A Pilot Study of Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination With Irinotecan and Temozolomide in the Post-Consolidation Setting for High-Risk Neuroblastoma
Phase: PHASE2
Conditions: Ganglioneuroblastoma, Nodular, Neuroblastoma
Sponsor: Children's Oncology Group

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Activated: 11/30/2020 
Version Date: 
08/19/2022 
Closed: 
06/30/2023 
Amendment #:  
1 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
ANBL19P1 
 
 
A Pilot Study of Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination with 
Irinotecan and Temozolomide in the Post-Consolidation Setting for High-Risk Neuroblastoma 
 
 
A COG Groupwide Pilot Study 
 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
  
 
 

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CONTACT INFORMATION 
For Regulatory Requirements 
For Regulatory Requirements 
For Regulatory Requirements 
Regulatory documentation must be 
submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal. 
 (Sign in at https://www.ctsu.org, 
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-CTSU (2878) 
for regulatory assistance. 
Regulatory documentation must be submitted 
to the Cancer Trials Support Unit (CTSU) via 
the Regulatory Submission Portal. 
 (Sign in at https://www.ctsu.org, and select 
the Regulatory > Regulatory Submission.)  
 
Institutions with patients waiting that are 
unable to use the Portal should alert the CTSU 
Regulatory Office immediately by phone or 
email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to receive further 
instruction and support. 
 
Contact the CTSU Regulatory Help Desk at 
1-866-651-CTSU (2878) for regulatory 
assistance. 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
 (Sign in at 
https://www.ctsu.org, and select 
the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory assistance. 
The most current version of the study protocol and all supporting documents must be downloaded from the protocol-
specific page located on the CTSU members’ website (https://www.ctsu.org). Access to the CTSU members’ website is 
managed through the Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) 
registration system and requires log in with a CTEP-IAM username and password.  
 
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 Regulatory Support System (RSS). 
For clinical questions (i.e. patient eligibility or treatment-related)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will be 
triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 
 

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TABLE OF CONTENTS 
 
SECTION 
PAGE 
 
TABLE OF CONTENTS 
3 
STUDY COMMITTEE 
6 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
9 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
10 
1.1 
Primary Aims 
10 
1.2 
Secondary Aims 
10 
1.3 
Exploratory Aims 
10 
2.0 
BACKGROUND 
10 
2.1 
Introduction/Rationale for Development 
10 
2.2 
Current COG Standard Immunotherapy in the Post-Consolidation Setting for  
High-Risk Neuroblastoma 
11 
2.3 
Chemo-Immunotherapy for High-Risk Neuroblastoma 
12 
2.4 
Dosing Rationale 
14 
2.5 
Rationale for Correlative Studies 
14 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
15 
3.1 
Study Enrollment 
15 
3.2 
Patient Eligibility Criteria 
19 
4.0 
TREATMENT PLAN 
25 
4.1 
Overview of Treatment Plan 
25 
4.2 
General Guidelines for Therapy 
25 
4.3 
Concomitant Therapy 
26 
4.4 
Cycle 1 
28 
4.5 
Cycles 2-5 
38 
4.6 
Cycle 6 
49 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
53 
5.1 
Dose Modifications for Hematologic Toxicity 
53 
5.2 
Dose Modifications for Non-hematologic Toxicity 
53 
5.3 
Inability to Tolerate Enteral Temozolomide 
63 
6.0 
DRUG INFORMATION 
64 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
65 
7.1 
End of Therapy & Follow-up 
65 
7.2 
Research Studies for which Patient Participation is Optional 
66 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY     
CRITERIA 
66 
8.1 
Criteria for Removal from Protocol Therapy 
66 
8.2 
Off Study Criteria 
66 

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9.0 
STATISTICAL CONSIDERATIONS 
67 
9.1 
Sample Size and Study Duration 
67 
9.2 
Study Design 
68 
9.3 
Methods of Analysis 
68 
9.4 
Evaluability for Response 
73 
9.5 
Evaluability for Toxicity 
73 
9.6 
Evaluability of No Treatment 
73 
9.7 
Gender and Minority Accrual Estimates 
73 
10.0 
EVALUATION CRITERIA 
74 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
74 
10.2 
Response Criteria 
74 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
79 
11.1 
Purpose 
79 
11.2 
Determination of Reporting Requirements 
79 
11.3 
Reporting of Adverse Events for Commercial Agents – via CTEP-AERS 
80 
11.4 
Protocol Specific Additional Instructions and Reporting Exceptions 
80 
11.5 
Routine Adverse Event Reporting 
81 
11.6 
Syndrome Reporting 
81 
12.0 
RECORDS AND REPORTING 
82 
12.1 
Demography Monitoring 
82 
13.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
82 
14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
82 
14.1 
Required Studies 
82 
14.2 
Optional Studies 
85 
14.3 
Shipping Instructions for Specimens Submitted to the Biopathology Center 
89 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
91 
15.1 
Cross Sectional Imaging Studies 
91 
15.2 
123I-MIBG Scintigraphy 
92 
15.3 
[18F]–Fluorodeoxyglucose (18FDG)-PET Scintigraphy 
92 
15.4 
Tumor Measurement 
93 
15.5 
Curie Scoring 
94 
16.0 
RADIATION THERAPY GUIDELINES 
94 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
95 
APPENDIX II: INTERNATIONAL NEUROBLASTOMA RISK GROUP (INRG) STAGING 
SYSTEM33,34 
98 
APPENDIX III: PERFORMANCE STATUS SCALES/SCORES 
100 
APPENDIX IV: RECOMMENDED NON-ENZYME INDUCING ANTICONVULSANTS AND 
UNACCEPTABLE ENZYME INDUCING ANTICONVULSANTS 
101 
APPENDIX V: PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
102 
APPENDIX VI: POSSIBLE DRUG INTERACTIONS 
104 

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APPENDIX VII: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
106 
APPENDIX VIII: TEMOZOLOMIDE DOSING (100 MG/M2) NOMOGRAM 
111 
APPENDIX IX: TEMOZOLOMIDE REDUCED (75 MG/M2) DOSING NOMOGRAM 
112 
APPENDIX X: SUMMARY OF BIOLOGIC CORRELATIVE LAB STUDIES 
113 
APPENDIX XI: EMERGENCY MANAGEMENT OF DINUTUXIMAB TOXICITIES 
115 
APPENDIX XII: CURIE SCORING SUMMARY SHEET 
116 
APPENDIX XIII: OVERALL RESPONSE CRITERIA 
117 
APPENDIX XIV: YOUTH INFORMATION SHEETS 
118 
REFERENCES 
120 
 
 

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STUDY COMMITTEE 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
  
 
 
 
  
  
 
 
 
  
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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AGENT 
 
NSC#  
Supplier 
Dinutuximab 
 
764038  
Commercial 
Irinotecan 
 
616348  
Commercial 
Isotretinoin 
 
329481  
Commercial 
Sargramostim  
613795  
Commercial 
Temozolomide  
362856  
Commercial 
 
 
SEE SECTION 14.0 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 
Post-Consolidation therapy consisting of the chimeric anti-GD2 monoclonal antibody dinutuximab in 
conjunction with the cytokines sargramostim (GM-CSF) and aldesleukin (IL-2) and the differentiating 
agent isotretinoin has improved survival for newly diagnosed patients with high-risk neuroblastoma. 
Nevertheless, 25-35% of children will still experience recurrence, and their long-term survival is dismal 
More effective approaches to eliminate minimal residual disease in the Post-Consolidation setting are 
needed to prevent recurrence in children with high-risk neuroblastoma. Data from the Children’s Oncology 
Group (COG) Phase 2 study ANBL1221 indicate that the combination of irinotecan and temozolomide with 
dinutuximab and GM-CSF is active in the relapsed/refractory disease setting, with a response rate of 
approximately 40%. While ANBL1221 has demonstrated a role for chemo-immunotherapy in this context, 
planned administration of myelosuppressive chemotherapy shortly after recovery from autologous stem cell 
transplant has not been attempted in a COG neuroblastoma trial. Therefore, this pilot study will assess the 
feasibility of administering chemo-immunotherapy in the frontline, Post-Consolidation setting in patients 
with high-risk neuroblastoma. If the current trial demonstrates that delivery of chemo-immunotherapy is 
feasible in relatively close proximity to stem cell transplant, future trials may test the hypothesis that 
dinutuximab in combination with chemotherapy will be superior to standard Post-Consolidation 
immunotherapy. 
 
 
 

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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
Generic Drug Name 
Abbreviation 
Temozolomide 
TEMO 
Irinotecan 
IRIN 
Dinutuximab 
DIN 
Sargramostim 
GM-CSF 
Isotretinoin 
ISOT 
Cycle 4 
TEMO + IRIN 
DIN, GM-CSF, ISOT 
Cycle 5 
TEMO + IRIN 
DIN, GM-CSF, ISOT 
Cycle 6 
ISOT 
Disease Evaluation and 
Completion of  
Protocol Therapy 
Cycle 3 
TEMO + IRIN 
DIN, GM-CSF, ISOT 
Disease Evaluation 
After Cycle 3 
ANBL19P1 STUDY 
ENROLLMENT 
Cycle 1 
TEMO + IRIN 
DIN, GM-CSF, ISOT 
Cycle 2 
TEMO + IRIN 
DIN, GM-CSF, ISOT 
Standard of Care  
Disease Evaluation 
Progressive Disease:  
Off Protocol Therapy 
Stable Disease or 
Better: Continue 
Protocol Therapy 

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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To determine the feasibility of administering dinutuximab, GM-CSF, and 
isotretinoin in combination with irinotecan and temozolomide in the frontline Post-
Consolidation setting in patients with high-risk neuroblastoma who have 
undergone Induction and Consolidation therapy with tandem high-dose 
chemotherapy with stem cell rescue (ASCT). 
 
1.2 
Secondary Aims 
 
1.2.1 
To describe the toxicity profile of dinutuximab, GM-CSF, and isotretinoin in 
combination with irinotecan and temozolomide in the Post-Consolidation setting. 
 
1.2.2 
To describe the event-free survival and overall survival of patients who receive 
dinutuximab in combination with irinotecan and temozolomide, GM-CSF and 
isotretinoin in the Post-Consolidation setting. 
 
1.3 
Exploratory Aims 
 
1.3.1 
To describe the toxicity profiles associated with chemo-immunotherapy in the 
Post-Consolidation setting according to the type of prior therapy. 
 
1.3.2 
To describe response to chemo-immunotherapy in the Post-Consolidation setting 
using the revised International Neuroblastoma Risk Classification (INRC) in 
patients with evaluable or measurable disease at study entry. 
 
1.3.3 
To characterize immune and cytokine profiles in patients receiving Post-
Consolidation chemo-immunotherapy. 
 
1.3.4 
To bank serial blood samples to investigate the relationship between factors related 
to the tumor, host, and immune environment and clinical outcomes in patients 
treated with chemo-immunotherapy. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
Post-Consolidation therapy consisting of the chimeric anti-GD2 monoclonal antibody, 
dinutuximab, in conjunction with the cytokines sargramostim (GM-CSF) and aldesleukin 
(IL-2) and the differentiating agent isotretinoin has improved survival for newly diagnosed 
patients with high-risk neuroblastoma.1 However, approximately 25-35% of children 
treated with multi-modality Induction, high-dose Consolidation chemotherapy and 
autologous stem cell transplant and this Post-Consolidation immunotherapy will 
experience recurrence1,2 and their long-term survival is dismal.3 
 
Data from the Children’s Oncology Group (COG) Phase 2 study ANBL1221 indicate that 
the combination of irinotecan and temozolomide with dinutuximab and GM-CSF is active 
in the relapsed/refractory disease setting, with a response rate of approximately 40% in the 
full cohort of patients treated.4,5 The high response rates observed in patients with 

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refractory or relapsed disease in ANBL1221 support the hypothesis that augmentation of 
Post-Consolidation immunotherapy with a chemo-immunotherapy approach may further 
improve outcome for children with high risk neuroblastoma. Hematologic toxicities were 
tolerable on ANBL1221. However, the toxicities associated with this regimen administered 
shortly following autologous stem cell transplant (ASCT) are unknown and have not been 
assessed in the context of a clinical trial. This pilot study will evaluate the feasibility of 
delivering dinutuximab in combination with irinotecan and temozolomide + GM-CSF 
(chemo-immunotherapy) in children with high-risk neuroblastoma who have received 
Consolidation therapy that includes tandem myeloablative chemotherapy and ASCT in the 
frontline setting. We hypothesize that the administration of dinutuximab in combination 
with chemotherapy (temozolomide and irinotecan) will be feasible in the Post-
Consolidation setting. If the current trial demonstrates that delivery of chemo-
immunotherapy is feasible in relatively close proximity to stem cell transplant, future trials 
may test the hypothesis that dinutuximab in combination with chemotherapy is superior to 
standard immunotherapy. 
 
2.2 
Current COG Standard Immunotherapy in the Post-Consolidation Setting for High-
Risk Neuroblastoma 
The current standard immunotherapy regimen recommended by the COG Neuroblastoma 
Committee includes dinutuximab, GM-CSF, and isotretinoin. The results of the 
randomized Phase 3 COG study ANBL0032 support this approach, as patients with at least 
a partial response to Induction therapy who were randomized to receive immunotherapy 
during Post-Consolidation with dinutuximab + cytokines + isotretinoin (n=113) had a 
significantly higher event-free survival (EFS) and overall survival (OS) at 2 years 
compared to patients randomized to isotretinoin alone (n=113), with EFS 66±5% vs. 
46±5% (p=0.01) and OS 86±4% vs. 75±5% (p=0.02), respectively. Twenty-five patients 
with biopsy-proven persistent disease after ASCT were non-randomly assigned to 
immunotherapy with dinutuximab + cytokines + isotretinoin. The estimated 2-year EFS 
and OS rates for this cohort were 36±10% and 76±9%, respectively.1 This seminal study 
led to a new COG standard-of-care for high-risk neuroblastoma, with administration of 
immunotherapy with dinutuximab plus cytokines and isotretinoin following ASCT. 
Common toxicities of the immunotherapy regimen include pain, fever, nausea, emesis, 
diarrhea, urticaria, mild elevation of hepatic transaminases, capillary leak syndrome, and 
hypotension.1,6 Based on the results of ANBL0032, the FDA approved dinutuximab in 
combination with GM-CSF, IL-2, and isotretinoin for patients with high-risk 
neuroblastoma who have had at least a partial response to prior multimodality frontline 
therapy.7,8 
 
While the addition of dinutuximab-based Post-Consolidation therapy clearly improved 
outcomes for children with newly diagnosed high-risk neuroblastoma, approximately one-
third of patients who were eligible for randomization on ANBL0032 relapsed, and 
outcomes for those with biopsy proven disease following Consolidation remain 
unacceptable. There is a critical need to develop more effective Post-Consolidation therapy 
that will improve survival for all high-risk patients, including those with persistent disease 
following ASCT. 
 
It is clear that the use of IL-2 as a component of Post-Consolidation therapy is associated 
with toxicity. To evaluate the contribution of IL-2 to survival outcomes and toxicity, the 
International Society of Pediatric Oncology Europe Neuroblastoma (SIOPEN) group 
conducted a trial in which patients were randomized to receive either dinutuximab derived 
from Chinese hamster ovary cells (dinutuximab beta) alone or dinutuximab beta with 

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subcutaneous IL-2.9 In an intention-to-treat analysis, no differences in 3-year EFS or 
cumulative incidence of relapse/progression were detected between patients treated with 
or without IL-2, nor was a difference in 5-year OS detected.9 Patients assigned to receive 
IL-2 had higher rates of fever, pain, allergic reaction, capillary leak syndrome, hematologic 
toxicity, neurotoxicity, and GI toxicity. Only 62% of patients randomized to the IL-2 + 
dinutuximab beta arm received the planned therapy while 87% of patients assigned to 
dinutuximab beta alone received the planned therapy.9 Therefore, while the results raised 
questions regarding the relative contribution of IL-2 to this Post-Consolidation regimen, 
concern regarding the lack of receipt of assigned therapy suggested that further study of 
IL-2 as a component of Post-Consolidation therapy was necessary. 
 
SIOPEN subsequently conducted a trial designed to reduce treatment-related toxicity 
overall so that a larger portion of patients would be expected to receive planned therapy. 
Dinutuximab beta (10 mg/m2/day) was delivered over 10 days as a continuous infusion to 
all patients. For those assigned to the IL-2-containing arm, a reduced dose of subcutaneous 
IL-2 (3 million IU/m2/day) was administered. During this trial, similar portions of patients 
on each arm completed therapy.10 Rates of Grade 3 or higher fever and pain were reported 
among patients assigned to the IL2-containing therapy. Among evaluable patients, 
response rates and 2-year EFS/OS in the two arms did not differ significantly. Based on 
these results, SIOPEN has made the determination to eliminate IL-2 from standard Post-
Consolidation therapy.10 
 
Additional data also support the removal of IL-2 from dinutuximab beta-containing 
therapy. SIOPEN demonstrated in a randomized Phase 2 trial in patients with 
relapsed/refractory neuroblastoma that response rate, EFS and OS were similar among 
patients assigned to dinutuximab beta as a long-term infusion with or without the addition 
of subcutaneous IL-2.11 In this study, rates of Grade 3 or higher fever, allergic reaction, 
hematological toxicity and neurotoxicity were higher in patients randomized to the 
IL-2-containing arm.  
 
In addition, unpublished data suggest that treatment with dinutuximab and GM-CSF may 
result in elevation of soluble IL-2 receptor levels in the absence of IL-2 administration, 
potentially obviating the need for IL-2 administration to activate NK cells and promote 
antibody dependent cellular cytotoxicity (Paul Sondel, MD, PhD, personal 
communication). 
 
Based upon these data, the COG Neuroblastoma Committee has concluded that there is a 
lack of clear benefit associated with IL-2, and the higher rate of toxicity associated with 
IL-2-containing regimens is cause for concern. Therefore, patients on frontline COG 
neuroblastoma trials no longer receive IL-2 as a component of standard Post-Consolidation 
therapy. Instead, GM-CSF is administered with all five dinutuximab-containing Post-
Consolidation cycles. 
 
2.3 
Chemo-Immunotherapy for High-Risk Neuroblastoma 
ANBL1221 evaluated response in patients with relapsed or refractory neuroblastoma 
following treatment with irinotecan and temozolomide in combination with either 
dinutuximab + GM-CSF or temsirolimus. The rationale for combining chemotherapy with 
immunotherapy in this study was based on pre-clinical data in small cell lung cancer and 
neuroblastoma that indicate that anti-GD2 antibodies augment the effect of chemotherapy 
through enhanced cytotoxicity.12,13 Further, the use of monoclonal antibodies in 
combination with chemotherapy is supported by adult studies conducted for malignancies 

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such as breast and colon cancer. Trastuzumab has been combined with doxorubicin and 
cyclophosphamide for women with HER-2 positive breast cancer, and use of the 
combination has been associated with improved progression-free and overall survival.14 
Cetuximab in combination with irinotecan has been approved for EGFR-expressing 
metastatic colon cancer refractory to irinotecan-based therapy.15  
 
Irinotecan/temozolomide was chosen as the chemotherapy backbone in ANBL1221 based 
on data regarding pre-clinical16 as well as clinical activity in neuroblastoma.17,18 Thirty-five 
patients were enrolled on the randomized portion of ANBL1221; 18 patients were 
randomized to Arm A (temsirolimus + irinotecan and temozolomide) and 17 patients were 
randomized to Arm B (dinutuximab + GM-CSF + irinotecan and temozolomide). 
Randomization was stratified based on prior therapy and MYCN status. Nine out of 17 
patients (53%) on Arm B (dinutuximab + irinotecan and temozolomide) were found to have 
an objective response, defined as a complete response (CR, n=5) or partial response (PR, 
n=4), whereas only one patient (5%) on Arm A had a PR. One-year progression-free 
survival (PFS) among those who received dinutuximab + GM-CSF + irinotecan and 
temozolomide (Arm B) was 76.5% (95% CI, 56.3–96.7). In contrast, PFS among those 
who received temsirolimus + irinotecan and temozolomide (Arm A) was 24.7% (95% CI, 
0.4–49.0).4  
 
ANBL1221 reopened to continue accrual on Arm B to increase the precision around the 
point estimate of response rate. Objective responses were reported in 13 of 36 patients 
(36.1%, 95% CI [20.4%, 51.8%]) in this expansion cohort. In total (randomized patients 
and expansion cohort), 22/53 patients had objective responses (41.5%, 95% CI [28.2%, 
54.8%]). This response rate exceeds the benchmark of 15% for irinotecan and 
temozolomide in this population18 and the response rate reported for other regimens 
commonly used in the treatment of patients with relapsed neuroblastoma (e.g., 
131I-MIBG).19 
 
Of the 16 patients randomized to the dinutuximab + GM-CSF + irinotecan and 
temozolomide arm who were evaluable for toxicity, the following CTCAE v4.0 ≥ Grade 3 
hematologic toxicities were noted: neutropenia (4/16; 25%), thrombocytopenia 
(4/16; 25%), and anemia (4/16; 25%). Only 1 of 16 patients had CTCAE v4.0 Grade 3 
diarrhea. Additional CTCAE v4.0 Grade 3 toxicities included pain (7/16; 44%), 
hypokalemia (6/16; 38%), fever and infection (4/16; 25%), and hypoxia (4/16; 25%); one 
patient had Grade 4 hypoxia related to therapy. Ten patients on the dinutuximab + GM-CSF 
+ irinotecan and temozolomide arm required dose modifications; 4/16 patients required 
temozolomide dose modifications and 6/16 patients required dinutuximab dose 
modifications. Hematologic toxicity was defined as neutropenia or thrombocytopenia that 
caused a delay of ≥ 14 days between treatment cycles. Only two required dose 
modifications for hematologic toxicity (neutropenia, n=1; thrombocytopenia, n=1). Thus, 
hematologic toxicity was manageable on the dinutuximab + GM-CSF + irinotecan and 
temozolomide arm.4 
 
Of the 35 patients evaluable for toxicity in the expansion cohort, the following 
CTCAE v4.0 ≥ Grade 3 hematologic toxicities were noted: thrombocytopenia (1/35; 2.9%) 
and neutropenia (12/35; 34.3%). Among the 51 patients evaluable for toxicity in the full 
cohort treated with this combination (randomized patients and patients in the expansion 
cohort), the most common ≥ Grade 3 toxicities were fever/infection (18/51; 35.3%), 
neutropenia (17/51; 33.3%), pain (15/51; 29.4%), and diarrhea (10/51; 19.6%). Grade 3 or 
higher thrombocytopenia was noted in 9.8% (5/51) of patients in the full cohort. Overall, 

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the hematologic as well as non-hematologic toxicities were tolerable in the expansion 
cohort (Rochelle Bagatell, MD, personal communication).5  
 
The mechanism for the high level of anti-neuroblastoma activity observed in patients 
treated with the chemo-immunotherapy regimen has not yet been elucidated. Analysis of 
correlative biology samples collected during the ANBL1221 study is ongoing. It is possible 
that one or both chemotherapy agents may be altering the tumor microenvironment and/or 
inducing changes in tumor cell immunogenicity. The combination of irinotecan and 
temozolomide has been demonstrated to be well tolerated.18 Therefore, both 
chemotherapeutic agents are included as part of the regimen for this study. 
 
2.4 
Dosing Rationale 
In this pilot study, irinotecan and temozolomide will be administered using the same doses 
shown to be tolerable in ANBL1221. Isotretinoin, which has been shown to improve EFS 
following Consolidation therapy20 and was incorporated with dinutuximab and cytokines 
in ANBL0032,1 will be included in each cycle at standard dosing (80 mg/m2/dose BID). 
Based on in vitro data indicating that isotretinoin reduces the activity of cytotoxic 
chemotherapeutic agents in neuroblastoma cell lines,21 a break between the completion of 
isotretinoin and the start of the next cycle of therapy has been incorporated into the 
treatment schema. This schedule mirrors the administration of isotretinoin delivered in 
ANBL0032.1 
 
2.5 
Rationale for Correlative Studies 
An understanding of the baseline Post-Consolidation immune status and changes in 
immune effector cells in response to immune modulating drugs will be important for the 
design of future passive immunotherapy regimens for patients with neuroblastoma. Key 
immune assessments of interest in this context include evaluation of the number of NK and 
NK-T cells, evaluation of T cell subsets and assessment of expression of NK activation and 
inhibitory receptors. For example, in ANBL0032, pre-immunotherapy expression of NK 
markers, including KIR, CD161 and NKp44, was associated with outcome (ANR 2018, 
Abstract 376), suggesting that patients with NK populations expressing these markers may 
be most responsive to dinutuximab. The importance of these markers in the context of 
chemo-immunotherapy rather than conventional Post-Consolidation immunotherapy as per 
ANBL0032 is not known, and ANBL19P1 provides an ideal context in which to obtain 
these data. In addition, this work will also improve our understanding of the potential 
impact of early chemo-immunotherapy on immune reconstitution following autologous 
stem cell transplant. A retrospective study of 39 patients with high-risk neuroblastoma 
demonstrated that most patients do not have full immune reconstitution at the start of 
immunotherapy after ASCT. Further, in this study, patients who remained in remission 
were noted to have higher white blood cell counts and absolute lymphocyte counts 3 
months after completion of therapy, implying that tumor immune surveillance may impact 
outcomes.22 Data regarding T-cell function in the peripheral blood of newly diagnosed 
children with neuroblastoma indicate that T-cell proliferative capacity is limited.23 
Additional studies in children with neuroblastoma and other solid tumors suggest that 
systemic immune dysfunction may also vary over time (David Barrett, MD, PhD, personal 
communication). There are ongoing efforts to collect data on immune and cytokine during 
frontline high-risk neuroblastoma therapy on the Phase 3 study, ANBL1531. As a result, 
an opportunity exists to compare immune profiles in those patients receiving standard 
immunotherapy on ANBL1531 versus chemo-immunotherapy on this pilot trial. 
 

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For children with neuroblastoma, cytokine levels and changes in these levels throughout 
treatment may be associated with therapeutic response to immunotherapy. Cytokines can 
be released by cancer cells or by cells of the tumor microenvironment and have a multitude 
of effects that either promote tumor cell growth or potentiate the effect of 
immunotherapy.24 Cytokines have been associated with outcome in patients with cancer. 
In particular, elevated IL-6 levels at diagnosis have been associated with poor outcome in 
numerous cancers, including neuroblastoma.25,26 In ANBL0931, a study of Post-
Consolidation 
immunotherapy 
in 
patients 
with 
high-risk 
neuroblastoma, 
15 
cytokines/chemokines were measured throughout treatment. Samples were obtained during 
each cycle of immunotherapy. Results showed that patients developed significant increases 
(p < 0.001) in serum levels of IL-6, IL-1ra, IFN-ɣ, IL-10, TNFα, IL-5, IL-17A, CXCL9, 
IL-15 and nitric oxide compared to baseline levels (ANR 2018, Abstract 378). However, 
only a low pretreatment (baseline) level of CXCL9 was associated with an improved event 
free survival (p = 0.05) in patients receiving standard immunotherapy. Therefore, samples 
will be obtained on ANBL19P1 to evaluate the levels of these cytokines at baseline and 
during therapy to evaluate the effect of chemo-immunotherapy during therapy. 
 
Importantly, samples and testing for immune profiling and cytokine analysis from this 
study parallel those being collected from patients in first relapse or with refractory 
neuroblastoma receiving identical chemo-immunotherapy on the Phase 2 trial ANBL1821 
(Arm A). Thus, there is an opportunity to examine the differences in immune profiles both 
prior to and following chemo-immunotherapy across COG studies in patients in the 
frontline Post-Consolidative and relapsed/refractory setting. 
 
 
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 Patient Registry module in OPEN 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. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every 
patient with a known or suspected neoplasm needs to be offered participation in 
APEC14B1, Project:EveryChild A Registry, Eligibility Screening, Biology and 
Outcome Study. 
 
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; requirements for site 

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registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.1.2 
IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases after March 1, 2019, all U.S.-based sites must 
be members of the NCI Central Institutional Review Board (NCI CIRB). In 
addition, U.S.-based sites must accept the NCI CIRB review to activate new 
studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was 
previously open at the site under the local IRB. International sites should continue 
to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
(SSW) for Local Context to the CIRB using IRBManager to indicate their intent 
to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the 
CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. Site 
preferences can be set at the network or protocol level. Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by 
emailing the email address above or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on 
the IRB/REB approval) must meet the following criteria to complete processing of 
the IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating organization’s 
roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable 
CIRB Signatory Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form 
FDA 1572 in the RCR profile;  
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form 
FDA 1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 

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Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or 
a Participating Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least one 
CIRB Signatory Institution (US sites only); and 
• 
Compliance with all protocol-specific requirements (PSRs).  
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately by phone or email at 
1-866-651-CTSU (2878), or CTSURegHelp@coccg.org in order to receive further 
instruction and support. For general (non-regulatory) questions call the CTSU 
General Helpdesk at: 1-888-823-5923. 
 
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. 
 
3.1.3 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system. Patients must 
be enrolled within 5 calendar days of making a reservation or the reservation will 
need to be renewed, if an open slot remains available. 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in the 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 ensure 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 the patient to this study.  
 
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 username 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: 
www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_QuickRefere
nce_SiteUserGuide_102612.pdf&ftype=PDF 
 
 
 
3.1.4 
Study Enrollment 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration 
system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and 
roster data and with the LPOs registration/randomization systems or Theradex 
Interactive 
Web 
Response 
System 
(IWRS) 
for 
retrieval 
of 
patient 
registration/randomization assignment. OPEN will populate the patient enrollment 
data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Be on a LPO roster, 
ETCTN Corresponding roster, or PO roster with the role of Registrar. 
Registrars must hold a minimum of an AP registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the 
registrar(s) must hold the OPEN Registrar task on the DTL for the site; 
and 
• 
Have an approved site registration for a protocol prior to patient 
enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving investigator 
for a patient transfer in OPEN, the IVR or NPIVR must list the IRB number used 
on the site’s IRB approval on their Form FDA 1572 in RCR. If a DTL is required 
for the study, the IVR or NPIVR must be assigned the appropriate OPEN-related 
tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated 
timeframes; and  
• 
All patients have signed an appropriate consent form and Health 
Insurance Portability and Accountability Act (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.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website. Further instructional information is in the OPEN section of the 
CTSU website at https://www.ctsu.org or 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 enrollment.  

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• 
Enrollment must occur after completion of external beam radiotherapy, if 
given, and after completion of the standard Post-Consolidation disease 
assessment. The standard Post-Consolidation disease assessment must 
occur after completion of radiotherapy, if given, and must occur within 
21 days prior to enrollment (repeat if out of window).  
• 
Patients who do not undergo radiotherapy (those with unidentifiable 
primary tumors and no persistent metastatic disease) may enroll upon 
recovery from the last dose of high-dose chemotherapy and ASCT and 
completion of disease evaluations.  
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived. 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.  
 
Laboratory Studies 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated.  
 
The following laboratory studies must be repeated prior to the start of protocol therapy 
if > 7 days have elapsed from their most recent prior assessment: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. Laboratory tests need not 
be repeated if therapy starts within seven (7) days of their most recent prior 
assessment. 
 
If the result of a laboratory study that is repeated at any time post-enrollment and 
prior to the start of protocol therapy is outside the limits for eligibility, then the 
evaluation must be rechecked within 48 hours prior to initiating protocol therapy. 
The results of the recheck must be within the limits for eligibility to proceed. If the 
result of the recheck is outside the limits of eligibility, the patient may not receive 
protocol therapy and will be considered off protocol therapy.  
 
Clinical Studies  
Clinical studies (e.g., cardiac imaging, pulmonary function tests), if applicable, must 
be obtained within 21 days prior to enrollment (repeat if necessary). 
 
Disease/Staging Imaging 
Disease/staging imaging studies, if applicable, must be obtained within 21 days prior 
to enrollment (repeat if necessary). 
 
Inclusion Criteria 
 
3.2.1 
Age 
Patients must be < 31 years of age at the time of enrollment. 
 
3.2.2 
Diagnosis 
Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma 
(nodular) [verified by tumor pathology analysis or demonstration of clumps of 
tumor cells in bone marrow with elevated urinary catecholamine metabolites at the 

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time of diagnosis] and have been designated as having high-risk disease based on 
COG risk classification. The following disease groups are eligible:  
 
• 
Patients with INRG Stage M disease with any of the following features: 
a) MYCN amplification (> 4-fold increase in MYCN signals as compared to 
reference signals), regardless of additional biologic features; OR  
b) Age > 547 days at the time of diagnosis regardless of biologic features; OR 
c) Age 365-547 days at the time of diagnosis with tumors with unfavorable 
histology and/or DNA index = 1. 
 
• 
Patients with INRG Stage MS disease with MYCN amplification  
 
• 
Patients with INRG Stage L2 disease with either of the following features: 
a) MYCN amplification (> 4-fold increase in MYCN signals as compared to 
reference signals), regardless of additional biologic features; OR 
b) Age > 547 days at the time of diagnosis with MYCN non-amplified tumors 
with unfavorable histology. 
 
Note: Patients observed or patients treated with a single cycle of chemotherapy per 
a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, 
ANBL1232 or similar) for what initially appeared to be non-high-risk disease but 
subsequently found to meet the criteria in Section 3.2.2 will also be eligible. 
 
See Appendix II for INRG Staging System. 
 
3.2.3 
Performance Level 
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 (Appendix III). 
 
3.2.4 
Prior Therapy 
• 
All patients must have completed high-risk Induction therapy with 4-6 cycles 
of chemotherapy 
• 
After completion of Induction therapy, patients may have received no more 
than 4 cycles of bridging chemotherapy or chemo-immunotherapy prior to 
ASCT. 
• 
Patients cannot have previously progressed on immunotherapy with 
dinutuximab or other anti-GD2 monoclonal antibody. 
• 
All patients must have had undergone surgical resection of their primary tumor 
as part of frontline therapy. Exceptions to this requirement include patients 
who had a complete response to Induction chemotherapy, patients with no 
identifiable primary tumor, and patients for whom the institutional surgical 
team determined that potential risks outweighed potential benefits of resection. 
• 
All patients must have undergone tandem high-dose chemotherapy with ASCT 
as part of Consolidation. 
• 
Patients must enroll between Day +56 and Day +200 from the peripheral blood 
stem cell (PBSC) infusion following the last dose of high-dose chemotherapy 
during Consolidation.  
• 
All patients must have undergone external beam radiation therapy. Exceptions 
to this requirement include patients who had no identifiable primary tumor and 

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no persistent metastatic disease at the end of Induction. For patients who 
received radiotherapy, at least 7 days must have elapsed between completion 
of radiotherapy and enrollment on this study. 
 
3.2.5 
Concomitant Medications Restrictions 
Please see Section 4.3 for the concomitant therapy restrictions for patients during 
treatment.  
 
Patients must not have received long-acting myeloid growth factors (e.g., 
Neulesta) 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/L  
- 
Platelet count  50,000/L (transfusion independent for  7 days) 
 
3.2.6.2 
Adequate Renal Function Defined As: 
- 
Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2, or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
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 GFR27 utilizing child length and stature data 
published by the CDC. 
 
Note: Patients with history of transplant associated-thrombotic 
microangiopathy (TA-TMA) must have a creatinine clearance or 
radioisotope GFR at baseline to assess renal function and must 
meet the above criteria. 
 
3.2.6.3 
Adequate Liver Function Defined As: 
- 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and 
- 
SGPT (ALT) ≤ 5.0 x ULN for age (≤ 225 U/L) 
 
Note: For the purpose of this study, the ULN for SGPT (ALT) has 
been set to the value of 45 U/L. 
 
3.2.6.4 
Adequate Cardiac Function Defined As: 
- 
Shortening fraction of  27% by echocardiogram, or 

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- 
Ejection fraction of ≥ 50% by echocardiogram or radionuclide 
angiogram 
 
3.2.6.5 
Adequate Pulmonary Function Defined As: 
- 
Absence of dyspnea at rest 
- 
If pulmonary function tests (PFTs) are performed, FEV1/FVC must 
be > 60% 
 
3.2.6.6 
Central Nervous System Function Defined As: 
- 
No clinical evidence of active CNS disease at the time of study 
enrollment. 
- 
Patients with seizure disorder may be enrolled if on non-enzyme-
inducing anticonvulsants and well controlled. 
- 
CNS toxicity from prior therapy  Grade 2. 
 
Exclusion Criteria 
 
3.2.7 
Patients must not have had progressive disease (PD) per the revised International 
Neuroblastoma Risk Criteria (INRC)28 since the initial diagnosis of high-risk 
neuroblastoma. 
Exception: Progressive disease within the first 2 cycles of Induction 
chemotherapy consisting of cyclophosphamide and topotecan is allowed. Patients 
with progression subsequent to initial cyclophosphamide and topotecan cycles are 
excluded. 
 
3.2.8 
Patients may not have received additional systemic cancer-directed therapy 
following completion of the last planned high-dose chemotherapy with ASCT 
prior to enrollment on this trial. 
 
3.2.9 
Patients may not have received 131I-MIBG therapy at any time prior to enrollment 
on this trial. 
 
3.2.10 Patients who received single (rather than tandem) high-dose chemotherapy with 
ASCT are excluded. 
 
3.2.11 Patients cannot be receiving other ongoing anticancer therapy. 
 
3.2.12 Patients who were enrolled onto ANBL1531 AND underwent arm assignment are 
not eligible. Patients who enrolled onto ANBL1531 who declined second consent 
may be eligible for ANBL19P1 if all other criteria are met. 
 
3.2.13 Patients enrolled onto ANBL17P1 are not eligible. 
 
3.2.14 Systemic Steroids and Immunosuppressive Medications 
3.2.14.1 Patients must have been off pharmacologic doses of systemic steroids 
for at least 7 days prior to enrollment.  
 
3.2.14.2 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 

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corticosteroid) as premedication for blood product administration in 
order to avoid allergic transfusion reactions.  
 
Note: 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. 
 
3.2.14.3 Patients on any other immunosuppressive medications (e.g., 
cyclosporine, tacrolimus) are not eligible. However, prior or planned 
concomitant treatment with eculizumab is permitted (e.g., treatment of 
TA-TMA). 
 
3.2.15 Patients must not have received enzyme-inducing anticonvulsants including 
phenytoin, phenobarbital, valproic acid, or carbamazepine for at least 7 days prior 
to study enrollment.  
 
Note: Patients receiving non-enzyme inducing anticonvulsants such as gabapentin 
or levetiracetam are eligible. (See Appendix IV for additional enzyme-inducing 
anticonvulsants and acceptable alternative options.) 
 
3.2.16 Patients must not have received drugs that are strong inducers or inhibitors of 
CYP3A4 within 7 days prior to study enrollment. (See Appendix VII for a list of 
CYP3A4 active agents.) 
 
3.2.17 Patients must not have been diagnosed with myelodysplastic syndrome or with any 
malignancy other than neuroblastoma. 
 
3.2.18 Patients with symptoms of congestive heart failure are not eligible. 
 
3.2.19 Patients with moderate or large pericardial effusions are not eligible. 
 
3.2.20 Patients must not have ≥ Grade 2 diarrhea. 
 
3.2.21 Patients must not have uncontrolled infection. 
 
3.2.22 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. 
 
3.2.23 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. 
 
3.2.24 Pregnancy and Breastfeeding 
 
3.2.24.1 Female patients who are pregnant since fetal toxicities and teratogenic 
effects have been noted for several of the study drugs. A pregnancy test 
is required for female patients of childbearing potential. 
 
3.2.24.2 Lactating females who plan to breastfeed their infants. 

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3.2.24.3 Sexually active patients of reproductive potential who have not agreed 
to use an effective contraceptive method for the duration of their study 
participation. 
 
3.2.25 Regulatory Requirements 
 
3.2.25.1 All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.25.2 All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 
 

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4.0 
TREATMENT PLAN 
 
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 (except where 
explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
This is a single-arm pilot study of dinutuximab in combination with irinotecan, 
temozolomide, sargramostim (GM-CSF), and isotretinoin in the Post-Consolidation setting 
for patients receiving frontline therapy for high-risk neuroblastoma. 
 
Each cycle of therapy will be 28 days in length. During Cycles 1-5 (Table 1), patients will 
receive irinotecan and temozolomide (Days 1-5), dinutuximab (Days 2-5), GM-CSF (Days 
6-12) and ISOtretinoin (Days 8-21). Cycle 6 (Table 2) will consist of isotretinoin alone 
(Days 8-21). 
 
Disease evaluations will occur at baseline (within 21 days prior to study enrollment), after 
Cycle 3, and after completion of Cycle 6 (end of therapy). [Note: Patients who discontinue 
isotretinoin prior to Cycle 6 must complete full disease evaluations and end of protocol 
therapy requirements at the end of Cycle 5.] Imaging evaluations are to be performed 
during follow-up as detailed in Section 7.1. 
 
Table 1. Post-Consolidation Cycles 1-5 
Days 
1 
2 
3 
4 
5 
6-12 
13-21 
22-28 
Temozolomide 
X 
X 
X 
X 
X 
 
 
 
Irinotecan  
X 
X 
X 
X 
X 
 
 
 
Dinutuximab 
 
X 
X 
X 
X 
 
 
 
GM-CSF 
 
 
 
 
 
X 
 
 
ISOtretinoin 
 
 
 
 
 
(D8-12) 
X 
 
 
Table 2. Post-Consolidation Cycle 6 
Days 
1-7 
8-21 
22-28 
ISOtretinoin 
 
X 
 
 
4.2 
General Guidelines for Therapy 
See the Chemotherapy Administration Guidelines (CAG) for children on the COG website 
at: https://www.cogmembers.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. 
 
For COG Supportive Care Guidelines see: 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
 

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4.2.1 
Diarrhea Prophylaxis 
Cefixime (8 mg/kg/day PO once daily, maximum dose 400mg/day) or an available 
equivalent oral cephalosporin (e.g., cefpodoxime 10 mg/kg/day PO divided BID, 
maximum dose 400 mg/day) should be started 2 days prior to the first dose of 
irinotecan and continued until 3 days after the last dose of irinotecan for a total of 
10 days in each cycle. For patients who have a documented allergy to 
cephalosporins, institutional guidelines for diarrhea prophylaxis should be 
followed. 
 
See Appendix V for specific guidelines for supportive care measures for patients 
who develop therapy-associated diarrhea. Patients receiving prolonged exposure 
to antibiotics who develop diarrhea should have stool samples evaluated for 
evidence of infection (viral, C. difficile, etc.). Patients should be tested for 
infectious etiologies if they have fever with diarrhea, bloody diarrhea, or other 
concerns for infection. 
 
4.2.2 
Pneumocystis Jiroveci Pneumonia (PJP) Prophylaxis 
Patients must receive PJP prophylaxis during study therapy per institutional 
guidelines. 
 
4.2.3 
Other Supportive Care 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and 
general supportive care are to be used as necessary. To reduce opiate requirements 
during dinutuximab therapy, gabapentin use is recommended. Dosing should 
follow institutional standards; however, dosing guidance is provided in Section 
4.4.3. 
 
Note: Steroids (dexamethasone) may not be used as an anti-emetic. A multiple day 
aprepitant regimen may result in moderate CYP3A4 inhibition and should be 
avoided if reasonable alternatives exist. A single dose of aprepitant or fosaprepitant 
does not substantially inhibit CYP3A4 and can be utilized. 
 
4.3 
Concomitant Therapy 
 
4.3.1 
Chemotherapy or Immunomodulating Agents 
No other systemic anti-cancer or immunomodulatory therapy (including steroids) 
will be permitted. Pharmacologic doses of systemic corticosteroids should be used 
ONLY for life-threatening conditions (i.e. 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). Physiologic doses of steroid for patients with known adrenal 
insufficiency is acceptable. The use of steroids during protocol therapy 
requires clear justification and documentation. See Appendix VI for possible 
drug interactions. 
 
4.3.2 
External Beam Radiotherapy 
Radiotherapy to localized painful lesions is not permitted on study. 
 

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4.3.3 
Cytokines or Growth Factors 
Cytokines or growth factors (G-CSF, Interferon, etc.) not included in the treatment 
plan are prohibited during protocol therapy. 
 
4.3.4 
CYP3A4 Active Agents 
See Appendix VII for a list of CYP3A4 active agents. 
 
Irinotecan is a substrate for CYP3A4 (major). Patients who have received drugs 
that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study 
enrollment are not eligible. The use of strong inhibitors or inducers of CYP3A4 
(Appendix VII) should be avoided for the duration of protocol therapy. Consult 
drug information references for further information. 
 
In addition, concomitant use of BCRP inhibitors (cyclosporine, eltrombopag, 
gefitinib), and UGT1A1 inhibitors (diclofenac, ketoconazole, probenecid, 
silibinin, nilotinib, and atazanavir) should be avoided due to potential increased 
risk of irinotecan toxicity. 
 
Moderate inducers or inhibitors of CYP3A4 (Appendix VII) should also be 
avoided during protocol therapy, if reasonable alternatives exist. 
 
 

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4.4 
Cycle 1 
 
4.4.1 
Criteria to Start Immunotherapy – Cycle 1 
Laboratory parameters must be within the range defined under eligibility (Section 
3.2.6). 
 
4.4.2 
Criteria to Start ISOtretinoin – Cycle 1 
• 
ALT < 10 x ULN for age. For the purposes of this study, ULN for ALT is 45 U/L. 
• 
Serum triglycerides < 500 mg/dL. 
• 
A serum creatinine based on age/gender as described in Section 3.2.6.2. 
 
Note: Observations may be obtained within 4 days prior to start of ISOtretinoin 
(i.e., Days 5-8 of protocol therapy). 
 
As per Section 5.2.8 Management of Concurrent Transplant Associated-Thrombotic 
Microangiopathy (TA-TMA), ISOtretinoin may be dose-reduced or omitted per 
institutional practice in patients with TA-TMA. 
 
4.4.3 
Premedication and Supportive Care Recommended for the Prevention of Anticipated 
Toxicities Associated with Dinutuximab  
Neuropathic pain, allergic reactions, and fever are commonly seen in patients 
receiving this antibody. Institutional guidelines for supportive care during this 
portion of therapy should be followed. The use of the following premedications are 
recommended:  
• 
IV hydration: Administer NS 10-20 mL/kg IV over 60-90 minutes just prior 
to each dinutuximab infusion.  
• 
Diphenhydramine 1 mg/kg/dose (maximum 50 mg) IV/PO 20 minutes prior 
to 
dinutuximab 
infusion 
and 
scheduled 
q6h. 
Hydroxyzine 
PO 
(0.5-1.0 mg/kg; max dose 50 mg) may be used instead of diphenhydramine 
in patients for whom there is a specific indication. 
• 
H2 antagonist (e.g., famotidine IV dose: 0.25 mg/kg/dose every 12 hours; 
maximum dose: 20 mg/dose) 
• 
Acetaminophen PO/IV: 15 mg/kg/dose (maximum 650 mg) 20 minutes prior 
to each dinutuximab infusion and scheduled q4-6h prn. 
• 
Consider use of cetirizine for patients with a history of allergic reactions 
• 
To reduce opiate requirements during dinutuximab therapy, 
gabapentin dosing is recommended. To optimize the effect of gabapentin, 
it should be initiated 1 week prior to expected start of antibody so that it can 
be increased to full dose by the start of dinutuximab administration. Dosing 
should follow institutional standards; however, the following dosing may be 
considered: 
▪ First day of gabapentin: 5 mg/kg/dose (max 300 mg/dose) at bedtime 
▪ Second day of gabapentin: 5 mg/kg/dose (max 300 mg/dose) BID 
▪ Third day of gabapentin: 5 mg/kg/dose (max 300 mg/dose) TID – patients 
should be at this dose by the time of admission for Cycle 1 dinutuximab 
▪ Gabapentin doses can be increased further if necessary; institutional 
guidelines should be followed. 
• 
Use of a patient controlled analgesia device (PCA) or continuous opioid 
infusion during the dinutuximab infusion is recommended. Morphine is the 
most commonly administered opioid. Hydromorphone or fentanyl may be 

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used in patients with known indications for use of hydromorphone or 
fentanyl. If the patient tolerates the dinutuximab infusion without 
pain/discomfort, consider removing the continuous opioid infusion rate 
during periods when dinutuximab is not infusing. 
• 
Recommended starting dose of analgesics:  
▪ Morphine 0.1 mg/kg/dose 20 minutes prior to initiation of dinutuximab 
infusion. At the same time, start a continuous morphine infusion of 
0.02 mg/kg/hr with bolus doses of 0.01 mg/kg/dose q15 minutes prn for 
pain.  
▪ If hydromorphone PCA is used, recommend hydromorphone pre-
infusion dose of 0.02 mg/kg/dose 20 minutes prior to starting the infusion 
of dinutuximab. At the same time, start a continuous hydromorphone 
infusion of 0.004 mg/kg/hr (maximum initial rate: 0.2 mg/hour for opioid 
naïve patients) with bolus doses of 0.002 mg/kg/dose q15 minutes prn for 
pain.  
▪ If fentanyl PCA is used, recommend fentanyl 1 mcg/kg 10 minutes prior 
to starting dinutuximab infusion. At the same time, start a continuous 
fentanyl infusion of 0.5 micrograms/kg/hr with bolus doses of 
0.25 micrograms/kg/dose q10 minutes prn pain.  
▪ Doses should be titrated as needed in accordance with institutional 
guidelines. 
 
For patients unable to use a PCA, a continuous basal infusion of morphine (or 
alternative medication) and as-needed boluses of the same medication may be used. 
Starting doses of the basal infusion and boluses should be based on patient weight, 
institutional standard practices, and doses required by individual patients for 
treatment of pain associated with previous interventions. Doses should be titrated as 
needed in accordance with institutional guidelines. 
 
Fluid shifts and increased insensible volume losses due to fever are commonly seen 
in patients receiving dinutuximab. In addition to the IV saline bolus given 
immediately prior to the start of dinutuximab, the administration of maintenance IV 
fluids should be considered. Fluids can be adjusted as needed based on intravascular 
volume status. 
 
Have immediately available during the dinutuximab infusion: 
a. Albuterol and oxygen 
b. Epinephrine  
c. Hydrocortisone: Use only for life-threatening reactions (hypotension, 
bronchospasm, angioedema involving the airway) not responsive to other 
measures.  
 
Monitoring during the dinutuximab infusion: 
• 
Check vital signs every 15 minutes for the first hour; if stable check vitals 
hourly until dinutuximab infusion is complete 
• 
Strict intake and output every 4 hours 
• 
Call front line clinician for:  
a. Altered blood pressure (refer to baseline values for patient and normal 
values for age/gender/height of patient), tachycardia, tachypnea, fever  
b. Pain requiring an increase in narcotic infusion rate 

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c. Urticaria, bronchospasm, peripheral/sensory neurotoxicity, new persistent 
cough 
 
 
 
4.4.4 
Additional Guidance 
• 
Due to the requirement for multiple supportive care medications concurrent with 
dinutuximab administration, the number of lumens available for venous access 
should be carefully considered. Many centers use 2 central lumens routinely; 
institutional standards should be followed. 
 
• 
Capillary leak syndrome is an expected side effect of dinutuximab therapy. 
Complications of capillary leak syndrome can be mitigated if euvolemia is 
maintained. Close monitoring of heart rate and urine output is required, and 
fluids should be adjusted to compensate for third space losses. Use of furosemide 
or other diuretics is indicated in cases of pulmonary capillary leak but is not 
required routinely. 
 
• 
Corticosteroid therapy should be used only for life-threatening conditions (i.e. 
treatment of increased intracranial pressure in patients with CNS metastases, 
symptomatic bronchospasm, stridor unresponsive to other measures or life-
threatening allergic reactions). Corticosteroids will impair the immune response 
that is a critical part of the protocol therapy. The use of steroids at any time 
during immunotherapy requires clear justification and documentation. 
 
• 
The use of intravenous immunoglobulin (IVIG) during Post-Consolidation 
therapy is discouraged. If necessary, its use should be limited to the first 100 
days post-ASCT because IVIG may interfere with antibody (dinutuximab) 
dependent cellular cytotoxicity. IVIG should not be given within 2 weeks of 
starting dinutuximab treatment and 1 week after completing dinutuximab 
therapy. 
 
 
• 
Cytokines or growth factors (G-CSF, Interferon, etc.) not included in the 
Treatment Plan are prohibited during immunotherapy. 
o 
 
 
Following completion of this cycle, Cycle 2 starts on Day 29 or when peripheral 
counts recover with ANC ≥ 750/µL and platelets ≥ 50,000/µL (whichever occurs 
later). Please refer to Section 4.5.1 for additional criteria to start next cycle. 
 
 

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4.4.5 
Therapy Delivery Map – Cycle 1 
 
Cycle 1 is 4 weeks (28 days) in length. 
____________________________         ________________________ 
 
Patient COG ID number 
 
 
      DOB 
Start Cycle 1 once criteria in Section 4.4.1 have been met. 
This TDM is on three (3) pages in length. 
DRUG 
 ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Temozolomide  
(TEMO) 
PO (preferred) or  
via enteral tube 
BSA  ≥ 0.6 m2: 100 mg/m2/dose 
 
BSA < 0.6 m2: See Dosing Table in 4.4.7. 
 
See Dosing Nomogram for Full Dosing in 
Appendix VIII  
 
Dosing Nomogram for Reduced Dosing is 
in Appendix IX 
1 - 5 
Maximum dose = 200 mg 
See treatment details in Section 4.4.7 for dose rounding instructions.  
 
For patients unable to tolerate enteral TEMO, IV TEMO may be 
substituted for enteral TEMO at the same dose (Section 5.3). 
 
Administer enteral doses at least 1 hour prior to IRIN 
administration. 
 
Irinotecan  
(IRIN) 
IV over 90 minutes 
BSA ≥ 0.6 m2: 50 mg/m2/dose  
 
BSA < 0.6 m2: See Dosing Table in 4.4.7 
 
1 - 5 
Administer IRIN at least 1 hour after the completion of enteral TEMO,  
see Section 4.4.7. 
 
IRIN may be administered immediately after the completion of IV 
TEMO. 
Dinutuximab  
(DIN) 
IV over 10 hours* 
17.5 mg/m2/dose 
2 - 5 
*Infusion duration may be extended up to 20 hours if needed. Infusions 
should not extend beyond 20 hours, even if the full dose has not been 
administered. 
 
Start immediately after completion of NS bolus and IRIN infusion. 
 
See Section 4.4.7 for detailed DIN administration guidelines, and 
Section 4.4.3 for premedications and monitoring during the infusion. 
Sargramostim  
(GM-CSF) 
SubQ (preferred) or  
IV over 2 hours 
250 micrograms/m2/dose 
6 - 12 
See Section 4.4.7 for GM-CSF administration guidelines. 
ISOtretinoin  
(ISOT) 
PO 
BSA ≥ 0.6 m2: 80 mg/m2/dose BID  
 
BSA < 0.6 m2: See Dosing Table in 4.4.7 
 
8 - 21 
BID dosing. 
See additional starting criteria for ISOT in Section 4.4.7. 
Round doses to nearest 10 mg to accommodate capsule strength. 
Continue to the next page for the therapy log. 
 
 
 
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Cycle 1 is 4 weeks (28 days) in length. 
____________________________         ________________________ 
 
Patient COG ID number 
 
 
      DOB 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
 
Date Due 
Date 
Given 
Day 
TEMO 
_____ mg 
IRIN 
_____ mg 
DIN 
_____ mg 
GM-CSF 
_____ 
micrograms 
ISOT 
_____ mg  _____ mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
Prior to 
start 
 
 
 
 
 
a – m  
 
 
1 
_____ mg 
_____ mg 
 
 
 
 
 
 
2 
_____ mg 
_____ mg 
_____ mg 
 
 
d, e 
 
 
3 
_____ mg 
_____ mg 
_____ mg 
 
 
e 
 
 
4 
_____ mg 
_____ mg 
_____ mg 
 
 
e  
 
 
5 
_____ mg 
_____ mg 
_____ mg 
 
 
e 
 
 
6 
 
 
 
_____ mcg 
 
d, e, f*, g*, m* 
 
 
7 
 
 
 
_____ mcg 
 
 
 
 
8 
 
 
 
_____ mcg 
_____ mg  _____ mg 
 
 
 
9 
 
 
 
_____ mcg 
_____ mg  _____ mg 
 
 
 
10 
 
 
 
_____ mcg 
_____ mg  _____ mg 
 
 
 
11 
 
 
 
_____ mcg 
_____ mg  _____ mg 
d 
 
 
12 
 
 
 
_____ mcg 
_____ mg  _____ mg 
 
 
 
13 
 
 
 
 
_____ mg  _____ mg 
 
 
 
14 
 
 
 
 
_____ mg  _____ mg 
 
 
 
15 
 
 
 
 
_____ mg  _____ mg 
d, e, f 
 
 
16 
 
 
 
 
_____ mg  _____ mg 
 
 
 
17 
 
 
 
 
_____ mg  _____ mg 
 
 
 
18 
 
 
 
 
_____ mg  _____ mg 
 
 
 
19 
 
 
 
 
_____ mg  _____ mg 
 
 
 
20 
 
 
 
 
_____ mg  _____ mg 
 
 
 
21 
 
 
 
 
_____ mg  _____ mg 
d, e, f 
 
 
 
 
 
 
 
 
 
 
 
29 
Begin Cycle 2 on Day 29 or when starting criteria are met, whichever occurs later (see Section 4.5.1). 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Page 2 of 3 

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4.4.6 
Required Observations – Cycle 1 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below. 
 
a. 
History, physical exam with vital signs 
b. Height, weight, BSA  
c. 
Performance status 
d. CBC with differential and platelets (patients who experience Grade 4 
neutropenia or thrombocytopenia should have CBCs checked at least twice per 
week until recovery to Grade 3) 
e. 
Electrolytes, BUN, creatinine, calcium, magnesium, phosphorus  
f. 
ALT, AST, total bilirubin, albumin* 
g. Triglycerides* 
h. Pregnancy test (obtain for females of childbearing potential) 
i. 
GFR or Creatinine Clearance (only required for patients with TA-TMA) 
j. 
ECHO or MUGA 
k. Tumor Imaging Evaluation (Cross sectional tumor imaging [MRI or CT]; and 
123I-MIBG or alternatively FDG-PET scan for patients with MIBG non-avid 
disease at diagnosis) 
l. 
Bilateral bone marrow aspirates and biopsies 
m. Specimens for correlative studies. Post-dinutuximab specimen should be collected 
at a single time point between Day 5 (post-dinutuximab) and Day 8 (pre-
ISOtretinoin). See Section 14.0 and Appendix X for details.* 
 
*Observations may be obtained between Days 5-8 (pre-ISOtretinoin) 
 
This listing only includes evaluations necessary to answer the study aims. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL 
CARE. 
 
Comments 
 
 
 
 
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4.4.7 
Treatment Details – Cycle 1 
Drug doses should be calculated based on the height and weight obtained within 
1 week prior to beginning Cycle 1. 
 
Suggested 
administration 
schedule 
for 
chemotherapy 
(Days 
1-5; 
temozolomide and irinotecan) and dinutuximab (Days 2-5): 
• 
At hour 0: patient should receive oral temozolomide. 
• 
At hour 1: start IV irinotecan over 90 minutes. On days the patient is 
receiving dinutuximab infusion (Days 2-5 of each cycle), start IVF bolus 
of normal saline (10-20 mL/kg) over 60-90 minutes. 
• 
At hour 2.5: on days patient is receiving dinutuximab infusion (Days 2-5), 
start dinutuximab infusion. 
• 
Note: Irinotecan must be administered at least 1 hour AFTER enteral 
temozolomide. 
 
Temozolomide: PO daily (NG or G-tube administration is allowed)  
Days: 1-5 
Dose: For BSA ≥ 0.6 m2, the dose for temozolomide is 100 mg/m2/dose 
MAXIMUM dose = 200 mg 
 
For patients receiving capsule formulation, see dosing nomogram in Appendix 
VIII and reduced dosing nomogram in Appendix IX (if dose modification is 
required).  
 
For patients receiving oral liquid formulation, round according to institutional 
standard. 
 
For BSA < 0.6 m2, please see the table below. The dose of temozolomide in the 
table is expressed as final dose in mg to be administered regardless of formulation 
used.  
 
TEMOZOLOMIDE Dosing 
If BSA < 0.6 m2 
BSA (m2) 
Dose  
0.25-0.29 
15 mg 
0.30-0.34 
20 mg 
0.35-0.39 
30 mg 
0.40-0.44 
35 mg 
0.45-0.49 
40 mg 
0.50-0.54 
50 mg 
0.55-0.59 
55 mg 
 
Note: For patients unable to tolerate enteral temozolomide, IV temozolomide may 
be administered. Please refer to Section 5.3 for guidance on IV temozolomide 
administration. 
 
Sequencing: Enteral temozolomide must be administered at least 1 hour PRIOR 
to irinotecan. 
 

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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. Antiemetics are 
recommended 30-60 minutes prior to each dose to prevent nausea and vomiting. 
When using temozolomide capsules, dose according to Temozolomide Dosing 
Nomogram in Appendix VIII. For ease of swallowing, the capsule content may be 
mixed with applesauce or apple juice. An oral suspension may also be compounded 
by a pharmacist. If emesis occurs within 20 minutes of taking a dose of 
temozolomide, the dose should be repeated once. If emesis occurs after 20 minutes, 
the dose should not be repeated. 
 
Administration of enteral temozolomide should be documented; missed doses 
should be noted on 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 hyperlink to the drug 
monograph provided in Section 6.0 for additional details and examples. 
 
Irinotecan: IV over 90 minutes daily 
Days: 1-5 
Dose: For BSA ≥ 0.6 m2, the dose of irinotecan is 50 mg/m2/dose. 
 
For BSA < 0.6 m2, please see the table below. The dose of irinotecan in the table 
is expressed as final dose in mg to be administered.  
 
IRINOTECAN Dosing 
If BSA < 0.6 m2 
BSA (m2) 
Dose 
0.25-0.29 
8 mg 
0.3-0.34 
12 mg 
0.35-0.39 
15 mg 
0.4-0.44 
18 mg 
0.45-0.49 
22 mg 
0.5-0.54 
24 mg 
0.55-0.59 
28 mg 
 
Note: Irinotecan should be administered at least 1 hour after enteral temozolomide 
has been given. 
 
Higher incidence of cholinergic symptoms has been reported with more rapid 
infusion rates.  
 

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See the Parenteral Chemotherapy Administration Guidelines (CAG) for special 
precautions, suggestions for patient monitoring, and hydration on the COG 
website at: 
https://www.cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
 
Dinutuximab: IV over 10 hours* daily 
Days: 2-5 
Dose: 17.5 mg/m2/dose 
 
Note: Due to the increased risk of capillary leak and respiratory compromise with 
dinutuximab administration, patients should not have dyspnea at rest or an oxygen 
requirement when starting the first dose of dinutuximab. Before starting 
dinutuximab, please obtain a copy of management recommendations for 
anaphylaxis and hypotension available in Appendix XI. It is recommended that 
these be available on the inpatient unit to facilitate treatment decisions should these 
symptoms occur. 
 
Refer to Section 4.4.3 for premedication and supportive care for the prevention of 
anticipated toxicities associated with dinutuximab, and for monitoring during the 
dinutuximab infusion. Additional information can be found in Appendix XI.  
 
Prior to dinutuximab administration (morning start recommended), administer IV 
bolus of normal saline (10-20 mL/kg) over 60-90 minutes. Bolus should be given 
concurrently with irinotecan infusion. On Day 2-5, start dinutuximab immediately 
following the completion of normal saline bolus and irinotecan infusion. 
Dinutuximab dose should start at 0.88 mg/m2/hour x 0.5 hour, then gradually 
increase to 1.75 mg/m2/hour for the remainder of the dose, if tolerated. 
 
*The infusion duration may be extended up to 20 hours for anticipated toxicities 
(hypotension, tachypnea, etc.), not responding to other supportive measures, and 
the duration used should be recorded. In the setting of dose reductions described 
in Section 5.0, the infusion time must be no longer than 20 hours from 
initiation of dinutuximab, even if the full dose of dinutuximab antibody has 
not been delivered in that timeframe. Antibody administration should not be 
given beyond the specified schedule regardless of whether doses were 
modified or held per guidelines in Section 5.0. The total dose given in 20 hours 
should be recorded. 
 
Sargramostim: Subcutaneous injection (preferred) or IV over 2 hours daily 
Days: 6 through 12 
Dose: 250 micrograms/m2/dose  
 
Start sargramostim on Day 6 any time after the completion of Day 5 dinutuximab. 
 
The standard route of administration is subcutaneous; in extenuating 
circumstances, IV administration over 2 hours is permitted. The reason for IV 
administration of this agent must be documented. 
 
Sargramostim dose will be held if the total white cell count is > 50,000/L. This 
is not a toxicity of sargramostim but rather a possible outcome related to its use. 
The sargramostim will be held until the total white cell count is less than 20,000/L 

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Cycle 1 
and then sargramostim will be resumed at 50% dose for the remainder of that cycle. 
Full dose sargramostim will be used for subsequent sargramostim cycles.  
 
ISOtretinoin: PO BID 
Days: 8-21 See additional starting criteria for ISOT in Section 4.4.2. 
Dose: For BSA ≥ 0.6 m2, the dose of ISOtretinoin is 80 mg/m2/dose BID, rounded 
to nearest 10 mg to accommodate capsule strength.  
 
For BSA < 0.6 m2, please see table below. The dose of ISOtretinoin in the table is 
expressed as final dose in mg to be administered.  
 
NOTE: dose BID. For example, if BSA ≥ 0.6 m2, administer 80 mg/m2/dose 
BID. The total daily dose is 160 mg/m2/day.  
 
ISOtretinoin Dosing 
If BSA < 0.6 m2 
BSA (m2) 
Dose  
0.25-0.29 
10 mg BID 
0.3-0.39 
20 mg BID 
0.4-0.49 
30 mg BID 
0.5-0.59 
40 mg BID 
 
Note: Capsules can be cut and the contents squeezed into a high fat food such as 
ice cream or peanut butter immediately prior to administration. Capsules can be 
chewed (best absorbed if chewed with high fat food) or the child taught to swallow 
entire capsules, which is feasible and to be encouraged. Under no circumstances 
should ISOtretinoin be removed from the capsules for more than 1 hour prior to 
administering to the patient (see hyperlink to the drug monograph provided in 
Section 6.0). Administration via nasogastric tube or orally via syringe is 
discouraged. 
 
Missed doses of isotretinoin should NOT be made up during the one week break 
between the scheduled end of isotretinoin therapy and the start of chemotherapy in 
the subsequent cycle to avoid delays in therapy. A duration of one week  between 
the scheduled end of isotretinoin (day 21) and the start of chemotherapy in the 
subsequent cycle should be maintained (e.g., last dose of isotretinoin is on day 21 
regardless of start date or missed doses and the subsequent cycle starts on day 29 
if all other criteria are met).  
 
See Section 5.0 for Dose Modifications based on Toxicities. 
 
  

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Cycles 2-5 
Cycles 2-5 
4.5 
Cycles 2-5 
 
4.5.1 
Criteria to Start Immunotherapy – Cycles 2-5 
a. ANC  750/L and platelet count  50,000/L (transfusion independent for 
 7 days). 
b. ALT ≤ 5 x ULN for age 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. For the 
purposes of this study, ULN for ALT is 45 U/L.  
c.  Total bilirubin ≤ 1.5 x ULN for age 
d. No evidence of serious infection, or infection under control (e.g., negative blood 
culture).  
e. A serum creatinine based on age/sex as described in Section 3.2.6.2. 
f.    Any diarrhea from preceding cycle improved to CTCAEv5.0 Grade 1 or better.   
g. All other non-hematologic toxicities not otherwise specified from the previous 
cycle must improve to CTCAEv5.0 Grade 2 or better 
h. To proceed to Cycle 4, patients must have no evidence of disease progression on 
the post-Cycle 3 evaluation. For patients with no evidence of residual soft tissue 
disease at the start of Post-Consolidation, cross sectional imaging (CT or MRI) 
may be omitted from the post-Cycle 3 evaluation; all other patients should 
undergo cross sectional imaging. For patients with no evidence of marrow 
disease at the start of Post-Consolidation therapy, bone marrow aspirates and 
biopsies may be omitted from the post-Cycle 3 evaluation. Patients with marrow 
involvement at the start of Post-Consolidation therapy should undergo bilateral 
bone marrow aspirates/biopsies as part of the post-Cycle 3 evaluation. 
 
4.5.2 
Criteria to Start ISOtretinoin – Cycles 2-5 
• 
ALT < 10 x ULN for age. For the purposes of this study, ULN for ALT is 45 U/L. 
• 
Serum triglycerides < 500 mg/dL. 
• 
A serum creatinine based on age/gender a described in Section 3.2.6.2. 
 
Note: Observations may be obtained within 4 days prior to start of ISOtretinoin 
(i.e., Days 5-8 of protocol therapy). 
 
As per Section 5.2.8 Management of Concurrent Transplant Associated-Thrombotic 
Microangiopathy (TA-TMA), ISOtretinoin may be dose-reduced or omitted per 
institutional practice in patients with TA-TMA. 
 
4.5.3 
Premedication and Supportive Care Recommended for the Prevention of Anticipated 
Toxicities Associated with Dinutuximab  
Neuropathic pain, allergic reactions, and fever are commonly seen in patients 
receiving this antibody. Institutional guidelines for supportive care during this 
portion of therapy should be followed. The use of the following premedications are 
recommended:  
• 
IV hydration: Administer NS 10-20 mL/kg IV over 60-90 minutes just prior 
to each dinutuximab infusion.  
• 
Diphenhydramine 1 mg/kg/dose (maximum 50 mg) IV/PO 20 minutes prior 
to dinutuximab infusion and scheduled q6h. Hydroxyzine PO (0.5-1.0 
mg/kg; max dose 50 mg) may be used instead of diphenhydramine in 
patients for whom there is a specific indication. 

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Cycles 2-5 
Cycles 2-5 
• 
H2 antagonist (e.g., famotidine IV dose: 0.25 mg/kg/dose every 12 hours; 
maximum dose: 20 mg/dose) 
• 
Acetaminophen PO/IV: 15 mg/kg/dose (maximum 650 mg) 20 minutes prior 
to each dinutuximab infusion and scheduled q4-6h prn. 
• 
Consider use of cetirizine for patients with a history of allergic reactions 
• 
To reduce opiate requirements during dinutuximab therapy, 
gabapentin dosing is recommended. To optimize the effect of gabapentin, 
it should be initiated 1 week prior to expected start of antibody so that it can 
be increased to full dose by the start of dinutuximab administration. Dosing 
should follow institutional standards; however, the following dosing may be 
considered: 
▪ First day of gabapentin: 5 mg/kg/dose (max 300 mg/dose) at bedtime 
▪ Second day of gabapentin: 5 mg/kg/dose (max 300 mg/dose) BID 
▪ Third day of gabapentin: 5 mg/kg/dose (max 300 mg/dose) TID – patients 
should be at this dose by the time of admission for Cycle 1 dinutuximab 
▪ Gabapentin doses can be increased further if necessary; institutional 
guidelines should be followed. 
• 
Use of a patient-controlled analgesia device (PCA) or continuous opioid 
infusion during the dinutuximab infusion is recommended. Morphine is the 
most commonly administered opioid. Hydromorphone or fentanyl may be 
used in patients with known indications for use of hydromorphone or 
fentanyl. If the patient tolerates the dinutuximab infusion without 
pain/discomfort, consider removing the continuous opioid infusion rate 
during periods when dinutuximab is not infusing. 
• 
Recommended starting dose of analgesics:  
▪ Morphine 0.1 mg/kg/dose 20 minutes prior to initiation of dinutuximab 
infusion. At the same time, start a continuous morphine infusion of 
0.02 mg/kg/hr with bolus doses of 0.01 mg/kg/dose q15 minutes prn for 
pain.  
▪ If hydromorphone PCA is used, recommend hydromorphone pre-
infusion dose of 0.02 mg/kg/dose 20 minutes prior to starting the infusion 
of dinutuximab. At the same time, start a continuous hydromorphone 
infusion of 0.004 mg/kg/hr (maximum initial rate: 0.2 mg/hour for opioid 
naïve patients) with bolus doses of 0.002 mg/kg/dose q15 minutes prn for 
pain.  
▪ If fentanyl PCA is used, recommend fentanyl 1 mcg/kg 10 minutes prior 
to starting dinutuximab infusion. At the same time, start a continuous 
fentanyl infusion of 0.5 micrograms/kg/hr with bolus doses of 
0.25 micrograms/kg/dose q10 minutes prn pain.  
▪ Doses should be titrated as needed in accordance with institutional 
guidelines. 
 
For patients unable to use a PCA, a continuous basal infusion of morphine (or 
alternative medication) and as-needed boluses of the same medication may be used. 
Starting doses of the basal infusion and boluses should be based on patient weight, 
institutional standard practices, and doses required by individual patients for treatment 
of pain associated with previous interventions. Doses should be titrated as needed in 
accordance with institutional guidelines. 
 

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Cycles 2-5 
Cycles 2-5 
Fluid shifts and increased insensible volume losses due to fever are commonly seen 
in patients receiving dinutuximab. In addition to the IV saline bolus given 
immediately prior to the start of dinutuximab, the administration of maintenance IV 
fluids should be considered. Fluids can be adjusted as needed based on intravascular 
volume status. 
 
Have immediately available during the dinutuximab infusion: 
a. Albuterol and oxygen 
b. Epinephrine  
c. Hydrocortisone: Use only for life-threatening reactions (hypotension, 
bronchospasm, angioedema involving the airway) not responsive to other 
measures.  
 
Monitoring during the dinutuximab infusion: 
• 
Check vital signs every 15 minutes for the first hour; if stable check vitals 
hourly until dinutuximab infusion is complete 
• 
Strict intake and output every 4 hours 
• 
Call front line clinician for:  
a. Altered blood pressure (refer to baseline values for patient and normal 
values for age/gender/height of patient), tachycardia, tachypnea, fever  
b. Pain requiring an increase in narcotic infusion rate 
c. Urticaria, bronchospasm, peripheral/sensory neurotoxicity, new persistent 
cough 
 
 
 
4.5.4 
Additional Guidance 
• 
Due to the requirement for multiple supportive care medications concurrent with 
dinutuximab administration, the number of lumens available for venous access 
should be carefully considered. Many centers use 2 central lumens routinely; 
institutional standards should be followed. 
 
• 
Capillary leak syndrome is an expected side effect of dinutuximab therapy. 
Complications of capillary leak syndrome can be mitigated if euvolemia is 
maintained. Close monitoring of heart rate and urine output is required, and 
fluids should be adjusted to compensate for third space losses. Use of furosemide 
or other diuretics is indicated in cases of pulmonary capillary leak but is not 
required routinely. 
 
• 
Corticosteroid therapy should be used only for life-threatening conditions (i.e. 
treatment of increased intracranial pressure in patients with CNS metastases, 
symptomatic bronchospasm, stridor unresponsive to other measures or life-
threatening allergic reactions). Corticosteroids will impair the immune response 
that is a critical part of the protocol therapy. The use of steroids at any time 
during immunotherapy requires clear justification and documentation.  
 
• 
The use of Intravenous Immunoglobulin (IVIG) during Post-Consolidation 
therapy is discouraged. If necessary, its use should be limited to the first 100 
days post-ASCT because IVIG may interfere with antibody (dinutuximab) 
dependent cellular cytotoxicity. IVIG should not be given within 2 weeks of 
starting dinutuximab treatment and 1 week after completing dinutuximab 
therapy. 

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Cycles 2-5 
Cycles 2-5 
 
• 
Cytokines or growth factors (G-CSF, Interferon, etc.) not included in the 
Treatment Plan are prohibited during immunotherapy. 
o 
 
 
Following completion of each cycle, the subsequent cycle starts on Day 29 or when 
peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 50,000/µL (whichever 
occurs later). Please refer to Section 4.5.1 for criteria to start next cycle (for 
Cycles 3-5) or see Section 4.6.1 for criteria to start Cycle 6. 
 
 

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Cycles 2-5 
Cycles 2-5 
 
4.5.5 
Therapy Delivery Map - Cycles 2-5  
 
Cycles 2 to 5 are each 4 weeks (28 days) in length. 
____________________________         ________________________ 
 
Patient COG ID number 
 
 
      DOB 
Treatment details and criteria to start are in Section 4.5.1. 
This TDM is on 3 pages. 
DRUG 
 ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Temozolomide  
(TEMO) 
PO (preferred) or  
via enteral tube  
BSA  ≥ 0.6 m2: 100 mg/m2/dose 
 
BSA < 0.6 m2: See Dosing Table in 4.5.7. 
 
See Dosing Nomogram for Full Dosing in 
Appendix VIII. 
 
Dosing Nomogram for Reduced Dosing is in 
Appendix IX. 
1 - 5 
Max dose = 200 mg 
See treatment details in Section 4.5.7 for dose rounding instructions.   
 
For patients unable to tolerate enteral TEMO, IV TEMO may be 
substituted for enteral TEMO at the same dose (Section 5.3). 
 
Administer enteral doses at least 1 hour prior to IRIN 
administration.  
Irinotecan  
(IRIN) 
IV over 90 minutes 
BSA ≥ 0.6 m2: 50 mg/m2/dose  
 
BSA < 0.6 m2: See Dosing Table in 4.5.7 
 
1 - 5 
Administer IRIN at least 1 hour after the completion of enteral TEMO, 
see Section 4.5.7.  
 
IRIN may be administered immediately after the completion of IV 
TEMO. 
Dinutuximab  
(DIN) 
IV over 10 hours* 
17.5 mg/m2/dose 
2 - 5 
*Infusion duration may be extended up to 20 hours if needed. Infusions 
should not extend beyond 20 hours, even if the full dose has not been 
administered. 
 
Start immediately after completion of NS bolus and IRIN infusion. 
 
See Section 4.5.7 for detailed DIN administration guidelines, and 
Section 4.5.3 for premedications and monitoring during the infusion. 
Sargramostim  
(GM-CSF) 
SubQ (preferred) or 
IV over 2 hours 
250 micrograms/m2/dose 
6 - 12 
See Section 4.5.7 for GM-CSF administration guidelines. 
ISOtretinoin  
(ISOT) 
PO 
 
BSA ≥ 0.6 m2: 80 mg/m2/dose BID  
 
BSA < 0.6 m2: See Dosing Table in 4.5.7 
 
8 - 21 
BID dosing. 
See additional starting criteria for ISOT in Section 4.5.2. 
Round doses to nearest 10 mg to accommodate capsule strength. 
Continue to the next page for the therapy log. 
 
 
Page 1 of 3 

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Cycles 2-5 
Cycles 2-5 
 
Cycles 2 to 5 are each 4 weeks (28 days) in length. 
____________________________         ________________________ 
 
Patient COG ID number 
 
 
      DOB 
 
Enter Cycle #: _____  
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
 
Date Due 
Date 
Given 
Day 
TEMO 
_____ mg 
IRIN 
_____ mg 
DIN 
_____ mg 
GM-CSF 
_____ 
micrograms 
ISOT 
_____ mg  _____ mg 
Cycles  
2, 4, and 5 
Studies 
Cycle 3 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
_____ mg 
_____ mg 
 
 
 
a – e, g, j a – e, g, j 
 
 
2 
_____ mg 
_____ mg 
_____ mg 
 
 
c, d 
c, d 
 
 
3 
_____ mg 
_____ mg 
_____ mg 
 
 
d 
d 
 
 
4 
_____ mg 
_____ mg 
_____ mg 
 
 
d 
d 
 
 
5 
_____ mg 
_____ mg 
_____ mg 
 
 
d 
d 
 
 
6 
 
 
 
_____ mcg 
 
c, d, e*, 
f* 
c, d, e*, 
f* 
 
 
7 
 
 
 
_____ mcg 
 
 
 
 
 
8 
 
 
 
_____ mcg 
_____ mg  _____ mg 
 
 
 
 
9 
 
 
 
_____ mcg 
_____ mg  _____ mg 
 
 
 
 
10 
 
 
 
_____ mcg 
_____ mg  _____ mg 
 
 
 
 
11 
 
 
 
_____ mcg 
_____ mg  _____ mg 
c 
c 
 
 
12 
 
 
 
_____ mcg 
_____ mg  _____ mg 
 
 
 
 
13 
 
 
 
 
_____ mg  _____ mg 
 
 
 
 
14 
 
 
 
 
_____ mg  _____ mg 
 
 
 
 
15 
 
 
 
 
_____ mg  _____ mg 
c, d, e 
c, d, e 
 
 
16 
 
 
 
 
_____ mg  _____ mg 
 
 
 
 
17 
 
 
 
 
_____ mg  _____ mg 
 
 
 
 
18 
 
 
 
 
_____ mg  _____ mg 
 
 
 
 
19 
 
 
 
 
_____ mg  _____ mg 
 
 
 
 
20 
 
 
 
 
_____ mg  _____ mg 
 
 
 
 
21 
 
 
 
 
_____ mg  _____ mg 
c, d, e 
c, d, e 
 
 
 
 
 
 
 
 
 
h, i 
 
 
29 
Begin the next cycle on Day 29 or when starting criteria are met, whichever occurs later (for Cycles 3-5 see Section 4.5.1; for Cycle 6 see Section 
4.6.1). 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Page 2 of 3 

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Cycles 2-5 
Cycles 2-5 
4.5.6 
Required Observations – Cycles 2-5  
 
a. 
History, physical exam with vital signs 
b. Height, weight, BSA 
c. 
CBC with differential and platelets (patients who experience Grade 4 
neutropenia or thrombocytopenia should have CBCs checked at least twice per 
week until recovery to Grade 3) 
d. Electrolytes, BUN, creatinine, calcium, magnesium, phosphorus 
e. 
ALT, AST, total bilirubin, albumin* 
f. 
Triglycerides* 
g. Pregnancy test (obtain for females of childbearing potential) 
h. Tumor Imaging Evaluation: 123I-MIBG or alternatively FDG-PET scan for 
patients with MIBG non-avid disease at diagnosis. Cross sectional tumor 
imaging (MRI or CT) is only required after Cycle 3 for patients with residual 
soft tissue disease detected at the start of Post-Consolidation  
i. 
Bilateral bone marrow aspirates and biopsies are only required after Cycle 3 
for patients with detectable bone marrow involvement at the start of Post-
Consolidation 
j. 
Specimens for correlative studies. See Section 14.0 and Appendix X for details.** 
 
*Observations may be obtained between Days 5-8 (pre-ISOtretinoin) 
 ** Collect for Cycles 2 and 3 only. 
 
Disease evaluations may be performed between Days 22 and 28 of Cycle 3. 
 
 
This listing only includes evaluations necessary to answer the study aims. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL 
CARE. 
 
Comments 
 
 
 
Page 3 of 3 

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Cycles 2-5 
Cycles 2-5 
4.5.7 
Treatment Details – Cycles 2-5  
Drug doses should be calculated based on the height and weight obtained within 1 
week prior to the beginning of each cycle. 
 
Suggested 
administration 
schedule 
for 
chemotherapy 
(Days 
1-5; 
temozolomide and irinotecan) and dinutuximab (Days 2-5): 
• 
At hour 0: patient should receive oral temozolomide. 
• 
At hour 1: start IV irinotecan over 90 minutes. On days the patient is 
receiving dinutuximab infusion (Days 2-5 of each cycle), start IVF bolus 
of normal saline (10-20 mL/kg) over 60-90 minutes. 
• 
At hour 2.5: on days patient is receiving dinutuximab infusion (Days 2-5 
of each cycle), start dinutuximab infusion. 
• 
Note: Irinotecan must be administered at least 1 hour AFTER enteral 
temozolomide. 
 
Temozolomide: PO daily (NG or G-tube administration is allowed)  
Days: 1-5 
Dose: For BSA ≥ 0.6 m2, the dose for temozolomide is 100 mg/m2/dose 
MAXIMUM dose = 200 mg 
 
For patients receiving capsule formulation, see dosing nomogram in Appendix 
VIII and reduced dosing nomogram in Appendix IX (if dose modification is 
required). 
 
For patients receiving oral liquid formulation, round according to institutional 
standard. 
 
For BSA < 0.6 m2, please see the table below. The dose of temozolomide in the 
table is expressed as final dose in mg to be administered regardless of formulation 
used. 
 
TEMOZOLOMIDE Dosing 
If BSA < 0.6 m2 
BSA (m2) 
Dose  
0.25-0.29 
15 mg 
0.30-0.34 
20 mg 
0.35-0.39 
30 mg 
0.40-0.44 
35 mg 
0.45-0.49 
40 mg 
0.50-0.54 
50 mg 
0.55-0.59 
55 mg 
 
Note: For patients unable to tolerate enteral temozolomide, IV temozolomide may 
be administered. Please refer to Section 5.3 for guidance on IV temozolomide 
administration. 
 
Sequencing: Enteral temozolomide must be administered at least 1 hour PRIOR 
to irinotecan  
 

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Cycles 2-5 
Cycles 2-5 
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. Antiemetics are 
recommended 30-60 minutes prior to each dose to prevent nausea and vomiting. 
When using temozolomide capsules, dose according to Temozolomide Dosing 
Nomogram in Appendix VIII. For ease of swallowing, the capsule content may be 
mixed with applesauce or apple juice. An oral suspension may also be compounded 
by a pharmacist. If emesis occurs within 20 minutes of taking a dose of 
temozolomide, then the dose should be repeated once. If emesis occurs after 20 
minutes, the dose should not be repeated. 
 
Administration of enteral temozolomide should be documented; missed doses 
should be noted on 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 hyperlink to the drug 
monograph provided in Section 6.0 for additional details and examples.  
 
Irinotecan: IV over 90 minutes daily 
Days: 1-5 
Dose: For BSA ≥ 0.6 m2, the dose of irinotecan is 50 mg/m2/dose. 
 
For BSA < 0.6 m2, please see the table below. The dose of irinotecan in the table 
is expressed as final dose in mg to be administered.  
 
IRINOTECAN Dosing 
If BSA < 0.6 m2 
BSA (m2) 
Dose 
0.25-0.29 
8 mg 
0.3-0.34 
12 mg 
0.35-0.39 
15 mg 
0.4-0.44 
18 mg 
0.45-0.49 
22 mg 
0.5-0.54 
24 mg 
0.55-0.59 
28 mg 
 
Note: Irinotecan should be administered at least 1 hour after enteral temozolomide 
has been given. 
 
Higher incidence of cholinergic symptoms has been reported with more rapid 
infusion rates.  
 

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Cycles 2-5 
Cycles 2-5 
See the Parenteral Chemotherapy Administration Guidelines (CAG) for special 
precautions, suggestions for patient monitoring, and hydration on the COG 
website at: 
https://www.cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
 
Dinutuximab: IV over 10 hours* daily 
Days: 2-5 
Dose: 17.5 mg/m2/dose 
 
Note: Due to the increased risk of capillary leak and respiratory compromise with 
dinutuximab administration, patients should not have dyspnea at rest or an oxygen 
requirement when starting the first dose of dinutuximab. Before starting 
dinutuximab, please obtain a copy of management recommendations for 
anaphylaxis and hypotension available in Appendix XI. It is recommended that 
these be available on the inpatient unit to facilitate treatment decisions should these 
symptoms occur. 
 
Refer to Section 4.5.3 for premedication and supportive care for the prevention of 
anticipated toxicities associated with dinutuximab, and for monitoring during the 
dinutuximab infusion. Additional information can be found in Appendix XI.  
 
Prior to dinutuximab administration (morning start recommended), administer IV 
bolus of normal saline (10-20 mL/kg) over 60-90 minutes. Bolus should be given 
concurrently with irinotecan infusion. On Day 2-5, start dinutuximab immediately 
following the completion of normal saline bolus and irinotecan infusion. 
Dinutuximab dose should start at 0.88 mg/m2/hour x 0.5 hour, then gradually 
increase to 1.75 mg/m2/hour for the remainder of the dose, if tolerated. 
 
*The infusion duration may be extended up to 20 hours for anticipated toxicities 
(hypotension, tachypnea, etc.), not responding to other supportive measures, and 
the duration used should be recorded. In the setting of dose reductions described 
in Section 5.0, the infusion time must be no longer than 20 hours from 
initiation of dinutuximab, even if the full dose of dinutuximab antibody has 
not been delivered in that timeframe. Antibody administration should not be 
given beyond the specified schedule regardless of whether doses were 
modified or held per guidelines in Section 5.0. The total dose given in 20 hours 
should be recorded. 
 
Sargramostim: Subcutaneous injection (preferred) or IV over 2 hours daily 
Days: 6 through 12 
Dose: 250 micrograms/m2/dose  
 
Start sargramostim on Day 6 any time after the completion of Day 5 dinutuximab.  
 
The standard route of administration is subcutaneous; in extenuating 
circumstances, IV administration over 2 hours is permitted. The reason for IV 
administration of this agent must be documented. 
 
Sargramostim dose will be held if the total white cell count is > 50,000/L. This 
is not a toxicity of sargramostim but rather a possible outcome related to its use. 
The sargramostim will be held until the total white cell count is less than 20,000/L 

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Cycles 2-5 
Cycles 2-5 
and then sargramostim will be resumed at 50% dose for the remainder of that cycle. 
Full dose sargramostim will be used for subsequent sargramostim cycles.  
 
ISOtretinoin: PO BID  
Days: 8-21 See additional starting criteria for ISOT in Section 4.5.2. 
Dose: For BSA ≥ 0.6 m2, the dose of ISOtretinoin is 80 mg/m2/dose BID, rounded 
to nearest 10 mg to accommodate capsule strength.  
 
For BSA < 0.6 m2, please see table below. The dose of ISOtretinoin in the table is 
expressed as final dose in mg to be administered.  
 
NOTE: dose BID. For example, if BSA ≥ 0.6 m2, administer 80 mg/m2/dose 
BID. The total daily dose is 160 mg/m2/day.  
 
ISOtretinoin Dosing 
If BSA < 0.6 m2 
BSA (m2) 
Dose  
0.25-0.29 
10 mg BID 
0.3-0.39 
20 mg BID 
0.4-0.49 
30 mg BID 
0.5-0.59 
40 mg BID 
 
Note: Capsules can be cut and the contents squeezed into a high fat food such as 
ice cream or peanut butter immediately prior to administration. Capsules can be 
chewed (best absorbed if chewed with high fat food) or the child taught to swallow 
entire capsules, which is feasible and to be encouraged. Under no circumstances 
should ISOtretinoin be removed from the capsules for more than 1 hour prior to 
administering to the patient (see hyperlink to the drug monograph provided in 
Section 6.0). Administration via nasogastric tube or orally via syringe is 
discouraged. 
 
Missed doses of isotretinoin should NOT be made up during the one week break 
between the scheduled end of isotretinoin therapy and the start of chemotherapy in 
the subsequent cycle to avoid delays in therapy. A duration of one week  between 
the scheduled end of isotretinoin (day 21) and the start of chemotherapy in the 
subsequent cycle should be maintained (e.g., last dose of isotretinoin is on day 21 
regardless of start date or missed doses and the subsequent cycle starts on day 29 
if all other criteria are met).  
 
Note: Patients who discontinue ISOtretinoin prior to Cycle 6 must complete full 
disease evaluations and end of protocol therapy requirements (Section 7.1) within 
two weeks of the end of Cycle 5. 
 
See Section 5.0 for Dose Modifications based on Toxicities. 
 
 

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Cycle 6 
Cycle 6 
4.6 
Cycle 6 
 
4.6.1 
Criteria to Start ISOtretinoin – Cycle 6 
• 
ALT < 10 x ULN for age. For the purposes of this study, ULN for ALT is 
45 U/L. 
• 
Serum triglycerides < 500 mg/dL. 
• 
A serum creatinine based on age/gender a described in Section 3.2.6.2. 
 
Note: Observations may be obtained within 4 days prior to start of 
ISOtretinoin (i.e., Days 5-8 of protocol therapy). 
 
As per Section 5.2.8 Management of Concurrent Transplant Associated-
Thrombotic Microangiopathy (TA-TMA), ISOtretinoin may be dose-reduced or 
omitted per institutional practice in patients with TA-TMA. 
 
 
 

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Cycle 6 
Cycle 6 
4.6.2 
Therapy Delivery Map – Cycle 6  
 
Cycle 6 lasts 4 weeks (28 days) in length. 
_____________________ 
Patient COG ID number 
_____________ 
DOB 
 
Start Cycle 6 once criteria in Section 4.6.1 have been met. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
ISOtretinoin 
(ISOT) 
PO 
BSA ≥ 0.6 m2: 80 mg/m2/dose BID  
BSA < 0.6 m2: See Dosing Table in 4.6.4 
8 - 21 
BID dosing. 
See additional starting criteria for 
ISOT in Section 4.6.4. 
Round doses to nearest 10 mg to 
accommodate capsule strength. 
 
 
 
 
 
 
Ht _________cm  
Wt _________kg  
BSA _________m2 
 
 
Date 
Due 
Date 
Given 
Day 
ISOT 
_____ mg  _____ mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered 
below 
 
 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
_____ mg  _____ mg 
a – h  
 
 
9 
_____ mg  _____ mg 
 
 
 
10 
_____ mg  _____ mg 
 
 
 
11 
_____ mg  _____ mg 
 
 
 
12 
_____ mg  _____ mg 
 
 
 
13 
_____ mg  _____ mg 
 
 
 
14 
_____ mg  _____ mg 
 
 
 
15 
_____ mg  _____ mg 
 
 
 
16 
_____ mg  _____ mg 
 
 
 
17 
_____ mg  _____ mg 
 
 
 
18 
_____ mg  _____ mg 
 
 
 
19 
_____ mg  _____ mg 
 
 
 
20 
_____ mg  _____ mg 
 
 
 
21 
_____ mg  _____ mg 
 
 
 
 
 
 
 
 
29 
Upon completion of Cycle 6, protocol therapy is complete. For 
required observations to be obtained within 2 weeks of end of 
therapy, see Section 7.1. 
h 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care 
Guidelines. 
 
 
Page 1 of 2 

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Cycle 6 
Cycle 6 
4.6.3 
Required Observations – Cycle 6 
 
a. 
History, physical exam with vital signs 
b. Height, weight, BSA 
c. 
CBC with differential and platelets (patients who experience Grade 4 neutropenia 
or thrombocytopenia should have CBCs checked at least twice per week until 
recovery to Grade 3) 
d. Electrolytes, BUN, creatinine, calcium, magnesium, phosphorus 
e. 
ALT, AST, total bilirubin, albumin 
f. 
Triglycerides 
g. Pregnancy test (obtain for females of childbearing potential) 
h. Correlative studies sample (see Appendix X) 
 
Day 8 observations may be obtained within 4 days prior to start of ISOtretinoin (i.e., 
Days 5-8 of protocol therapy). 
 
This listing only includes evaluations necessary to answer the study aims. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL 
CARE. 
 
Comments 
 
 
 
 
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Cycle 6 
Cycle 6 
4.6.4 
Treatment Details – Cycle 6 
 
ISOtretinoin: PO BID 
Days: 8-21 
Dose: For BSA ≥ 0.6 m2, the dose of ISOtretinoin is 80 mg/m2/dose BID, rounded 
to nearest 10 mg to accommodate capsule strength.  
 
For BSA < 0.6 m2, please see table below. The dose of ISOtretinoin in the table is 
expressed as final dose in mg to be administered.  
 
NOTE: dose BID. For example, if BSA ≥ 0.6 m2, administer 80 mg/m2/dose 
BID. The total daily dose is 160 mg/m2/day.  
 
ISOtretinoin Dosing 
If BSA < 0.6 m2 
BSA (m2) 
Dose  
0.25-0.29 
10 mg BID 
0.3-0.39 
20 mg BID 
0.4-0.49 
30 mg BID 
0.5-0.59 
40 mg BID 
 
Note: Capsules can be cut and the contents squeezed into a high fat food such as 
ice cream or peanut butter immediately prior to administration. Capsules can be 
chewed (best absorbed if chewed with high fat food) or the child taught to swallow 
entire capsules, which is feasible and to be encouraged. Under no circumstances 
should ISOtretinoin be removed from the capsules for more than 1 hour prior to 
administering to the patient (see hyperlink to the drug monograph provided in 
Section 6.0). Administration via nasogastric tube or orally via syringe is not 
encouraged. 
 
See Section 7.1 for end of therapy evaluations to be conducted within two weeks 
of completion of Cycle 6. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
 
 

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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, in general all protocol 
therapy should be discontinued and the patient would be taken off protocol therapy. 
However, if a patient requires permanent discontinuation of isotretinoin, the patient may 
continue on protocol therapy and receive the other therapy components (e.g., irinotecan, 
temozolomide, dinutuximab, GM-CSF).  
 
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 
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 IX). If patient experiences neutropenia that 
causes a delay of ≥ 14 days between treatment cycles despite this dose reduction, 
protocol therapy must be discontinued and patient must be removed from protocol 
therapy. 
 
5.1.2 
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 IX). If patient experiences thrombocytopenia that causes 
a delay of ≥ 14 days between treatment cycles despite this dose reduction, protocol 
therapy must 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 4.5.1 
or Section 4.6.1) within 28 days after the planned subsequent cycle start date (i.e. 
there is a ≥ 4 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. Section 4.5.1 and Section 4.6.1 
describe criteria to be met prior to starting subsequent cycles. 
 
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 with no 
evidence of infectious etiology and despite maximal use of anti-diarrheal 
medications (Appendix V) and appropriate use of prophylactic antibiotics 

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(Section 4.2.1), the dose of irinotecan should be reduced by 25% for 
subsequent cycles (i.e., irinotecan dose 37.5 mg/m2/dose for patients with BSA 
> 0.6 m2). 
• 
If Grade 4 therapy-associated diarrhea recurs without an infectious etiology 
despite reducing the dose of irinotecan by 25%, the dinutuximab dose should 
also be decreased by 25% for subsequent cycles (i.e. dinutuximab dose 
13 mg/m2/day). 
• 
If Grade 4 diarrhea recurs despite maximal use of anti-diarrheals, prophylactic 
antibiotics, and these dose reductions, the patient must 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 of therapy.  
• 
If severe (Grade 4 or Grade 3 > 7 days) regimen-related nausea and vomiting 
recurs despite optimized anti-emetic usage, doses of irinotecan and 
temozolomide should both be reduced by 25% for subsequent cycles (i.e. 
irinotecan dose 37.5 mg/m2/dose; for temozolomide see dose reduction 
nomogram in Appendix IX). 
• 
If severe regimen-related nausea and vomiting recurs despite the dose 
reduction, the patient must come off protocol therapy. 
 
5.2.3 
Dose Modifications for Dehydration 
• 
If dehydration is related to diarrhea or nausea/vomiting, the guidance in 
Section 5.2.1 or Section 5.2.2 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 both be reduced by 25% for subsequent cycles (i.e. 
irinotecan dose is 37.5 mg/m2 for patients with BSA > 0.6 m2; for 
temozolomide see dose reduction nomogram in Appendix IX).  
• 
If ≥ Grade 3 regimen-related dehydration recurs and persists for > 3 days 
despite the dose reduction, the patient must 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, the dose of dinutuximab should be reduced by 25% for subsequent 
cycles (i.e. dinutuximab dose 13 mg/m2/day). 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 in dinutuximab, the dose of temozolomide should be 
reduced by 25% for subsequent cycles (i.e. for temozolomide see dose 
reduction nomogram in Appendix IX). If the dose limiting elevations of the 
same liver enzyme(s) recur despite the temozolomide dose reduction, the 
patient must 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 dinutuximab for all subsequent 

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cycles (i.e. dinutuximab dose 13 mg/m2/day). 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. 
• 
For hepatic function parameters to begin isotretinoin during each cycle, please 
refer to treatment guidelines (Cycle 1 see Section 4.4.2; Cycles 2-5 see Section 
4.5.2; Cycle 6 see Section 4.6.1). Refer to Section 5.2.7 for isotretinoin-
specific dose modifications if hepatic function abnormalities are attributed to 
isotretinoin. 
 
5.2.5 
Dinutuximab 
Specific 
Dose 
Modifications 
and 
Toxicity 
Management 
Recommendations 
 
5.2.5.1 
Treatment of dinutuximab-induced severe hypotension (without 
evidence of allergic reaction) 
a. If hypotension is severe and accompanied by poor perfusion, end 
organ dysfunction, or acidemia – Pediatric Advanced Life Support 
(PALS) guidelines should be followed and dinutuximab infusion 
should be discontinued. 
 
b. Treatment of moderate hypotension (without poor perfusion, end 
organ dysfunction or acidemia):   
 
i. 
Immediately hold dinutuximab 
ii. 
Give normal saline bolus (20 mL/kg as rapidly as possible) 
iii. 
Stop or adjust doses of narcotics and sedating H1 blockers 
iv. 
Consider use of Trendelenberg position 
 
If hypotension persists after the above measures have been taken: 
v. 
Reassess perfusion and end organ function 
vi. 
Follow PALS algorithm if indicated 
vii. 
Repeat NS bolus OR 
viii. 
Consider use of albumin if albumin < 3 gm/dL 
ix. 
Consider use of PRBCs if Hb < 8 gm/dL 
x. 
Consider use of platelets if count <50,000/µL 
xi. 
Consider transfer to the intensive care setting  
 
If hypotension persists following 2 volume boluses, give an 
additional bolus and prepare to administer pressors: epinephrine or 
norepinephrine is preferred over dopamine, if possible 
 
Note: Moderate Hypotension is defined as: 
i. 
Symptomatic decreases in blood pressure (BP) and/or 
ii. 
Systolic BP < 5th percentile based on age and height and 
baseline BPs OR 
iii. 
Systolic or diastolic BP decreased by > 20% below baseline 
 
c. Resumption of dinutuximab  
i. 
For patients whose hypotension resolves promptly and 
completely with limited volume resuscitation (≤ 40 mL/kg) 
and without requirement for pressor support, dinutuximab 
may be restarted at 50% of the previous infusion rate. 

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Restart on the same day within 20 hours of the start of the 
day’s infusion, if possible. If blood pressures are stable for 
2 hours, the infusion may be given at full rate for the 
remainder of that day and subsequent days. If the patient 
again experiences hypotension requiring multiple volume 
boluses (e.g., > 40 mL/kg) when dinutuximab is given at 
full rate, but the patient tolerates the 50% infusion rate, then 
the remaining dinutuximab dose for that day and subsequent 
days should be given at 50% rate of the initial infusion rate. 
Do not continue an infusion for >20 hours. If the patient’s 
hypotension has resolved, a newly formulated dose should 
be started on the calendar day following the day on which 
the patient experienced the hypotensive reaction, with the 
dose given at 50% of the initial infusion rate. 
• 
If blood pressures are stable for 2 hours after 
resumption of 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 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, then the 
remaining dinutuximab dose for that day and doses on 
subsequent days should be given at 50% of the initial 
infusion rate. 
ii. 
For patients who require multiple volume boluses for 
hemodynamic 
stabilization, 
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 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 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 

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remaining days’ doses of dinutuximab should be given 
at the 50% rate of infusion. 
iii. 
For patients who require pressors for treatment of 
hypotension, if blood pressure is stable off pressors for at 
least 6 hours, administration of dinutuximab may be 
resumed at 50% of the initial infusion rate on the day 
following the hypotensive episode. Care should be taken to 
ensure that the patient is volume replete. 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 dinutuximab is resumed must discontinue protocol 
therapy.  
 
5.2.5.2 
Treatment of allergic reactions/infusion reactions  
a. Mild allergic reactions/infusion reactions to dinutuximab infusion 
i. 
A mild allergic reaction is limited to rash, flushing, 
urticaria, mild dyspnea – Grade 1 or 2 
ii. 
The following recommendations do NOT apply to Grade 3 
or 4 allergic reactions, including anaphylaxis 
iii. 
Management 
o Decrease rate of 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 dinutuximab has been administered or not); 
document total amount of drug given in the 20 hour 
time period. 
 
b. Moderate to severe allergic reactions/infusion reactions to 
dinutuximab infusion 
i. 
Moderate to severe reactions include any of the following: 
symptomatic 
bronchospasm, 
allergy-related 
edema/angioedema, hypotension, or anaphylaxis – Grade 3 
or 4 
ii. 
The following recommendations do NOT apply to Grade 1 
or 2 allergic reactions 
iii. 
Management 
o Immediately hold dinutuximab  
o Assess airway, breathing and circulation 
o Follow institutional guidelines for rapid response team 
notification if clinically indicated 
o For airway concerns 

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▪ 
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 
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 
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, 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 
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 must 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 5.2.5.1 should be 
followed. 
 
5.2.5.3 
Management of capillary leak syndrome (≥ Grade 3) 
• 
Hold dinutuximab infusion 
• 
Provide oxygen, fluids as needed 
• 
Diuretics should be used with caution and hypotension avoided 
• 
See Section 5.2.5.1 for management of hypotension, anemia and 
hypoalbuminemia. 

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• 
Do NOT resume dinutuximab therapy if symptoms of severe 
capillary leak syndrome persist on the same day or subsequent days 
of a given cycle. Only resume dinutuximab therapy when the 
capillary leak syndrome resolves or requires less significant 
intervention (Grade 2 or less). 
• 
If capillary leak resolves, may resume 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 must 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 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 dinutuximab at 50% 
rate. If renal function normalizes by the following day, 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 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 dinutuximab 
is permitted. 
 
5.2.5.5 
Management of hyponatremia (≥ Grade 3; Na < 130 mEq/L and 
symptomatic or 120-124 mEq/L regardless of symptoms) 
• 
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 dinutuximab for the remainder of the cycle. Sodium 
should be monitored closely during the next cycle of therapy. If 
hyponatremia improves to Grade 2 or better, or baseline, empiric 
dose reduction is not required at the start of the next cycle of therapy, 
though dinutuximab would again be discontinued if Grade 4 
hyponatremia were to persist despite optimal fluid management. In 
such cases, patient must discontinue protocol therapy. 
 

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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 dinutuximab therapy should be given to patients who 
experience treatment related Grade 3 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 Grade 3 pain requiring 
intravenous narcotics for ≥ 48 hours following completion of 
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 
dinutuximab therapy) recurs during a subsequent cycle despite this 
intervention, the patient must discontinue protocol therapy. 
 
5.2.5.8 
Management of visual changes 
• 
Dinutuximab may cause impaired accommodation and/or dilated 
pupils with sluggish light reflex with or without photophobia. No 
dose modifications, dose reductions, or changes in infusion rate 
should be made unless there is associated vision loss. If this occurs 
in conjunction with Grade 3 decrease in vision, dinutuximab must 
be discontinued. If visual loss improves to Grade 1 or better before 
the next immunotherapy course is due, the patient should receive 
dinutuximab at a dose that is 50% reduced compared to the prior 
dose. Full dose sargramostim (GM-CSF) should be given. If the 
lower dose of dinutuximab is tolerated without worsening of ocular 
toxicity, full dose dinutuximab should be given in subsequent 
courses. If visual toxicity worsens, the patient must discontinue 
protocol therapy. 
• 
Dose reductions for dilated pupils or changes in accommodation 
without vision loss 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. 
• 
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 must discontinue protocol 
therapy. 
• 
For Grade 2 serum sickness, antihistamines should be prescribed. 
 

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5.2.5.10 Management of neurotoxicity 
• 
Patients who develop Grade 4 neurotoxicity should discontinue 
protocol therapy. 
• 
Dinutuximab must 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 dinutuximab (i.e. dinutuximab dose 8.75 mg/m2/day). If 
symptoms do not completely resolve or recur with dinutuximab then 
the patient must discontinue protocol therapy. 
 
5.2.6 
Management of Sargramostim Related Toxicities 
• 
Hold sargramostim 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 sargramostim are common, and sargramostim 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 sargramostim for the current cycle and discontinue 
sargramostim 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 sargramostim in a particular cycle. This 
syndrome generally resolves with symptomatic treatment and usually does not 
recur with subsequent doses of sargramostim in the same cycle of treatment. 
For safety purposes in this study, if such a “first dose reaction” occurs, the 
sargramostim dose will be reduced to 50% for the next dose (i.e. sargramostim 
dose 125 micrograms/m2/dose). If a similar reaction occurs at the 50% dose, 
the sargramostim 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 sargramostim will 
be discontinued for subsequent cycles of therapy. 
 
5.2.7 
Isotretinoin Specific Dose Modifications 
If criteria to begin a 14-day course of isotretinoin are not met by the date the 
therapy is due to begin, delay therapy for one week. If criteria are still not met, 
hold therapy until criteria are met. If an observed toxicity is possibly, probably or 
definitely due to isotretinoin, reduce the isotretinoin dose to 125 mg/m2/day 
divided BID for patients with BSA > 0.6 m2 (for patients < 0.6 m2 BSA see 
suggested Dose Reduction 1 in the table below). An additional dose reduction to 
100 mg/m²/day divided BID for patients with BSA > 0.6 m2 (for patients < 0.6 m2 
BSA see suggested Dose Reduction 2 in the table below) should occur if criteria 
are still not met one week after the due date for subsequent cycles and the toxicity 
is possibly, probably or definitely due to isotretinoin. 
 

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Note: If there is a delay in beginning isotretinoin, patients need to maintain at least 
one week off isotretinoin before starting the next cycle of protocol therapy). 
Missed doses of isotretinoin should NOT be made up during the one week break 
between the scheduled end of isotretinoin therapy and the start of chemotherapy in 
the subsequent cycle to avoid delays in therapy. 
 
SUGGESTED ISOTRETINOIN DOSE REDUCTION 
BSA (m2) 
Dose Reduction 1 
Dose Reduction 2 
0.25-0.29 
10 mg PO BID x 4 days/wk and  
10 mg PO once daily x 3 days/wk 
10 mg PO daily x 6 days/wk and 
10 mg PO BID x 1 day/wk 
0.3-0.39 
20 mg PO BID x 4 days/wk and 
10 mg PO BID x 3 days/wk 
10 mg PO BID x 6 days/wk and 
20 mg PO BID x 1 day/wk 
0.4-0.49 
20 mg PO BID x 5 days/wk and 
30 mg PO BID x 2 days/wk 
20 mg PO BID  x 5 days/wk, 10 
mg PO BID x 2 days/wk 
0.5-0.59 
30 mg PO BID 
20 mg PO BID 
 
Decrease isotretinoin dose to 125 mg/m2/day (see suggested Dose Reduction 1 in 
the table above for patients with BSA < 0.6 m2 or reduce dose by ~25%) for 
subsequent cycles for the occurrence of any Grade 3 or 4 toxicities possibly, 
probably, or definitely attributable to isotretinoin EXCLUDING:  
• 
Grade 3 or 4 hematologic toxicities 
• 
Grade 3 hepatic toxicity 
• 
Grade 3 nausea and vomiting 
• 
Grade 3 fever 
 
If the same Grade 3 or 4 toxicity recurs at 125 mg/m2/day, decrease dose to 100 
mg/m²/day (see suggested Dose Reduction 2 in the table above for patients with 
BSA < 0.6 m2 or reduce dose by ~25%). If the same toxicity recurs at 100 
mg/m²/day (Dose Reduction 2), discontinue isotretinoin. Patients can continue to 
receive protocol therapy with irinotecan, temozolomide, dinutuximab, and GM-
CSF, and isotretinoin will be omitted from the remaining cycles of protocol 
therapy. 
 
 
 
If serum creatinine at the time of the planned start of isotretinoin during Cycles 2-6 
is > 2x baseline value documented at the start of Post-Consolidation therapy, a 
creatinine clearance (or nuclear medicine GFR) should be done prior to starting 
isotretinoin. If the creatinine clearance and/or GFR are < 50 mL/min/1.73 m², 
decrease the isotretinoin dose by 50%, and monitor serum creatinine twice per 
week. If the patient develops worsening hematuria, and/or proteinuria, 
hypertension, and/or a further increase in creatinine, hold isotretinoin until these 
parameters return to baseline levels. 
 
If the patient develops > Grade 1 hematuria, > Grade 1 proteinuria, and/or > Grade 
1 hypertension during any cycle of therapy, hold isotretinoin until these symptoms 
resolve or return to baseline. Please refer to Section 5.2.8 for isotretinoin 
administration in the setting of TA-TMA. 
 
For localized cheilitis, topical agents (e.g., Vitamin E) may be applied to lips for 
subsequent cycles. If this does not control symptoms sufficiently to allow oral 
intake, decrease the isotretinoin dose to 125 mg/m²/day for patients with BSA 

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> 0.6 m2 (for patients < 0.6 m2 BSA see suggested Dose Reduction 1 in the table 
above or reduce dose by ~25%). 
 
If fasting serum triglycerides are > 500 mg/dL when isotretinoin is due to begin, 
hold isotretinoin and repeat fasting triglyceride level. If triglycerides remain 
> 500 mg/dL, start medical therapy for serum triglyceride reduction and begin 
isotretinoin (full dose) when triglycerides are ≤ 500 mg/dL. If triglycerides are still 
> 500 mg/dL by the time the next cycle of isotretinoin is due, then reduce dose to 
125 mg/m2/day for patients with BSA > 0.6 m2 (for patients < 0.6 m2 BSA see 
suggested Dose Reduction 1 in the table above or reduce dose by ~25%) for 
subsequent cycles. 
 
Isotretinoin has been associated with pseudotumor cerebri. This drug should be 
discontinued in patients who are found to have papilledema. 
 
5.2.8 
Management of Concurrent Transplant Associated-Thrombotic Microangiopathy 
(TA-TMA) 
Isotretinoin may be dose-reduced or omitted per institutional practice in patients 
with TA-TMA. 
 
5.2.9 
Other Non-Hematologic Toxicities 
The above sections cover dose modifications for most anticipated adverse events 
with this regimen.  For Grade 3 or higher non-hematologic toxicities not specified 
above or for non-hematologic toxicities not specified above that prolong the start 
of subsequent cycles by > 14 days, the doses of both irinotecan and temozolomide 
should be reduced by 25% in the subsequent cycle.  If Grade 3 or higher non-
hematologic toxicity recurs or cycles are again delayed by > 14 days, the patient 
should be removed from protocol therapy.   
 
5.2.10 Prolonged Non-Hematologic Toxicity 
Patients who do not meet criteria to start the next treatment cycle (see Section 4.5.1 
or Section 4.6.1) within 28 days after the planned subsequent cycle start date (i.e. 
there is a ≥ 4 week delay in start of next cycle) due to any ongoing non-
hematologic toxicity must be removed from protocol therapy. 
 
5.3 
Inability to Tolerate Enteral Temozolomide 
For patients unable to tolerate PO temozolomide (i.e., due to nausea, vomiting), IV 
temozolomide may be administered. 
 
Suggested administration schedule for chemotherapy (Days 1-5; IV temozolomide 
and irinotecan) and dinutuximab (Days 2-5): 
• 
At hour 0: patient should receive IV temozolomide over 90 minutes. 
• 
At hour 1.5 patient should start IV irinotecan over 90 minutes. On days patient is 
receiving dinutuximab infusion (Days 2-5 of each cycle), start IVF bolus of normal 
saline saline (10-20 mL/kg) over 60-90 minutes. 
• 
At hour 3: on days patient is receiving dinutuximab infusion (Days 2-5 of each 
cycle), start dinutuximab infusion. 
• 
Note: Irinotecan may be administered immediately after the completion of IV 
temozolomide. 
 
 

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Temozolomide: IV over 90 minutes daily  
Days: 1-5 
Dose for IV infusion: IV temozolomide may be substituted at the same dose for patients 
unable to tolerate enteral dosage forms. The line must be flushed before and after 
administration. 
 
Sequencing: IV temozolomide may be administered immediately prior to irinotecan. 
 
Special Precautions: IV temozolomide contains polysorbate 80, which may increase the 
risk of infusion or allergic reactions. If reaction occurs, premedication with 
diphenhydramine 1 mg/kg (maximum dose 50 mg) and hydrocortisone 2 mg/kg (maximum 
dose 200 mg) may be considered. Re-challenging with enteral temozolomide is also an 
acceptable alternative as it does not contain polysorbate 80. May be administered through 
the same IV line as NS. Do not administer other medications through the same IV line. 
 
6.0 
DRUG INFORMATION 
 
See the consent document for toxicities. All other information is available on the COG website in the 
Commercial Agent Monographs (https://www.cogmembers.org/_files/disc/pharmacy/CommercialAgents
Monographs.pdf). 
 
 
 

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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 (except where 
explicitly prohibited within the protocol) 
 
7.1 
End of Therapy & Follow-up 
 
1Obtain within 2 weeks of completing Cycle 6, or Cycle 5 for patients that discontinue isotretinoin. 
2FDG-PET only in patients with MIBG non-avid disease at diagnosis who are followed by FDG-PET in place 
of 123I-MIBG scan. 
 
 
STUDIES TO 
BE 
OBTAINED 
End of 
Therapy1 
Time from End of Therapy (Months) 
At 
Relapse 
 
3  
6 
9 
12 
15 
18 
24 
30 
36 
42 
48 
54 
60 
 
History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
with VS 
(including BP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ht, Wt, BSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC, 
differential, 
platelets 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Electrolytes 
including Ca++, 
PO4, Mg++ 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Creatinine, 
ALT, bilirubin 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
ECHO 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Cross sectional 
imaging of 
primary tumor 
site (MRI or 
CT)  
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
X 
123I-MIBG 
scan2  
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
X 
FDG-PET 
scan2 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
X 
Bilateral bone 
marrow 
aspirates and 
biopsies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biologic 
correlative 
studies (see 
Section 14.0 & 
Appendix X) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Note: If enrolled in APEC14B1/ANBL00B1 and consented to optional cell banking, 
submit PB and BM specimens if relapse occurs. 
 
 
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. 
 
7.2 
Research Studies for which Patient Participation is Optional 
See Section 14.0 for Special Studies requirements. Required studies are detailed in Section 
14.1 and optional studies are detailed in Section 14.2. 
 
A summary of specimens to be collected is provided in Appendix X. Every effort should 
be made to obtain samples from all time points, including the pre-therapy time point. 
However, if the pre-ANBL19P1 therapy sample cannot be obtained, subsequent samples 
should still be collected as specified. 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 
Criteria for Removal from Protocol Therapy 
a) Progressive disease. 
b) Refusal of further protocol therapy by patient/parent/guardian. 
c) Completion of planned therapy. 
d) Physician determines it is in patient’s best interest. 
e) Unacceptable toxicity due to protocol therapy or delays in therapy that meet the 
criteria in Section 5.0. 
f) Development of a second malignancy. 
g) Repeat eligibility studies (if required) prior to the initiation of protocol therapy are 
outside the parameters required for eligibility (see Section 3.2). 
h) Pregnancy 
 
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 patient is taken off study. 
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG anti-cancer therapeutic study (e.g., at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) Fifth anniversary of the date the patient was enrolled on this study. 
f) Patient never received protocol therapy. 
 
 
 

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9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Sample Size and Study Duration 
Forty eligible and evaluable patients will be necessary to analyze the primary objective, 
assessing the feasibility of dinutuximab, GM-CSF, and isotretinoin administration in 
combination with irinotecan and temozolomide during Post-Consolidation for patients with 
prior tandem ASCT. Enrollment of up to 45 patients will be required in order to generate 
the 40 eligible and evaluable patients that will be analyzed for the feasibility primary 
objective, accounting for potential ineligible patients. With 40 eligible and evaluable 
patients with prior tandem ASCT, the estimate of feasibility will have a standard error of 
at most 0.0791. 
 
Approximately 223 patients/year enrolled on ANBL00B1 have high-risk neuroblastoma. 
Estimated accrual on high-risk neuroblastoma frontline therapeutic trials ANBL1531 and 
ANBL17P1 is 163 patients/year and 29 patients/year, respectively. Therefore, 
approximately 31 patients/year with high-risk neuroblastoma will not enroll on a frontline 
therapeutic trial and will be potentially eligible for the proposed study (Figure 1). Of the 
patients enrolled on ANBL1531 (163 patients/year), 124 patients/year are expected to be 
eligible for randomization and, if they proceed with randomization, will not be eligible for 
this study. Patients assigned to a treatment arm and not eligible for randomization (i.e., 
patients with MIBG non-avid disease [Arm D] or tumors demonstrating an ALK aberration 
[Arm E]) will also not be eligible for our pilot study. We predict that 15% of those eligible 
for randomization on ANBL1531 will refuse randomization and will be eligible for the 
proposed study (19 patients/year). Therefore, we anticipate that approximately 50 
patients/year will be potentially eligible to enroll on ANBL19P1. If we assume 50-60% of 
the potentially eligible patients choose to enroll on this study and meet eligibility criteria, 
our expected accrual is 25-30 patients/year. 
 
We estimate an accrual duration of approximately 1.5-2 years and an additional 6 months 
for completion of therapy and feasibility evaluation, for a total study duration of 
approximately 2.5 years. 
 

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Figure 1. Accrual Diagram 
 
9.2 
Study Design 
This trial is a prospective, single arm pilot study to assess the feasibility of administering 
dinutuximab in combination with irinotecan, temozolomide, and GM-CSF in the frontline, 
Post-Consolidation setting in patients with high-risk neuroblastoma who have received 
prior tandem transplant. All patients will receive the same treatment on this trial. A 
stopping rule for feasibility will be used to monitor patients for early indication of inability 
to successfully administer all intended cycles of therapy. In addition, patients will be 
monitored for the occurrence of excessive toxicities. 
 
9.3 
Methods of Analysis 
 
9.3.1 
Primary Endpoint 
The primary objective of the study is to determine the feasibility of administering 
5 cycles of dinutuximab + GM-CSF and isotretinoin in combination with 
chemotherapy (irinotecan and temozolomide) in patients with high-risk 
neuroblastoma in the front-line setting following Consolidation with tandem 
transplant. In the absence of treatment delays, each cycle of dinutuximab-
containing therapy will be completed in approximately 4 weeks, and there are 5 
cycles of dinutuximab/chemotherapy-containing therapy included on this trial. 
Patients with disease progression detected at any time during protocol therapy or 
who meet pre-specified toxicity criteria will discontinue protocol-specified 
treatment and count against the feasibility of protocol therapy. The primary 
endpoint is the proportion of patients who complete 5 cycles of dinutuximab + 
chemotherapy without progressive disease within 30 weeks from the date of first 
treatment among patients who start protocol therapy. 
 
Of the 108 patients randomized to tandem transplant on ANBL0532 that enrolled 
on ANBL0032 after randomization was halted, 87 (80.6%) completed at least 5 
cycles of dinutuximab without progressive disease within 30 weeks. A feasibility 
therapy completion rate of 75% will be targeted on this study. With a sample size 
of 40 eligible and evaluable patients, at the 5% significance level, there will be 

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80% and 90% power, respectively, to detect a reduction in the therapy completion 
rate from target of 75% to 55.0% and 51.5%. This therapy will be declared feasible 
if a 95% Wilson confidence interval (CI) placed on the percentage of patients that 
complete at least 5 cycles of dinutuximab + chemotherapy without PD within 30 
weeks contains 75% and the interim monitoring rules for feasibility and excessive 
toxicity (see Section 9.3.3) are not triggered. Using the closed-form formula for a 
95% Wilson CI and resolving, the probability of this CI covering the value 75% 
when the true feasibility therapy completion rate is 50% or 60% is 0.0769 and 
0.4402, respectively. 
 
Patients who have dose modifications but remain on therapy and are able to 
complete the 5 cycles without PD within 30 weeks will not count against 
feasibility. Patients who meet off protocol criteria due to toxicity (i.e., require 
greater than one dose modification for irinotecan or temozolomide, or meet off 
protocol criteria for dinutuximab per Section 5.0) or other criteria for removal from 
protocol therapy (see Section 8.1)  before completion of 5 cycles will count against 
feasibility. Any eligible patient with prior tandem ASCT who receives at least one 
dose of protocol therapy will be considered evaluable for the primary endpoint.  
 
Note: Discontinuation of isotretinoin will not count against the feasibility 
endpoint on this study. 
 
9.3.2 
Secondary Endpoints 
For event-free survival, time to event will be calculated from the time of start of 
protocol therapy to the occurrence of disease relapse or progression, secondary 
malignancy, or death. For overall survival, death will be the only event considered 
and time to death will be calculated from the time of start of protocol therapy. 
Patients without an event or death will be censored at the time of last follow-up. 
 
9.3.3 
Monitoring 
Any eligible patient who receives at least one dose of protocol therapy will be 
considered evaluable for the monitoring rules. The study will not be halted while 
the data are gathered for the assessment of the monitoring rules. 
 
9.3.3.1 
Feasibility 
We will monitor for early indication of inability to administer all 5 
intended cycles of dinutuximab + chemotherapy without PD within 30 
weeks. Of the 108 patients randomized to tandem transplant on 
ANBL0532 that enrolled on ANBL0032 after randomization was halted, 
89 (82.4%) completed at least 3 cycles of dinutuximab without 
progressive disease within 18 weeks. This feasibility monitoring rule 
will monitor that ≥75% of patients will complete at least 3 cycles of 
dinutuximab + chemotherapy without PD within 18 weeks among 
patients who start protocol therapy. Patients who have dose 
modifications but remain on therapy and are able to complete the cycles 
without PD within the specified time frame above will not count against 
the feasibility monitoring rule.  
 
A one-sided Pocock group-sequential boundary with a sample size of 40 
will be used to monitor the number of patients that fail to receive at least 
3 cycles of chemo-immunotherapy without progressive disease within 

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18 weeks. Interim monitoring will be done after 1/4 and 1/2 of patients 
have been evaluated for completion of at least 3 cycles of protocol 
therapy without PD (Table 3). The upper bound on the number of 
patients not receiving at least 3 cycles of protocol therapy without PD 
within 18 weeks that are needed to declare the therapy not feasible uses 
a cumulative alpha level of 0.125. The probability of declaring the 
regimen not feasible under the alternative hypothesis non-completion 
rates of 45% and 50% appears in Table 4. The average sample size when 
the non-completion rate is 25%, 45%, and 50% is 38.00, 25.32, and 
20.86, respectively. 
 
Table 3. Interim monitoring plan and number of observed patients that do not complete at least 3 
cycles of chemo-immunotherapy without PD within 18 weeks needed to declare therapy not 
feasible. 
Monitoring 
percent of total 
information 
Number of patients 
evaluated for therapy 
completion 
Monitoring 
boundary  
Number of observed non-
completions to declare 
not feasible 
25% 
10 
1.6989 (p=0.04467) 
≥ 6 (60%) 
50% 
20 
1.6276 (p=0.05180) 
≥ 9 (45%) 
 
 
Table 4. Probability of detecting regimen not feasible under various alternative hypothesis therapy 
non-completion rates. 
Monitoring 
percent of total 
information 
Number of patients 
evaluated for therapy 
completion 
Power under a true 
non-completion rate of 
45% 
Power under a true 
non-completion rate of 
50% 
25% 
10 
0.2616 
0.3770 
50% 
20 
0.5857 
0.7483 
 
9.3.3.2 
Excessive Toxicity 
Many of the toxicities that occur due to the therapy are expected. 
However, we plan to consider a subset of the toxicities unacceptable. 
Those designated as unacceptable are listed below with the associated 
CTCAE v5.0 MedDRA code in parentheses:  
 
1. Toxicity requiring the use of pressors for ≥ 24 hours, including 
Grade 4 capillary leak syndrome (10007196), Grade 4 
anaphylaxis/allergic reaction (10002218 or 10001718) or Grade 3/4 
hypotension (10021097) requiring pressors. 
 
2. Toxicity requiring ventilatory support ≥ 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 cycle of therapy (10034580). 
 

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4. Peripheral sensory neuropathy Grade 4 or Grade 3 that does not 
resolve prior to start of next cycle of therapy (10034620). 
 
5. Grade 4 Cytokine Release Syndrome/Acute Infusion Reaction 
(10052015). 
 
6. Toxic death. 
 
7. Grade 4 documented infection [(infections and infestations-other, 
specify); 10021881]. 
 
8. Grade 4 diarrhea (10012727) that persists despite supportive care as 
detailed in Section 4.2.1 and Appendix V. 
 
The unacceptable toxicities parallel those listed in ANBL1221 (#1-6) 
with the addition of documented infection (#7), as this regimen is given 
in the immediate Post-Consolidation setting, and diarrhea (#8) since 
irinotecan is included in this Post-Consolidation regimen. 
 
There may be cause to stop the trial early if the unacceptable toxicity rate 
appears too high. An unacceptable toxicity rate statistically significantly 
>10% would be considered excessive on this trial. Of the 104 patients 
treated on ANBL0931 (Cycles 1, 3, 5- dinutuximab + GM-CSF + 
isotretinoin), the cumulative unacceptable toxicity rate for Grade ≥4 
infection (n=3) and diarrhea (n=0) was 2.9%. Among patients who 
received irinotecan, temozolomide and dinutuximab on ANBL1221, one 
had an unacceptable toxicity (Grade 4 hypoxia possibly related to 
therapy).  
 
A patient will be counted as having experienced an unacceptable toxicity 
if at least one of the unacceptable toxicities listed above occurs during 
protocol therapy. Only toxicities designated as possibly, probably, or 
definitely attributed to dinutuximab, chemotherapy, or isotretinoin will 
be considered. 
 
A one-sided Pocock group-sequential boundary with a sample size of 40 
will be used to monitor the number of patients who experience at least 
one unacceptable toxicity. Interim monitoring will be done after 1/4 and 
1/2 of patients have been evaluated for the occurrence of unacceptable 
toxicity, with a final analysis at full information (Table 5). The upper 
bound on the number of unacceptable toxicity events needed to declare 
the therapy too toxic uses a cumulative alpha level of 0.155. 
 
 
 

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Table 5. Interim monitoring plan and number of observed unacceptable toxicities needed to declare 
therapy too toxic. 
Monitoring percent 
of total information 
Number of patients 
evaluated for 
toxicity 
Monitoring boundary  
Number of observed 
unacceptable toxicities 
to declare too toxic 
25% 
10 
1.5947 (p=0.05539) 
≥ 4 (40%) 
50% 
20 
1.5072 (p=0.06588) 
≥ 5 (25%) 
100% (final analysis) 
40 
1.2752 (p=0.10112) 
≥ 7 (17.5%) 
 
After the first 5 patients have completed at least one cycle of protocol 
therapy, the study committee will prepare an early safety-briefing 
document for review by the DSMC and CTEP. The document will 
include a tabulation of Grade ≥3 non-hematologic toxicities, specifically 
targeting hematologic and gastrointestinal toxicities. Time to recovery 
from the first cycle of therapy will be documented as part of this initial 
safety evaluation. During preparation of this safety-briefing document, 
enrollment on the study will continue.  
 
9.3.4 
Assessment of Study Objectives 
The primary study objective (Aim 1.1.1) related to feasibility will be assessed by 
estimation of the feasibility therapy completion rate together with a 95% Wilson 
CI. The therapy will be deemed feasible if the 95% CI placed on the percentage of 
patients that complete at least 5 cycles of dinutuximab + chemotherapy without 
PD within 30 weeks contains 75% and the interim monitoring rules for feasibility 
and excessive toxicity (Section 9.3.3) are not triggered.  
 
To address Secondary Aim 1.2.1, adverse events (Grade ≥3) experienced by 
patients evaluable for toxicity will be descriptively summarized. 
 
To assess Secondary Aim 1.2.2, EFS and OS Kaplan-Meier curves and estimates 
will be generated. 
 
Exploratory Aim 1.3.1 will be assessed by a descriptive comparison of adverse 
events (Grade ≥3) experienced by patients evaluable for toxicity according to prior 
anti-GD2 directed therapy (yes vs. no) status. 
 
To address Exploratory Aim 1.3.2, response will be assessed by the revised INRC28 
and descriptively summarized among those evaluable for response (see Section 
9.4). 
 
To address Exploratory Aim 1.3.3, immune and cytokine profiles will be described 
at baseline and the change in immune and cytokine profiles from baseline will be 
descriptively summarized. There will be a descriptive comparison of the immune 
and cytokine profiles of those receiving chemo-immunotherapy on this pilot in the 
frontline setting and those receiving chemo-immunotherapy (Arm A) in the 
relapsed/refractory setting on ANBL1821. There will also be a descriptive 
comparison of immune profiles at the start and end of Post-Consolidation therapy 
between those who receive chemo-immunotherapy on this pilot versus standard 
immunotherapy on ANBL1531 (Arm A) to assess the impact of these regimens on 
immune reconstitution. 

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9.4 
Evaluability for Response 
All eligible patients with evaluable or measurable disease at study entry and received at least 
one dose of irinotecan or temozolomide will be considered evaluable for response. 
 
9.5 
Evaluability for Toxicity 
All eligible patients treated with at least one dose of irinotecan or temozolomide will be 
considered evaluable for toxicity. 
 
9.6 
Evaluability of No Treatment 
If an eligible patient is “off protocol therapy” prior to treatment initiation, that patient 
remains eligible for the trial but will be inevaluable for feasibility and toxicity assessments. 
 
9.7 
Gender and Minority Accrual Estimates 
The gender and minority distribution of the study population is expected to be: 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian 
/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian 
or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
2 
4 
0 
0 
6 
White 
11 
15 
3 
2 
31 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
13 
20 
3 
2 
38 
 
 
 

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INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian 
/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian 
or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
0 
0 
0 
0 
0 
White 
3 
4 
0 
0 
7 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
3 
4 
0 
0 
7 
 
This distribution was derived from ANBL0532. 
 
 
10.0 
EVALUATION CRITERIA 
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 5.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP website  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Note: ‘CTCAE v5.0’ is understood to represent the most current version of CTCAE v5.0 
as referenced on the CTEP website (i.e., v5.02 and all subsequent iterations prior to version 
6.0). 
 
10.2 
Response Criteria  
This study will use the revised International Neuroblastoma Response Criteria for disease 
assessment.28 The updated response criteria incorporate current approaches to imaging of 
neuroblastoma, including functional imaging. Furthermore, a standardized approach to 
assessment of bone marrow involvement is included. The current INRC do not include 
methods of disease assessment that are less sensitive and/or specific for neuroblastoma 
(99Tc bone scan and catecholamine levels). 
 
10.2.1 Definitions 
Evaluable for response: All eligible patients with evaluable or measurable disease 
at study entry and received at least one dose of irintoecan or temozolomide will be 
considered evaluable for response. 
 
Evaluable for toxicity: All eligible patients treated with at least one dose of 
irinotecan or temozolomide will be considered evaluable for toxicity. 
 

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10.2.2 Key Sites and Terms 
 
10.2.2.1 Primary site: The primary site will be identified as a measurable lesion 
≥ 10 mm in diameter as assessed by cross sectional imaging (CT or MRI 
scan). Primary site measurements must be recorded in millimeters (or 
decimal fractions of centimeters). The longest diameter of the primary 
tumor will be recorded at baseline. Serial measurements of the primary 
tumor will include assessment of tumor size in the same orthogonal plane 
at the time of each evaluation.29 In patients with bilateral adrenal lesions, 
response will be based on the sum of the longest dimensions of both 
adrenal lesions unless biopsy proves one to be ganglioneuroma rather 
than neuroblastoma/ganglioneuroblastoma. In patients with multi-focal 
non-adrenal disease, the largest tumor will be considered the primary 
tumor. Response in additional lesions will be assessed as described 
below for metastatic lesions. 
 
Tracer avidity (123I-MIBG or FDG-PET) in the primary site will be 
recorded at baseline. The scan appropriate for serial disease assessments 
should be used at each disease re-evaluation time point (e.g., 123I-MIBG 
avid primary lesions should be followed using 123I-MIBG scans during 
therapy). 
 
10.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a metastatic lymph node must be ≥ 15 mm in short axis 
when assessed by CT or MRI scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis of a discreet lymph node will be measured and 
followed as per RECIST criteria. Patients with neuroblastoma may have 
conglomerate masses of non-discrete lymph nodes (i.e. multiple 
contiguous retroperitoneal nodes). When a short axis of a discreet node 
cannot be identified, a lymph node conglomerate can be measured using 
the longest diameter of the composite lesion. Tracer avidity of metastatic 
nodes will be recorded at baseline and during disease evaluations. 
 
For the purposes of response assessment, target lesions are disease sites 
that are measurable (non-nodal soft tissue mass ≥ 10 mm in longest 
dimension or lymph node ≥ 15 mm in short axis) and tracer avid OR are 
biopsy positive for neuroblastoma or ganglioneuroblastoma. The sum of 
diameters of target lesions is defined as the sum of the short axis of 
discrete lymph nodes (i.e., cervical, axillary nodes) added to the sum of 
the longest diameters of non-lymph node soft tissue metastases. 
 
10.2.2.3 Non-measurable disease: All other lesions (or sites of disease), 
including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis), are considered non-
measurable disease. Bone lesions, leptomeningeal disease, and ascites, 
pleural/pericardial effusions are considered non-measurable. 
 
10.2.2.4 Bone lesions: Osteomedullary disease will be assessed using 123I-MIBG 
scans or FDG-PET scans. Technitium bone scans are no longer used as 
part of the revised INRC and are not included as part of disease 

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reassessments during this trial. The extent of tracer avid disease will be 
evaluated using the Curie scoring system (see Appendix XII for 
worksheet). SPECT may be used to confirm the presence or absence of 
lesions in a given segment of the body. The absolute Curie score should 
be reported at baseline. A relative score (Curie score at the time of 
disease assessment divided by baseline Curie score) should be recorded 
at the time of each disease evaluation. 
 
10.2.2.5 Bone marrow disease: Bilateral bone marrow aspirates and trephine 
biopsies are required at disease assessment time points. The extent of 
marrow involvement in all four samples should be recorded. Use of 
immunohistochemical staining for evaluation of trephine biopsies is 
strongly encouraged. The percentage of tumor infiltration of bone 
marrow space assessed by histologic evaluation of trephine/biopsies or 
counting the number of tumor cells in aspirates by cytology or 
immunocytology (recommended if available) divided by the number of 
hematopoietic/mononuclear cells evaluated to obtain a percentage 
involvement (methodology described by Burchill et al.).30 The bone 
marrow sample with the highest percentage of tumor infiltration is used 
for response assessment. If > 0% to ≤ 5% tumor infiltration is the highest 
percentage seen among samples obtained, the result should be recorded 
as minimal marrow disease. 
 
10.2.3 Response Criteria 
 
PRIMARY (SOFT TISSUE) TUMOR RESPONSE1  
RESPONSE 
ANATOMICAL IMAGING + MIBG (FDG-PET2) IMAGING 
Complete Response (CR) 
• 
< 10 mm residual soft tissue at primary site, AND 
• 
complete resolution of MIBG or FDG-PET uptake (for MIBG 
non-avid tumors) at primary site 
Partial Response (PR) 
• 
≥ 30% decrease in longest diameter (LD) of primary site 
• 
MIBG or FDG-PET uptake at primary site stable, improved or 
resolved 
Progressive Disease (PD) 
• 
> 20% increase in longest diameter taking as reference the 
smallest sum on study (this includes the baseline sum if that is 
the smallest on study), AND  
• 
a minimum absolute increase of 5 mm in longest dimension3  
Stable Disease (SD) 
Neither sufficient shrinkage for PR nor sufficient increase for PD at the 
primary site 
1 Not for use in assessment of metastatic sites 
2 For 123I-MIBG non-avid tumors 
3 A mass that has not met PD measurement criteria but has fluctuating 123I-MIBG avidity will not be considered 
progressive disease. 
 
 

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RESPONSE AT METASTATIC SOFT TISSUE AND BONE SITES4 
RESPONSE 
ANATOMICAL IMAGING + MIBG (FDG-PET1) IMAGING 
Complete Response (CR) 
• 
Resolution of all sites of disease defined as: 
• 
Non-primary target and non-target lesions measure 
< 10 mm AND 
• 
Lymph nodes identified as target lesions decrease to a 
short axis < 15 mm, AND  
• 
MIBG uptake or FDG-PET uptake (for MIBG non-avid 
tumors) of non-primary lesions resolves completely 
Partial Response (PR) 
• 
≥ 30% decrease in sum of diameters2 of non-primary target 
lesions compared to baseline, AND all of the following: 
• 
Non-target lesions may be stable or smaller in size AND 
• 
No new lesions AND 
• 
≥ 50% reduction in MIBG absolute bone score (Relative 
MIBG bone score ≥ 0.1 to ≤ 0.5 using as reference the 
absolute score for bone lesions from time of enrollment5) 
or ≥ 50% reduction in number of FDG-PET avid bone 
lesions3,4 
Progressive Disease (PD) 
Any of the following: 
• 
Any new soft tissue lesion detected by CT or MRI that is also MIBG 
avid or FDG-PET avid; 
• 
Any new soft tissue lesion seen on anatomic imaging that is biopsied 
and confirmed to be a neuroblastoma or ganglioneuroblastoma; 
• 
Any bone site that is MIBG avid and that was not seen on the 
immediate prior scan or on the scan performed at the time of 
enrollment; 
• 
A new bone site that is FDG-PET avid (for MIBG non-avid tumors) 
AND has CT or MRI findings consistent with tumor OR has been 
confirmed histologically to be neuroblastoma or 
ganglioneuroblastoma; 
• 
> 20% increase in longest diameter taking as reference the 
smallest sum on study (this includes the baseline sum if that is 
the smallest on study), AND a minimum absolute increase of 5 
mm in sum of diameters of target soft tissue lesions; 
• 
Relative MIBG score ≥ 1.2 using as reference the lowest absolute 
score for bone lesions since enrollment.6 
Stable Disease (SD) 
Neither sufficient shrinkage for PR nor sufficient increase for PD of non-
primary lesions 
1 Used for MIBG non-avid tumors 
2 Sum of diameters is defined as the sum of the short axis of discrete lymph nodes (i.e., cervical, axillary nodes) 
added to the sum of the longest diameters of non-lymph node soft tissue metastases. Masses of conglomerate non-
discrete lymph nodes will be measured using longest diameter. 
3 For patients with soft tissue metastatic disease, resolution of MIBG and/or FDG-PET uptake at the soft tissue sites 
is not required; all size reduction criteria must be fulfilled. 
4Criteria for soft tissue metastasis not applicable if the patient has only bone metastasis; criteria for bone 
metastasis not applicable if the patient has only soft tissue metastasis.   

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5Relative Curie score when assessing patient for partial response: [Current Curie score for bone sites] / 
[Curie score for bone sites at enrollment]. 
6Relative Curie score when assessing patient for progressive disease: [Current Curie score for bone sites] 
/ [Lowest Curie score for bone sites since enrollment]. 
 
 
BONE MARROW RESPONSE 
RESPONSE 
BONE MARROW STATUS1 
Complete response (CR) 
Bone marrow with no tumor infiltration upon reassessment, independent 
of baseline tumor involvement.  
Progressive disease (PD) 
Any of the following: 
• 
Bone marrow without tumor infiltration that becomes > 5% tumor 
infiltration upon reassessment; or 
• 
Bone marrow with tumor infiltration that increases by > 2 fold and 
has > 20% tumor infiltration upon reassessment. 
Minimal disease (MD) 
Any of the following: 
• 
Bone marrow with ≤ 5% tumor infiltration and remains > 0-≤ 5% 
tumor infiltration upon reassessment; or 
• 
Bone marrow with no tumor infiltration that becomes ≤ 5% tumor 
infiltration upon reassessment; or 
• 
Bone marrow with >5% tumor infiltration that has > 0-≤ 5% tumor 
infiltration upon reassessment. 
Stable disease (SD) 
Bone marrow with tumor infiltration that remains positive with > 5% 
tumor infiltration upon reassessment but does not meet CR, MD or PD 
criteria. 
1Immunohistochemistry strongly encouraged 
 
DETERMINATION OF OVERALL RESPONSE 
RESPONSE 
CRITERIA 
Complete Response (CR) 
All components meet criteria for CR 
Partial Response (PR) 
PR in at least one component and all other components are either CR, MD 
(Bone marrow), PR (Soft tissue or Bone) or Not involved (NI); no 
component with PD.  
Minor Response (MR) 
PR or CR in at least one component but at least one other component with 
SD; no component with PD.* 
Stable Disease (SD) 
SD in one component with no better than SD or NI in any other 
component; no component with PD. 
Progressive Disease (PD) 
Any component with PD 
NI = Not involved, site not involved at study entry and remains not involved 
MD = Minimal Disease, for bone marrow assessment only 
*Patients who enroll with marrow only disease who have a marrow response of Minimal Disease will also 
be considered to have an overall response of Stable Disease.   
 
See Appendix XIII for additional information regarding overall response assessment 
 
 
 

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11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. 
 
11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics of 
the adverse event including the grade (severity); 2) the relationship to the study therapy 
(attribution); and 3) the prior experience (expectedness) of the adverse event. 
  
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. In some cases an agent obtained commercially may be used for 
indications not included in the package label. In addition, NCI may on some occasions 
distribute commercial supplies for a trial. Even in these cases, the agent is still considered 
to be a commercial agent and the procedures described below should be followed. 
 
Determine the prior experience Expected events are those that have been previously 
identified as resulting from administration of the agent. An adverse event is considered 
unexpected, for reporting purposes only, when either the type of event or the severity of 
the event is not listed in:  
 
• 
the current known toxicities for each commercial agent as provided in the Drug 
Information for Commercial Agents Used by the Children’s Oncology Group 
posted on the COG website; or 
• 
the drug package insert. 
 
11.2.1 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via 
CTEP-AERS. Three 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) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
11.2.2 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 

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11.3 
Reporting of Adverse Events for Commercial Agents – via CTEP-AERS 
Expedited AE reporting must use CTEP-AERS (Adverse Event Expedited 
Reporting System), accessed via https://ctepcore.nci.nih.gov/ctepaers 
 
Commercial reporting requirements are provided in Table B. The commercial agent(s) used 
in this study are listed in the front of this protocol immediately following the Study 
Committee roster.  
 
• 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of 
learning of the event. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
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 that can be 
attributed (possibly, probably, or definitely) to the agent and is not due to 
cancer recurrence must be reported via CTEP-AERS. 
 
11.4 
Protocol Specific Additional Instructions and Reporting Exceptions 
For all patients, the following events require CTEP-AERS reports and submission of the 
AE Case Report Form: 
• 
Toxic Death 
• 
Pulmonary Complications 
- 
Grade 4 respiratory failure requiring intubation and mechanical ventilation 
- 
Grade 3 or 4 ARDS requiring ventilatory support >24 hours 
- 
Grade 4 bronchospasm requiring ventilatory support >24 hours 
- 
Grade 4 dyspnea requiring ventilatory support >24 hours 
- 
Grade 4 hypoxia requiring ventilatory support >24 hours 

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• 
Immune 
- 
Grade 4 anaphylaxis/allergic reaction requiring pressors >24 hours or requiring 
ventilatory support >24 hours 
- 
Grade 4 Cytokine Release Syndrome/Acute Infusion Reaction 
• 
Cardiovascular 
- 
Grade 3 or 4 hypotension requiring pressors >24 hours 
- 
Grade 4 capillary leak syndrome requiring pressors >24 hours 
• 
Hepatic Complications: 
- 
Grade 3 and 4 liver failure 
- 
Grade 3 and 4 sinusoidal obstruction syndrome 
• 
Neurologic 
- 
Grade 4 peripheral motor or sensory neuropathy 
- 
Grade 3 peripheral motor or sensory neuropathy that does not resolve prior to the 
next course of therapy 
• 
Infectious 
- 
All Grade 4 documented infections (infections and infestations-other, specify) 
• 
All Grade 4 diarrhea that is persistent despite supportive care detailed in protocol 
(Section 4.2.1, Appendix V) 
 
11.5 
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. 
 
The NCI defines both routine and expedited AE reporting. Routine reporting is 
accomplished via the Adverse Event (AE) Case Report Form (CRF) within the study 
database. For this study, routine reporting will include all toxicities reported via CTEP-
AERS, Grade 3 and higher non-hematologic Adverse Events, and Grade 4 and higher 
hematologic Adverse Events.  
 
11.6 
Syndrome Reporting 
Unless otherwise specified in this protocol, syndromes should be reported as a single event 
using the CTCAE term for the composite syndrome, and not as the individual events that 
make up the syndrome. For example, Tumor Lysis Syndrome should be reported under the 
composite definition rather than reporting the component events (hyperkalemia, 
hyperphosphatemia, hypocalcemia, hyperuricemia) separately. 
 
Transplant-Associated Thrombotic Microangiopathy (TA-TMA) will be defined by (1) 
lactate dehydrogenase (LDH) elevated above the upper limit of normal for age; (2) de novo 
thrombocytopenia with a platelet count <50 × 109/L or a ≥50% decrease in the platelet 
count (from post-transplant recovery baseline, discuss with transplant physician); (3) de 
novo anemia with a hemoglobin below the lower limit of normal or anemia requiring 
transfusion support; (4) microangiopathic changes defined as the presence of schistocytes 
in the peripheral blood or histologic evidence of microangiopathy on a tissue specimen; 
and (5) absence of a coagulopathy and a negative Coombs test. All laboratory criteria must 
occur concurrently, and criteria 1 to 4 must be documented on at least 2 consecutive tests 
to be classified as positive. TA-TMA will be reported as CTCAE term “blood and 
lymphatic system disorder – other” and will be specified as TA-TMA in the free text. 
 
 

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12.0 
RECORDS AND REPORTING 
 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
12.1 
Demography Monitoring 
Required submission of patient demographic data to NCI for this study will be submitted 
automatically via OPEN.   
 
 
13.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
 
No pathology review is planned for this study. Bone marrow aspirates and biopsies will be 
performed and reviewed at participating institutions. 
 
 
14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
 
If the patient consents to banking, any specimens left over after the required research studies 
described below have been performed will be banked at the Biopathology Center for future research 
studies. 
 
A table of specimens to be collected is available in Appendix X.  
 
Study prioritization:  
If blood volumes approach maximum allowance per institutional standards for small children at a 
time point, please follow the priority list below. The list is written from highest to lowest priority. 
See the section numbers provided and Appendix X for sample details.  
 
1. Required samples: Immune Phenotyping (Section 14.1.1) and Cytokine Analysis 
(Section 14.1.2) 
2. Whole Blood Collection for Plasma (EDTA tube) (Section 14.2.1.1) 
3. Whole Blood Collection (Streck Cell Free DNA tube) (Section 14.2.1.2) 
4. Whole Blood Collection (PAXgene RNA tube) (Section 14.2.1.3) 
 
14.1 
Required Studies 
All patients will be eligible for all required special studies on ANBL19P1. 
 
For Australia and New Zealand sites, please do not collect or send the immune 
phenotyping samples as these samples should not be refrigerated or frozen and would not 
be viable for testing by the time they are delivered to the CCTDC at Emory University.  
 
14.1.1 Immune Profiling: Immune Phenotyping 
 
14.1.1.1 Specimen Schedule and Requirements 
At each time point, collect either two sodium heparin (green top) tubes 
with 5 mL each of peripheral blood or one sodium heparin (green top) 
10 mL tube (total of 10 mL). 
 
Samples are requested at the following time points: 
• 
Pre-therapy (between study enrollment and start of therapy)  

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• 
Cycle 1, post-completion of dinutuximab (collect a single sample 
between Day 5 and Day 8, pre-isotretinoin) 
• 
Cycle 2, Day 1 (prior to initiation of Cycle 2 therapy) 
• 
End of therapy  
• 
Relapse/Progression 
 
Please do not collect the first sample until you contact the Children’s 
Clinical Translation Discovery Core at Emory (CCTDC@emory.edu) 
to coordinate the date of first sample delivery, and before shipping 
each sample. 
 
14.1.1.2 Specimen Processing 
Samples must be shipped the same day they are collected. Sites 
should plan ahead to avoid Friday or Saturday sample collection. 
Samples should not be refrigerated or frozen. Samples should be kept at 
room temperature until shipped. Specimen will be shipped at room 
temperature for overnight delivery. 
 
14.1.1.3 Specimen Labeling 
Tubes must be labeled with: 
• 
The patient’s COG ID number 
• 
Specimen type (blood)  
• 
Collection time point (e.g., Cycle 1, Day 6) 
• 
Date collected 
 
14.1.1.4 Specimen Shipping 
These specimens will be shipped fresh (do NOT batch) by FedEx 
Priority Overnight delivery directly to the Emory University Children’s 
Clinical and Translational Discovery Core (CCTDC).  
 
The peripheral blood sample for immune profiling by flow cytometry 
should be sent on the same day it was obtained. The sample should be 
shipped at room temperature overnight via FedEx Priority Overnight 
delivery.  
 
Samples should only be shipped on Mondays-Thursdays to allow for 
weekday delivery. NO Friday or Saturday shipments will be 
allowed. 
 
Please do not collect the first sample until you contact the Children’s 
Clinical 
Translation 
Discovery 
Core 
at 
Emory 
(CCTDC@emory.edu) to coordinate the date of first sample 
delivery, and before shipping each sample. 
 
Specimens should be shipped the same day they are collected at room 
temperature but in an insulated Styrofoam container (provided by the 
institution) to prevent temperature fluctuations by Federal Express 
Priority Overnight delivery to the following address: 
 

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Emory University Children’s Clinical and Translational 
Discovery Core (CCTDC) 
 
Health Sciences Research Building – E264 
1760 Haygood Drive 
Atlanta, GA 30322 
 
Phone: (404) 727-2342 
Email:  CCTDC@emory.edu  
 
For questions about sample processing and shipping, please contact the 
CCTDC directly.  
 
14.1.1.5 Methodology 
We will obtain preliminary data regarding the number of T, B, and NK 
cells present in the circulation at baseline and after treatment with 
chemo-immunotherapy. This T-B-NK panel quantifies these cells using 
flow cytometry. We will also freeze peripheral blood mononuclear cells 
(PBMCs), RNA and DNA for these immunogenomic studies.  
 
Flow cytometry panel: 
 
Lineage 
Panel 
Live/Dead (L/D), CD45, CD3, CD4, CD8, CD19, 
CD14, CD45RA, CCR7, CD25, CD127, HLA-DR 
NK Cell 
Panel 
L/D, CD45, CD3, CD8, CD16, CD56, CD57, 
CD107a, CD158, CD314, CD335 
 
14.1.2 Immune Profiling: Cytokine Analysis 
 
14.1.2.1 Specimen Schedule and Requirements 
At each time point, collect 5 mL of peripheral blood in a sodium heparin 
(green top) tube and process for plasma. If patient blood volumes require 
reduction, can reduce to 2.5 mL. 
 
Samples are requested at the following time points: 
• 
Pre-therapy (between study enrollment and start of therapy)  
• 
Cycle 1, post-completion of dinutuximab (collect a single sample 
between Day 5 and Day 8, pre-isotretinoin) 
• 
Cycle 2, Day 1 (prior to initiation of Cycle 2 therapy) 
• 
End of therapy  
• 
Relapse/Progression 
 
14.1.2.2 Specimen Processing 
Process the sample within 30 minutes of collection. Centrifuge the blood 
at 1200 x g for 15 minutes at 4°C (preferred) or room temperature to 
separate the plasma (top layer) from the red blood cells (bottom, red 
layer). Quickly, evenly dispense (aliquot) the plasma into pre-labeled 
cryoprotective vials and cap the vials securely. Place a minimum of 
0.25 mL into each cryovial. Immediately freeze the vials upright in a -
70°C to -80°C freezer. Store frozen until ready for shipment.  

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14.1.2.3 Specimen Labeling and Shipping 
Each cryovial must be labeled with: 
• 
The patient’s COG ID number 
• 
Specimen type (plasma) 
• 
Collection time point (e.g., Cycle 1, Day 1) 
• 
Date collected  
 
Plasma for cytokine analysis can be batched and shipped on dry ice to 
the Emory University Children’s Clinical and Translational Discovery 
Core (CCTDC) after the Cycle 4, Day 1 sample is drawn and processed. 
 
Specimens should be batch shipped on dry ice in an insulated Styrofoam 
container (provided by the institution) to prevent temperature 
fluctuations. Ship by Federal Express Priority Overnight delivery (see 
Section 14.1.1). See Section 14.1.1.4 for shipping instructions and 
address. 
 
14.1.2.4 Methodology 
The Emory University Children’s Clinical and Translational Discovery 
Core (CCTDC) will perform ELISA to analyze the cytokines/chemokine 
changes due to chemo-immunotherapy during the course of treatment. 
This testing will be performed using a multiplex cytokine array on a 
Luminex platform. 
 
39-plex: IL-1α, IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, 
IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, EGF, 
Eotaxin, FGF-2, Flt-3-ligand, Fractalkine, G-CSF, GM-CSF, GRO, 
IFN-α2, INF-γ, IP-10, MCP-1, MCP-3/CCL7, MDC/CCL22, MIP-1α, 
MIP-1β, TNFα, TNFβ, VEGF, sCD40L, TGFas, IL-2R   
 
Single-plex: sIL6-R 
 
14.2 
Optional Studies 
 
14.2.1 Specimens for Biobanking 
Biobanking of samples is strongly encouraged. If the patient has consented to 
banking of material for future research whole blood should be collected and 
submitted as detailed below. Every effort should be made to obtain samples from 
all time points, as appropriate for consenting patients. 
 
All material to be used for future research will be banked at the Biopathology 
Center (BPC). 
 
14.2.1.1 Whole Blood Collection for Plasma (EDTA tube collection) for potential 
future studies, such as HACA 
 
Specimen Schedule and Requirements 
At each time point, 2 mL of whole blood will be collected in an EDTA 
tube  
  

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Samples are requested at the following time points: 
• 
Pre-therapy (between study enrollment and start of therapy)  
• 
Cycle 3, Day 1 (pre-treatment)  
• 
Cycle 6, Day 8 (pre-treatment)  
 
Specimen Processing 
Immediately after collection, gently invert the blood collection tube 5-
10 times to mix the blood and EDTA. Centrifuge the blood at 1200xg 
for 15 minutes at 4ºC (preferred) or room temperature to separate the 
plasma (top layer) from the red blood cells (bottom, red layer). Remove 
the top, straw-colored layer (plasma), evenly dispense (aliquot) the 
plasma into pre-labeled cryoprotective 2 mL vials (minimum of 0.25 mL 
into each) and cap the vials securely. Immediately freeze the vials 
upright in a -70oC to -80oC freezer. Retain frozen until ready for batch 
shipment. 
 
Specimen Labeling 
Tubes must be labeled with: 
• 
The patient’s COG ID number 
• 
BPC number 
• 
Specimen type (plasma) 
• 
Time point (cycle number and day) 
• 
Date collected 
 
Tubes should be sent to the BPC frozen on dry ice in batch shipments. 
See Section 14.3 for shipping address and additional shipping 
instructions. 
 
For questions about sample processing and shipping, please contact the 
BPC directly. 
 
14.2.1.2 Whole Blood Collection (Streck Cell Free DNA tube collection) for 
future studies, such as circulating tumor (ct)DNA studies 
 
Specimen Schedule and Requirements 
Streck Cell-Free DNA BCT Tubes will be provided to sites in North 
America, upon request. If the patient has consented to optional banking 
studies, then tubes should be ordered via the BPC Kit Management 
system as soon as possible to allow time for tubes to be shipped. 
Shipments will be sent by ground transportation and shipping will take 
3-5 business days.  
 
For all time points, please refer to the instructions in Section 14.2.1.3 to 
order a kit containing both Streck and PAXgene tubes so that the blood 
can be sent in one shipment. 
 
At each time point, 10 mL of whole blood will be collected in one tube. 
If blood volumes require reduction, minimum of 5 mL can be submitted. 
Obtain as much as feasible, not to exceed 10 mL.  
 

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Samples are requested at the following time points: 
• 
Pre-therapy (between study enrollment and start of therapy) 
• 
Cycle 2, Day 1 (pre-treatment) 
• 
Cycle 3, Day 1 (pre-treatment) 
• 
End of therapy 
• 
Relapse/progression 
 
Established institutional guidelines should be followed for blood 
collection via vascular access devices. Heparin should be avoided in pre-
collection flush procedures. If therapeutic heparin dosing contamination is 
a possibility, venipuncture is recommended as a first choice collection 
method. If a Streck Cell-Free DNA BCT tube immediately follows a 
heparin tube in the draw order, we recommend collecting an EDTA tube 
as a waste tube prior to collection in the Streck Cell-Free DNA BCT.  
 
For patients who do not have indwelling catheters, blood should be 
collected via venipuncture. To guard against backflow, observe the 
following precautions:  
• 
Keep patient’s arm in the downward position during the collection 
procedure.  
•  Hold the tube with the stopper in the uppermost position so that 
the tube contents do not touch the stopper or the end of the needle 
during sample collection.  
• 
Release tourniquet once blood starts to flow in the tube, or within 
2 minutes of application.  
• 
 Fill tube completely.  
•  Remove tube from adapter and immediately mix by gentle 
inversion 8 to 10 times. Inadequate or delayed mixing may result 
in inaccurate test results.  
•  Store blood in Streck tube at room temperature until shipment.  
 
Specimen Processing 
Blood should be drawn directly into the Streck tube. The tube should be 
completely inverted 8-10 times after sample collection. No other on-site 
processing is required. Sample should be kept at room temperature 
until shipped. 
 
Specimen Labeling and Shipment 
Tubes must be labeled with: 
• 
The patient’s COG ID number 
• 
BPC number 
• 
Specimen type (blood) 
• 
Time point (cycle number and day) 
• 
Date collected  
 
Each sample should be sent on the day the sample was obtained. 
Sample should be SHIPPED AT ROOM TEMPERATURE. Ship to 
the BPC using a Federal Express shipping label obtained through the 
BPC Kit Management application. See Section 14.3.2 for instructions 
on accessing the BPC Kit Management application. Blood may be 

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shipped on Monday through Friday for a Tuesday through Saturday 
delivery. Do not ship blood the day before a holiday.  
 
14.2.1.3 Whole Blood Collection (PAXgene RNA tube collection) for potential 
future studies, such as gene expression/sequencing studies 
 
Specimen Schedule and Requirements 
PAXgene RNA tubes will be provided by the BPC to sites in North 
America. Since all PAXgene collection timepoints correspond to a 
collection time point for blood in Streck Cell-Free DNA, one ambient 
shipper with both a Streck and a PAXgene tube will be provided for 
each of the collection time points below. Please only order kits for one 
or two time points per patient at a time as the PAXgene tubes have a 
short shelf life. 
 
To request Streck/PAXgene tube kits, please access the BPC Kit 
Management system (https://kits.bpc-apps.nchri.org/) and select 
ANBL19P1 for the protocol and Streck Cell Free DNA/PAXgene 
Tubes for the kit type. 
 
At each time point, 2.5 mL of peripheral blood in a PAXgene RNA tube 
should be collected. 
 
Samples are requested at the following time points: 
• 
Pre-therapy (between study enrollment and start of therapy) 
• 
Cycle 2, Day 1 (pre-treatment) 
• 
Cycle 3, Day 1 (pre-treatment) 
• 
End of Therapy 
• 
Relapse/Progression 
 
Specimen Processing 
Once blood is collected in the PAXgene RNA tube, the tube should be 
gently inverted 8-10 times to mix. Keep the tube at room temperature 
until shipment. 
 
Specimen Labeling 
Tubes must be labeled with: 
• 
The patient’s COG ID number 
• 
BPC number 
• 
Specimen type (blood) 
• 
Collection time point (i.e. Pretreatment, End of Induction) 
• 
Collection date 
 
Tubes should be sent to the BPC at room temperature in an ambient 
shipper. See Section 14.3 for shipping address and additional shipping 
instructions. 
 
For questions about sample processing and shipping, please contact the 
BPC directly. 
 

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14.2.1.4 Future Studies with Banked Biospecimens 
An amendment for any correlative science studies to be performed on 
biological samples that are biobanked will be submitted to CTEP, NCI 
for review and approval according to NCTN guidelines. Amendments to 
the protocol and/or proposals for use of banked tissue or blood samples 
will include the appropriate background, experimental plans with assay 
details, and a detailed statistical section. Samples for testing will not be 
released for testing until the appropriate NCI approvals have been 
obtained. 
 
14.3 
Shipping Instructions for Specimens Submitted to the Biopathology Center 
 
14.3.1 Ambient Blood 
Ship to the COG BPC using a Federal Express shipping label obtained through the 
BPC Kit Management application.   
 
Streck and PAXgene tubes must be kept at room temperature both prior to and 
during shipment. Tubes should be shipped in an ambient shipper with a SAF-T-
Temp Pak to maintain an ambient temperature. Instructions for packaging the 
blood are provided in the kit. 
 
An ANBL19P1 BPC specimen transmittal form must be completed in RAVE, 
saved and then printed and sent with the specimens.   
 
Blood may be shipped on Monday through Friday for a Tuesday through Saturday 
delivery. See Section 14.3.3 for shipping address. 
 
14.3.2 Frozen Plasma  
Send frozen plasma in batch shipments to the BPC on dry ice in a specimen 
procurement kit. Leave enough space in the kit chamber for sufficient dry ice (4-5 
lb.) to keep specimens frozen during shipment. 
 
Ordering a Kit for the submission of frozen specimens: 
The BPC will provide a specimen procurement kit upon request to institutions in 
North America for batch shipments of frozen specimens.  
Kits are ordered via the BPC Kit Management application (https://kits.bpc-
apps.nchri.org/). 
 
An ANBL19P1 BPC specimen transmittal form must be completed in RAVE, 
saved and then printed and sent with the specimen.  
 
Specimen Procurement Kit Instructions 
1. Before specimens are placed into the specimen procurement kit, they first need 
to be placed in three separate layers of packaging. A set of biohazard and 
Tyvek diagnostic envelopes are provided in the kit for this purpose. 
a. Place the specimens in zip lock bags (one bag per specimen type/time 
point). Because specimens will be batch shipped from multiple time 
points, it is extremely important that all specimens be clearly labeled with 
the specimen type and time point. 
b. Place the zip lock bags in a biohazard envelope with the absorbent 
material. Expel as much air as possible and seal the envelope. 

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c. Place the biohazard envelope inside a Tyvek envelope. Expel as much air 
as possible and seal the envelope. 
2. 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. 
Place the foam lid on top to insulate the specimens during shipment. 
3. Place the transmittal form(s) on top of the foam lid. 
4. Close the outer lid of the specimen procurement kit and secure with filament 
or other durable sealing tape. 
5. Sites in North American will print a shipping label via the BPC Kit 
Management application and attach to the top of the kit. 
6. Complete the dry ice label (UN 1845). Place the dry ice and Exempt Human 
Specimen labels on the side of the kit. 
7. Arrange for Federal Express pickup per your usual institutional procedure or 
by calling 1-800-238-5355. 
 
Ship frozen specimens on Monday through Thursday for a Tuesday through Friday 
delivery. Do not ship frozen specimens the day before a national holiday. See 
Section 14.3.3 for shipping address. 
 
14.3.3 Shipping Address 
Specimens that are designated to be shipped to the COG BPC should be shipped 
to the following address: 
 
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
Fax: 
(614) 722-2897 
Email: NBLPG@nationwidechildrens.org 
 
*Be sure to include the room number. Packages received without the room number 
may be returned to the sender. 
 
 
 
 

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15.0 
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 (except where explicitly prohibited within the protocol). 
 
15.1 
Cross Sectional Imaging Studies 
MRI or CT will be utilized for optimum visualization of all areas of bulk tumor (primary 
and metastases). This imaging is required for patients with measurable disease at 
enrollment: (1) pre-treatment, (2) after Cycle 3 of Post-Consolidation,* (3) at the end of 
therapy, (4) every 6 months x 4, (5) every year x 1, and (6) at relapse. 
 
*Cross sectional tumor imaging (MRI or CT) is only required after Cycle 3 for patients 
with residual soft tissue disease detected at the start of Post-Consolidation 
 
15.1.1 MRI Scans 
Typically, MRI will be performed on 1.5 T or 3 T MRI units per institutional 
standard. Axial and at least 1 additional plane (coronal or sagittal) of the primary 
tumor will be performed using at least 2 pulse sequences (T1, T2, STIR, FLAIR, 
in/out phase, post contrast). The radiologist performing the study will determine 
the appropriateness of the use of intravenous gadolinium (0.2 mL/kg). Slice 
thickness will be determined by patient size and region covered, but should be less 
than 7 mm. The smallest appropriate coil should be used. The longest diameter of 
the primary tumor will be recorded at baseline. Serial measurements of the primary 
tumor will include assessment of tumor size in the same orthogonal plane at the 
time of each evaluation. 
 
15.1.2 CT Scans 
Axial imaging of the site of the primary tumor will be performed using low-dose 
technique according to the ALARA (As Low As Reasonably Achievable) concept. 
The studies will be performed using current-generation single or multi-detector 
systems. CT slice thickness should be 5 mm or less. Imaging will be performed 
during the administration of intravenous contrast, whenever possible, generally at 
2 mL/kg. The use of oral contrast will be determined by the individual radiologist 
performing the study, but may be helpful in abdominal imaging. Images will be 
reconstructed in soft tissue and edge-enhanced bone/lung and liver algorithms. 
Coronal and sagittal multiplanar reconstructions may be helpful. As noted in the 
preceding section, serial measurements of the primary tumor will include 
assessment of tumor size in the same orthogonal plane at the time of each 
evaluation. 
 
MRI is superior to CT in characterizing epidural tumor extension or 
leptomeningeal disease, and is the preferred imaging modality in such cases (neck, 
chest, nonadrenal retroperitoneum) with spinal cord or canal encroachment.31 It 
may also be useful in evaluating an MIBG-avid focus detected in the skeleton or 
soft tissues. With the exceptions noted above, the choice of MRI or CT will be left 
to the referring pediatric radiologist. 
 

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15.2 
123I-MIBG Scintigraphy 
123I-MIBG scintigraphy is required for this trial and is the preferred study for assessment 
of osteomedullary disease. Technitium bone scans are no longer recommended. All patients 
will undergo a diagnostic quality 123I–MIBG scan within 21 days from enrollment. For 
patients with MIBG avid disease, an MIBG scan is also required: (1) pre-treatment, (2) 
after Cycle 3 of Post-Consolidation, (3) at the end of therapy, (4) every 3 months x 2, (5) 
every 6 months x 3, (6) every year x1, and (7) at relapse. 
 
Patients with MIBG non-avid disease at diagnosis are not required to undergo subsequent 
diagnostic MIBG scans. In such circumstances, PET scans should be substituted for MIBG 
scans, at the same required time points.  
 
15.2.1 Thyroid Blockade 
Potassium iodide will be administered to reduce thyroid accumulation of free 
radioiodine. A recommended regimen is 13% KI (100 mg iodide/mL) to be 
administered daily beginning on the day prior to radionuclide injection, and 
continuing daily for a total of 5 days. Dose is by weight; 1.2 mg iodine/kg 
(4 mg/drop).  
 
15.2.2 
123I-MIBG Scintigraphy Procedures 
Dose: 5.2 MBq/kg or 0.14 mCi/kg; maximum 370MBq32 or 10 mCi 
 
Scintigraphy: Performed to obtain both planar and tomographic images. For 
planar imaging, anterior and posterior spot views from the top of the head to the 
distal lower extremities are obtained for 10 minutes each at approximately 24 
hours after injection and may be done 48 hours after injection. A large field of view 
dual-head gamma camera with medium-energy collimators is preferred. A whole 
body planar acquisition can be performed with a suggested scan rate of 5 cm/s. 
Additional orthogonal spot views of the head are recommended. 
 
SPECT imaging with 123I-MIBG is recommended when available, and should be 
performed approximately 24 hours after injection using a single or multiheaded 
camera with low-energy collimator. Institutional guidelines regarding data 
acquisition and reconstruction should be followed. MIBG-SPECT or MIBG-
SPECT/CT may be used, however the same imaging methodology should be used 
for all evaluations other than the post-therapy scan that follow 131I-MIBG 
treatment. 
 
15.3 
[18F]–Fluorodeoxyglucose (18FDG)-PET Scintigraphy 
18FDG-PET scan is indicated for patients whose tumors are not 123I-MIBG avid. FDG-PET 
is performed at the following time-points: (1) pre-treatment, (2) after Cycle 3 of Post-
Consolidation, (3) at the end of therapy, (4) every 3 months x 2, (5) every 6 months x 3, 
(6) every year x1, and (7) at relapse. 
 
It is recommended that the PET scan be performed following count recovery if possible in 
order to minimize the likelihood that augmented marrow signal is related to colony 
stimulating factor effect/marrow recovery.  
 
The patient should be fasted for at least 4 hours prior to injection of FDG. Plasma glucose 
should be checked and, if the patient is substantially hyperglycemic, the study should be 
rescheduled when adequate glucose control has been established. FDG is administered 

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intravenously per institutional guidelines. Good hydration is required as the primary route 
of FDG excretion is renal. The patient should drink water or receive intravenous fluids 
after injection to promote urinary FDG excretion. After injection, the patient is kept at rest 
for 45-60 minutes and imaging is then performed. The FDG dose range for a PET/CT scan 
is 3.7-5.2 MBq/kg (0.1-0.14 mCi/kg) and for a PET/MR scan is 2.59 -3.7 MBq (0.07 to 
0.1 mCi/kg). The patient should void his/her bladder immediately prior to imaging if he/she 
is continent of urine. Whole body imaging (including extremities) should be obtained using 
institutional techniques. 
 
Because of the short physical half-life of 1.8 hours and the high photon energy of 511 
keV, FDG imaging may follow MIBG (either I-123 or I-131) or a MUGA study on the 
same day. If needed, the FDG imaging may be performed on the day preceding the 
MUGA. 
 
Imaging with a dedicated PET/CT or PET/MR camera is preferred, but imaging with a 
stand-alone PET scanner is acceptable.  
 
The FDG-PET study is processed for display by an iterative reconstruction algorithm. FDG 
activity should be corrected for attenuation, scatter, and radioactive decay. Attenuation 
correction is necessary, as apparent uptake will otherwise vary with depth of the lesion in 
the body and the nature of surrounding tissues. The procedure used for attenuation 
correction should be recorded. The level of tumor uptake is assessed subjectively by visual 
inspection and semi-quantitatively by determination of SUV. Uptake time, glucose levels, 
and partial volume effects influence both methods. The SUV method is also dependent on 
body weight and correction of SUV by normalizing for body surface area (BSA) reduces 
this dependency on body weight. Small lesions may have underestimated SUVs due to 
partial volume averaging effects. To calculate the SUV, a region of interest (ROI) should 
be carefully drawn around the area of elevated FDG uptake in the lesion to minimize partial 
volume effects. The SUV should be calculated as SUVBSA=ROI activity concentration 
(nCi/cc) X BSA / injected activity (nCi). The BSA is calculated from body mass (kg) and 
height (cm) using an appropriate algorithm. The SUVBSA for each measured lesion should 
be recorded and the technique for assessing SUVBSA should be consistent on follow-up 
studies. SUV measurements are directly available on almost all PET/CT display programs 
using simple ROIs. 
 
PET may be performed in combination with CT on dual modality PET/CT scanners or in 
combination with MRI on dual modality PET/MR scanners. Typically attenuation 
correction imaging (low-dose, non-contrast-enhanced CT, contrast-enhanced CT) is 
performed from the neck through the pelvis with the patient breathing shallow, followed 
by emission imaging at 3-5 minutes per bed position PET/MR simultaneous scanner or 
PET/MR sequential scanner attenuation correction will be performed using MR based 
attenuation correction techniques. Data are reconstructed as described above. Non 
attenuation corrected and attenuation corrected PET data should be submitted for both 
PET/CT and PET/MR. For PET/CT, CT images should be submitted. For PET/MR, 3D T1 
and axial T2 images should be submitted. Coronal fluid sensitive sequences can also be 
submitted if acquired. 
 
15.4 
Tumor Measurement 
Tumors will be measured according to the COG Radiology Group guidelines. Diameter of 
a “measurable mass” must be at least twice the reconstructed slice thickness. Target lesions 
at baseline must be greater than 1 cm. When multiple or metastatic masses are present, all 

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masses will be described, and up to 5 target masses will be measured using the same 
method in subsequent follow-ups. See response evaluation section for information 
regarding measurement of soft tissue masses in accordance with revised INRC criteria 
(Section 10.2).  
 
15.5 
Curie Scoring  
Curie scoring (Appendix XII) will be mandated for all patients at each time point that an 
MIBG scan is obtained. At all time points, Curie scoring will be determined by local 
institutions. 
 
Exception: Curie scoring will not be performed for patients who are found to have MIBG 
non-avid disease at diagnosis. 
 
 
16.0 
RADIATION THERAPY GUIDELINES 
 
No radiation therapy is planned for this study. 
 
 
 
 

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APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program 
(CTEP) Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In 
addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator 
(NPIVR), or Associate Plus (AP) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System (RUMS), OPEN, Rave, acting as a primary 
site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs 
must list all clinical practice sites and Institutional Review Boards (IRBs) covering their practice 
sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 

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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be rostered 
at the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at https://ctep.cancer.gov/
investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Protocol Specific Requirements For ANBL19P1 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
• 
IROC Credentialing Status Inquiry (CSI) Form– this form is submitted to IROC to verify 
credentialing status or to begin a new modality credentialing process.  
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
Checking Your Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
Data Submission / Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 

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• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website in the Rave 
section under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com.  
 
 
 
 

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APPENDIX II: INTERNATIONAL NEUROBLASTOMA RISK GROUP (INRG) STAGING 
SYSTEM33,34 
 
INRG Stage  
Description  
L1 
Localized tumor not involving vital structures as defined by the list of image-
defined risk factors* and confined to one body compartment. 
L2 
Locoregional tumor with presence of one or more image-defined risk factors.* 
M 
Distant metastatic disease (except MS). 
MS 
Metastatic disease in children younger than 18 months with metastases 
confined to skin, liver, and/or bone marrow (bone marrow involvement should 
be limited to < 10% of total nucleated cells on smears or biopsy). 
Primary tumor may be L1 or L2 as defined above. 
 
Bone marrow disease is determined by morphology on smears and aspirates. 
 
*INTERNATIONAL NEUROBLASTOMA RISK GROUP (INRG) IMAGE DEFINED RISK 
FACTORS 
 
Risk factors related to localization: 
1) Neck: 
• 
Tumor encasing carotid and/or vertebral artery and/or internal jugular vein 
• 
Tumor extending to base of skull 
• 
Tumor compressing the trachea 
 
2) Cervico-thoracic junction: 
• 
Tumor encasing brachial plexus roots 
• 
Tumor encasing subclavian vessels and/or vertebral and/or carotid artery 
• 
Tumor compressing the trachea 
 
3) Thorax: 
• 
Tumor encasing the aorta and/or major branches 
• 
Tumor compressing the trachea and/or principal bronchi 
• 
Lower mediastinal tumor, infiltrating the costo-vertebral junction between T9 and T12 
 
4) Thoraco-abdominal: 
• 
Tumor encasing the aorta and/or vena cava 
 
5) Abdomen/Pelvis: 
• 
Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament 
• 
Tumor encasing branches of the superior mesenteric artery at the mesenteric root 
• 
Tumor encasing the origin of the celiac axis, and/or of the superior mesenteric artery 
• 
Tumor invading one or both renal pedicles 

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• 
Tumor encasing the aorta and/or vena cava 
• 
Tumor encasing the iliac vessels 
• 
Pelvic tumor crossing the sciatic notch 
 
6) Dumbbell tumors with or without symptoms of spinal cord compression: 
• 
Whatever the localization 
 
7) Infiltration of adjacent organs/structures: 
• 
Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery 
 
 
 

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APPENDIX III: PERFORMANCE STATUS SCALES/SCORES 
 
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease 
100 
Fully active, normal. 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g., light housework, 
office work. 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry 
on normal activity or do active 
work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
self-care but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours 
60 
Required occasional assistance, 
but is able to care for most of 
his/her needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play, 
able to participate in all quiet play 
and activities. 
3 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours.  
40 
Disabled, requires special care 
and assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 
 
 

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*Denotes weak inducer of CYP3A4 isozyme. Therapy with this agent can be  
continued if the risk of switching to an alternative anticonvulsant outweighs  
the benefit of avoiding a possible drug interaction  
APPENDIX IV: RECOMMENDED NON-ENZYME INDUCING ANTICONVULSANTS AND 
UNACCEPTABLE ENZYME INDUCING ANTICONVULSANTS 
 
 
 
 
 
 
 
 
 
 
 
Recommended Non-enzyme inducing anticonvulsants 
 
Brivaracetam 
Clonazepam 
Diazepam 
Ethosuximide 
Fenfluramine 
Gabapentin 
Lacosamide 
Lamotrigine 
Levetiracetam  
Lorazepam 
Methsuximide 
Midazolam 
Perampanel 
Pregabalin 
Tiagabine 
Topiramate 
Valproic Acid 
Zonisamide 
 
Unacceptable Enzyme inducing anticonvulsants 
 
Carbamazepine 
Clobazam* 
Eslicarbazepine 
Felbamate 
Phenobarbital 
Fosphenytoin 
Phenytoin 
Primidone 
Oxcarbazepine* 

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APPENDIX V: PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
Guidelines for the Treatment of Diarrhea 
 
Institutional practice may be used in place of these guidelines. 
 
You should purchase or will be given a prescription for loperamide to have available to 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.  
 
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.  
 
Be aware of your child's bowel movements. At the first sign they become softer than usual or if your child 
has any notable 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 __ hours until the diarrhea slows or the 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 
 
 
 
 

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LOPERAMIDE DOSING RECOMMENDATIONS 
(NOTE: maximum dose of loperamide for adults is 16 mg/day) 
ALL patients: discontinue loperamide when the patient is no longer experiencing significant diarrhea. 
Weight (kg) 
ACTION 
<13 kg   
Take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral solution) after 
the first loose bowel movement, followed by 0.5 mg (2.5 mL [one-half 
teaspoonful] of the 1 mg/5 mL oral solution) every 3 hours.  During the night, the 
patient may take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral 
solution) every 4 hours.  Do not exceed 4 mg (20 mL or 4 teaspoonfuls) per day. 
 
≥ 13 kg to < 20 kg 
Take 1 mg (5 mL [1 teaspoonful] of the 1 mg/5 mL oral solution or one-half  
tablet) after the first loose bowel movement, followed by 1 mg (5 mL [one 
teaspoonful] of the 1 mg/5 mL oral solution or one-half tablet) every 3 hours. 
During the night, the patient may take 1 mg (5 mL [one teaspoonful] of the 1 mg/5 
mL oral solution or one-half tablet) every 4 hours.  Do not exceed 6 mg (30 mL or 
6 teaspoonfuls) per day. 
 
≥ 20 kg to < 30 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] 
of the 1 mg/5 mL oral solution or one-half tablet) every 3 hours.  During the night, 
the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution 
or 1 tablet) every 4 hours. Do not exceed 8 mg (40 mL or 8 teaspoonfuls) per day. 
 
≥ 30 kg to < 43 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1  tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] 
of the 1 mg/5 mL oral solution or one-half tablet) every 2 hours.  During the night, 
the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution 
or 1 tablet) every 4 hours. Do not exceed 12 mg (60 mL or 12 teaspoonfuls) per 
day. 
 
Over 43 kg 
Take 4 mg (20 mL [4 teaspoonfuls] 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 
[2 teaspoonfuls] 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 [4 teaspoonfuls] of 
the 1 mg/5 mL oral solution or 2 capsules or tablets) every 4 hours. Do not exceed 
16 mg (80 mL or 16 teaspoonfuls) 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. 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  
- 
Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
- 
Clozapine, nefazodone 
• Antifungals  
- 
Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
- 
Leflunomide, tofacitinib 
• Anti-rejection medications 
- 
Cyclosporine 
• Antiretrovirals and antivirals  
- 
Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, telaprevir, tipranavir 
• Anti-seizure medications  
- 
Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• Heart medications  
- 
Amiodarone, carvedilol, dronedenarone, diltiazem, propafenone, quinidine, ranolazine, 
verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
- 
Aprepitant, bosentan, cobicistat, conivaptan, ivacaftor, mifepristone, modafinil, 
natalizumab  
 
Food and supplements that may interact with irinotecan 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
Temozolomide  
Drugs that may interact with temozolomide 
• Clozapine, leflunomide, natalizumab, tofacitinib, valproate products 
 
Food and supplements that may interact with temozolomide 
• Echinacea 

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Isotretinoin 
Drugs that may interact with isotretinoin 
• Aminolevulinic acid 
• Carbamazepine  
• Some oral contraceptives 
• Some antibiotics, like doxycycline, tetracycline, and tigecycline 
 
Food and supplements that may interact with isotretinoin 
• St. John’s Wort 
• Vitamin A supplements or multivitamins that contain vitamin A 
 
 
 

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APPENDIX VII: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is 
important to regularly consult frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers 
abemaciclib 
acalabrutinib5 
alfentanil4,5  
alprazolam5 
amiodarone4 
amlodipine 
aprepitant/fosaprepitant 
atorvastatin 
avanafil5 
axitinib 
bortezomib 
bosutinib5 
brexpiprazole 
brigatinib 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
colchicine5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
ebastine5 
eletriptan5 
eliglustat5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
atazanavir 
boceprevir 
clarithromycin 
ceritinib 
cobicistat 
danoprevir/ritonavir 
darunavir 
delavirdine 
elvitegravir/ritonavir 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir/ritonavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
paritaprevir/ritonavir/ 
ombitasvir +/- dasabuvir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
tipranavir/ritonavir 
tucatinib 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
duvelisib 
erythromycin 
fedratinib 
fluconazole 
fosamprenavir 
fosnetupitant 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
lefamulin 
letermovir 
mifepristone 
netupitant 
nilotinib 
ribociclib 
verapamil 
apalutamide 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
lumacaftor/ 
ivacaftor 
mitotane 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
cenobamate 
dabrafenib 
efavirenz 
eslicarbazepine 
etravirine 
lorlatinib 
modafinil 
nafcillin 
pexidartinib 
rifabutin 
rifapentin 
 
 
 

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felodipine5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
lomitapide5 
lorlatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
naloxegol5 
nefazodone 
nilotinib 
nisoldipine5 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
pimozide5 
quetiapine5 
quinidine4  
regorafenib 
rilpivirine5 
rivaroxaban5 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
tadalafil5 

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telaprevir 
temsirolimus 
teniposide 
tetracycline 
ticagrelor5 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 4.3.1 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors) 
 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers 
abemaciclib 
acalabrutinib5 
alfentanil4,5  
alprazolam5 
amiodarone4 
amlodipine 
aprepitant/fosaprepitant 
atorvastatin 
avanafil5 
axitinib 
bortezomib 
bosutinib5 
brexpiprazole 
brigatinib 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
colchicine5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
atazanavir 
boceprevir 
clarithromycin 
ceritinib 
cobicistat 
danoprevir/ritonavir 
darunavir 
delavirdine 
elvitegravir/ritonavir 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir/ritonavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
paritaprevir/ritonavir/ 
ombitasvir +/- dasabuvir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
tipranavir/ritonavir 
tucatinib 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
duvelisib 
erythromycin 
fedratinib 
fluconazole 
fosamprenavir 
fosnetupitant 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
lefamulin 
letermovir 
mifepristone 
netupitant 
nilotinib 
ribociclib 
verapamil 
apalutamide 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
lumacaftor/ 
ivacaftor 
mitotane 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
cenobamate 
dabrafenib 
efavirenz 
eslicarbazepine 
etravirine 
lorlatinib 
modafinil 
nafcillin 
pexidartinib 
rifabutin 
rifapentin 
 
 
 

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dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
ebastine5 
eletriptan5 
eliglustat5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
felodipine5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
lomitapide5 
lorlatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
naloxegol5 
nefazodone 
nilotinib 
nisoldipine5 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 

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pimozide5 
quetiapine5 
quinidine4  
regorafenib 
rilpivirine5 
rivaroxaban5 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
tadalafil5 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
ticagrelor5 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 4.3.1 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors) 
 
 

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APPENDIX VIII: TEMOZOLOMIDE CAPSULE DOSING (100 MG/M2) NOMOGRAM 
 
Use this nomogram for patients whose BSA is at least 0.6 m2 receiving capsule formulation. For 
patients with BSA <0.6 m2, please see dosing table in the treatment section of the protocol.  
 
Example: For a patient with BSA of  0.66 m2, the calculated dose is 0.66 m2 x 100 mg/m2 = 66 mg/day; 
administered dose per nomogram = 65 mg temozolomide/day. 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
0.6-0.62 
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 
106-114 
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 IX: TEMOZOLOMIDE REDUCED (75 MG/M2) DOSING NOMOGRAMS 
 
For patients with BSA < 0.6 m2 who require a dose reduction, use the table below.   
 
The dose of temozolomide in the table is expressed as final dose in mg to be administered.   
 
TEMOZOLOMIDE Dose Reduction 
If BSA < 0.6 m2 
BSA (m2) 
Dose  
0.25-0.29 
10 mg 
0.30-0.34 
15 mg 
0.35-0.39 
20 mg 
0.40-0.44 
25 mg 
0.45-0.49 
30 mg 
0.50-0.54 
35 mg 
0.55-0.59 
40 mg 
 
Use the nomogram below for patients whose BSA is at least 0.6 m2 receiving capsule formulation.  
 
Example: 
For a patient with a BSA of 0.66 m2, the calculated dose = 49.5 mg/dose; administered dose 
per nomogram = 50 mg temozolomide/dose. 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
0.6-0.63 
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 
148 
150 
 
 

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APPENDIX X: SUMMARY OF BIOLOGIC CORRELATIVE LAB STUDIES 
 
Time point 
Sample 
Typeb 
Volume per 
tubec 
Quantity 
Tube Type / Sample Prep 
Notes 
Destination 
Lab 
Section 
Number 
CORRELATIVE STUDIES: POST-CONSOLIDATION 
Pre-therapy 
Blood 
5 mL 
2 tubes 
Sodium heparin (Green top) tube 
REQUIRED; 
Ship same day 
Immune Phenotyping 
Emory 
14.1.1 
5 mL 
1 tube 
Sodium heparin (Green top) tube 
REQUIRED; 
Process for plasma 
Cytokine Analysis 
Emory 
14.1.2 
2 mL 
1 tube 
EDTA 
Process for plasma 
Batch ship 
BPC 
14.2.1.1 
10 mL 
1 tube 
Streck Cell Free DNA tubea 
Ship same day 
BPC 
14.2.1.2 
2.5 mL 
1 tube 
PAXgene RNA tubea 
Ship same day  
BPC 
14.2.1.3 
Cycle 1, post 
completion of 
dinutuximab 
(collect single 
sample 
between Day 
5-Day 8) 
Blood 
5 mL 
2 tubes 
Sodium heparin (Green top) tube 
REQUIRED; 
Ship same day 
Immune Phenotyping 
Emory 
14.1.1 
5 mL 
1 tube 
Sodium heparin (Green top) tube 
REQUIRED; 
Process for plasma 
Cytokine Analysis 
Emory 
14.1.2 
Cycle 2, Day 1 
 
Blood 
 
5 mL 
2 tubes 
Sodium heparin (Green top) tube 
REQUIRED; 
Ship same day 
Immune Phenotyping 
Emory 
14.1.1 
5 mL 
1 tube 
Sodium heparin (Green top) tube 
REQUIRED; 
Process for plasma 
Cytokine Analysis 
Emory 
14.1.2 
10 mL 
1 tube 
Streck Cell Free DNA tubea 
Ship same day 
BPC 
14.2.1.2 
2.5 mL 
1 tube 
PAXgene RNA tubea 
Ship same day 
BPC 
14.2.1.3 
Cycle 3, Day 1 
Blood 
2 mL 
1 tube 
EDTA 
Process for plasma 
Batch ship 
BPC 
14.2.1.1 
10 mL 
1 tube 
Streck Cell Free DNA tubea 
Ship same day 
BPC 
14.2.1.2 
2.5 mL 
1 tube 
PAXgene RNA tubea 
Ship same day 
BPC 
14.2.1.3 
Cycle 6, Day 8 
Blood 
2 mL 
1 tube 
EDTA 
Process for plasma 
Batch Ship 
BPC 
14.2.1.1 
End of 
therapy 
Blood 
5 mL 
2 tubes 
Sodium heparin (Green top) tube 
REQUIRED; 
Ship same day 
Immune Phenotyping 
Emory 
14.1.1 
Blood 
5 mL 
1 tube 
Sodium heparin (Green top) tube 
REQUIRED; 
Process for plasma 
Cytokine Analysis 
Emory 
14.1.2 
Blood 
10 mL 
1 tube 
Streck Cell Free DNA tubea 
Ship same day 
BPC 
14.2.1.2 
Blood 
2.5 mL 
1 tube 
PAXgene RNA tubea 
Ship same day 
BPC 
14.2.1.3 
Relapse / 
Progression 
Blood 
5 mL 
2 tubes 
Sodium heparin (Green top) tube 
REQUIRED; 
Ship same day 
Immune Phenotyping 
Emory 
14.1.1 
Blood 
5 mL 
1 tube 
Sodium heparin (Green top) tube 
REQUIRED; 
Process for plasma 
Cytokine Analysis 
Emory 
14.1.2 

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Blood 
10 mL 
1 tube 
Streck Cell Free DNA tubea 
Ship same day 
BPC 
14.2.1.2 
Blood 
2.5 mL 
1 tube 
PAXgene RNA tubea 
Ship same day 
BPC 
14.2.1.3 
 
a. If the patient has consented to optional banking studies, both PAXgene RNA tubes and Streck Cell 
Free DNA BCT tubes should be ordered via the BPC Kit Management system as soon as possible 
after patient enrollment to allow time for tubes to be shipped. Please see Section 14.2.1.2 for contact 
information. 
b. Please refer to appropriate section regarding blood volume adjustments if applicable. 
c. Prioritization of samples if blood volumes approach maximum allowance per institutional 
standards for small children.  
1. Required samples (sodium heparin [Green top] tubes) 
2. EDTA tube  
3. Streck Cell Free DNA tube 
4.  PAXgene RNA tube 
 
Please refer to appropriate section regarding blood volume adjustments if applicable. 
 
 
 

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APPENDIX XI: EMERGENCY MANAGEMENT OF DINUTUXIMAB TOXICITIES 
 
This document is for rapid reference. See Section 5.2.5 for further information regarding 
management of acute toxicities during dinutuximab-containing cycles of therapy. 
 
Severe Allergic Reaction 
 
Definition (any of the following): symptomatic bronchospasm with or without urticaria, IV meds required, 
allergy‐related edema/angioedema, or anaphylaxis (Grade 3 or 4). 
 
Treatment: 
• 
Immediately hold dinutuximab infusion  
• 
Assess airway, breathing and circulation 
 
For airway concerns: 
• 
Administer oxygen and albuterol immediately for bronchospasm 
• 
Administer diphenhydramine (if not already being given) 
• 
Administer epinephrine immediately if upper airway involved or if airway issues are accompanied 
by cardiovascular collapse 
• 
Administer hydrocortisone if any of the following are true 
o patient has frank anaphylaxis with cardiorespiratory collapse 
o two or more doses of epinephrine are required 
o moderate to severe symptoms recur upon rechallenge with dinutuximab  
 
For hypotension in setting of allergic reaction: 
• 
Hold dinutuximab and give normal saline bolus (see hypotension guidelines) 
• 
Stop or adjust doses of narcotics  
• 
For patients with hypotension that resolves with initial volume bolus, resume dinutuximab at half 
rate 
 
Reassess need for additional volume resuscitation, ICU transfer and use of vasopressors.  
 
For patients with angioedema that does not affect the airway or patients with mild bronchospasm and no 
other symptoms: 
• 
If symptoms resolve rapidly, dinutuximab can be resumed at half rate with very close observation 
 
Minimal criteria for resumption of dinutuximab infusion: 
• 
Complete resolution of airway symptoms 
• 
Complete resolution of hypotension 
 
 
 

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APPENDIX XII: CURIE SCORING SUMMARY SHEET 
 
COG Registration Number:   
____ 
Radiology reviewer: ____________________________ 
 
 
 
 
 
(6 digits) 
 
 
 
 
(print name) 
 
Date of scan:  
 
__ 
Type of Scan (check 1):  I-123 MIBG  
        I-131 MIBG  
 
 
 
 
(DD/MM/YYYY) 
 
Scan time point (circle 1): 
Baseline 
 
End of Cycle 3  
 
End of therapy   
 
 
Off therapy Surveillance (months from end of therapy):  
 
3 
6 
12 
18 
24 
36 
 
 
Relapse/Progression 
 
 
 
 
 
Other (specify):  
 
Table 1a. Scoring skeletal disease 
 
Table 1b. Scoring soft tissue disease 
 
 
Regions 1 – 9 
Region 10 (Primary soft tissue site) 
Scoring 
MIBG uptake 
Scoring  
MIBG uptake 
0 
No MIBG uptake 
0 
No soft tissue uptake 
1 
1 focal site  
1 
1 focal soft tissue site 
2 
> 1 focal site  
2 
> 1 focal soft tissue site 
3 
≥ 50% of a region  
3 
≥ 50% of a region (chest, abdomen) 
 
 
Region 
Site 
Curie 
score 
1 
Head / Neck 
 
 
2 
Cervico-Thoracic spine 
 
 
3 
Ribs / Sternum / Clavicles/ Chest 
 
 
4 
Lumbar / Sacral spine 
 
 
5 
Abdomen/Pelvis 
 
 
6 
Upper Extremity (Proximal) 
 
 
7 
Upper Extremity (Distal) 
 
 
8 
Lower Extremity (Proximal) 
 
 
9 
Lower Extremity (Distal) 
 
 
10 
Soft Tissue 
 
 
TOTAL 
Total scores from Regions 1 - 10 
 

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APPENDIX XIII: OVERALL RESPONSE CRITERIA 
 
Primary Tumor 
Soft Tissue and Bone Metastatic Disease 
(MIBG or FDG-PET/CT or PET/MR) 
Bone Marrow Metastatic Disease  
Overall 
CR 
CR 
CR 
CR 
CR for one response component with either CR or NI for other components 
CR 
CR 
CR 
MD 
PR 
CR 
PR 
CR 
PR 
CR 
PR 
MD 
PR 
CR 
PR 
NI 
PR 
CR 
NI 
MD 
PR 
PR 
CR 
CR 
PR 
PR 
CR 
NI 
PR 
PR 
CR 
MD 
PR 
PR 
PR 
CR 
PR 
PR 
PR 
NI 
PR 
PR 
PR 
MD 
PR 
PR 
NI 
CR 
PR 
PR 
NI 
NI 
PR 
PR 
NI 
MD 
PR 
NI 
CR 
MD 
PR 
NI 
PR 
CR 
PR 
NI 
PR 
MD 
PR 
CR 
CR 
SD 
MR 
CR 
PR 
SD 
MR 
CR 
SD 
CR 
MR 
CR 
SD 
MD 
MR 
CR 
SD 
SD 
MR 
CR 
SD 
NI 
MR 
CR 
NI 
SD 
MR 
PR 
CR 
SD 
MR 
PR 
PR 
SD 
MR 
PR 
SD 
CR 
MR 
PR 
SD 
MD 
MR 
PR 
SD 
SD 
MR 
PR 
SD 
NI 
MR 
PR 
NI 
SD 
MR 
SD 
CR 
CR 
MR 
SD 
CR 
MD 
MR 
SD 
CR 
SD 
MR 
SD 
CR 
NI 
MR 
SD 
PR 
CR 
MR 
SD 
PR 
MD 
MR 
SD 
PR 
SD 
MR 
SD 
PR 
NI 
MR 
SD 
SD 
CR 
MR 
SD 
NI 
CR 
MR 
NI 
CR 
SD 
MR 
NI 
PR 
SD 
MR 
NI 
SD 
CR 
MR 
SD 
SD 
MD 
SD 
NI 
SD 
MD 
SD 
SD 
NI 
MD 
SD 
NI 
NI 
MD 
SD 
SD 
SD 
SD 
SD 
SD 
NI 
SD 
SD 
NI 
SD 
SD 
SD 
NI 
SD 
NI 
SD 
NI 
NI 
SD 
SD 
PD in any one component 
PD 
Response of Not Evaluable for any one of the 3 components that had measurable/evaluable tumor at study enrollment and no 
PD for any component 
Not Evaluable 
No response evaluation performed for any of the 3 components 
Not Done 
CR: Complete Response; MD: Minimal Disease; PR: Partial Response; MR: Minor Response; SD: Stable Disease; PD: Progressive disease; NI: 
not involved; site not involved at study entry and remains not involved.  
 
 
 

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APPENDIX XIV: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY 
(for children from 7 through 12 years of age) 
 
A Study of a New Treatment for People with High-Risk Neuroblastoma (NBL) 
 
1. We have been talking with you about your illness, neuroblastoma (NBL). NBL is a type of cancer 
that grows in the soft tissue of your body. It can grow in different parts of the body. You have had 
some treatment for this cancer already but more treatment is needed.  
 
2. We are asking you to take part in a research study because you have high-risk NBL. A research 
study is when doctors work together to try out new ways to help people who are sick. This 
research wants to learn what effects a new treatment has on your cancer. 
 
3. Children who are part of this study will be treated with two types of medicine at the same time. 
These medicines work in different ways to help get rid of cancer cells. The children in this study 
will be given the drug, dinutuximab. This drug has been shown to help treat NBL in children like 
you. They will also be given other drugs, irinotecan and temozolomide, which are commonly 
used to treat NBL. Study doctors would like to learn if your cancer stays away better with these 
two types of medicines given together. 
 
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 have more 
side effects and might not work as well as other treatments. Other things may happen to you that 
we don’t yet know about. 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 are asking your permission to collect additional blood. We want to see if there are ways to tell 
how the cancer will respond to treatment. These samples would be taken when other standard 
blood tests are being performed, so there would be no extra procedures. You can still take part in 
this study even if you don't allow us to collect the extra blood samples for research.  
 
 
 

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INFORMATION SHEET REGARDING RESEARCH STUDY 
(for children from 13 through 17 years of age) 
 
Treatment with Dinutuximab in combination with Irinotecan and Temozolomide for People with 
High-Risk Neuroblastoma (NBL) 
 
1. We have been talking with you about your illness, neuroblastoma (NBL). NBL is a type of cancer 
that grows in the soft tissue of your body. It can grow in different parts of the body. You have had 
some treatment for this cancer already and this study takes place during the last part of treatment.  
 
2. We are asking you to take part in a research study because you have high-risk NBL. A research 
study is when doctors work together to try out new ways to help people who are sick. This 
research study wants to learn what effects a new combination of therapy has on your cancer. 
 
3. Children and teens who are part of this study will be treated with immunotherapy and 
chemotherapy. Both immunotherapy and chemotherapy are types of medicine that help get rid of 
cancer cells. The children and teens in this study will be given the immunotherapy drug 
dinutuximab which has been shown to help treat NBL in children and teens like you. They will 
also be given chemotherapy drugs, irinotecan and temozolomide. Study doctors would like to 
learn if your cancer stays away better with this combination of therapy. 
 
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 are asking your permission to collect additional blood. We want to see if there are ways to tell 
how the cancer will respond to treatment. These samples would be taken when other standard 
blood tests are being performed, so there would be no extra procedures. You can still be treated 
on this study even if you don't allow us to collect the extra blood samples for research.  
 
 
 

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REFERENCES 
 
1. 
Yu AL, Gilman AL, Ozkaynak MF, et al: Anti-GD2 antibody with GM-CSF, interleukin-2, and 
isotretinoin for neuroblastoma. N Engl J Med 363:1324-34, 2010 
2. 
Park JR, Kreissman SG, London WB, et al: Effect of Tandem Autologous Stem Cell Transplant vs 
Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A 
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3. 
London WB, Bagatell R, Weigel BJ, et al: Historical time to disease progression and progression-
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Mody R, Naranjo A, Van Ryn C, et al: Irinotecan-temozolomide with temsirolimus or dinutuximab 
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Gilman AL, Ozkaynak MF, Matthay KK, et al: Phase I study of ch14.18 with granulocyte-
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Dhillon S: Dinutuximab: first global approval. Drugs 75:923-7, 2015 
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Lode HN, Troschke-Meurer S, Marx M, et al: Association of regulatory- and helper-T- cells with 
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Yoshida S, Kawaguchi H, Sato S, et al: An anti-GD2 monoclonal antibody enhances apoptotic 
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Kowalczyk A, Gil M, Horwacik I, et al: The GD2-specific 14G2a monoclonal antibody induces 
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Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan 
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Houghton PJ, Stewart CF, Cheshire PJ, et al: Antitumor activity of temozolomide combined with 
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Wilson JS, Gains JE, Moroz V, et al: A systematic review of 131I-meta iodobenzylguanidine 
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Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with 
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Pistoia V, Bianchi G, Borgonovo G, et al: Cytokines in neuroblastoma: from pathogenesis to 
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Egler RA, Burlingame SM, Nuchtern JG, et al: Interleukin-6 and soluble interleukin-6 receptor 
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Park JR, Bagatell R, Cohn SL, et al: Revisions to the International Neuroblastoma Response 
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29. 
Bagatell R, McHugh K, Naranjo A, et al: Assessment of Primary Site Response in Children With 
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30. 
Burchill SA, Beiske K, Shimada H, et al: Recommendations for the standardization of bone marrow 
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Neuroblastoma Response Criteria Bone Marrow Working Group. Cancer 123:1095-1105, 2017 
31. 
Kushner BH: Neuroblastoma: a disease requiring a multitude of imaging studies. J Nucl Med 
45:1172-88, 2004 
32. 
Treves ST, Gelfand MJ, Fahey FH, et al: 2016 Update of the North American Consensus Guidelines 
for Pediatric Administered Radiopharmaceutical Activities. J Nucl Med 57:15N-18N, 2016 
33. 
Cohn SL, Pearson AD, London WB, et al: The International Neuroblastoma Risk Group (INRG) 
classification system: an INRG Task Force report. J Clin Oncol 27:289-97, 2009 
34. 
Monclair T, Brodeur GM, Ambros PF, et al: The International Neuroblastoma Risk Group (INRG) 
staging system: an INRG Task Force report. J Clin Oncol 27:298-303, 2009