelets and neutrophils 
Patients who do not meet criteria to start the next treatment cycle (see Section 4.2) within 21 days after the 
planned subsequent cycle start date (ie, there is a ≥ 3 week delay in start of next cycle) must be removed 
from protocol therapy.  
 
5.2 
Dose Modifications for Non-hematologic Toxicity 
Patients who have experienced non-hematologic toxicity should receive subsequent doses of study 
medications as described in the following sections.  
 
5.2.1 
Dose modifications for diarrhea 
See Appendix V for patient/family instructions for supportive care measures for patients who develop 
therapy-associated diarrhea. Also included are specific instructions for loperamide dosing. 
 
• 
If Grade 4 therapy-associated diarrhea is experienced by a patient despite maximal use of anti-
diarrheal medications and appropriate use of prophylactic antibiotics, the dose of irinotecan 
should be reduced by 25% for subsequent cycles (ie, irinotecan dose 37.5 mg/m2). 
• 
If Grade 4 therapy-associated diarrhea recurs despite reducing the dose of irinotecan by 25%, 
the ch14.18 (dinutuximab) dose should also be decreased by 25% for subsequent cycles (ie, 
ch14.18 (dinutuximab) dose 13.13 mg/m2). 
• 
If Grade 4 diarrhea recurs despite maximal use of anti-diarrheals, prophylactic antibiotics, and 
the dose reductions, the patient should come off protocol therapy. 
 
5.2.2 
Dose modifications for nausea and vomiting 
• 
For patients with Grade 4 regimen-related nausea and vomiting and for patients with Grade 3 
regimen-related nausea and vomiting > 7 days in duration who did not receive appropriate anti-
emetic therapy, adjustments in the anti-emetic regimen should be made during the next cycle 


 
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of therapy.  
• 
If severe regimen-related nausea and vomiting recurs despite optimized anti-emetic usage, 
doses of irinotecan and temozolomide should be reduced by 25% for subsequent cycles (ie, 
irinotecan dose 37.5 mg/m2; for temozolomide see dose reduction nomogram in Appendix III). 
• 
If severe regimen-related nausea and vomiting recurs despite the dose reduction, the patient 
should come off protocol therapy. 
 
5.2.3 
Dose modifications for dehydration 
• 
If dehydration is related to diarrhea or nausea/vomiting, the guidance in the preceding section 
should be followed.   
• 
If regimen-related ≥ Grade 3 dehydration persists for > 3 days in the absence of significant 
diarrhea or nausea/vomiting, doses of irinotecan and temozolomide should be reduced by 25% 
for subsequent cycles (ie, irinotecan dose is 37.5 mg/m2; for temozolomide see dose reduction 
nomogram in Appendix III).  
• 
If ≥ Grade 3 regimen-related dehydration recurs and persists for > 3 days despite the dose 
reduction, the patient should come off protocol therapy. 
 
5.2.4 
Dose modifications for elevations in ALT, AST, or GGT 
• 
If elevations in ALT, AST or GGT occur such that values are > 20x ULN for any duration of 
time OR > 10x ULN but < 20x ULN and persisting for > 7 days occur in patients receiving 
irinotecan, temozolomide, and ch14.18 (dinutuximab)/GM-CSF, the dose of ch14.18 
(dinutuximab) should be reduced by 25% for subsequent cycles (ie, ch14.18 (dinutuximab) 
dose: 13.13 mg/m2). For the purposes of this trial the ULN for ALT is defined as 45 U/L; 
institutional ULN values for AST and GGT should be used. If elevations of this magnitude 
involving same liver enzyme(s) recur despite the first dose reduction, the dose of ch14.18 
(dinutuximab) should again be reduced by 25% for subsequent cycles (ie, ch14.18 
(dinutuximab) dose: 8.75 mg/m2). If the dose limiting elevations of the same liver enzyme(s) 
recur despite the second dose reduction, the patient should come off protocol therapy. An 
elevation in ALT that causes a delay of ≥ 14 days between treatment cycles will also require a 
25% reduction in the dose of ch14.18 (dinutuximab) for subsequent cycles (ie, ch14.18 
(dinutuximab) dose: 13.13 mg/m2). If a delay of ≥ 14 days between treatment cycles recurs due 
to elevation in ALT despite the dose reduction, the patient should come off protocol therapy. 
 
5.2.5 
ch14.18 (dinutuximab)/GM-CSF specific dose modifications and toxicity management 
recommendations 
5.2.5.1 Treatment of ch14.18 (dinutuximab) induced hypotension (without evidence of allergic reaction) 
• 
If hypotension is severe and accompanied by poor perfusion, end organ dysfunction, or 
acidemia – Pediatric Advanced Life Support (PALS) guidelines should be followed and 
ch14.18 (dinutuximab) infusion should be discontinued. 
• 
In the absence of poor perfusion, end organ dysfunction or acidemia, moderate hypotension is 
defined as 
o Symptomatic decreases in blood pressure and/or 
o Systolic blood pressure (SBP) < 80 mmHg for age > 12 years 
o SBP < 70 mmHg for age 1-12 years 
o SBP < 65 mmHg for age < 1 year  OR 
o SBP or DBP decreased by > 15% below baseline 
• 
If moderate hypotension is observed: 
o Immediately hold ch14.18 (dinutuximab) 
o Give normal saline bolus (20 mL/kg as rapidly as possible) 
o Stop or adjust doses of narcotics and sedating H1 blockers 


 
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o Consider use of Trendelenberg position 
• 
If hypotension persists after the above measures have been taken: 
o Reassess perfusion and end organ function; follow PALS algorithm if needed 
o Repeat NS bolus 
o Consider use of albumin if albumin < 3 gm/dL 
o Consider use of PRBCs if Hb < 10 gm/dL 
o Consider transfer to intensive care setting  
• 
If hypotension persists following 2 volume boluses, give an additional bolus and prepare to 
administer pressors 
o Epinephrine is preferred over dopamine if possible 
• 
Resumption of ch14.18 (dinutuximab)  
o For patients whose hypotension resolves promptly and completely with limited volume 
resuscitation and without requirement for pressor support, ch14.8 may be restarted at 
50% of the previous infusion rate. The ch14.18 (dinutuximab) may be restarted on 
same day if it is possible to do so within 20 hours of the start of the day’s infusion. If 
blood pressures are stable for 2 hours, the infusion may be given at full rate for that 
day and subsequent days. If the patient again experiences hypotension requiring 
multiple volume boluses (eg, > 60 mL/kg) when ch14.18 (dinutuximab) is given at full 
rate but tolerates the 50% infusion rate, the remaining days’ doses of ch14.18 
(dinutuximab) should be given at the 50% rate of infusion. If > 20 hours have elapsed 
since the start of the infusion, restart ch14.18 (dinutuximab) the following day. 
▪ 
If blood pressures are stable for 2 hours after resumption of ch14.18 
(dinutuximab) at the reduced rate, the remainder of the antibody infusion 
may be given at the full rate 
▪ 
If hypotension recurs at the reduced rate, the measures above should again 
be taken and no further ch14.18 (dinutuximab) should be given that day. 
The antibody infusion may be restarted the following day after ensuring 
that the patient is volume replete. The antibody rate upon resumption of 
treatment should be 50% of the initial rate. If blood pressures are stable 
for 2 hours, the infusion may be given at full rate for that day and 
subsequent days. If the patient’s blood pressures are only stable at the 50% 
rate and not at full rate, the remaining days’ doses of ch14.18 
(dinutuximab) should be given at the 50% rate of infusion. 
o For patients who require multiple volume boluses for hemodynamic stabilization, 
ch14.18 (dinutuximab) should be resumed the following day at 50% of the initial 
infusion rate.  
▪ 
If blood pressures are stable for 2 hours after resumption of ch14.18 
(dinutuximab) at the reduced rate, the remainder of the antibody infusion 
may be given at the full rate 
▪ 
If hypotension recurs at the reduced rate, the measures above should again 
be taken and no further ch14.18 (dinutuximab) should be given that day. 
The antibody infusion may be restarted the following day after ensuring 
that the patient is volume replete. The antibody rate upon resumption of 
treatment should be 50% of the initial rate. If blood pressures are stable 
for 2 hours, the infusion may be given at full rate for that day and 
subsequent days. If the patient’s blood pressures are only stable at the 50% 
rate and not at full rate, the remaining days’ doses of ch14.18 
(dinutuximab) should be given at the 50% rate of infusion. 
o For patients who require pressors for treatment of hypotension, if blood pressure is 
stable off pressors for at least 6 hours, administration of ch14.18 (dinutuximab) may 
be resumed at 50% of the initial infusion rate on the day following the hypotensive 


 
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episode. Care should be taken to ensure that the patient is volume replete. Ch14.18 
(dinutuximab) should not be given to patients who continue to require pressor support. 
Patients who require pressor support for ≥ 24 hours due to treatment-related 
hypotension despite appropriate volume resuscitation should discontinue protocol 
therapy. Patients who again require pressor support when ch14.18 (dinutuximab) is 
resumed should discontinue protocol therapy.  
 
 
5.2.5.2 Treatment of Allergic Reactions/Infusion Reactions  
5.2.5.2.1 Mild allergic reactions/infusion reactions to ch14.18 (dinutuximab) infusion 
• 
A mild allergic reaction is limited to rash, flushing, urticaria, mild dyspnea – Grade 
1 or 2 
• 
The following recommendations do NOT apply to Grade 3 or 4 allergic reactions, 
including anaphylaxis 
• 
Management 
o Decrease rate of ch14.18 (dinutuximab) to 50% of full rate 
o Perform serial exams at bedside 
o Administer H1 blocker (diphenhydramine, cetirizine recommended) 
o Administer H2 blocker 
o When symptoms resolve, resume original infusion rate 
o If symptoms recur when original rate is resumed, decrease to 50% rate 
again 
o Infusion must be stopped after 20 hours (whether the full dose of ch14.18 
(dinutuximab) has been administered or not); document total amount of 
drug given in the 20 hour time period 
 
5.2.5.2.2 Moderate to severe allergic reactions/infusion reactions to ch14.18 (dinutuximab) infusion 
• 
Moderate to severe reactions include any of the following: symptomatic 
bronchospasm, allergy-related edema/angioedema, hypotension, or anaphylaxis – 
Grade 3 or 4 
• 
The following recommendations do NOT apply to Grade 1 or 2 allergic reactions 
• 
Management 
o Immediately hold ch14.18 (dinutuximab)  
o Assess airway, breathing and circulation 
o Follow institutional guidelines for rapid response team notification if 
clinically indicated 
o For airway concerns 
▪ 
Administer oxygen and albuterol immediately for bronchospasm 
▪ 
Administer IV diphenhydramine 
▪ 
Administer epinephrine (1:1000 IM recommended) immediately 
if upper airway involved or if airway issues are accompanied by 
cardiovascular collapse 
▪ 
Administer IV hydrocortisone (1-2 mg/kg) if the patient has frank 
anaphylaxis with cardiorespiratory collapse OR if ≥ 2 doses of 
epinephrine are required OR if moderate to severe symptoms recur 
upon rechallenge with ch14.18 (dinutuximab) 
o For hypotension in the setting of allergic reaction 
▪ 
Give normal saline bolus (20 mL/kg as rapidly as possible) 
▪ 
Stop or adjust doses of narcotics and sedating H1 blockers 
▪ 
Consider use of Trendelenberg position 
▪ 
See previous section for management of persistent hypotension 


 
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o For patients with mild bronchospasm or angioedema that does not impact 
breathing, completely resolves without the use of epinephrine and 
hydrocortisone and for patients whose hypotension resolves following 
volume bolus, ch14.18 (dinutuximab) may be resumed at 50% of the 
previous rate of infusion on the same day as the reaction occurred. If 
symptomatic angioedema or asymptomatic bronchospasm recurs when the 
ch14.18 (dinutuximab) is restarted, discontinue immunotherapy for that 
day and if symptoms/signs resolve completely that day, resume the next 
day with additional pre-medication of hydrocortisone 1-2 mg/kg IV. For 
this re-challenge, the infusion should be given in an ICU setting. 
o For patients whose bronchospasm or angioedema requires the use of 
systemic epinephrine, protocol therapy should be discontinued. 
o For patients with bronchospasm or angioedema that does not require 
systemic epinephrine but whose hypotension requires more extensive 
volume resuscitation, guidance in Section 5.2.6.1 should be followed. 
 
5.2.5.3 Management of capillary leak syndrome (≥ Grade 3) 
• 
Hold ch14.18 (dinutuximab) infusion 
• 
Provide oxygen, fluids as needed 
• 
Diuretics should be used with caution and hypotension avoided 
• 
See Section 5.2.6.1 for management of hypotension, anemia and 
hypoalbuminemia 
• 
Do NOT resume ch14.18 (dinutuximab) therapy if symptoms of severe capillary 
leak syndrome persist on the same day or subsequent days of a given cycle. Only 
resume ch14.18 (dinutuximab) therapy when the capillary leak syndrome resolves 
or requires less significant intervention (Grade 2 or less). 
• 
If capillary leak resolves, may resume ch14.18 (dinutuximab) infusion at 50% rate 
the same day and for subsequent doses during a given cycle. The infusion may be 
given at the full rate at the start of subsequent cycles 
• 
If mechanical ventilation (any duration) or pressor support for ≥ 24 hours is 
required due to therapy-related capillary leak syndrome, the patient should 
discontinue protocol therapy 
 
5.2.5.4 Management of renal insufficiency (unrelated to hypotension) 
• 
Consider the possibility of renal hypoperfusion in the context of borderline 
hypotension; administer volume if appropriate 
• 
If the patient’s creatinine is elevated to ≥ 2 x the upper limit of normal for 
age/gender (see table in Section 3.2.6.2) and elevation persists despite optimized 
fluid management, hold ch14.18 (dinutuximab) 
• 
Modify dosing of concomitant medications that may contribute to or be affected 
by renal insufficiency 
• 
When urine output returns to normal and creatinine returns to < 2 x upper limit of 
normal for age/gender, resume ch14.18 (dinutuximab) at 50% rate. If renal 
function normalizes by the following day, ch14.18 (dinutuximab) may be 
administered at full rate. If renal function is not sufficiently improved (urine output 
normal and creatinine < 2x ULN for age/gender) by Day 7, no further ch14.18 
(dinutuximab) should be given during that cycle of therapy. If renal function has 
normalized by the planned start date for the next cycle, retreatment with ch14.18 
(dinutuximab) is permitted 
 


 
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5.2.5.5 Management of hyponatremia (≥ Grade 3; Na < 130 mEq/L) 
• 
Change hypotonic fluids to isotonic fluids as compatibilities permit 
• 
Avoid administration of oral free water 
• 
Correct fluid losses due to diarrhea  
• 
3% saline is only indicated in the following settings: 
o hyponatremia leading to seizure 
o drop in sodium level > 10 points in 6 hours or less 
o sodium level < 117 mEq/L 
• 
If Grade 4 hyponatremia persists despite optimal fluid management, discontinue 
ch14.18 (dinutuximab) for the remainder of the cycle. Sodium should be monitored 
closely during the next cycle of therapy. Empiric dose reduction is not required at 
the start of the next cycle of therapy, though ch14.18 (dinutuximab) would again 
be discontinued if Grade 4 hyponatremia were to persist despite optimal fluid 
management. In such cases, no additional cycles of therapy would be given. 
 
5.2.5.6 Management of fever in the absence of hypotension 
• 
Administer antipyretics 
• 
Adjust fluids to account for insensible losses if fever is persistent 
• 
Obtain blood culture 
• 
Administer empiric antibiotics if suggested by institutional policy 
 
5.2.5.7 Management of treatment-related pain  
• 
No further ch14.18 (dinutuximab) therapy should be given to patients who 
experience treatment related pain that cannot be controlled by narcotics during a 
given cycle. Treatment with gabapentin or similar agent should be initiated if not 
already being administered. If pain that is not controlled with narcotics recurs 
during a subsequent cycle, the patient should discontinue protocol therapy  
• 
For patients with treatment-related pain requiring intravenous narcotics for 
≥ 48 hours following completion of ch14.18 (dinutuximab) therapy, gabapentin or 
similar agent should be initiated if not already being administered. If pain requiring 
prolonged intravenous narcotics (≥48 hours following completion of ch14.18 
(dinutuximab) therapy) recurs during a subsequent cycle despite this intervention, 
the patient should discontinue protocol therapy.  
 
5.2.5.8 Management of visual changes 
• 
Ch14.18 (dinutuximab) should be discontinued for patients who develop dilated 
pupils with sluggish light reflexes with or without photophobia during 
administration of the antibody. If papillary abnormalities remain stable or improve 
before the next immunotherapy course is due, the patient should receive ch14.18 
(dinutuximab) at a dose that is 50% reduced compared to the prior dose. Full dose 
GM-CSF should be given. If the lower dose of ch14.18 (dinutuximab) is tolerated 
without worsening of ocular toxicity, full dose ch14.18 (dinutuximab) should be 
given in subsequent courses. If visual toxicity worsens, the patient should 
discontinue all immunotherapy. 
• 
Dose reductions for changes in accommodation are not required 
 
5.2.5.9 Management of serum sickness 
• 
Identification of serum sickness – signs and symptoms include arthralgias/arthritis, 
splenomegaly, lymphadenopathy, glomerulonephritis in the presence of persistent 
fevers, cutaneous eruptions 


 
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• 
Serum sickness typically develops 1 to 3 weeks after administration of the 
causative agent, but can develop within 12-36 hours in patients who have 
previously been sensitized to the causative agent 
• 
Patients with ≥ Grade 3 serum sickness should discontinue protocol therapy. 
• 
For Grade 2 serum sickness, antihistamines should be prescribed 
 
5.2.5.10 Management of neurotoxicity 
• 
Patients who develop Grade 4 neurotoxicity should discontinue protocol therapy. 
• 
Ch14.18 (dinutuximab) should be discontinued for the remainder of the current 
cycle of therapy for patients who develop Grade 3 sensory neuropathy or Grade 3 
motor neuropathy. If abnormalities resolve by start of next cycle of therapy the 
patient may receive 50% dose of ch14.18 (dinutuximab) (ie, ch14.18 
(dinutuximab) dose: 8.75 mg/m2). If symptoms do not completely resolve or recur 
with ch14.18 (dinutuximab) then the patient should discontinue protocol therapy. 
 
5.2.6 
Management of GM-CSF related toxicities 
• 
Hold GM-CSF if total white blood cell count is > 50,000/µL; resume at 50% dose when 
the count is < 20,000/µL. Administer full dose with subsequent cycles and modify again if 
the count exceeds 50,000/µL 
• 
Localized skin reactions to GM-CSF are common, and GM-CSF can be continued when 
reactions are mild. Rotation of sites of injections is recommended rather than use of 
insuflon for subcutaneous injection when skin reactions occur. Consider use of 
antihistamines. If ≥ Grade 3 injection site reactions occur, stop GM-CSF for the current 
cycle and discontinue GM-CSF for subsequent cycles of therapy. 
• 
A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, 
and/or tachycardia has been reported following the administration of the first dose of GM-
CSF in a particular cycle. This syndrome generally resolves with symptomatic treatment 
and usually does not recur with subsequent doses of GM-CSF in the same cycle of 
treatment. For safety purposes in this study, if such a “first dose reaction” occurs, the GM-
CSF dose will be reduced to 50% for the next dose (ie, GM-CSF dose 125 mcg/m2). If a 
similar reaction occurs at the 50% dose, the GM-CSF will be discontinued for that patient. 
If the first dose at 50% does not cause any recurrent severe symptoms, subsequent doses 
can be escalated back to 100%. If recurrent severe symptoms are observed at 100% dose, 
then the dose will be reduced to 50%. If 50% is tolerated, that dose should be administered 
for all subsequent protocol treatment for that patient. If recurrent severe symptoms are seen 
at the 50% dose, the GM-CSF will be discontinued for subsequent cycles of therapy. 
 
 
6.0 
DRUG INFORMATION 
Please see Appendix VI for drug interactions associated with the drugs used in this study. 
 
6.1 
CHIMERIC MONOCLONAL ANTIBODY 14.18 
 
 
 
(05/12/17) 
(Chimeric Monoclonal Antibody 14.18; human/murine anti-GD2 monoclonal antibody; chimeric anti-GD2; 
chimeric mAb 14.18; ch14.18, dinutuximab, Unituxin®) NSC# 764038, IND# 4308 
 
Source and Pharmacology: 
Chimeric MOAB 14.18 (ch14.18, dinutuximab) is an anti-GD2 monoclonal antibody composed of the variable 
region heavy and light chain genes of the murine mAb 14.G2a and the human constant region genes for heavy 
chain IgG1 and light chain kappa. Ch14.18 (dinutuximab) exerts its antitumor effect by binding specifically to 
the disialoganglioside GD2, an antigen found in human tumors of neuroectodermal origin such as melanoma 


 
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and neuroblastoma. This chimeric antibody has been shown to lyse melanoma and neuroblastoma cells through 
the process of antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. By 
targeting the GD2 antigen on the cell surface, ch14.18 (dinutuximab) may also prevent attachment of circulating 
malignant cells to the extracellular matrix. Additionally, ch14.18 (dinutuximab) mediates lysis of several 
melanoma and neuroblastoma cell lines in a dose dependent manner in the presence of potent mediators of 
ch14.18 (dinutuximab)-dependent cytotoxicity, such as human peripheral blood mononuclear cells and 
granulocytes. This is most profound with neutrophils, especially in the presence of recombinant human 
granulocyte-macrophage colony-stimulating factor. 
 
The PK profile of ch14.18 (dinutuximab) has been determined in adults with melanoma and children with 
neuroblastoma. Although the plasma clearance for both groups of patients follow a two-compartment 
model, circulating antibody is cleared from the plasma at a much faster rate in children than adults (mean 
t½β = 66.6 ± 27.4 hours in children versus 123 ± 29 hours and 181 ± 73 hours in two adult trials, 
respectively). Maturation of the hepatic and renal systems with age is thought to impact on drug metabolism 
and elimination and could account for these differences. In general, the mAb half-life following the first 
course of treatment was longer than the half-lives following subsequent courses in a given patient. 
 
Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MoAb 14.18, chimeric (CH14.18, NSCs 623408 and 764038) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI 
(except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further 
clarification. Frequency is provided based on 351 patients. Below is the CAEPR for MoAb 14.18, chimeric 
(CH14.18).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
 


 
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  Version 2.8, April 10, 20171 
 
 Adverse Events with Possible  
 Relationship to MoAb 14.18, chimeric (CH14.18) 
 (CTCAE 4.0 Term) 
[n= 351] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
Disseminated 
intravascular 
coagulation 
 
 Disseminated 
intravascular 
coagulation (Gr 2) 
 
 
Hemolytic uremic syndrome2   
CARDIAC DISORDERS 
  
 
 
Cardiac arrest 
  
 
 
Sinus bradycardia 
  
 
Sinus tachycardia 
 
 Sinus tachycardia (Gr 3) 
EYE DISORDERS 
  
 
 
Eye disorders - Other (eye 
disorders)3 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fever 
 
 
 Fever (Gr 3) 
 
 
Infusion related reaction 
  
Pain 
 
 
 Pain (Gr 3) 
 
 
Sudden death NOS 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction (Gr 3) 
 
 
Anaphylaxis 
  
 
Serum sickness 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection4 (Gr 3) 
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine 
aminotransferase 
increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 3) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
Investigations 
- 
Other 
(elevated c-reactive proteins) 
 
 
 Investigations 
- 
Other 
(elevated c-reactive proteins) 
(Gr 2) 
 
Lymphocyte count decreased 
 Lymphocyte count decreased 
(Gr 4) 


 
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 Adverse Events with Possible  
 Relationship to MoAb 14.18, chimeric (CH14.18) 
 (CTCAE 4.0 Term) 
[n= 351] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Neutrophil count decreased  
 Neutrophil count decreased 
(Gr 3) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 
4) 
 
White blood cell decreased  
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 3) 
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
 Hypokalemia (Gr 4) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Back pain 
 
 Back pain (Gr 3) 
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Myelitis5 
  
 
Neuralgia 
 
 Neuralgia (Gr 2) 
 
 
Peripheral motor neuropathy   
 
Peripheral 
sensory 
neuropathy6 
 
 Peripheral 
sensory 
neuropathy6 (Gr 2) 
 
 
Reversible 
posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Renal and urinary disorders - 
Other 
(atonic 
urinary 
bladder)6 
  
 
Urinary retention6 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Bronchial obstruction 
 
  
Cough 
 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Hypoxia 
 
 Hypoxia (Gr 3) 
 
Stridor 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 3) 


 
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 Adverse Events with Possible  
 Relationship to MoAb 14.18, chimeric (CH14.18) 
 (CTCAE 4.0 Term) 
[n= 351] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
VASCULAR DISORDERS 
  
 
Capillary leak syndrome 
 
 Capillary leak syndrome (Gr 
3) 
 
Hypertension 
 
  
 
Hypotension 
 
 Hypotension (Gr 3) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail.  
 
2There have been rare instances of atypical hemolytic uremic syndrome in the absence of documented 
infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension. 
 
3Neurological disorders of the eye including blurred vision, diplopia, cycloplegia, mydriasis, photophobia, 
optic nerve disorder, eyelid ptosis, and fixed pupils have been observed.  
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5Myelitis expressed as transverse myelitis has occurred in patients treated with chimeric MoAb 14.18. 
Symptoms may include weakness, paresthesia, sensory loss, or incontinence. 
 
6Acute urinary retention occurs during therapy and is thought to be due to fluid shifts and narcotic 
administration that accompany ch14.18 administration.  Atonic urinary bladder results in chronic urinary 
retention (CUR) that requires intermittent urethral catheterization days to weeks following chimeric MoAb 
14.18 administration.  
 
Adverse events reported on MoAb 14.18, chimeric (CH14.18) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MoAb 14.18, chimeric (CH14.18) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(thrombotic microangiopathy [e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic 
syndrome [HUS]); Bone marrow hypocellular; Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (gallop on exam); 
Cardiac disorders - Other (N-terminal BNP); Chest pain - cardiac; Heart failure; Left ventricular systolic 
dysfunction; Mobitz (type) II atrioventricular block; Myocardial infarction; Palpitations; Pericardial 
effusion; Supraventricular tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain; Hearing impaired 
ENDOCRINE DISORDERS - Endocrine disorders - Other (transient hypoaldosteronism); 
Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Papilledema; Scleral disorder 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Cheilitis; Colitis; Constipation; 
Duodenal obstruction; Dysphagia; Enterocolitis; Esophageal stenosis; Esophageal ulcer; Esophagitis; 


 
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Gastrointestinal disorders - Other (pneumatosis intestinalis); Gastroparesis; Hemorrhoidal hemorrhage; 
Ileus; Intra-abdominal hemorrhage; Lower gastrointestinal hemorrhage; Mucositis oral; Oral pain; Rectal 
hemorrhage; Stomach pain; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; 
Edema trunk; Fatigue; General disorders and administration site conditions - Other (cold and clammy); 
Hypothermia; Injection site reaction; Irritability; Localized edema; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (cholestasis) 
IMMUNE SYSTEM DISORDERS - Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alkaline phosphatase increased; 
Blood bilirubin increased; Cardiac troponin I increased; Cholesterol high; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; Fibrinogen decreased; GGT increased; INR increased; 
Investigations - Other (isolated glycosuria); Lipase increased; Lymphocyte count increased; Urine output 
decreased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; 
Hyperglycemia; 
Hypermagnesemia; 
Hypernatremia; 
Hypertriglyceridemia; 
Hypoglycemia; 
Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Bone 
pain; Chest wall pain; Muscle weakness lower limb; Myalgia; Neck pain 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Depressed level of consciousness; 
Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Headache; Hydrocephalus; 
Meningismus; Movements involuntary; Nystagmus; Oculomotor nerve disorder; Paresthesia; Seizure; 
Somnolence; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Delirium; Hallucinations; Insomnia; 
Personality change; Restlessness 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Hematuria; Renal 
and urinary disorders - Other (acute renal insufficiency); Renal and urinary disorders - Other (urethritis); 
Renal hemorrhage 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Hematosalpinx; Ovarian hemorrhage; 
Pelvic pain; Penile pain; Prostatic hemorrhage; Spermatic cord hemorrhage; Testicular hemorrhage; 
Uterine hemorrhage; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Apnea; Atelectasis; Bronchospasm; Laryngeal edema; Laryngopharyngeal dysesthesia; 
Laryngospasm; Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumonitis; Pulmonary edema; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (tachypnea); Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Erythema multiforme; Hyperhidrosis; 
Periorbital edema 
VASCULAR DISORDERS – Flushing 
 
Note: MoAb 14.18, chimeric (CH14.18) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
Formulation and Stability:  
Ch14.18 (dinutuximab) is provided as a sterile solution in single-dose vials containing 17.5 mg/5 mL (3.5 
mg/mL) in 20 mM Histidine, 150 mM NaCl, 0.05% Tween 20 at pH 6.8. Intact vials should be stored in 
the refrigerator (2ºC to 8ºC). Stability studies of the intact vials are ongoing.  
 
Withdraw the required dose of ch14.18 (dinutuximab) from the vial(s) and inject the exact volume for the 
dose (17.5 mg/m2/dose) into a bag containing 100 mL of 0.9% sodium chloride. The use of a filter during 


 
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preparation is not required. The final prepared product of ch14.18 (dinutuximab) in NS is stable at room 
temperature for 24 hours when diluted to a concentration between 0.044 mg/mL and 0.56 mg/mL; however, 
the final dosage form should be prepared immediately prior to administration as there is a maximum 
infusion time of 20 hours. The minimum infusion time for the antibody infusion is 10 hours. There is no 
need to keep empty or partially used vials of ch14.18 (dinutuximab). 
 
Lot number information will be collected on the NCI Drug Accountability Record Form (DARF) (see the 
Agent Accountability section below). 
 
Guidelines for Administration:  
See Treatment, Dose Modifications and/or Supportive Care sections of the protocol. 
 
Patient Care Implications:  
Pain is one of the most common adverse effects of ch14.18 (dinutuximab). It is predominately neuropathic and 
manifests as abdominal cramps or back and extremity pain. Prophylactic administration of morphine by 
continuous infusion is required before and during the infusions of ch14.18 (dinutuximab). Other narcotics such 
as hydromorphone or fentanyl can be used. Gabapentin may be used in conjunction with other pain medications 
per institutional practice. Use of additional pain medications (lidocaine, ketamine) in extenuating circumstances 
should be undertaken in consultation with pediatric pain management specialists. 
 
Acute allergic or infusion reactions are common and may include hypotension, urticaria, hypoxia, and dyspnea. 
Premedication with antihistamines and acetaminophen are required for ch14.18 (dinutuximab) administration. 
 
Human anti-mouse antibodies (HAMA) may block the effectiveness of therapy by prematurely clearing the 
treatment antibody and limiting further immunotherapy. HAMA responses may also be associated with 
immune-complex related adverse events such as serum sickness and anaphylaxis. HAMA responses were 
detected in over 50% of the patients tested. Although no increase in allergic reactions has been observed in 
patients treated with ch14.18 (dinutuximab) in the presence of HAMA, immune complex formation may have 
induced serum sickness in some patients. 
 
Supplier:  
Manufactured by United Therapeutics and distributed by the CTEP, DCTD, NCI. Do not use commercial 
supply. 
 
Agent Ordering: 
NCI supplied agent may be requested by the Principal Investigator (or their authorized designee) at each 
participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped 
directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents 
between institutions (unless prior approval from PMB is obtained.) The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual submission of FDA form 
1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of one lead investigator at 
that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and ordering 
designees must submit agent requests through the PMB Online Agent Order Processing (OAOP) application 
< https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx >. Access to OAOP requires the establishment of 
a CTEP Identity and Access Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the 


 
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maintenance of an “active” account status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability: 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, dispensing and final disposition of all agents received from PMB 
using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the 
CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol. 
 
Agent Returns: 
Investigators/Designees must return unused DCTD supplied investigational agent to the NCI clinical 
repository as soon as possible when: the agent is no longer required because the study is completed or 
discontinued and the agent cannot be transferred to another DCTD sponsored protocol; the agent is outdated 
or the agent is damaged or unfit for use. Regulations require that all agents received from the DCTD, NCI 
be returned to the DCTD, NCI for accountability and disposition. Return only unused vials/bottles. Do NOT 
return opened or partially used vials/bottles unless specifically requested otherwise in the protocol. See the 
CTEP 
web 
site 
for 
Policy 
and 
Guidelines 
for 
Investigational 
agent 
Returns 
at: 
http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. The appropriate forms may be 
obtained at: http://ctep.cancer.gov/forms/docs/return_form.pdf. 
 
Investigator Brochure Availability: 
The current version(s) of the IB(s) for the agent will be accessible to site investigators and research staff 
through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an 
“active” account status and a “current” password. Questions about IB access may be directed to the PMB 
IB coordinator via email. 
 
Useful Links and Contacts: 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• 
CTEP Identity and Access Management (IAM) account: https://eapps-ctep.nci.nih.gov/iam/ 
• 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov 
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 
 
 


 
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6.2 
IRINOTECAN 
 
 
 
 
 
 
 
(05/09/11) 
[CPT-11,Camptothecin-11,7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin), 
Camptosar®], NSC #616348 
 
 
 
 
 
 
 
 
 
Source and Pharmacology:  
Irinotecan is a semisynthetic water-soluble analog of camptothecin (a plant alkaloid isolated from 
Camptotheca acuminata). Irinotecan is a prodrug that requires conversion, by the carboxylesterase enzyme 
to the topoisomerase-I inhibitor, SN-38 in order to exert anti-tumor activity. SN-38 is approximately 
1000 times more potent than irinotecan. Camptothecins interact specifically with the enzyme topoisomerase 
I which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its 
active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-
strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA 
damage produced during DNA synthesis when replication enzymes interact with the ternary complex 
formed by topoisomerase I, DNA, and either irinotecan or SN-38. Renal excretion is a minor route of 
elimination of irinotecan. The majority of the drug is metabolized in the liver. SN-38 is conjugated to 
glucuronic acid and this metabolite has no anti-tumor activity. The extent of conversion of SN-38 to its 
glucuronide has been inversely correlated with the risk of severe diarrhea, because the other major route of 
SN-38 excretion is biliary excretion by canalicular multispecific organic anion transporter (cMOAT) which 
presumably leads to mucosal injury. In addition, APC and NPC are oxidative metabolites of irinotecan 
dependent on the CYP3A4 isoenzyme. After intravenous infusion of irinotecan in humans, irinotecan 
plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of 
about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 
10 to 20 hours. Irinotecan is 30% to 68% bound to albumin and SN-38 is approximately 95% bound to 
albumin. 
 
Toxicity: 
 
 
Common 
Happens to 21-100 children out of every 
100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, anorexia, fever, 
asthenia, cholinergic symptoms: 
(rhinitis, increased salivation, miosis, 
lacrimation, diaphoresis, flushing, and 
intestinal hyperperistalsis that can 
cause abdominal cramping and early 
diarrhea)  
Constipation, headache, 
diarrhea (L)  
Anaphylaxis, dehydration with 
dizziness & hypotension, 
bradycardia, dyspnea and cough, 
disorientation/confusion, 
somnolence, pain at infusion site 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Neutropenia, alopecia, eosinophilia, 
elevations in transaminases, alkaline 
phosphatase, bilirubin, mucositis, 
infection 
Anemia, rash, dyspepsia, 
thrombocytopenia 
Colitis, renal failure (secondary to 
severe dehydration), 
thromboembolic events, ileus 
Delayed: 
Any time later 
during therapy 
 
 
Pneumonitis 
Late: 
Any time after 
completion of 
treatment 
 
 
 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of irinotecan have been noted in animals at doses similar or 
less than those used in humans. Toxicities include: decreased skeletal ossification, multiple 
anomalies, low birth weight and increased fetal mortality. It is not known if irinotecan is excreted 
into breast milk but it is excreted into rat milk. 
(L) Toxicity may also occur later. 
 


 
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Formulation & Stability:  
Each mL of irinotecan injection contains 20 mg irinotecan (on the basis of the trihydrate salt), 45 mg 
sorbitol, and 0.9 mg lactic acid. When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium 
hydroxide or hydrochloric acid. Irinotecan is available in single-dose amber glass vials in 40 mg 
(2 mL),100 mg (5 mL), 300 mg (15 mL), and 500 mg (25 mL). Store at controlled room temperature 15°-
30°C (59°-86°F). Protect from light. It is recommended that the vial (and backing/plastic blister) should 
remain in the carton until the time of use.  
 
Guidelines for Administration:  See Treatment and Dose Modifications sections of the protocol. 
 
Irinotecan must be diluted prior to infusion. Irinotecan should be diluted in D5W, (preferred) or NS to a 
final concentration range of 0.12-2.8 mg/mL. The solution is physically and chemically stable for up to 
24 hours at room temperature (approximately 25°C) and in ambient fluorescent lighting. Solutions diluted 
in D5W and stored at refrigerated temperatures (approximately 2°-8°C), and protected from light are 
physically and chemically stable for 48 hours. Refrigeration of admixtures using NS is not recommended 
due to a low and sporadic incidence of visible particulates. Care should be taken to avoid extravasation; the 
use of a central line is suggested. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for more detailed information. 
 
6.3 
SARGRAMOSTIM 
 
 
 
 
 
 
 
(04/16/14) 
(Granulocyte Macrophage Colony Stimulating Factor, rhu GM-CSF, rGM-CSF, GM-CSF, Leukine®) 
NSC #613795  
 
 
 
 
 
 
 
 
 
 
Source and Pharmacology: 
Sargramostim (recombinant human GM-CSF) is a glycoprotein produced in yeast (S. cerevisiae) by 
recombinant DNA technology. rGM-CSF is a hematopoietic growth factor which supports survival, clonal 
expansion, and differentiation of hematopoietic progenitor cells. rGM-CSF induces partially committed 
progenitor cells to divide and differentiate in the granulocyte-macrophage pathways. rGM-CSF stimulates 
the production of monocytes, granulocytes, erythrocytes, and sometimes, megakaryocytes in the bone 
marrow. It also induces mature neutrophil and monocytes to increase phagocytosis, superoxide generation, 
ADCC, tumoricidal killing and cytokine production (IL-1 and tumor necrosis factor). Recombinant human 
GM-CSF is a glycoprotein of 127 amino acids characterized by three primary molecular masses of 15500, 
16800, and 19500 daltons. The amino acid sequence differs from the natural sequence by a substitution of 
leucine at position 23 and the CHO moiety may be different from the native protein. After subcutaneous 
administration of sargramostim, peak levels were obtained in 1-4 hours and were detectable at therapeutic 
levels for 12-16 hours post injection. The elimination t½ ranges from 1.5-2.7 hours after SubQ or IV 
administration. 
 
 


 
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Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-
2 days of 
receiving drug 
Headache, malaise, fatigue, 
rash, pruritis, bone pain, 
myalgia, arthralgia, fever, 
chills 
Abdominal pain, weakness, 
anorexia, nausea, local injection 
reactions 
Anaphylaxis, “first dose reaction” 
(hypoxia, dyspnea, hypotension, fever, 
tachycardia, diaphoresis, flushing, 
back pain), vomiting, diarrhea, 
phlebitis, SVT, pericardial effusion 
Prompt: 
Within 2-
3 weeks, prior 
to the next 
course 
 
Weight gain 
In high doses: capillary leak syndrome: 
(pleural effusion, peripheral edema, 
ascites, weight gain, hypotension), 
pneumonitis, peripheral edema, 
elevation of creatinine, bilirubin and 
hepatic enzymes in patients with pre-
existing renal or hepatic dysfunction 
Delayed: 
Any time later 
during therapy 
 
Thrombocytopenia  
 
Unknown 
Frequency 
and Timing:  
Fetal and teratogenic toxicities: It is not known whether sargramostim can cause fetal harm or affect 
reproduction capacity when administered to a pregnant woman. It is unknown whether the drug is 
excreted in breast milk. 
 
Formulation and Stability: 
Sargramostim is available as a lyophilized sterile, white, preservative free powder with 250 mcg (1.4 million 
International Units) per vial and as a sterile, preserved injectable solution in a 500 mcg/mL (2.8 million 
International Units/mL) 1 mL vial. The sargramostim reconstituted lyophilized vial contains 40 mg/mL 
mannitol, USP; 10 mg/mL sucrose, NF; and 1.2 mg/mL tromethamine, USP, as excipients. The liquid 
formulation also contains 1.1% benzyl alcohol (11 mg/mL).Store refrigerated at 2-8°C (36-46°F). Do not 
freeze or shake. 
 
Guidelines for Administration: See Treatment and Dose Modifications and Supportive Care sections of 
the protocol. 
 
Reconstitute lyophilized powder for injection with 1 mL SWFI or 1 mL Bacteriostatic Water for Injection. 
Use SWFI without benzyl alcohol for neonates, infants, and children < 2 years of age or patients with 
hypersensitivity to benzyl alcohol. During reconstitution, direct the diluent at the side of the vial and gently 
swirl the contents to avoid foaming during dissolution. Avoid excessive or vigorous agitation; do not shake. 
Reconstituted solutions prepared with Bacteriostatic Water for Injection (0.9% benzyl alcohol) or the liquid 
preserved solution may be stored for up to 20 days following the first entry into the vial at 2°-8°C 
(36°-46°F). Discard reconstituted solution after 20 days have elapsed. Reconstituted solutions prepared 
with SWFI (without preservative) should be administered as soon as possible and within 6 hours following 
reconstitution.  
 
Use sargramostim for subcutaneous injection without further dilution. Perform dilution for IV infusion in 
NS. If the final concentration is < 10 mcg/mL, add albumin (human) at a final concentration of 0.1% to the 
saline prior to addition of sargramostim to prevent adsorption to the components of the drug delivery 
system. For a final concentration of 0.1% albumin (human), add 1 mg albumin (human) per 1 mL NS. For 
example, for a final volume of 50 mL NS, add 50 mg (or 1 mL) of 5% albumin [human]. Intravenous 
dilutions are stable for up to 48 hours at room temperature or refrigerated but should be used within 6 hours 
due to microbiological concerns. Do not use an in-line membrane filter for IV infusion.  
 


 
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Supplier: Commercially available. See package insert for more detailed information. Only sargramostim 
(yeast-derived recombinant human GM-CSF) will be used in this study. The Escherichia coli-derived 
product (molgramostim) will not be used. 
 
CANADIAN SITES 
Sargramostim is not commercially available in Canada. Sites may purchase and import the USA 
commercial supply of Liquid Leukine® (500 µg/1 mL) or Lyophylized Leukine® (250 µg/vial) 
manufactured by Genzyme USA via an International Distributor (Pharma Exports LLC; Contact: Pete 
Bigley, phone: 1-412-885-3700, fax: 1-412-885-8022, email: pharexp@aol.com or pbigley@pharma-
whitehall.com) under the authority of the protocol’s No Objection Letter (NOL).   
 
Consult the product monograph for appropriate reconstitution and infusion preparation instructions. 
The C17 Canadian Senior Medical Officer (SMO)’s office is responsible for coordinating the “Fax Back” 
for all lot numbers and expiry dates to Health Canada’s Biologics and Genetic Therapies Directorate for 
approval for use in Canada on behalf of all Canadian sites. Canadian sites are notified by the SMO’s Office 
of new lots as they are approved and a list of approved lot numbers is posted on www.c17.ca website under 
the protocol titled Sargramostim. If an unapproved lot is received from the distributor, quarantine the lot 
and contact the SMO’s office immediately (Ellen Morrison ellen.morrison4@albertahealthservices.ca or 
780-492-7064).    
 
Canadian sites must keep a drug accountability log (DAL) recording, at a minimum, manufacturer, lot 
number and expiry date of all formats for all doses dispensed to any registered study patient.   
 
Note: Sargramostim may have orders placed and Drug Accountability Logs maintained on a multiple 
protocol basis (Multiple Protocol—Imported Biologic) as long as each protocol has an NOL and the DAL 
clearly indicates which protocol the subject is registered on. 
 
6.4 
TEMOZOLOMIDE 
 
 
 
 
 
 
 
(06/30/14) 
(Temodar, Temodal) NSC #362856 
 
Source and Pharmacology:  
An orally administered alkylating agent, a second generation imidazotetrazine. A prodrug of MTIC, 
temozolomide spontaneously decomposes to MTIC at physiologic pH. Exerts its effect by cross-linking DNA. 
This is likely a site specific alkylation at the O6-position of guanine with some effect at the N7 position. 
Temozolomide reaches its peak concentration in 1 hour. Food reduces the rate and extent of absorption. It has 
an elimination half-life of 1.13 hr (intraperitoneally) and 1.29 hr (orally) with an oral bioavailability of 0.98. 
Total apparent body clearance is 100 mL/min/m2 and plasma elimination half-life is ~ 100 minutes.  
 
The table below lists the anticipated toxicity profile of temozolomide (oral): 
Incidence 
Toxicities 
Common 
(>20% of patients) 
Constipation, nausea, vomiting, diarrhea, anorexia, alopecia, alanine 
aminotransferase increased, aspartate aminotransferase increased, ataxia, 
anxiety, depression, insomnia, nervous system disorders – other: hemiparesis or 
paresis, dizziness, gait disturbance, amnesia, paresthesia, somnolence, 
headache, seizure, fatigue 
Occasional 
(4-20% of patients) 
Edema limbs, localized edema, rash maculopapular, dysphagia, mucositis oral, 
anemia, platelet count decreased, white blood cell count decreased, lymphocyte 
count decreased, aplastic anemia, blood bilirubin increased, urinary frequency, 
cough, upper respiratory infection, sinusitis 


 
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Incidence 
Toxicities 
Rare 
(≤ 3% of patients) 
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, 
hypercalcemia, lower gastrointestinal hemorrhage, upper gastrointestinal 
hemorrhage, cholecystitis, alkaline phosphatase increased, myelodysplastic 
syndrome, leukemia secondary to oncology chemotherapy, infections and 
infestations – other: Pneumocystis pneumonia, pulmonary fibrosis, anaphylaxis, 
allergic reaction, hepatic failure 
Pregnancy & 
Lactation 
Pregnancy Category D  
Adequate, well-controlled studies have not been conducted in humans. Women 
of childbearing potential should be advised against becoming pregnant while 
taking temozolomide and for at least 6 months following the end of therapy. 
Temozolomide administration to rats and rabbits at 3/8 and 3/4 the human dose 
resulted in the development of malformations of the external organs, soft tissues, 
and skeleton. These animal studies also demonstrated embryolethality (increased 
resorptions) at similar doses. There is no information available regarding the 
transmission of temozolomide during lactation; women should avoid 
breastfeeding while receiving temozolomide. 
 
Formulation and Stability:  
Temozolomide capsules are available in six different strengths (5, 20, 100, 140, 180, 250 mg). The capsules 
vary in size, color, and imprint according to strength. In the US, capsules are packaged in 5-count and 14-
count bottles. In other countries temozolomide may be packaged in 5-count, 14-count or 20-count bottles. 
Temozolomide capsules are stored at controlled room temperature. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
There is a potential for medication errors involving temozolomide capsules resulting in drug overdosages, 
which may have been caused by dispensing/taking the wrong number of capsules per day and/or product 
usage exceeding the prescribed dosing schedule. 
 
When dispensing, it is extremely important that prescribing and dispensing include clear instructions on 
which capsules, and how many of each capsule(s) are to be taken per day. Only dispense what is needed 
for the course, and clearly indicate how many days of dosing the patient will have and how many days are 
without temozolomide dosing. When counseling patients, it is important for each patient/parent to 
understand the number of capsules per day and the number of days that they take temozolomide. It is also 
important for the patient/parent to understand the number of days that they will be off the medication.  
 
Each strength of temozolomide must be dispensed in a separate vial or in its original container (e.g. bottle 
or sachet). Based on the dose prescribed, determine the number of each strength of temozolomide capsules 
needed for the full course as prescribed by the physician. For example, 275 mg/day for 5 days would be 
dispensed as five 250 mg capsules, five 20 mg capsules, and five 5 mg capsules. Label each container with 
the appropriate number of capsules to be taken each day. Dispense to the patient/parent, making sure each 
container lists the strength (mg) per capsule and that he or she understands to take the appropriate number 
of capsules of temozolomide from each bottle or vial to equal the total daily dose prescribed by the 
physician. Institutions that have the capability to dispense temozolomide as daily doses in a blister pack 
may do so, taking specific precautions to ensure that the appropriate dose is provided and that the patient is 
educated to understand the daily dosing regimen. 
 
For children unable to swallow the capsules whole, the oral capsules may be formulated into a suspension. To 
prepare a 10 mg/mL suspension triturate the contents of ten 100 mg capsules (1000 mg), 500 mg povidone 


 
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K-30 and 25 mg anhydrous citric acid dissolved in 1.5 mL purified water in a glass mortar to form a uniform 
paste. To the paste add 50 mL of Ora-Plus® by adding a small amount, mixing, and then adding the balance. 
Transfer to a glass graduated cylinder. Add Ora-Sweet® or Ora-Sweet® SF to a total volume of 100 mL by 
rinsing the mortar with small amounts of the syrup (Ora-Sweet® or Ora-Sweet® SF).  Rinse at least four 
times. Package in an amber plastic prescription bottle. The packaged suspension is stable for 7 days at room 
temperature or 60 days in the refrigerator. The suspension should be shaken well before each use. Procedures 
for proper handling and disposal of cytotoxic drugs should be used when preparing the suspension. (Trissel 
LA, Yanping Z, Koontz SE. Temozolomide stability in extemporaneously compounded oral suspensions. Int 
J Pharm Compounding 10:396-9, 2006). 
 
Alternatively, the capsules can be opened and mixed with apple sauce or juice (refer to Appendix IV). 
 
Supplier: Commercially available. See package insert for further information.  
 
  
 


 
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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). 
 
7.1 
Required Clinical, Laboratory and Disease Evaluations  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below. 
See Section 3.2 for eligibility requirements and for requirements to initiate protocol therapy, including the 
timing of imaging, clinical, and laboratory studies. 
Obtain other studies prior to start of cycle unless otherwise indicated.   
 
7.1.1 
Required and optional studies for all patients 
 
STUDIES TO BE OBTAINED 
Baseline 
During 
Cycle 1 
Subsequent Cycles^ 
History 
X 
X 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Height, weight, BSA 
X 
X 
X 
Performance Status 
X 
 
X 
CBC, differential, platelets 
X 
Weekly1 
Weekly1,2 
Electrolytes and Creatinine 
X 
Weekly through 
the cycle; daily 
during ch14.18 
(dinutuximab) 
administration 
Start of cycle and daily during ch14.18 
(dinutuximab) administration 
ALT, total bilirubin, PO4, Mg++ 
X 
Weekly 
X 
Albumin 
X 
 
X 
Pregnancy test3 
X 
 
 
PT  
X 
 
 
HVA/VMA 
X 
 
End of Cycles 2, 4 and 6, then following 
every 4th cycle thereafter4 
Pulmonary Function Tests 
X5 
 
 
ECHO or MUGA 
X 
 
 
Imaging Evaluation6 
X 
End of Cycles 2, 4 and 6, then following 
every 4th cycle thereafter7 
Bilateral bone marrow aspirates/biopsies 
X 
End of Cycles 2, 4 and 6, then following 
every 4th cycle thereafter for patients 
with known marrow involvement. 
Marrow should be evaluated following 
Cycle 6 for all patients (even if no 
history of marrow disease)7 
Optional Biology studies: Peripheral Blood 8  
 
X8 
X8 
Optional Biology studies: Tissue9 
X9 
 
 
 
^ 
Studies may be obtained within 3 days prior to the start of the subsequent cycle. 
1 
If patients have Grade 4 neutropenia, CBCs should be checked at least twice per week until recovery to Grade 3. 
2 
If patients remain on study for >4 cycles and cytopenias are not observed, CBCs may be obtained at the start of subsequent 
cycles and as clinically indicated. 
3 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually active patients must use 
an acceptable method of birth control. Abstinence is an acceptable method of birth control. 
4 
Obtain in patients who had elevated catecholamines (ie, > 2 x ULN) at initial diagnosis. 
5 
Normal pulmonary function tests (including DLCO) if there is clinical indication for determination. For patients who do not have 
respiratory symptoms, full PFTs are NOT required. 


 
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6 
For patients with measurable disease, the same modality (CT or MRI) should be used for serial disease evaluations. MIBG scans 
should be performed for all patients with MIBG avid disease, including those with disease also detectable by CT or MRI. Note: 
FDG-PET may be used to evaluate disease in patients whose tumors are MIBG non-avid.  
7 
Imaging and marrow aspirates/biopsies to assess disease burden may be performed within 1 week prior to the start of the next 
planned cycle of therapy. 
8 
See Section 13.1 for details. Note: Blood sample may be collected within 7 days prior to Day 1 of Cycle 1. 
9 
See Section 13.2 for details. 
 
These tables only includes evaluations necessary to answer the primary and secondary aims. Obtain 
other studies as indicated for good clinical care.  
 
7.2 
Follow-up  
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) schedule. 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Progressive disease. 
b) Intolerance of study therapy as described in Section 5. 
c) Refusal of further protocol therapy by patient/parent/guardian. 
d) Completion of the maximum allowable number of cycles of therapy (see Section 4.1). 
e) Physician determines it is in patient’s best interest. 
f) Second malignant neoplasm (SMN). 
g) Patients who do not meet criteria to start the next treatment cycle within 21 days after the planned 
subsequent cycle start date (ie, there is a ≥ 3 week delay in start of next cycle). 
h) Repeat eligibility studies (if required) are outside the parameters required for eligibility (see Section 3.2). 
 
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) The fifth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
Overview: This is a prospective, randomized Phase II selection design study to identify an agent that is 
sufficiently promising to be studied further in a Phase III trial. 
 


 
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Within each treatment regimen, we will concurrently conduct a 2-stage group sequential design (“Activity 
Design”) per Simon. In addition, we will use the same data for a randomized, prospective, 2-stage “pick 
the winner” design (“Selection Design”) per Steinberg and Venzon.14 The advantage of the pick-the-winner 
design is that it allows for a mathematical specification of the error rates while allowing clinical 
considerations to play a part in the decision when appropriate. The within-regimen 2-stage designs are 
needed to test for a minimum acceptable level of activity.  
 
The primary objective of the study was achieved when Regimen B (irinotecan/temozolomide/ 
dinutuximab) met the minimum acceptable level of activity required in Stage 1 of the Activity Design in 
order to be deemed worthy of additional study in patients with neuroblastoma. Regimen A 
(irinotecan/temozolomide/ temsirolimus) failed to do so, and randomization was halted. The “randomized 
portion of the trial” is the portion prior to Amendment #5 when patients were randomly assigned to Regimen 
A vs B. The “non-randomized portion of the trial” is the portion as of Amendment #5, when all newly 
enrolled patients are non-randomly assigned to Regimen B. The primary objective of the “non-randomized 
portion of the trial” is to determine the response rate of patients with relapsed, refractory or progressive 
neuroblastoma following treatment with irinotecan, temozolomide and dinutuximab and to compare this 
with the known response rate of patients treated with irinotecan and temozolomide alone. 
 
9.1 
Sample Size and Study Duration 
Randomized portion of the trial 
Enrollment of up to 37 patients per regimen (for a total of up to 74 patients) will be required in order to 
generate the 25 eligible, evaluable patients per regimen (50 total) that will be analyzed. Conservatively high 
estimates of ineligibility were used to arrive at the potential maximum enrollment. The 50 eligible evaluable 
patients will provide suitable operating characteristics to select the best agent for further study. If both 
agents are dropped at the first stage for insufficient activity, the study will require fewer patients (as few as 
34, if all patients enrolled are eligible). At an accrual rate of 24 patients per year and accounting for accrual 
closures and re-openings to assess stopping rules, the accrual to this study can be completed within 4 years, 
and possibly within 2 years. With the addition of 6 months for treatment and follow-up, the total study 
duration will be 2.5-4.5 years. 
 
A total of 36 patients, 35 of whom were eligible (1 patient ineligible in Regimen A), were enrolled (18 on 
Regimen A, 17 on Regimen B) during the randomized portion of the trial. In addition, 1 patient on Regimen 
B was not evaluable for toxicity and feasibility (see Section 9.2.2 for definition of evaluability). Prior to the 
suspension of randomization, annual accrual was about 20 patients per year. 
 
Non-randomized portion of the trial 
Enrollment of patients to the randomized portion of the trial was suspended in Fall 2015 when the COG 
Phase III Data and Safety Monitoring Committee released the interim study results demonstrating activity 
of Regimen B. To allow further study of feasibility and to more accurately estimate the response rate to this 
therapy, additional patients will be enrolled to Regimen B to permit accrual of a total of 50 eligible patients. 
This sample size will enable estimation of the response rate with a standard error of 0.07. This will require 
enrollment of up to an additional 40 patients on Regimen B in order to obtain the required 33 more eligible 
patients. Thus, enrollment may proceed up to a total of 76 patients, which includes the 36 patients that 
enrolled during the randomized portion of the study. 
 
The accrual rate of 20 patients per year observed prior to the suspension of randomization is expected to be 
sustained or exceeded. Thus, accrual of the non-randomized patients should be completed within 2 years. 
With the addition of 6 months for treatment and follow-up, the total study duration will be 2.5 years. 
 


 
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9.2 
Endpoints 
9.2.1 
Primary Endpoint 
The primary study endpoint will be the proportion of patients who are responders. However, in the case 
that both treatment regimens have enough responders to meet the activity design response level, then other 
criteria (toxicity, feasibility, PFS) will be used to subjectively select the winner and answer the primary 
study objective. Responders are defined patients who achieve a ≥ PR, per the INRC,88 as their best overall 
response. Patients with PD prior to attaining a ≥ PR will be considered failures for the analysis of response, 
and go off protocol therapy. In addition, patients who meet off protocol therapy criteria due to toxicity prior 
to attaining a ≥ PR will also be considered treatment failures. For a given patient, this primary endpoint is 
binary (responder, non-responder). 
 
If a patient becomes a responder and later has progressive disease or later goes off protocol therapy due to 
toxicity or by choice, then the patient will be counted as a responder. It is possible that a patient’s response 
to therapy may not occur until after many months of treatment. In order to prevent bias, the maximum 
duration of time/treatment over which a patient’s response is to be assessed for determination of the best 
overall response is after the completion of the first 6 cycles. This limit of 6 cycles applies to the inclusion 
of response data for the assessments of the Activity and Selection Designs as well as the non-randomized 
portion of the trial for the primary objective. 
 
9.2.2 
Exploratory Endpoints 
• 
Progression-free survival: For PFS, an event is defined as a relapse, progressive disease, or death 
attributable to tumor or treatment. Time to event for PFS will be calculated from the time of 
enrollment on the study until the occurrence of the first event or until the time of last contact if no 
event has occurred. Analysis of overall survival (event = death) will also be performed. 
• 
Toxicity: The toxicity endpoint will be defined as the occurrence of unacceptable toxicity per the 
CTCAE v4.0 toxicity grading scale as defined below.  
• 
Feasibility: Feasibility will be defined as the ability to maintain intended treatment with all agents 
(irinotecan, temozolomide and the experimental agent) without a dose reduction or going off 
protocol therapy for toxicity. 
• 
Response rates: a) using current INRC and b) using recently proposed revised INRC. In recent 
years, major pediatric cooperative groups from around the world have made considerable efforts to 
develop standard approaches to neuroblastoma risk stratification and disease evaluation. There is 
an ongoing international collaboration to redefine standardized response criteria for neuroblastoma 
with the ultimate goal to improve our ability to compare response evaluations across clinical trials. 
While the response rate endpoint for the conduct of this study will be evaluated using traditional 
INRC criteria, response based upon the newly revised INRC will be calculated from the multiple 
imaging response components, and concordance of INRC and revised INRC response will be 
checked.  
 
Evaluability 
All eligible, randomized and non-randomized patients will be evaluable for inclusion in the analysis of the 
primary objective and response. All analyses of response will be conducted as intent-to-treat.  
 
Any eligible patient who receives at least one dose of temsirolimus or ch14.18 (dinutuximab) on study will 
be considered evaluable for toxicity and feasibility. 
 


 
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9.3 
Study Design and Interim Monitoring 
We will first conduct a safety phase, whereby the first 6 patients treated on each regimen of the study will 
be closely monitored for toxicity. If the stopping rule in the safety phase is not triggered, we will move on 
to the efficacy phase (assessment of response using activity and selection rules), including the first 
12 patients from the safety phase. Accrual to the study will be halted at the following times in order to 
gather data for assessment of the monitoring rules before continuing accrual on the next stage: 
- Rule A, at the end of Stage 1 (the “safety phase”) and Stage 2; 
- Rule B, at the end of Stage 1; 
- Activity design, at the end of Stage 1; and, 
- Selection design, at the end of Stage 1. 
 
Analysis of response will be intent-to-treat of eligible, randomized patients. The primary study objective 
and interim monitoring will be accomplished using 2 distinct 2-stage designs:  
• 
A design within each treatment regimen. Each of these will determine that a given regimen 
meets the minimum level of activity. These designs will be referred to as the “activity” 
designs.  
• 
A second design that compares the 2 treatment regimens. This design will be referred to as 
the “selection” design.  
 
9.3.1 
Randomization/Strata 
Patients will be randomized 1:1 to Regimen-A (irinotecan/temozolomide/temsirolimus) or Regimen-B 
(irinotecan/temozolomide/ch14.18, dinutuximab), stratified by the extent of disease and prior therapy as 
well as MYCN status89 (Strata 1-12). 
 
Randomization will be stratified to ensure equal distribution of disease category, prior exposure to anti-
GD2 antibody therapy , and MYCN amplification between the 2 treatment regimens. The study is not 
powered nor designed to evaluate each stratum separately. 
 
The strata are: 
Stratum 1: Patients whose disease is measurable with conventional CT and/or MRI, no prior anti-
GD2 therapy; MYCN amplified tumor 
Stratum 2: Patients whose disease is detected by abnormal uptake at ≥ 1 site on MIBG scan, no 
prior anti-GD2 therapy; MYCN amplified tumor  
Stratum 3: Patients whose disease is measurable with conventional CT and/or MRI, with prior 
anti-GD2 antibody therapy; MYCN amplified tumor 
Stratum 4: Patients whose disease is detected by abnormal uptake at ≥ 1 site on MIBG scan, with 
prior anti-GD2 therapy; MYCN amplified tumor 
Stratum 5: Patients whose disease is measurable with conventional CT and/or MRI, no prior anti-
GD2 therapy; MYCN non-amplified tumor 
Stratum 6: Patients whose disease is detected by abnormal uptake at ≥ 1 site on MIBG scan, no 
prior anti-GD2 therapy; MYCN non-amplified tumor.  
Stratum 7: Patients whose disease is measurable with conventional CT and/or MRI, with prior 
anti-GD2 antibody therapy; MYCN non-amplified tumor 
Stratum 8: Patients whose disease is detected by abnormal uptake at ≥ 1 site on MIBG scan, with 
prior anti-GD2 therapy; MYCN non-amplified tumor 
Stratum 9: Patients whose disease is measurable with conventional CT and/or MRI, no prior anti-
GD2 therapy; MYCN unknown/unable to be determined 
Stratum 10: Patients whose disease is detected by abnormal uptake at ≥ 1 site on MIBG scan, no 
prior anti-GD2 therapy; MYCN unknown/unable to be determined.  


 
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Stratum 11: Patients whose disease is measurable with conventional CT and/or MRI, with prior 
anti-GD2 antibody therapy; MYCN unknown/unable to be determined 
Stratum 12: Patients whose disease is detected by abnormal uptake at ≥ 1 site on MIBG scan, with 
prior anti-GD2 therapy. MYCN unknown/unable to be determined 
 
Patients in Strata 2, 4, 6, 8, 10, and 12 may not have measurable disease on CT and/or MRI. 
 
9.3.2 
Safety Phase 
The first 6 patients treated on each regimen of the study will be closely monitored for toxicity during a 
safety phase, and accrual will be halted after the enrollment of 6 patients per treatment regimen in order to 
make this assessment. The presence or absence of an unacceptable toxicity will be determined for each 
patient during the first 2 cycles of each regimen. Any patient who receives at least one dose of temsirolimus 
or ch14.18 (dinutuximab) on study will be considered evaluable for toxicity. If 3 or more patients out of 6 
on a given regimen have at least one unacceptable toxicity, then that treatment regimen will be temporarily 
closed for DSMC review and reassessment of drug doses. Accelerated reporting of treatment data including 
toxicities will be required for the first 6 patients treated on each regimen. Reporting period data are to be 
completed on-line within 7 working days of the end of each cycle of therapy followed by routine toxicity 
reporting being completed on line within 10 working days of the end of each cycle. Toxicity data will be 
reviewed on a weekly basis by the study chair and study statistician.  
 
9.3.3 
Stopping Rule for Tolerability 
Definition of unacceptable toxicity 
Many of the toxicities that occur due to the therapy are not unexpected. However, we plan to consider a 
subset of the toxicities unacceptable. Those designated as unacceptable are listed below with the associated 
CTC v4 MeDRA code in parentheses: 
 
1. Toxicity requiring the use of pressors for ≥ 24 hrs, including Grade 4 capillary leak syndrome 
(10007196), Grade 4 anaphylaxis/allergic reaction (10002218 or 10001718) or Grade 3 and 4 
hypotension (10021097) requiring pressors. 
 
2. Toxicity requiring ventilatory support for more than 24 hours, including Grade 4 respiratory 
toxicity such as ARDS (10001409), Grade 4 bronchospasm (10006482), Grade 4 dyspnea 
(10013963), Grade 4 hypoxia (10021143), Grade 4 anaphylaxis/allergic reaction (10002218 or 
10001718), or Grade 4 respiratory failure (10038695) that requires intubation and mechanical 
ventilation. 
 
3. Peripheral motor neuropathy Grade 4 or Grade 3 that does not resolve prior to start of next 
course of therapy (10034580). 
 
4. Peripheral sensory neuropathy Grade 4 or Grade 3 that does not resolve prior to start of next 
course of therapy (10034620). 
 
5. Grade 4 Cytokine Release Syndrome/Acute Infusion Reaction (10052015). 
 
6. Toxic death. 
 
Rule A - Stopping rule for tolerability  
This is a 3-stage rule, and Stage 1 corresponds to the Safety Phase described above. This rule will be applied 
to each treatment regimen separately. 
 


 
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Stage 1 – Accrue 6 patients to a given treatment regimen. If 3 or more patients have at least one unacceptable 
toxicity, then the treatment regimen will be temporarily closed to new accrual to allow for DSMC review 
and reassessment of drug doses. If < 3 patients have an unacceptable toxicity, then continue to Stage 2. 
 
Stage 2 – Accrue 11 more patients for a total of 17 in a given treatment regimen. If 4 or more patients have 
at least one unacceptable toxicity, then the DSMC and study committee will review the treatment for 
reassessment of drug doses. If < 4 patients have an unacceptable toxicity, then continue to Stage 3. 
 
Stage 3 – Accrue 8 more patients for a total of 25 in a given treatment regimen. If 6 or more patients have 
at least one unacceptable toxicity, then the treatment regimen will be considered not sufficiently safe. If 
< 6 patients have an unacceptable toxicity, then the treatment regimen will be considered sufficiently 
tolerable for further study. 
 
This rule has the following operating characteristics: The null hypothesis is that the toxicity rate is more 
than 32% and the alternative hypothesis is that the toxicity rate is less than 10%. This rule has > 90% power 
and alpha < 0.10. Under the null hypothesis, the expected sample size is 15.0, the probability of stopping 
after the first stage is 0.294, and the probability of stopping after the second stage is 0.847. 
 
Non-randomized portion of the trial 
There may be cause to stop the trial early if the unacceptable toxicity (as defined in Section 9.3.3) rate on 
Regimen B appears too high. The presence or absence of an unacceptable toxicity will be determined for 
each evaluable patient during the first 2 cycles of therapy. During the randomized portion of the trial, 1 
unacceptable toxicity was observed, which will be counted in the monitoring rule below. 
 
If at any time 8 or more patients have at least one unacceptable toxicity, then Regimen B will be considered 
not sufficiently safe.  If 7 or less patients have an unacceptable toxicity, then Regimen B will be considered 
sufficiently tolerable for further study.  
 
For this single-stage rule, with N=50 evaluable patients, there is a 0.90 probability of concluding the 
toxicity rate is unacceptable when the true rate is 23.8% and there is a 0.10 probability of concluding the 
toxicity rate is unacceptable when the true rate is 10% (i.e., uses a null hypothesis toxicity rate of 10%, 
23.8% under the alternative, and has 90% power with a Type I error rate of 10%).  
 
Rule B – Stopping Rule for Feasibility 
We will monitor for inability to administer intended dose intensity of chemotherapy agents for the full 
protocol. This rule will be applied independently within each treatment regimen.  
 
Stage 1 – Accrue 17 patients in a given treatment regimen. If 9 or more patients have at least one dose 
modification (including patients who are taken off protocol therapy due to toxicity), then the DSMC and 
the study committee will review the treatment regimen for reassessment of drug doses. If < 9 patients have 
a dose modification, then continue to Stage 2. 
 
Stage 2 – Accrue 8 more patients for a total of 25 in a given treatment regimen. If 14 or more patients have 
at least one dose modification or are taken off protocol therapy due to toxicity, then the treatment regimen 
will be considered not sufficiently safe. If < 14 patients have a dose modification, then the treatment 
regimen will be considered sufficiently feasible for further study. 
 
This rule has the following operating characteristics: The null hypothesis is that the dose modification rate 
is more than 60% and the alternative hypothesis is that the dose modification rate is less than 32%. This 
rule has > 90% power and alpha < 0.07. Under the null hypothesis, the expected sample size is 18.59, and 
the probability of early termination is 0.801. 
 


 
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Non-randomized portion of the trial 
There may also be cause to stop the trial early if toxicity precludes the administration of the intended doses 
of irinotecan, temozolomide, and dinutuximab during the first 2 cycles of therapy. During the randomized 
portion of the trial, 3 patients on Regimen B had dose modifications >25% due to toxicity during the first 
2 cycles of therapy or were taken off protocol therapy due to toxicity during the first 2 cycles of therapy. 
These will be counted in the monitoring rule below. 
 
If at any time 21 or more patients have a modification of irinotecan, temozolomide or dinutuximab dose 
of >25% due to toxicity during the first 2 cycles of therapy or are taken off protocol therapy due to toxicity 
during the first 2 cycles of therapy, then Regimen B will be considered not sufficiently safe. If 20 or fewer 
patients have such dose modifications for toxicity, then Regimen B will be considered sufficiently feasible 
for further study. Dose modifications related to formulation issues or patient/family preference will not be 
counted during application of this rule.  
 
For this single-stage rule, with N=50 evaluable patients, there is a 0.90 probability of concluding the dose 
modification rate due to toxicity is unacceptable when the true rate is 50.1% and there is a 0.10 probability 
of concluding the dose modification rate due to toxicity rate is unacceptable when the true rate is 32% (i.e., 
uses a null hypothesis toxicity rate of 32%, 50.1% under the alternative, and has 90% power with a Type I 
error rate of 10%).  
 
Rule C: Stopping Rule for Toxic Death and Ventilator Support 
If at any time either a) a toxic death occurs; or, b) a patient requires intubation or ventilator support for 
> 24 hours, the treatment regimen will be temporarily closed to new accrual to allow for DSMC review and 
reassessment of drug doses. 
 
9.3.4 
Efficacy Phase 
For design descriptive purposes, designate the 2 agents being tested as X and Y. 
 
Activity design 
Within each regimen, the activity design will be used to determine if elimination of a regimen is necessary 
due to a given regimen not meeting the minimum level of activity.  
 
Stage 1 of the activity design: Accrue 17 patients to each agent. Evaluate the following with each treatment 
regimen: If an agent has 3 or fewer responders, then there is insufficient evidence of activity of that agent. 
If an agent has 4 or more responders, then the trial may continue to Stage 2 for that agent. 
 
Stage 2 of the activity design: Accrue 8 additional patients to the agent for a total of 25. If the agent has 6 
or fewer responders, then there is insufficient evidence of activity of that agent. If the agent has 7 or more 
responders, then it is reasonable to conclude that the agent is worthy of consideration in the Selection 
Design.   
 
This optimal two-stage design has 91.1% power to detect a 25% difference (15% under the null and 40% 
under the alternative hypothesis) and Type I error of 0.064. Furthermore, of interest is the probability that 
both regimens will be eliminated by application of the activity design rule; when the activity rate for both 
regimens is .15, this probability is equal to .88= (1-.064)(1-.064). The probability of both regimens meeting 
the activity criteria at the end of the study, when the true rate in both regimens is .4, is .83 = (.911*.911).   
 
Selection design 
The selection design is relevant only in the case where both agents have met the minimum level of activity 
at Stage 1 of the activity design. Stage 2 of the selection design is relevant only in the case where at least 
one agent has met the minimum level of activity at Stage 2 of the activity design. In other words, the 


 
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selection design will not be applied at all if one or both agents are eliminated at Stage 1 of the activity 
design; Stage 2 of the selection design will not be applied if both agents are eliminated by Stage 2 of the 
activity design. 
 
Stage 1 of the selection design: Using the first 17 patients accrued to each agent, 
a) Eliminate an inferior agent according to comparison of agents.  
i. Let agent Y be the agent with the most responders at Stage 1. If agent Y has 3 or more 
responders than agent X, then enrollment will stop on agent X regimen and Y will be 
declared the winner. In this case, we may conclude with high probability that Y is either 
superior to, or in the worst case, more or less equivalent to, X. Accrual to regimen Y will 
continue until we have determined if Y meets the minimum activity level in the activity 
design.   
ii. However, if neither agent has 3 or more responders than the other, then both regimens 
may continue to Stage 2. 
 
If an agent has not been eliminated at Stage 1, accrual will continue to Stage 2. 
 
Stage 2 of the selection design:  
a) If neither X or Y was eliminated: Accrue 8 additional patients to each regimen. 
i. Let agent Y be the agent with the most responders at Stage 2. If agent Y has 3 or more 
responders than agent X, then Y will be declared the winner. In this case, we may 
conclude with high probability that Y is either superior to, or in the worst case, more or 
less equivalent to, X.   
ii. However, if neither agent has 3 or more responders than the other, (and both agents have 
enough responders to meet the activity design response level), then other criteria will be 
used to subjectively select the winner. The specifics of these criteria are listed in Section 
9.4. 
b) If one agent was eliminated at Stage 1: Accrue 8 additional patients to the remaining regimen 
for use in the activity design. 
 
Table 1. Operating characteristics of the combined activity and selection designs, for hypothetical true 
response rates of agents X and Y for five possible scenarios. 
 
Scenario 
True 
response 
level of X 
True 
response 
level of Y 
Prob. 
Accept X 
Prob. 
Accept Y 
Both X and Y 
active, but 
neither selected 
Both X 
and Y  
not active 
Expected 
Sample 
Size 
A 
.15 
.15 
.057 
.060 
.0034 
.8796 
37.9 
B 
.15 
.4 
.0066 
.891 
.0245 
.0779 
42.7 
C 
.275 
.275 
.2955 
.3000 
.1834 
.2211 
44.8 
D 
.275 
.4 
.0602 
.57 
.234 
.0404 
45.4 
E 
.4 
.4 
.2919 
.2902 
.4094 
.0089 
46.8 
 
Accrual will not be permitted to continue while Stage 1 is evaluated.  
 
9.4 
Methods to Address Study Objectives 
To address primary objective 1.1.1, we will apply the activity and selection rules, as described above. The 
agent identified by the selection rule will be the optimal agent. In the case that both treatment regimens 
have enough responders to meet the activity design response level, and neither treatment regimen was 
identified by the selection rule, then the following criteria, in ranked order of importance, will be used to 
subjectively select the winner and answer the primary study objective: 
1. Toxic death; 


 
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2. Unacceptable toxicity rate (see definition in Section 9.3.3); 
3. PFS;  
4. Feasibility (dose modifications, off protocol therapy due to toxicity, concomitant medication 
usage), and 
5. Number of days hospitalized (overnight stays); number of overnight stays in the pediatric intensive 
care unit 
 
In addition, we will perform a descriptive analysis of the response of patients who received more than 
6 cycles of therapy. 
 
To address primary objective 1.1.2, the response rate to treatment with irinotecan, temozolomide and 
dinutuximab will be calculated among the 50 eligible patients accrued, including placement of a 95% 
confidence interval on the response rate. If the lower bound of the confidence interval is above the objective 
response rate of 15% observed on ANBL0421, then the addition of dinutuximab will be considered to 
improve response over treatment with irinotecan and temozolomide alone. 
 
To address exploratory objective 1.2.1, a Fisher’s exact test will be used to test for a difference in the 
proportion of patients who are responders, for temsirolimus versus ch14.18 (dinutuximab). This proportion 
(RR) will be calculated for each treatment group as the number of responders divided by the total number 
of patients in that treatment group. 
 
To address exploratory objective 1.2.2, Kaplan-Meier curves of PFS and OS will be generated by treatment 
group, and the curves will be compared using a log-rank test. The following factors have been shown to be 
prognostic of OS post-relapse in neuroblastoma patients: age at diagnosis, INSS stage, MYCN status, time 
from diagnosis to first relapse,89 and prior treatment. To further characterize the outcome of patients on this 
study’s treatments, and describe the treatment effect in context of known prognostic factors and prior 
treatment, Kaplan-Meier curves of PFS and OS will be generated for these factors, and log-rank tests 
performed. 
 
To address exploratory objective 1.2.3, Stopping Rule A will be applied. In addition, a Fisher’s exact test 
will be used to test for a difference in the proportion of patients who experience unacceptable toxicity, for 
temsirolimus versus ch14.18 (dinutuximab). This proportion will be calculated for each treatment group as 
the number of patients who experience unacceptable toxicity divided by the total number of patients in that 
treatment group. Also, the toxicities (Grade ≥ 3) for each treatment group will be descriptively summarized. 
 
To address exploratory objective 1.2.4, Stopping Rule B will be applied. In addition, a Fisher’s exact test 
will be used to test for a difference in the proportion of patients who required a dose modification, for 
temsirolimus versus ch14.18 (dinutuximab). This proportion will be calculated for each treatment group as 
the number of patients who required a dose modification divided by the total number of patients in that 
treatment group. Also, the dose modifications for each treatment group will be descriptively summarized. 
 
To address exploratory objective 1.2.5, for each patient the overall response (CR, PR, SD, PD) will be 
determined per INRC and per the revised INRC. The relative degree of concordance will be presented using 
a weighted kappa statistic (± standard error), where higher values of kappa indicate greater agreement 
between the 2 systems. These analyses will be repeated within each treatment group. In addition, the overall 
response rate (RR) per INRC and per revised INRC will be calculated, and the degree of concordance will 
be tested using a McNemar’s test. 
 
To address exploratory objective 1.2.6, within the ch14.18 (dinutuximab) treatment group, the incidence of 
naturally occurring anti-glycan antibodies will be calculated, including the placement of a 95% confidence 
interval on the incidence. 


 
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To address exploratory objective 1.2.7, the incidence of NK receptor NKp30 isoforms will be calculated, 
including the placement of a 95% confidence interval on the incidence. 
 
To address exploratory objective 1.2.8, the relationship between response to treatment with irinotecan, 
temozolomide, and dinutuximab (response vs. non-response) and naturally occurring anti-glycan 
antibodies, KIR/KIR-L genotyping, Fc receptor genotyping, and HACA will be explored with Fisher's exact 
test for categorical and Wilcoxon rank-sum test for continuous host factors. Both the presence/absence and 
level of naturally occurring anti-glycan antibodies will be considered. For the KIR/KIR-L analysis, patients 
will be categorized as either matched or mismatched. Patients will be grouped into one of the three genotype 
subgroups of Fc receptor genotyping for that analysis. The presence/absence of HACA, anti-idiotype and 
PATA/anti-allotype antibody will be considered for the HACA analysis. 
 
To address exploratory objective 1.2.9, the incidence of NK receptor NKp30 isoforms, immune checkpoint 
proteins (CD274 (PDL1) and CD276 (B7H3)) expression, and expression of GD2 will be calculated, 
including placement of a 95% confidence interval on each incidence rate. Summary statistics will also be 
generated for serum cytokine (IL1, IL6, TNF-alpha, IFN-gamma, etc.) and infiltrating TIL (including 
TAMs) levels. 
 
 
To address exploratory objective 1.2.10, the relationship between response to treatment with irinotecan, 
temozolomide, and dinutuximab (response vs. non-response) and NK receptor NKp30 isoforms, immune 
checkpoint proteins (CD274 (PDL1) and CD276 (B7H3)) expression, expression of GD2, serum cytokine 
levels (IL1, IL6, TNF-alpha, IFN-gamma, etc.), and infiltrating TILs (including TAMs) levels will be 
explored with Fisher's exact test for categorical and Wilcoxon rank-sum test for continuous tumor immune-
microenvironment factors. Patients will be categorized as either present/absent for NK receptor NKp30 
isoforms, immune checkpoint proteins expression, and expression of GD2 for these analyses. The levels of 
serum cytokines and infiltrating TILs will be considered. 
 
To address exploratory objective 1.2.11, the relationship between response to treatment with irinotecan, 
temozolomide, and dinutuximab (response vs. non-response) and gene expression (CHGA, DCX, DDC, 
PHOX2B, and TH) and circulating GD2 levels following therapy will be explored with a Wilcoxon rank-
sum test. Changes from baseline will also be analyzed. 
 
 
 


 
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9.5 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be:  
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
3 
6 
Not Hispanic or Latino 
29 
41 
70 
Ethnic Category: Total of all subjects 
32 
44 
*76 
Racial Category 
 
American Indian or Alaskan Native 
0 
1 
1 
Asian 
1 
1 
2 
Black or African American 
4 
6 
10 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
27 
35 
62 
Racial Category: Total of all subjects 
32 
44 
*76 
* These totals must agree 
This distribution was derived from ANBL0421 and ANBL00B1. 
 
 
10.0 
EVALUATION CRITERIA 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. A copy of the CTCAE version 4.0 can be downloaded from the NCI website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Additionally, toxicities are to be reported on the appropriate case report forms. Please note: ‘CTCAE v4.0’ 
is understood to represent the most current version of CTCAE v4.0 as referenced on the CTEP website (ie, 
v4.02 and all subsequent iterations prior to version 5.0). 
 
10.2 
Response Criteria For Patients with CT/MRI Lesions  
For CT/MRI lesions, response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria In Solid Tumors (RECIST) guideline (version 1.1).90 Key points are that a maximum 
of 5 target lesions are identified and that changes in the largest diameter (uni-dimensional measurement) 
of the tumor lesions are used in the RECIST v1.1 criteria.  
 
10.2.1 Definition of Measurable (Evaluable) Disease on CT/MRI Scan 
The presence of at least one lesion that can be accurately measured in at least one dimension with the longest 
diameter at least 10 mm (CT scan slice thickness no greater than 5 mm). The investigator will identify up 
to 5 measurable lesions to be followed for response. Previously irradiated lesions must demonstrate clear 
evidence of progression to be considered measurable. 
 
Serial measurements of lesions are to be done with CT or MRI. The same method of assessment is to be 
used to characterize each identified and reported lesion at baseline and during follow-up. 
 
10.2.2 Quantification of Disease Burden 
The sum of the longest diameter (LD) for all target lesions will be calculated and reported as the disease 
measurement. 
 
10.2.3 End-of-Cycle Response 


 
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a) Complete Response (CR) 
Disappearance of all target and non-target lesions. 
 
b) Very Good Partial Response (VGPR) 
Greater than 90% decrease of the disease measurement for CT/MRI lesions, taking as reference the 
disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI 
lesions stable to smaller in size. 
 
c) Partial Response (PR) 
At least a 30% decrease in the disease measurement, taking as reference the disease measurement 
done to confirm measurable disease at study enrollment. No new lesions or progression of any non-
target measurable lesion. 
 
d) Progressive Disease (PD) 
At least a 20% increase in the sum of the disease measurements for measurable lesions, taking as 
reference the smallest disease measurement recorded since the start of treatment, or the appearance 
of one or more new lesions. 
 
e) Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as 
reference the smallest disease measurement since the treatment started.  
 
10.2.4 Overall Best Response Assessment 
Each patient will be classified according to their “best response” for the purposes of analysis of treatment 
effect. Best response is determined as described in Section 10.5. 
 
10.3 
Response Criteria for Morphologic Bone Marrow Disease 
Note: patients with bone marrow as the ONLY site of disease are not eligible for this study. Response 
criteria in this section are intended to be used when assessing marrow involvement as a component of 
overall response. 
 
Histologic analysis at the local institution of marrow tumor cell involvement is required for all patients 
pre-therapy (Cycle 1) at the end of Cycles 2, 4, and 6, and then after every 4th cycle thereafter for patients 
with known marrow involvement. Marrow should be evaluated following Cycle 6 for all patients (even if 
no history of marrow disease). Note: If progressive disease is documented by RECIST criteria using tumor 
measurements or by MIBG scan, then a repeat BM is not needed to confirm PD. 
 
10.3.1 Bone Marrow Involvement  
Bone Marrow response is determined by H&E staining of bilateral bone marrow biopsies and aspirates. 
 
Complete Response 
No tumor cells detectable by routine morphology on 2 consecutive bilateral bone marrow aspirates and 
biopsies performed at least 3 weeks apart.  
 
Progressive Disease 
a) Patients who enroll without evidence of neuroblastoma in bone marrow will be defined as having 
progressive disease if tumor is detected in 2 consecutive bone marrow biopsies or aspirations done 
at least 3 weeks apart. 
 


 
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b) Patients who enroll with neuroblastoma in bone marrow by morphology have progressive disease 
if there is a doubling in the amount of tumor in the marrow AND a minimum of 25% tumor in bone 
marrow by morphology. (For example, a patient entering with 5% tumor in marrow by morphology 
must increase to ≥ 25% tumor to have progressive disease; a patient entering with 30% tumor must 
increase to ≥ 60%). 
 
Stable Disease 
Persistence of tumor in bone marrow that does not meet the criteria for either complete response or 
progressive disease. 
 
10.3.2 Overall Best Response Assessment 
Each patient will be classified according to their “best response” for the purposes of analysis of treatment 
effect. Best response is determined as described in Section 10.5. 
 
10.4 
Response Criteria for Patients with 123I-MIBG Positive Lesions 
Patients who have a positive 123I-MIBG scan at the start of therapy will be evaluable for MIBG response. 
MIBG scans will be evaluated by both the treating institution (Section 10.4.1) and subsequently by a COG 
central review (Section 10.4.2). An Overall Response assessment (Section 10.5) will be determined, using 
the MIBG grade from the central review. 
 
10.4.1 Critera for the Treating Institution 
The following criteria will be used to report MIBG response by the treating institution on the Reporting 
Period forms: 
Complete response: Complete resolution of all MIBG positive lesions 
Partial response: Resolution of at least one MIBG positive lesion, with persistence of other MIBG 
positive lesions. 
Stable disease: No change in MIBG scan in number of positive lesions. 
Progressive disease: Development of new MIBG positive lesions. 
 
The intensity of MIBG uptake is not to be considered in the above institutional evaluation. 
 
10.4.2 Critera for Central Review 
MIBG disease will be assessed by central review using the Curie scale as outlined below for all patients 
with MIBG avid lesions at study entry who respond to therapy or have long term stable disease on protocol 
therapy (see Section 14.2). 
 
NOTE: This scoring is NOT required to be done by the treating institution for end of cycle response 
assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th general sector allocated 
for any extra-osseous lesion visible on MIBG scan. In each region, the lesions are scored as follows. The 
absolute extension score is graded as: 
0 = no site per segment 
1 = 1 site per segment 
2 = more than one site per segment 
3 = massive involvement (> 50% of the segment). 
 
The absolute score is obtained by adding the score of all the segments. See diagram of sectors below: 
 


 
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The relative score is calculated by dividing the absolute score at each time point by the corresponding pre-
treatment absolute score. The relative score of each patient is calculated at each response assessment 
compared to baseline and classified as below: 
1) Complete response: all areas of uptake on MIBG scan completely resolved. 
2) Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 (lesions strongly 
reduced). 
3) Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) to 1.0 (lesions not 
reduced). 
4) Progressive disease: New lesions on MIBG scan. 
 
10.4.3 Overall Best Response Assessment 
Each patient will be classified according to their “best response” for the purposes of analysis of treatment 
effect. Best response is determined as described in Section 10.5. 
 
10.5 
Definition of Overall Response for Each Patient 
The International Neuroblastoma Response Criteria (INRC) will be used to define overall response for this 
study. The response criteria integrate response at all sites defined as measurable in this study, including 
CT/MRI lesions which meet RECIST criteria, MIBG positive lesions, and bone marrow disease. These 
criteria will be used to define the overall response for the patient in all strata in the statistical analysis. The 
treating Institution should grade overall response using the INRC criteria, with MIBG grading as listed in 
Section 10.4.1. NOTE: The central review of MIBG scans will be used for the formal statistical evaluation 
of overall response. 
 
10.5.1 Complete Response (CR) 
Disappearance of all target lesions. No evidence of tumor at any site (chest, abdomen, liver, bone, bone 
marrow, nodes, etc.). 
 
10.5.2 Very Good Partial Response (VGPR) 
Greater than 90% decrease of the disease measurement for CT/MRI target lesions, taking as reference the 
disease measurement done to confirm measurable disease in target lesions at study entry; all pre-existing 


 
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bone lesions with CR by MIBG; MIBG scan can be SD or CR in soft tissue lesions corresponding to lesions 
on CT/MRI. CR in bone marrow (by morphology criteria). No new sites of tumor.  
 
10.5.3 Partial Response (PR) 
At least a 30% decrease in the disease measurement for CT/MRI target lesions, taking as reference the 
disease measurement done to confirm measurable disease in target lesions at study entry. Bone marrow 
with CR (by morphology response criteria in Section 10.3). MIBG with either PR/CR in bone lesions; 
MIBG may be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. HVA/VMA may still 
be elevated. 
 
10.5.4 Progressive Disease (PD) 
Any one of the following: 
a) At least a 20% increase in the disease measurement for CT/MRI target lesions, taking as reference 
the smallest disease measurement recorded since the start of treatment. 
b) Appearance of one or more new lesions or new sites of tumor. 
c) PD as defined above for either bone marrow or MIBG lesions. 
 
10.5.5 Stable disease (SD) 
The patient will be classified as stable disease for overall response if there is stable disease by either 
CT/MRI lesion, bone marrow, or MIBG criteria. No new lesions; no new sites of disease.  
 
The overall response as assessed at any particular time point based on the various disease sites is 
summarized in the table below. 
 
Table 10.5.1. Overall Response 
 
Response by individual site 
Overall response 
CT/MRI lesions 
MIBG lesions 
Bone marrow  
Catechols 
 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
PD 
CR 
CR 
CR 
Normal 
CR 
VGPR 
CR in bone 
lesions; May have 
SD/CR in soft 
tissue sites 
corresponding to 
lesions on CT/MRI 
CR 
Normal 
VGPR 
PR 
PR/CR in bone 
lesions; May have 
SD/CR in soft 
tissue sites 
corresponding to 
lesions on CT/MRI  
CR 
Any 
PR 
SD 
SD/PR/CR 
SD/CR 
Any 
SD 
SD/PR/VGPR/CR 
SD 
SD/CR 
Any 
SD 
SD/PR/VGPR/CR 
SD/PR/CR 
SD 
Any 
SD 
 
The best response observed at any time point for each individual patient will be considered that patient’s 
best overall response on this study. 
 


 
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10.6 
Confirmation of Response Status Determined by MRI, CT, MIBG Scans or FDG-PET Scan 
by Central Review 
Any patient that is scored by his or her local institution as showing long term SD or a CR, VGPR or PR 
based on improvement in CT, MRI or MIBG scanning (or FDG-PET if tumor is not MIBG avid) will have 
scans evaluated centrally by COG, after completion of therapy. For this study, long term stable disease is 
defined as SD lasting 6 cycles or greater (minimum 4 months). See Section 14.2 for central review imaging 
guidelines and submission requirements. 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 
Purpose 
Adverse event (AE) 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 regimen, 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. 
 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI requires that AEs be 
submitted according to the timeframes in the AE reporting tables assigned to the protocol, using the NCI’s 
CTEP Adeverse Event Reporting System (CTEP-AERS). 
 


 
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Any AE that is serious qualifies for expedited reporting. An AE is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related. A Serious 
Adverse Event (SAE) is any adverse drug event (experience) occurring at any dose that results in ANY of 
the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing hospitalization 
(for ≥ 24 hours). This does not include hospitalizations which are part of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
11.4 
Special Situations for Expedited Reporting  
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last administration of the investigational 
agent/intervention and has an attribution of a possible, probable, or definite relationship to the study therapy 
must be reported according to the CTEP-AERS reporting tables in this protocol.  
 
11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions (formerly referred to as disabilities), congenital anomalies or birth defects, must be 
reported via CTEP-AERS if it occurs at any time following treatment with an agent under a NCI IND/IDE 
since these are considered to be serious AEs 
 
11.4.3 Death 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: A disorder characterized by cessation of life during the first 28 days of life.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the onset of symptoms) 
or an unobserved cessation of life that cannot be attributed to a CTCAE term associated with 
Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term associated with 
Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the 
system organ class (SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to the investigational 
agent/intervention requires expedited reporting within 24 hours.  
 


 
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Any death occurring greater than 30 days after the last dose of the investigational agent/intervention 
requires expedited reporting within 24 hours only if it is possibly, probably, or definitely related to the 
investigational agent/intervention. 
 
11.4.4 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.  
 
The NCI requires all secondary malignancies that occur following treatment with an agent under an NCI 
IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) must also be reported via the 
routine reporting mechanisms outlined in this protocol. 
 
11.4.5 Pregnancy, Fetal Death, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the 
Pregnancy Information Form, available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportForm.pdf, 
needs to be completed and faxed along with any additional medical information to 301-230-0159. The 
potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section of the CTEP-AERS report. 
 
11.4.5.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the fetus to agents which may be 
teratogenic. For this reason, pregnancy needs to be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other (pregnancy)” under the Pregnancy, 
puerperium and perinatal conditions SOC. 
 
There is a possibility that the sperm of male patients treated on studies involving possible teratogenic agents 
may have been damaged. For this reason, pregnancy in partners of men on study needs be reported and 
followed in the same manner as a patient pregnancy. 
 
Pregnancy needs to be followed until the outcome is known. If the baby is born with a birth defect or 
anomaly, then a second CTEP-AERS report is required. 
 
11.4.5.2 Fetal Death 
Fetal death, defined in CTCAE as “A disorder characterized by death in utero; failure of the product of 
conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation”, needs to be reported expeditiously, as 
Grade 4 “Pregnancy, puerperium and perinatal conditions - Other (pregnancy loss)”. Do NOT report a 
fetal death as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
11.4.5.3 Death Neonatal  
Neonatal death, defined in CTCAE as “A disorder characterized by cessation of life occurring during the 
first 28 days of life” needs to be reported expeditiously, as Grade 4 “General disorders and administration 


 
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- Other (neonatal loss)” when the death is the result of a patient pregnancy or pregnancy in partners 
of men on study. Do NOT report a neonatal death resulting from a patient pregnancy or pregnancy in 
partners of men on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event as a patient 
death.  
 
11.5 
Reporting Requirements for Specialized AEs  
11.5.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an AE, when possible it is to 
be documented as “Course Zero” using CTCAE terminology and grade. An expedited AE report is not 
required if a patient is entered on a protocol with a pre-existing condition (eg, elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported if it fulfills expedited AE 
reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must reassess the event to 
determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event to determine if an 
expedited report is required. 
c. No modification in grading is to be made to account for abnormalities existing at baseline. 
 
11.5.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between treatment cycles/courses. 
 
ROUTINE reporting: The AE must be reported only once unless the grade becomes more severe in a 
subsequent course. If the grade becomes more severe the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade becomes more severe in the 
same or a subsequent course. 
 
11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy and then reoccurs in a later 
cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent cycle/course must be 
reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent cycle/course does not 
require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.6 
Exceptions to Expedited Reporting 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and Potential Risks (CAEPR) that 
contains a list of events that are considered expected for CTEP-AERS reporting purposes. (Formerly 
referred to as the Agent Specific Adverse Event List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the NCI via CTEP-AERS 
ONLY if they exceed the grade of the event listed in parentheses after the event. If the CAEPR is part of a 
combination IND using multiple investigational agents and has an SAE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is listed as expected. The 
exception or acceptable reporting procedures will be specified in the protocol. The protocol specific 


 
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guidelines supersede the NCI Adverse Event Reporting Guidelines. These special situations are listed under 
the CTEP-AERS reporting Table A for this protocol. 
 
11.7 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the primary 
responsibility for AE identification, documentation, grading, and assignment of attribution to the 
investigational agent/intervention. It is the responsibility of the treating physician to supply the medical 
documentation needed to support the expedited AE reports in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine reporting. Routine 
reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) within the study database.   
 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
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/adverse_events.htm. All appropriate 
treatment areas should have access to a copy of the CTCAE. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be submitted 
electronically to NCI via CTEP-AERS at:  
https://eapps-ctep.nci.nih.gov/ctepaers. 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to be made to the 
NCI for agents supplied under a CTEP IND by telephone call to 301-897-7497.  
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned in must be entered 
into the electronic CTEP-AERS system by the original submitter of the report at the site.   
 
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-AERS within 
24 hours of learning of the event, followed by a complete expedited report within 5 calendar 
days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted within 
7 calendar days of the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect, or is an IME, which based upon 
the medical judgment of the investigator may jeopardize the patient and require intervention to 
prevent a serious AE, must be reported via CTEP-AERS if the event occurs following 
investigational agent administration.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an agent/intervention 
under an NCI IND/IDE requires expedited reporting within 24 hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of possible, probable, or 
definite to an agent/intervention under an NCI IND/IDE requires expedited reporting within 
24 hours.  
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 1) whether the 
patient has received at least one dose of an investigational agent on this study; 2) the characteristics of the 
adverse event including the grade (severity), the relationship to the study therapy (attribution), and the 


 
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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.  
 
Any medical documentation supporting an expedited report (eg, H & P, admission and/or notes, 
consultations, ECG results, etc.) MUST be faxed within 48-72 hours to the NCI. NOTE: English is 
required for supporting documentation submitted to the numbers listed below in order for the NCI 
to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied under a CTEP IND 
to: 301-230-0159 (back-up: 301-897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# 626-303-1768; email: 
COGAERS@childrensoncologygroup.org; Attention: COG AERS 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. 
 
 
 


 
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11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 
30 Days of the Last Administration of the Investigational Agent/Intervention 1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. This 
 
does not include hospitalizations which are part of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may 
 
be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
 
312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below.   
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Additional Special Situations as 
Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of learning 
of the AE.  
 
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention and have an 
attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
• 
All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  
 
 
 


 
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11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
The following do not require expedited reporting: 
 
For Regimen A:  
• 
Grade 1-2 dehydration or Grade 3 dehydration ≤ 3 days duration  
• 
Grade 1-3 hypersomnia, or insomnia  
• 
Grade 1-3 oliguria 
 
For Regimen B:  
• 
Grade 1-2 dehydration or Grade 3 dehydration ≤ 3 days duration 
• 
Grade 1-3 irritability  
• 
Grade 1-3 oliguria 
• 
Grade 1-2 visual changes or Grade 3 visual changes that resolve within 7 days of onset 
 
11.11 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 7 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, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This 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. 
 
 
11.12 Routine 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. 
 
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 toxicities reported via CTEP-AERS and all 
Grade 3 and higher Adverse Events.  


 
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12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are posted on the COG web site with each protocol under 
“Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
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. 
 
12.2 
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.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected frequency of 
serious events on the trial are 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 a regimen based on toxicity results or other trials reported, increasing target 
sample size, etc.). 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. 
 
12.3 
CRADA/CTA 
NCI/DCTD Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by a 
Clinical Trials Agreement (CTA), a Cooperative Research and Development Agreement (CRADA) or a 
Clinical Supply Agreement, hereinafter referred to as Collaborative Agreement: 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the 
following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI. If a copy of this protocol 
is requested by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 


 
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2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by 
each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be 
referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature 
of any agreements governing their collaboration with NCI, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by 
any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be 
made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional 
disclosure is required by law or court order as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, 
all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 
45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or 
PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines 
and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this 
clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 30 
days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must be provided 
to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also be forwarded 
to CTEP prior to release. Copies of any manuscript, abstract and/or press release/media presentation 
should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 


 
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13.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS  
Participation in the optional biology studies listed below is strongly encouraged.  
 
13.1 
Optional Biology Studies: Peripheral Blood 
If the patient consents, any specimens left over after the special studies listed below are performed will be 
banked at the Biopathology Center for future research studies. 
 
13.1.1 Prioritization of Blood Samples to be Used for Biology Studies 
If there is an inadequate amount of blood for all of the studies listed below, collection of the green top 
(heparinized) tubes should be prioritized. 
 
13.1.2 Peripheral blood sample collection and schedule 
Prior to the administration of the anticancer therapy described in this study, a baseline blood sample should 
be drawn. This can be obtained with pre-study labs within 7 days of starting therapy or on Day 1 of Cycle 1. 
 
Peripheral blood sampling requirements are summarized in the tables below: 
 
Children weighing  12 kg: 
 
Cycle 1 
Cycle 2 
Cycles 3, 4 
After 
Cycles 4 
and 6* 
 
Prior to 
start of 
therapy 
Day 5 (post 
completion of 
dinutuximab) 
Day 8 
optional# 
Day 15 
optional# 
Prior to 
start of 
therapy 
Day 5 
Day 8 
optional 
Day 15 
optional 
Prior to 
start of 
therapy 
Green top 
(heparin) tubes^ 
(See Sections 
13.1.3 & 13.1.4) 
5 mL 
 
 
 
5 mL 
 
 
 
5 mL 
4 mL 
Red top tubes 
(See Sections 
13.1.3 & 13.1.4) 
2 mL 
2 mL 
 
 
2 mL 
2 mL 
 
 
 
 
PAX gene tubes 
(See Sections 
13.1.6 & 13.1.7) 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
 
 
^ Samples collected in green top tubes should be drawn Monday through Thursday to allow for immediate shipping 
as they should NOT be stored over a weekend or holiday 
# Even if the patient has consented to peripheral blood collection, samples collected on Days 8 and 15 of Cycles 1 and 
2 are not mandatory, but strongly encouraged.  
* Can be drawn on the days of disease evaluations or at any point prior to the start of Cycle 5 and Cycle 7 therapy 
 
 
 


 
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Children weighing <12 kg: 
 
Cycle 1 
Cycle 2 
Cycles 3, 4 
After 
Cycles 4 
and 6* 
 
Prior to 
start of 
therapy 
Day 5 (post 
completion of 
dinutuximab) 
Day 8 
optional# 
Day 15 
optional# 
Prior to 
start of 
therapy 
Day 5 
Day 8 
optional 
Day 15 
optional 
Prior to 
start of 
therapy 
Green top 
(heparin) tubes^ 
(See Sections 
13.1.3 & 13.1.4) 
5 mL 
 
 
 
5 mL 
 
 
 
5 mL 
4 mL 
Red top tubes 
(See Sections 
13.1.3 & 13.1.4) 
2 mL 
2 mL 
 
 
2 mL 
2 mL 
 
 
 
 
PAX gene tubes 
(See Sections 
13.1.6 & 13.1.7) 
2.5 mL 
2.5 mL 
2.5 mL 
2.5 mL 
2.5 mL 
2.5 mL 
2.5 mL 
2.5 mL 
 
 
^ Samples collected in green top tubes should be drawn Monday through Thursday to allow for immediate shipping 
as they should NOT be stored over a weekend or holiday 
# Even if the patient has consented to peripheral blood collection, samples collected on Days 8 and 15 of Cycles 1 and 
2 are not mandatory, but strongly encouraged.  
* Can be drawn on the days of disease evaluations or at any point prior to the start of Cycle 5 and Cycle 7 therapy 
 
13.1.3 Sample Processing: Green and Red Top Tubes 
Green Top Tubes: 
Samples in green top tubes should be collected Monday through Thursday and sent at the appropriate 
temperature by overnight carrier (see below). Do NOT batch the green top samples. 
 
It is particularly important that the baseline blood sample be drawn on a Monday through Thursday and 
the green top tubes shipped immediately. Baseline blood samples should NOT be collected on Fridays, 
Saturdays, Sundays or national holidays. Subsequent day green top samples should also be collected 
Monday through Thursday and sent at the appropriate temperature.  
 
Red Top Tubes: 
After the blood in red top tubes has clotted, tubes should be centrifuged at 1,100-1,300 x g for 
15 minutes at room temperature. Serum should be collected and transferred to a conical tube for mixing. 
Evenly dispense at least 0.5 mL of the serum into pre-labeled 1.8 mL screw-cap cryotubes. Cap the 
cryovial securely and freeze upright if possible. Storage in an ultra-cold freezer (≤ -70oC) or in liquid 
nitrogen is ideal; use of a non-cycling -20oC freezer is acceptable but should be avoided if possible. 
The serum should be shipped overnight (frozen) on the following Monday or the next day that would 
permit delivery on a working day. Batching of serum samples is acceptable. 
 
13.1.4 Sample Labeling and Shipping: Green and Red Top Tubes 
EACH sample should be labeled with: 
1) Patient's COG registration number 
2) Study number ANBL1221 
3) Cycle and day of therapy blood was drawn 
 
Each specimen must be sent with a completed Specimen Transmittal Form. In addition, details of CBC with 
differentials should be provided, if available. 
 
As noted above, samples will be received Tuesday through Friday only. 
 
Samples should be sent to the address below at the appropriate temperature via Federal Express Priority 
Overnight using the COG account number (refer to https://members.childrensoncologygroup.org/_files/
reference/FEDEXmemo.pdf). Green top tubes must be shipped with insulation or cold pack to avoid 


 
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freezing or over-heating respectively. Red top tubes should be batched and sent frozen) 
 
Alice Yu, MD, PhD 
UCSD Medical Center 
Clinical Teaching Facility, B-114 
212 Dickinson Street 
San Diego, CA 92103-8447 
Lab Phone: (619)-543-2438 
Lab FAX: (619)-543-5413 
E-mail: 
yulab@ucsd.edu 
 
Lab contact: Jenna Mielke 
 
13.1.5 Subsequent Processing by Dr. Yu’s Lab 
Samples will be processed by Yu laboratory personnel, and assays for antiglycan antibodies, cytokine 
levels, NK receptors and immune cell subsets will be performed on site. Yu laboratory personnel will 
distribute components of the samples collected to other investigators conducting correlative studies being 
performed using blood samples. 
 
DNA for KIR/KIR ligand and Fc receptor genotyping as well as plasma for HACA testing will be sent to 
the Sondel laboratory at the University of Wisconsin and to the Chinnaiyan laboratory at the University of 
Michigan. Plasma will be sent to the Balis laboratory at the Children’s Hospital of Philadelphia.  
 
Remaining components of blood samples will be stored at the Biopathology Center for additional testing if 
necessary. If additional testing is not required, the sample will be banked for future research. 
 
13.1.6 Sample Processing: PAX Gene Tubes 
1) For samples collected in PAXgene tubes blood is placed immediately into the tube, which is then 
inverted 8 - 10 times to mix. Blood should be stored upright in a wire rack and placed in -20°C 
freezer until shipment. Do not freeze tubes upright in a styrofoam tray as this may cause the tubes 
to crack. Please note that if tubes are to be kept at temperatures below -20°C, they must first be 
stored at -20°C for 24 hours before being transferred into a -70°C or -80°C freezer. PAX Gene 
blood is stored frozen and it must be shipped on dry ice. 
 
2) PAX gene tubes should be batched for each cycle and shipped prior to the next cycle. Please ship 
on dry ice overnight on a day that would permit delivery on a working day.  
 
Note: If the PAXgene tube is the only tube to be drawn, blood should be drawn into a “Discard 
Tube” prior to drawing blood into the PAXgene tube.  Otherwise the PAXgene tube should be the 
last tube drawn. 
 
13.1.7 Sample Labeling and Shipping: PAXgene Tubes 
EACH sample should be labeled with: 
1) Patient's COG registration number 
2) Study number ANBL1221 
3) Cycle and day of therapy blood was drawn 
 
Each specimen must be sent with a completed Specimen Transmittal Form. In addition, details of CBC with 
differentials should be provided, if available. 
 
Samples should be sent to the address below via Federal Express Priority Overnight using the COG 


 
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account number (refer to 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf). 
 
Shahab Asgharzadeh, MD 
Children’s Hospital Los Angeles 
Smith Research Tower, 515 
4650 Sunset Boulevard 
Los Angeles, CA 90024 
Lab Phone: (323) 361-4503 
Lab FAX: (323) 361-4902 
Lab Contact: Rebekah Kennedy 
E-mail: rekennedy@chla.usc.edu or shahab@chla.usc.edu 
 
13.1.8 Subsequent Processing by Dr. Asgharzadeh’s Lab 
Samples will be processed by Asgharzadeh laboratory personnel, and assays for immune-related gene 
expression and the NB5 assay will be performed on site. Asgharzadeh laboratory personnel will distribute 
components of the samples collected to other investigators conducting correlative studies being performed 
using blood samples. 
 
RNA for NKp30 testing will be sent to the Yu lab at the University of California San Diego.  
 
13.2 
Collection of Tumor Tissue and Bone Marrow-derived Tumor Cells 
The importance of submitting tumor-containing specimens obtained at the time of disease progression or 
relapse cannot be overstated. Collection of tumor cells derived from involved marrow in patients with 
relapsed neuroblastoma is strongly encouraged as is collection of tumor tissue from biopsy samples (if 
biopsy is performed either for clinical reasons or to document disease as per eligibility requirements 
outlined in Section 3.2.2.3). For patients previously enrolled on ANBL00B1, please see Appendix IV of 
the ANBL00B1 protocol for specific information regarding sample collection, handling, and shipping. 
 
13.3 
Optional Biology Studies: Tumor Tissue 
Tumor from the time of initial diagnosis is also requested for all patients (regardless of prior enrollment 
or submission on ANBL00B1) for analyses described in Section 2.7.7 and 2.7.10. See Section 13.3.1 for 
details. 
 
Specimens collected on ANBL00B1 at relapse for patients enrolled on ANBL1221 will be flagged and 
used for correlative studies described in Sections 2.7.7 and 2.7.10.  
 
For consenting patients who have not enrolled on or submitted tumor specimen at relapse on ANBL00B1 
see Section 13.3.1 for specimen requirements. 
 
13.3.1 Specimen Collection and Labeling 
Tumor may be sent in the form of a paraffin block, or as tissue scrolls (10 scrolls 15µm thick) AND 10-25 
unstained slides. Frozen tumor should also be sent if available. If scrolls AND slides are submitted, they 
should be cut sequentially from one representative block.  
 
Specimens must be labeled with the COG patient ID, specimen type (P for primary or M for metastatic), 
the surgical pathology ID number and block number from the corresponding pathology report. 
 
13.3.2 Specimen Shipment 
A Single Chamber Specimen Procurement Kit for shipping frozen tumor tissue to the BPC are provided 
upon request. To request a Specimen Procurement Kit, click on the ‘Biopathology Center Application’ link 


 
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on either the Protocol or the CRA Home Page of the COG web site. On the Biopathology Center 
Applications page, select the BPC Kit Management link to enter the Kit Management application. Select 
‘ANBL1221’ to order kits for the submission of frozen tumor tissue.  
 
Blocks, slides and scrolls must be shipped in your own shipping container using the institution’s courier 
account or by USPS.   
 
Include a copy of the specimen transmittal form and the corresponding pathology report with each 
shipment. 
 
Shipping Frozen Tumor in a Single Chamber Kit: 
1. Before the frozen tissue is placed into the Specimen Procurement Kit, it must first be placed in 
three separate layers of packaging : 
a. Place the tissue in a zip-lock bag. 
b. Place the zip-lock bag in the plastic watertight biohazard diagnostic envelope and seal the 
envelope securely. 
c. Place the clear plastic biohazard diagnostic envelope inside the pressure-proof Tyvek 
diagnostic envelope and seal securely. 
2. Place the tissue inside the kit compartment with dry ice. Layer the bottom of the compartment with 
dry ice until it is approximately one-third full. Place the frozen specimens on top of the dry ice. 
Cover the specimens with the dry ice until the compartment is almost completely full. 
3. Place the transmittal form and corresponding pathology report inside the compartment. 
4. Place the stryofoam lid on top to secure specimns during shipment. 
5. Close the outer lid of the Specimen Procurement Kit and tape with filament or other durable tape. 
6. Access the BPC Kit Management application to print a Federal Express shipping label. A blank 
adhesive label is provided in the Specimen Procurement Kit to use when printing the shipping label. 
Attach the shipping label to the top of the kit. Complete the dry ice label (UN 1845). Stick the dry 
ice and Exempt Human Specimen labels to the side of the kit 
7. Arrange for Federal Express pick-up per your usual institutional procedure or by calling 1-800-
238-5355. 
 
Shipping Address: 
Biopathology Center 
700 Children’s Drive, Room WA1340 
Columbus, OH 43205 
Telephone: (614) 722-2865 (include on all packages) 
Fax: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
Specimens are to be shipped Monday through Thursday for delivery Tuesday through Friday. Weekend and 
holiday deliveries are not accepted. If tumor is obtained on a Friday, Saturday or on the day before a holiday, 
please ship on the next business day.  
 
The Biopathology Center will distribute tumor samples to the Asgharzadeh laboratory at Children’s 
Hospital Los Angeles and to the Chinnaiyan laboratory at the University of Michigan. 
 
 


 
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14.0 
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). 
 
14.1 
Timing of Imaging 
To document tumor, standard CT, MRI and MIBG (FDG PET scan if tumor is not MIBG avid) scans must 
be performed at the following time points: 
• 
within 3 weeks preceding enrollment into the study 
• 
end of Cycles 2, 4 and 6, then following every 4th cycle thereafter 
 
14.2 
Imaging Required for Confirmation of Response Status 
The pertinent imaging studies (CT/MRI and MIBG or FDG PET) of those patients who respond to therapy 
or have long term stable disease on protocol therapy will be centrally reviewed.  
 
A retrospective central review will be performed by the Diagnostic Imaging Specialists of the Study 
Committee. They will review baseline scans and scans documenting best response for patients who are 
scored by their local institution as showing a CR, VGPR, PR or long term SD (≥ 6 cycles; minimum of 
4 months) based on imaging studies (CT, MRI, MIBG or FDG PET). Radiology scans and corresponding 
reports will be sent to the IROC Rhode Island (formerly QARC). The results of the central review will not 
be returned to the institution. 
 
For all patients through the first 6 cycles of therapy who show a CR, VGPR or PR, the following must 
be submitted for review: 
 
Baseline and Best Response Scans: 
- CT/MRI 
- MIBG scan (see MIBG scan guidelines in Appendix VII) 
- FDG PET scan if tumor is not MIBG avid 
- Copies of the reports for the scans submitted 
 
For any patient who achieves long-term stable disease (defined as SD for ≥ 6 cycles) or a patient who 
achieves a CR, VGPR or PR after the first 6 cycles of therapy, the following must also be submitted 
for review. 
 
Baseline and Scans Documenting Long-Term Stable Disease and/or Overall Best Response: 
- CT/MRI 
- MIBG scan (see MIBG scan guidelines in Appendix VII)  
- FDG PET scan if tumor is not MIBG avid 
- Copies of the reports for the scans submitted 
 
For PET scan guidelines please refer to the NCI guidelines for the recommended set of procedures for the 
acquisition and analysis of 18F-FDG PET scans of patients participating in NCI-sponsored diagnostic and 
therapeutic clinical trials, which can be found at the following link:  
http://imaging.cancer.gov/programsandresources/reportsandpublications/publications/clinical-trials-
guidelines.91  


 
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Submission of Diagnostic Imaging data in digital format is required. Digital files must be in Dicom format. 
These files can 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. Electronic 
submission of the scans is acceptable via Dicommunicator. Contact IROC Rhode Island  at 
Dicommunicator@QARC.org for further information. Alternative electronic methods, eg, sFTP are possible. 
Contact IROC Rhode Island for more information. 
 
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 
 
 


 
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APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
 
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>. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 


 
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Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the ANBL1221 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS.     
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
▪ 
Click on the Protocols tab in the upper left of your screen 
▪ 
Click on the COG link to expand, then select trial protocol ANBL1221 
▪ 
Click on the Site Registration Documents link 
 
Requirements for ANBL1221 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB) 
 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS site registration status page 
of the members’ section of the CTSU website. (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 


 
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APPENDIX II:  TEMOZOLOMIDE DOSING (100 mg/m2) NOMOGRAM 
Temozolomide is dosed based on body surface area for patients whose BSA is at least 0.5 m2. For 
these patients, doses are rounded to the nearest 5 mg. For patients with BSA <0.5 m2, dosing is based 
on body weight (kg).  
 
For patients with a BSA < 0.5 m2: Use 3.3 mg/kg. 
 
Examples: 
Patient is 0.3 m2 and weighs 5 kg. Patient administered dose = 5 kg x 3.3 mg/kg = 16.5 mg  
 
Patient is 0.66 m2. Calculated dose is 0.66 m2 x 100 mg/m2 = 66 mg/day; Administered dose = 65 mg 
temozolomide/day. 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
 
0.2-0.49 
 
3.3 mg/kg 
 
3.3 mg/kg 
0.50-0.52 
50-52 
50 
0.53-0.57 
53-57 
55 
0.58-0.62 
58-62 
60 
0.63-0.67 
63-67 
65 
0.68-0.72 
68-72 
70 
0.73-0.77 
73-77 
75 
0.78-0.82 
78-82 
80 
0.83-0.87 
83-87 
85 
0.88-0.92 
88-92 
90 
0.93-0.97 
93-97 
95 
0.98-1.0 
98-100 
100 
1.01-1.05 
100-105 
105 
1.06-1.14 
105-114 
110 
1.15-1.24 
115-124 
120 
1.25-1.34 
125-134 
130 
1.35-1.44 
135-144 
140 
1.45-1.54 
145-154 
150 
1.55-1.64 
155-164 
160 
1.65-1.74 
165-174 
170 
1.75-1.84 
175-184 
180 
1.85-1.94 
185-194 
190 
1.95-2.00 
195-200 
200 
> 2.0 
> 200 
200 
 
 


 
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APPENDIX III:  TEMOZOLOMIDE REDUCED (75 mg/m2) DOSING NOMOGRAM 
Temozolomide is dosed based on body surface area for patients whose BSA is at least 0.5 m2. For 
these patients, doses are rounded to the nearest 5 mg. For patients with BSA <0.5 m2, dosing is based 
on body weight (kg).  
 
For patients with a BSA < 0.5 m2: Use 2.5 mg/kg.  
 
Examples: For a patient that is 0.3 m2 and weighs 5 kg, the calculated dose is 5 kg x 2.5 mg/kg = 12.5 mg  
 
For a patient with a BSA of 0.66 m2, the calculated dose = 49.5 mg/dose; administered dose = 
50 mg temozolomide/dose. 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
0.2-0.49 
2.5mg/kg 
2.5mg/kg 
0.50-0.56 
38-42 
40 
0.57-0.63 
43-47 
45 
0.64-0.70 
48-52 
50 
0.71-0.76 
53-57 
55 
0.77-0.83 
58-62 
60 
0.84-0.90 
63-67 
65 
0.91-0.96 
68-72 
70 
0.97-1.03 
73-77 
75 
1.04-1.10 
78-82 
80 
1.11-1.16 
83-87 
85 
1.17-1.23 
88-92 
90 
1.24-1.30 
93-97 
95 
1.31-1.36 
98-102 
100 
1.37-1.43 
103-107 
105 
1.44-1.50 
108-112 
110 
1.51-1.56 
113-117 
115 
1.57-1.63 
118-122 
120 
1.64-1.70 
123-127 
125 
1.71-1.76 
128-132 
130 
1.77-1.83 
133-137 
135 
1.84-1.90 
138-142 
140 
1.91-1.96 
143-147 
145 
1.97-2.00 
148-152 
150 
> 2.0 
> 152 
155 
 
 
 
 


 
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APPENDIX IV:  RECOMMENDATIONS FOR ADMINISTRATION OF TEMOZOLOMIDE  
(Patients who are unable to swallow capsules and cannot obtain a suspension) 
 
Temozolomide is an oral cancer medicine that your child will be taking for treatment of his/her cancer. If 
your child is unable to swallow capsules, the following instructions must be followed for safe administration 
of this medicine. 
 
• 
Temozolomide must be kept in a dark container. 
• 
Temozolomide should be taken the same time every day. 
• 
If your child requires nausea medicine it should be taken prior to the temozolomide. 
• 
If the dose of temozolomide is vomited (which is unusual) within the first 20 minutes after it is taken, 
the dose should be repeated. If your child vomits more than 20 minutes after the temozolomide has 
been taken, do not repeat the dose. 
• 
If the person dispensing this medicine is pregnant, breastfeeding or suspects she is pregnant, she should 
not dispense this medicine. 
 
Since temozolomide is an anti-cancer agent, special precautions must be taken when handling this medicine. 
There is potential hazard to anyone who handles this medicine once the protective capsule is opened. Since 
your child is unable to swallow the capsule you will be required to open the capsules and mix the contents 
of the capsule in apple sauce or apple juice. This process must be done according to the following guidelines 
to ensure safe administration of this medicine. 
 
• 
Find a place that is free from drafts or wind and is not an area where food is stored or prepared. 
• 
The work surface should be covered with an impermeable and disposable mat such as the one a 
pharmacy uses to reduce exposure to other members of the family. 
• 
Temozolomide can be mixed in apple sauce or apple juice. 
• 
Place the apple sauce or apple juice in a disposable container. 
• 
Put on gloves, a mask and a pair of goggles (eye protection). 
• 
Open each capsule required for the daily dose and place the powder in a medicine cup. 
• 
Add the whole contents of the medicine cup to either apple sauce or apple juice. The medicine will not 
dissolve completely if mixing in apple juice so have extra apple juice on hand so you can add it to any 
remaining powder in the bottom of the cup. 
• 
If you need to have additional juice or apple sauce remove your gloves before touching the main 
container then place new gloves on before adding the additional juice or apple sauce to the medicine. 
(You do not want to contaminate the main container with any powder that may be on your gloves.) 
• 
Anything that comes into contact with the medicine must be disposable, such as the spoon used for 
mixing or eating the apple sauce. 
• 
Once all of the medicine is taken, throw away the following in a Ziploc-type plastic bag: Medicine cup, 
the container the medicine was mixed in, the covers/mats for the work surface, masks, gloves and 
anything else that has been in contact with the medicine. 
• 
Once a course of medicine is completed bring the plastic bag with you to the clinic so it can be disposed 
of properly. 
 
 
 
 


 
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APPENDIX V:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
Treatment of Diarrhea 
 
Early diarrhea 
Early onset diarrhea associated with irinotecan is usually preceded by sweating and abdominal cramping. 
Patients who have the onset of these symptoms followed by diarrhea within several hours after taking 
irinotecan should contact the treating physician immediately. The treating physician may consider treatment 
with atropine. If symptoms do not improve with administration of atropine, treatment for late diarrhea (as 
outlined below) should be started. 
 
Late diarrhea (more than 24 hours after the administration of the first dose of irinotecan) 
Each family will be instructed to have antidiarrheal medication available and begin treatment at the first 
episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than 
normally expected for the patient. Patients will also be instructed to contact their physician if any diarrhea 
occurs. Patients will be given Loperamide based on body weight. The doses and schedules for loperamide 
included here are higher than the standard but consistent with COG protocols D9802, P9761, and 
ARST0121. 
 
Be aware of your child's bowel movements. At the first sign they become softer than usual or if your child 
has any increase in the number of bowel movements over what is normal for him/her, begin taking 
loperamide (Imodium). If he/she does not start taking the loperamide right away, the diarrhea may 
become severe and last several days or require hospitalization. 
 
Please follow these directions carefully, using dosing guidelines below: 
• 
Take _____________ at the first sign of diarrhea. 
• 
Continue taking ____ every 2 hours until your normal pattern of bowel movements returns. 
Repeat the same doses and frequency if the diarrhea returns. 
• 
Do not exceed ___________ in a 24 hour period. 
• 
Please call your doctor if you have any questions about taking loperamide, if your child's 
diarrhea is not under control after two days, or if he/she is feeling extremely weak, 
lightheaded, or dizzy. 
• 
Make an extra effort to give your child lots of fluids (several glasses of pedialyte, fruit 
juices, soda, soup, etc.) while your child is participating in this study. 
• 
Side effects may include tiredness, drowsiness or dizziness. If your child experiences these 
side effects, or if your child is urinating less frequently than usual, please contact your 
child's physician. 
• 
Do not give your child any laxatives without consulting with his/her physician. 
 
Loperamide dosing recommendations for late diarrhea (maximum dose of Loperamide for adults is 
16 mg/day): 
 
 
 


 
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LOPERAMIDE DOSING RECOMMENDATIONS FOR LATE DIARRHEA 
(maximum dose of Loperamide for adults is 16 mg/day) 
Weight (kg) 
ACTION 
<13 kg   
Take 0.5 mg (2.5 mL of the 1 mg/5 mL oral solution) after the first loose bowel 
movement, followed by 0.5 mg (2.5 mL of the 1 mg/5 mL oral solution) every 
3 hours. During the night, the patient may take 0.5 mg (2.5 mL of the 1 mg/5 mL 
oral solution) every 4 hours. Do not exceed 4 mg per day. 
 
≥ 13 kg to < 20 kg 
Take 1 mg (5 mL of the 1 mg/5 mL oral solution or one-half capsule or tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL of the 1 mg/5 mL 
oral solution) every 3 hours. During the night, the patient may take 1.0 mg (5 mL 
of the 1 mg/5 mL oral solution) every 4 hours. Do not exceed 6 mg per day. 
 
≥ 20 kg to < 30 kg 
Take 2 mg (10 mL of the 1 mg/5 mL oral solution or 1 capsule or tablet) after the 
first loose bowel movement, followed by 1 mg (5 mL of the 1 mg/5 mL oral 
solution or one-half capsule or tablet) every 3 hours. During the night, the patient 
may take 2 mg (10 mL of the 1 mg/5 mL oral solution or 1 caplet) every 4 hours. 
Do not exceed 8 mg per day. 
 
≥ 30 kg to < 43 kg 
Take 2 mg (10 mL of the 1 mg/5 mL oral solution or 1 capsule or tablet) after the 
first loose bowel movement, followed by 1 mg (5 mL of the 1 mg/5 mL oral 
solution or one-half capsule or tablet) every 2 hours. During the night, the patient 
may take 2 mg (10 mL of the 1 mg/5 mL oral solution or 1 capsule or tablet) every 
4 hours. Do not exceed 12 mg per day. 
 
Over 43 kg 
Take 4 mg (20 mL of the 1 mg/5 mL oral solution or 2 capsules or tablets) after 
the first loose bowel movement, followed by 2 mg (10 mL of the 1 mg/5 mL oral 
solution or 1 capsule or tablet) every 2 hours. During the night, the patient may 
take 4 mg (20 mL of the 1 mg/5 mL oral solution or 2 capsules or tablets) every 
4 hours. Do not exceed 16 mg per day. 
 
 
  
 


 
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APPENDIX VI:  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. 
 
Temozolomide 
Drugs that may interact with temozolomide 
• Clozapine, leflunomide, natalizumab, tofacitinib 
 
Food and supplements that may interact with temozolomide** 
• Echinacea 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Irinotecan 
Drugs that may interact with irinotecan 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Citalopram, clozapine, desipramine, nefazodone, sertraline 
• 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, diltiazem, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Bosentan, sitaxentan, aprepitant, dexamethasone, ivacaftor, lomitapide, mifepristone, 
natalizumab, succinylcholine 
 
Food and supplements that may interact with irinotecan** 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 


 
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APPENDIX VII:  RECOMMENDED PROCEDURE FOR PERFORMING MIBG SCANS 
MIBG (meta-iodobenzylguanidine) was developed by Dr. Donald Wieland of the University of Michigan in 
the late 1970’s for scintigraphic imaging of neuroendocrine tumors, specifically pheochromocytomas and 
neuroblastomas. MIBG is an aralkylguanidine which bears structural similarity to the neurotransmitter and 
catecholamine hormone norepinephrine and the ganglionic blocking drug guanethidine. When MIBG is labeled 
with radioactive iodine, gamma camera imaging of patients injected with this compound produces images of 
the sites of the tumors and of the related structures of the sympathetic nervous system. The I-123 labeled form 
of this agent has been approved for use by the US Food and Drug Administration for the diagnostic imaging of 
neuroblastoma and pheochromocytoma, and this agent is commercially available as Adreview (GE). MIBG 
has considerably assisted the diagnostic evaluation of patients with known or suspected neuroblastoma, since 
it provides information about the tumor behavior all along the course of the disease from diagnosis to 
completion of therapy. Scores of publications from around the world have documented its utility in the 
diagnosis and monitoring of neuroblastoma. It alone is the single best imaging test for monitoring disease 
activity. MIBG imaging is performed routinely at many institutions. The following protocol is recommended, 
to assure high quality images are obtained at all institutions which participate in neuroblastoma evaluations.92  
 
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), are administered to 
reduce thyroidal accumulation of free radioiodine, preferably beginning the day prior to injection and 
continuing for 3 additional days (4 days total). For infants and children, one drop t.i.d. is sufficient, for 
adolescents 2 drops t.i.d., and for adults 3 drops t.i.d. Patients and/or parents are always asked about 
exposure to potential interfering agents. If none is noted, an indwelling intravenous line is established. The 
dose of MIBG is administered by slow intravenous injection over 90 seconds. 
 
Images from the head to the distal lower extremities should be obtained. 
 
A. 
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images. 
1. Planar – Anterior and posterior views from the top of the head to the proximal lower extremities 
are obtained for 10 minutes at 24 hours and occasionally at 48 hours following injection of 10 
mCi/1.7 square meters of body surface area (~150 Ci/kg, maximum 10 mCi). Anterior views 
of the distal lower extremities are adequate. A large field of view dual head gamma camera 
with low energy collimators is preferred. 
2. SPECT - Most patients receiving I-123 MIBG also undergo SPECT at 24 hours, using a single 
or multi-headed camera with a low energy collimator. The camera is rotated through 360 
degrees, 120 projections at 25 seconds per stop. Data are reconstructed using filtered back 
projections with a Butterworth filter and a cut off frequency of 0.2-0.5. SPECT/CT may be 
performed at institutions with this capacity. 
 
Please refer to Section 14.0 for requirements of central review (including the time-points and address to 
submit the required reports). 
 
 
 
 


 
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APPENDIX VIII  YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ANBL1221 
(for children from 7 through 12 years of age) 
 
A trial to compare 2 ways to treat children with NBL that  
is not responding to treatment or has come back after treatment 
 
1. We have been talking with you about your illness, neuroblastoma (NBL). NBL is a kind of cancer 
that grows in the soft issue in your body. It can grow in different parts of the body. After doing 
tests, we have found that you have this type of cancer. You have had treatment for this cancer 
already but the cancer did not go away or has come back after treatment. 
 
2. We are asking you to take part in a research study because you have NBL that is not responding 
to treatment or has come back after treatment. A research study is when doctors work together to 
try out new ways to help people who are sick.  
 
3. All children who are part of this study will be treated with chemotherapy using the drug 
“ch14.18” (also called dinutuximab). Chemotherapy is a type of medicine that destroys cancer 
cells. Study doctors would like to learn if your cancer responds to treatment with ch14.18. 
 
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 of being part of this study is a better 
chance of getting rid of the cancer for as long as possible. But we do not know for sure if there is 
any benefit of being part of this study. 
 
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 are that the study treatment may not work as 
well as other therapies. Also, the study treatment may cause more side effects than other 
therapies. Your doctors will watch you for signs of any side effects. 
 
6. Your family can choose to be part of this study or not. Your family can also decide 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 want to learn more about how people respond to treatment with ch14.18. We are asking your 
permission to collect extra blood and use the blood for research studies. We would take extra 
when we collect blood for regular tests. You can still take part in this study even if you do not 
agree to let us collect the extra samples for research. 
 
 
 


 
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Page 102 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ANBL1221 
(for teens from 13 through 17 years of age) 
 
A trial to compare 2 ways to treat patients with NBL that  
is not responding to treatment or has come back after treatment 
 
1. We have been talking with you about your illness, neuroblastoma (NBL). NBL is a type of cancer 
that grows in the soft issue in your body. It can grow in different parts of the body. After doing 
tests, we have found that you have this type of cancer.  
 
2. We are asking you to take part in a research study because you have NBL that is recurrent or 
refractory. Recurrent means that the cancer has come back after treatment. Refractory means that 
the cancer has not responded to treatment. A research study is when doctors work together to try 
out new ways to help people who are sick.  
 
3. Children and teens who are part of this study will be treated with chemotherapy using the drug 
ch14.18 (also called dinutuximab). Chemotherapy is a type of medicine that destroys cancer cells. 
Study doctors would like to learn if your cancer responds to treatment with ch14.18. 
 
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 of being part of this study is a better 
chance of getting rid of your cancer for as long as possible. But we don’t know for sure if there is 
any benefit of being part of this study. 
 
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 are that the study treatment may be less 
effective than other therapy options. It is also possible that the study treatment may cause more 
side effects than other therapies. Your doctors will monitor you closely for signs of any side 
effects. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide 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 want to learn more about how people respond to treatment with ch14.18. We are asking your 
permission to collect extra blood and use the blood for research studies. We would take extra 
when we collect blood for regular tests. You can still take part in this study even if you do not 
agree to let us collect the extra samples for research. 
 
 


 
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