A Phase 2 Randomized Study of Irinotecan/Temozolomide/Dinutuximab With or Without Eflornithine (DFMO) in Children With Relapsed, Refractory or Progressive Neuroblastoma
Phase: PHASE2
Conditions: High Risk Neuroblastoma, Recurrent Neuroblastoma, Refractory Neuroblastoma
Sponsor: Children's Oncology Group

 
 
 
ANBL1821 
 
 
Activated: 
     05/28/19 
Version Date: 
06/22/2021 
Closed: 
     09/30/2024 
Amendment #: 
4 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
ANBL1821 
 
 
A Phase 2 Randomized Study of Irinotecan/Temozolomide/Dinutuximab with or without 
Eflornithine (DFMO) (
 in Children with Relapsed, Refractory or Progressive 
Neuroblastoma 
 
 
A COG Groupwide Phase 2 Study  
 
IND Sponsor for Eflornithine: COG 
 
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 patient enrollments: 
For Data Submission 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
 (Sign in at 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 at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or email:  
1-888-823-5923, or  ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
Schedule in the CRF packet for 
further instructions. 
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 (ie, patient eligibility or treatment-related)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (ie, 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 
STUDY COMMITTEE 
6 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
12 
1.1 
Primary Aims 
12 
1.2 
Secondary Aims 
12 
1.3 
Exploratory Aims 
12 
2.0 
BACKGROUND 
12 
2.1 
Introduction/Rationale for Development 
12 
2.2 
Preclinical Studies 
15 
2.3 
Adult Studies 
16 
2.4 
Pediatric Studies 
17 
2.5 
Dosing Rationale 
18 
2.6 
Rationale for Correlative Studies 
19 
2.7 
Importance of trial and impact on future clinical practice 
21 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
22 
3.1 
Study Enrollment 
22 
3.2 
Patient Eligibility Criteria 
26 
4.0 
TREATMENT PROGRAM 
33 
4.1 
Overview of Treatment Plan 
33 
4.2 
General Guidelines for therapy 
33 
4.3 
Concomitant Therapy 
34 
4.4 
Regimen A Cycle 1 
36 
4.5 
Regimen A Cycle 2 and Subsequent Cycles 
43 
4.6 
Regimen B Cycle 1 
51 
4.7 
Regimen B Cycle 2 and Subsequent Cycles 
59 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
68 
5.1 
Dose Modifications for Hematologic Toxicity 
68 
5.2 
Dose Modifications for Non-hematologic Toxicity 
69 
6.0 
DRUG INFORMATION 
78 
6.1 
EFLORNITHINE 
78 
6.2 
DINUTUXIMAB 
81 
6.3 
IRINOTECAN 
86 
6.4 
SARGRAMOSTIM 
89 
6.5 
TEMOZOLOMIDE - ORAL 
91 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
94 
7.1 
End of Therapy & Follow-up 
94 
7.2 
Research Studies for which Patient Participation is Required or Optional 
95 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY      
CRITERIA 
95 

  
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8.1 
Criteria for Removal from Protocol Therapy 
95 
8.2 
Off Study Criteria 
95 
9.0 
STATISTICAL CONSIDERATIONS 
95 
9.1 
Sample Size and Study Duration 
95 
9.2 
Study Design 
96 
9.3 
Methods of Analysis 
96 
9.4 
Evaluability for Response 
99 
9.5 
Evaluability for Toxicity 
99 
9.6 
Gender and Minority Accrual Estimates 
99 
10.0 
EVALUATION CRITERIA 
100 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
100 
10.2 
Response Criteria for Patients with Solid Tumors 
101 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
107 
11.1 
Purpose 
107 
11.2 
Determination of reporting requirements 
107 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
108 
11.4 
Special Situations for Expedited Reporting 
108 
11.5 
Reporting Requirements for Specialized AEs 
110 
11.6 
Exceptions to Expedited Reporting 
111 
11.7 
Reporting Requirements - Investigator Responsibility 
111 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
111 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
113 
11.10 
Protocol Specific Additional Instructions and Reporting Exceptions 
114 
11.11 
Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated                           
pathway 
114 
11.12 
Routine Adverse Event Reporting 
114 
12.0 
STUDY REPORTING AND MONITORING 
115 
12.1 
CDUS 
115 
12.2 
Data and Safety Monitoring Committee 
115 
13.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
116 
14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
116 
14.1 
Required Studies 
116 
14.2 
Optional Studies 
119 
14.3 
Shipping Instructions for Specimens Submitted to the Biopathology Center 
123 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
125 
15.1 
Timing of Imaging 
125 
15.2 
Imaging Required for Confirmation of Response Status 
126 
15.3 
Image Submission 
126 
16.0 
RADIATION THERAPY GUIDELINES 
127 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
128 
APPENDIX II: PATIENT STRATIFICATION FLOWCHART 
131 
APPENDIX III:  UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-      
ENZYME INDUCING ANTICONVULSANTS 
132 
APPENDIX IV:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
133 

  
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APPENDIX V: PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
136 
APPENDIX VI:  TEMOZOLOMIDE DOSING (100 MG/M2) NOMOGRAM 
138 
APPENDIX VII:  TEMOZOLOMIDE REDUCED (75 MG/M2) DOSING NOMOGRAM 
139 
APPENDIX VIII:  INSTRUCTIONS FOR TEMOZOLOMIDE PREPARATION, ADMINISTRATION 
AND SAFE HANDLING 
140 
APPENDIX IX: CURIE SCORING SUMMARY SHEET (SUBMIT THIS SHEET VIA RAVE) 
141 
APPENDIX X:  BIOLOGIC CORRELATIVE LAB STUDIES 
143 
APPENDIX XI: EMERGENCY MANAGEMENT OF DINUTUXIMAB TOXICITIES 
145 
APPENDIX XII: EFLORNITHINE (DFMO) DOSING TABLES 
146 
APPENDIX XIII: INSTRUCTIONS FOR PREPARATION AND ADMINISTRATION OF 
EFLORNITHINE (DFMO) 
148 
APPENDIX XIV: OVERALL RESPONSE CRITERIA 
149 
APPENDIX XV: POSSIBLE DRUG INTERACTIONS 
151 
APPENDIX XVI: YOUTH INFORMATION SHEETS 
153 
REFERENCES 
155 
 
 
 

  
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AGENT 
NSC# 
Supplier 
Eflornithine (DFMO) 
337250 
CPP 
Irinotecan 
616348 
Commercial 
Temozolomide 
362856 
Commercial 
Dinutuximab 
764038 
Commercial 
Sargramostim (GM-CSF) 
613795 
Commercial 
 
 
  
IND Sponsor for Eflornithine: COG 
 
 
 
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 
Long-term survival rates for children with high-risk neuroblastoma remain poor. Moreover, survivors 
experience significant immediate and late toxicities that limit further dose intensification of conventional 
chemotherapy and radiotherapy. Novel biological therapies are therefore needed. This randomized phase 2 
study for patients with refractory or relapsed neuroblastoma is designed to compare response rates (RR) 
and progression free survival (PFS) for patients treated with dinutuximab, irinotecan and temozolomide 
alone compared to dinutuximab, irinotecan and temozolomide with difluoromethylornithine (DFMO, 
Eflornithine). The combination of dinutuximab, irinotecan, and temozolomide has shown promising 
activity in patients with refractory, relapsed, and progressive neuroblastoma, however the overall objective 
response rate on a Phase 2 trial of the regimen was less than 50%. This study proposes the addition of 
DFMO to the chemo-immunotherapy backbone. ODC1 is a downstream transcriptional target of MYCN 
and a key enzyme in the polyamine synthesis pathway. DFMO is an irreversible inhibitor of ODC1 and 
thus depletes essential polyamines necessary for tumor survival. DFMO has been studied alone and in 
combination with chemotherapy in patients with relapsed and refractory neuroblastoma and has shown no 
significant toxicity. Additionally, preclinical data support a role for DFMO in regulating the tumor 
microenvironment to reinstate anti-tumor immune responses. These data support the rationale to evaluate 
the addition of DFMO to the dinutuximab/irinotecan/temozolomide regimen for children with refractory, 
relapsed 
or 
progressive 
neuroblastoma. 
Should 
this 
trial 
prove 
successful, 
the 
DFMO/chemotherapy/immunotherapy regimen will be integrated into frontline induction therapy for future 
patients with high-risk neuroblastoma.   
 
 
 
 
 
 
 
 
 

  
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EXPERIMENTAL DESIGN SCHEMA: PATIENTS ENROLLED PRIOR TO AMENDMENT 4 
 
 
 
 
On Study Randomization
Regimen A
Irinotecan/Temozolomide/
Dinutuximab/GMCSF
Regimen B
Irinotecan/Temozolomide/
Dinutuximab/GMCSF/DFMO
No PD
2 cycles of therapy
Continue therapy for 11 
additional cycles
(17 total)
Disease Evaluation
2 cycles of therapy
CR, PR, MR
PD
Off 
protocol
therapy
SD or PD
No PD
2 cycles of therapy
Disease Evaluation
2 cycles of therapy
CR, PR, MR
2 cycles of therapy
No PD
No PD
2 cycles of therapy
Continue therapy for 11 
additional cycles
(17 total)
PD
PD
PD: Progressive Disease; CR: Complete Response; PR: Partial Response; MR: Minor Response; 
SD: Stable Disease 
PD: Progressive Disease; CR: Complete Response; PR: Partial Response; MR: Minor Response; 
SD: Stable Disease 

  
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EXPERIMENTAL DESIGN SCHEMA: PATIENTS ENROLLED ON AMENDMENT 4 AND 
LATER 
 
 
 
 
 
PD: Progressive Disease; CR: Complete Response; PR: Partial Response; MR: Minor Response; 
SD: Stable Disease 

  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Aims 
 
1.1.1 
To determine whether administration of eflornithine (DFMO) in combination with 
dinutuximab, irinotecan and temozolomide results in an improved response rate 
compared to dinutuximab, irinotecan and temozolomide in patients with relapsed 
or refractory neuroblastoma and therefore is a therapeutic regimen worthy of 
further testing in patients with newly-diagnosed high-risk neuroblastoma.  
 
1.2 
Secondary Aims 
 
1.2.1 
To compare progression-free survival and overall survival between patients 
receiving dinutuximab, irinotecan and temozolomide with and without the addition 
of DFMO. 
 
1.2.2 
To define the toxicity profile of DFMO administered with dinutuximab, irinotecan 
and temozolomide. 
 
1.3 
Exploratory Aims 
 
1.3.1 
To characterize the immune and cytokine profiles of patients treated with 
DFMO/chemotherapy/dinutuximab combination and correlate with response to 
therapy. 
 
1.3.2 
To evaluate GD2 levels in tumor cells from patient bone marrow samples and 
correlate with response to therapy. 
 
1.3.3 
To explore whether the addition of DFMO to the dinutuximab and chemotherapy 
backbone affects pain as determined by patient report and opiate usage.  
 
 
2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
Despite improvements with intensified therapy, high-risk neuroblastoma (NBL) still 
portends a poor prognosis, with approximately 50% of patients failing to respond to therapy 
or relapsing, leaving an unmet critical need to improve upon current therapies with more 
tumor targeted regimens.1, 
2 The results of a randomized Phase 2 study of 
irinotecan/temozolomide in combination with either temsirolimus (mTOR inhibitor) or 
dinutuximab (GD2 targeted chimeric monoclonal antibody) for patients with relapsed or 
refractory NBL (ANBL1221) showed promising results for patients treated on the 
dinutuximab arm. In total, 22/53 patients (41.5%) had an objective response.3 Sixteen 
(72.7%) of the patients with confirmed responses had partial response or better after the 

  
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first 2 cycles with best response seen by Cycle 6. However, this regimen is associated with 
several important toxicities. Grade 3 or higher pain was observed in 25% of patients 
assigned to irinotecan/temozolomide/dinutuximab.3-5 This study represents an effort to 
improve upon the response rate observed in ANBL1221. The goal of this study is to utilize 
DFMO 
to 
improve 
response 
rates 
in 
combination 
with 
dinutuximab/irinotecan/temozolomide compared to those seen in patients assigned to 
receive dinutuximab/irinotecan/temozolomide alone. The hypothesis is that DFMO will 
improve the anti-tumor activity of the ANBL1221 regimen by depleting polyamines, 
enhancing 
chemosensitivity, 
and 
improving 
dinutuximab 
response 
through 
immunomodulatory effects on the tumor microenvironment. 
 
Difluoromethylornithine (DFMO, Eflornithine) is an irreversible covalent inhibitor of 
ODC1 protein6 with potential for anti-neuroblastoma activity through several pathways. 
Amplification of the MYCN oncogene in neuroblastoma is a predictor of poor outcome. 
Ornithine decarboxylase (ODC1, encoded by ODC1) is a transcriptional target of MYCN 
and the rate-limiting enzyme in polyamine biosynthesis. ODC1 is not only a MYC target 
gene, but is itself somatically amplified in approximately 15% of neuroblastomas that 
harbor MYCN amplification, further deregulating polyamine signaling.7 Polyamine 
homeostasis is essential for cell survival and has been implicated in the pathogenesis of 
many cancers, including neuroblastoma.8 MYCN amplified tumors have coordinated 
deregulation of all polyamine regulatory enzymes, including ODC1.9 MYCN non-amplified 
high-risk neuroblastomas have less profound pathway deregulation, but still demonstrate 
markedly altered regulation of the rate-limiting polyamine enzyme ODC1, that even in the 
absence of MYCN amplification predicts poor prognosis.7, 10 While ~40% of high-risk NBL 
have MYCN amplification, expression data assessing “MYC signatures” support the 
concept that hyperactive MYC signaling occurs in most, if not all, high-risk tumors.11-13 A 
COG supported study also showed that a subset of MYCN non-amplified primary NBLs 
have high C-MYC protein expression; outcomes for patients with tumors with this feature 
were poor.14 Similarly, expression data show that polyamine signaling, which is 
coordinately regulated by MYC, is broadly deregulated in NBL and correlates with 
survival.7 Expression of ODC1, the rate-limiting enzyme in polyamine biosynthesis and 
the target of DFMO, is not only correlated with survival when analyzed in all NBL patients, 
but in high-risk patients only, and in high-risk patients whose tumors are absent MYCN 
amplification.7 Beyond depriving MYC-driven tumor cells of essential polyamines to 
induce stress, emerging evidence shows a role for arginine-polyamine signaling in 
maintaining a tumor-permissive and immune-hostile microenvironment.15 
 
The goal of this study is to utilize DFMO to improve response rates in combination with 
dinutuximab/irinotecan/temozolomide compared to those seen in patients assigned to 
receive dinutuximab/irinotecan/temozolomide alone. DFMO covalently and irreversibly 
inhibits ODC1. ODC1 is somatically amplified in a subset of NBL tumors, justifying 
targeting this enzyme with DFMO. Therefore, this randomized 2-arm study will allow for 
a direct comparison of chemo-immunotherapy to the same regimen with the addition of 
DFMO. With the low toxicity profile of DFMO, its MYCN-targeting effects, and the 
immunomodulatory effects that may potentiate antibody efficacy, DFMO warrants further 
investigation in combination with neuroblastoma-specific immunotherapy such as 
dinutuximab. This trial proposes the addition of DFMO to the ANBL1221 backbone of 
irinotecan/temozolomide/dinutuximab with the hypothesis that DFMO will improve the 
anti-tumor activity of the ANBL1221 regimen by depleting polyamines, enhancing 

  
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chemosensitivity, and improving dinutuximab response through immunomodulatory 
effects on the tumor microenvironment. 
 
Despite the early success of the dinutuximab/chemotherapy combination in relapsed and 
refractory neuroblastoma, less than half of all patients assigned to this regimen had an 
objective response, and biomarkers of response to this chemo-immunotherapy regimen, as 
well as DFMO, remain to be identified. The effects of DFMO on NK cell number and 
function are currently unknown; however, prior work supports NK cell activation as a 
potential mechanism of activity.16 As the effects of DFMO on key effector cells regulating 
antibody dependent cellular cytotoxicity (ADCC) deserve further investigation, peripheral 
blood mononuclear cells (PBMCs) will be collected to assess immune cell subsets during 
Course 1 of therapy, with a focus on NK fractions. The planned 7-day single agent lead-in 
with DFMO provides the opportunity to gain specific information about immune cell 
subsets prior to DFMO treatment, after 7 days of daily DFMO, and prior to chemo-
immunotherapy. This trial will allow for the exploration of such biomarkers in a controlled 
fashion given that the DFMO with chemo-immunotherapy is being compared to chemo-
immunotherapy alone. 
 
Rationale for irinotecan, temozolomide, and dinutuximab backbone 
ANBL1221 showed that irinotecan/temozolomide/dinutuximab (I/T/DIN) has significant 
activity when used at first declaration of refractory or relapsed disease. The randomized 
portion of the trial used a “pick the winner” design to select the preferred molecularly-
targeted anti-cancer agent (temsirolimus or dinutuximab) that merited further study. At 
interim analysis, among the 17 patients assigned to I/T/DIN, 9 had objective responses (5 
CR, 4 PR). Responses were observed in patients with both relapsed disease (5/10; 3 PR, 2 
CR) and refractory disease (4/7; 3 CR, 1 PR).3 Among I/T/DIN responders, prior frontline 
therapy included high dose chemotherapy with stem cell rescue in 5 and anti-GD2 therapy 
in 3 patients. While I/T/DIN was shown be the optimal combination for further study based 
on the a priori definitions that were part of the selection design, the confidence intervals 
around the 53% response rate were wide (95% CI: 0.31, 0.74). Therefore, the protocol was 
amended to permit enrollment of an additional 36 patients, all of whom were to be treated 
with I/T/DIN. An overall objective response rate of ~41.5% (95% CI: 0.29, 0.55) was 
observed.4 Of the 53 patients assigned to the regimen in total, 51 received I/T/DIN therapy. 
Among these, 22 demonstrated objective responses, including 11 with complete response 
(CR) and 11 with partial response (PR). In addition, 22 had stable disease (SD) and 7 had 
progressive disease (PD).4, 5  
 
I/T/DIN therapy was generally well tolerated; however, several important toxicities were 
noted.4, 5 Of the 51 patients evaluable for toxicity, 13 (25%) had  Grade 3 pain, 8 (16%) 
had  Grade 3 diarrhea, and 4 (8%) had  Grade 3 vomiting. Neutropenia ( Grade 3) was 
observed in 14 (27%),  Grade 3 thrombocytopenia in 5 (10%), and  Grade 3 
fever/infection in 11 (22%). One patient experienced Grade 4 hypoxia and required 
mechanical ventilation for more than 24 hours. A second patient required discontinuation 
of dinutuximab therapy due to bronchospasm. One patient developed Grade 3 motor 
neuropathy which recovered 6 weeks following discontinuation of dinutuximab therapy. 
One patient died of sudden death 2 days following completion of the 14th cycle of 
dinutuximab based therapy and cause of death was undetermined despite all investigations 
including full autopsy. While the response rate to this regimen is quite promising, there 
remains room for improvement in terms of both response rate and regimen-associated 
toxicity.  

  
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2.2 
Preclinical Studies  
There is preclinical evidence that the activity of DFMO is related to both cancer cell 
intrinsic and immunomodulatory mechanisms, making it appealing in this combination 
setting. Complementary neuroblastoma tumor models demonstrate a benefit for DFMO 
treatment. Preclinical data recurrently demonstrate anti-tumor activity for DFMO alone 
and in combination with chemotherapy in mouse models of neuroblastoma, both transgenic 
models driven by MYCN and xenografts of genomically diverse human neuroblastomas.7, 
17 These studies have used 1 gram% DFMO in drinking water, with measured DFMO 
intake providing an exposure of ~7,000 mg/m2/day human equivalent dose (HED) when 
allometrically scaled from rodent to human. DFMO monotherapy was studied in the TH-
MYCN transgenic neuroblastoma model at doses of 0.25, 0.5 and 1 gram% DFMO ad 
libitum. Only 1 gram% DFMO extended survival compared to vehicle treated mice 
(p < 0.0001; M. Hogarty, personal communication). Similarly, in a syngeneic mouse NXS2 
neuroblastoma model only 1 gram% DFMO extended survival, whereas 0.25 and 
0.5 gram% did not (p < 0.05; A. Yu, personal communication). Serum concentrations in 
the mouse models varied widely but maximal concentrations measured were ~50 μM at 
0.25 gram%, ~120 μM at 0.5 gram%, and ~140 μM at 1 gram% DFMO (only the higher 
dose demonstrated anti-tumor activity). 
 
The mechanisms of anti-tumor activity for DFMO beyond depletion of essential 
polyamines remain under investigation; however, inhibition of oncogenic protein 
translation and modulation of immune surveillance have been identified as key 
contributors. The global protein translation factor eIF5A is inactive until activated by a 
modification requiring the polyamine spermidine. This hypusination step has been shown 
to be inhibited in neuroblastoma cell lines by DFMO at > 150 μM exposures, with 
concomitant reduction in global protein translation (M. Hogarty, personal communication). 
 
Along with the tumor intrinsic effects of inhibiting polyamine biosynthesis to induce tumor 
cell stress, DFMO also influences the tumor microenvironment (TME). Polyamines and 
their precursor, arginine, regulate the activity of tumor associated lymphocytes, 
macrophages, NK cells and neutrophils in favor of tumor growth.18 Through increased 
ornithine intake and increased synthesis of polyamines, tumor cells increase arginase 
(ARG1) activity. ARG1 activity contributes to the induction of immunosuppressive 
ARG1-expressing tumor associated macrophages (TAMs) and the inhibition of anti-tumor 
NK cells.19 DFMO inhibits the activity of ARG1 directly as well as indirectly by inhibiting 
ODC1 to prevent increased ornithine consumption.15 These ARG1 inhibitory properties 
credential a role for DFMO in restoring NK cell activity for ADCC.20 In preclinical mouse 
models, DFMO given with a polyamine transport inhibitor (AMXT1501) had potent 
antitumor effects against Myc-driven carcinomas grown in an immune competent mouse, 
but had no effect on the same tumors grown in an immunocompromised mouse, 
demonstrating an effect of DFMO through the immune cells themselves.21 This aspect of 
the anti-tumor activity of DFMO may be particularly relevant in high-risk neuroblastoma, 
where the tumor microenvironment has increased regulatory T-cells as well as inhibitory 
TAMS.22, 23 Given that anti-GD2 antibody therapy has shown marked efficacy in 
combination with chemotherapy at relapse3, 24 and that a major barrier to further improve 
outcomes is likely the immunosuppressive TME, the immunomodulatory effects of DFMO 
and its potential to enhance dinutuximab response deserve to be investigated.  
 

  
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2.3 
Adult Studies 
DFMO is FDA approved for the treatment of Trypanosomiasis, specifically “sleeping 
sickness” encephalitis and is only distributed in Africa through the World Health 
Organization 
(WHO). 
The 
adult 
recommended 
IV 
dose 
is 
equivalent 
to 
12,000-18,000 mg/m2/day25 and the bioavailability of the oral dose is 55%.26 The main 
toxicities at the adult MTD were gastrointestinal, with diarrhea, nausea and vomiting in up 
to 40% of patients.26 Seizures were seen in 7% of adults treated for encephalitis, which was 
likely related to the CNS inflammation from infection.25, 27 Neurologic toxicity has only 
rarely been reported in cancer trials with DFMO, specifically in patients with gliomas.28-31 
Ototoxicity, defined by modest hearing loss across a range of frequencies, is seen with high 
dose chronic exposures, increases with older age and is reversible.32, 33 Interestingly, it 
appears to affect patients with normal hearing at baseline more than those with baseline 
hearing deficits.33 Regular audiologic assessments will be performed on this trial to monitor 
for this toxicity.  
A large trial to assess DFMO safety in trypanosomiasis used a dose of 600 mg/kg/day IV 
divided every 6 hours, and included 226 children less than 15 years of age.27. Despite the 
high doses of DFMO used in this study, and the debilitated status of many of the patients, 
toxicity was acceptable. Grade 3 or 4 toxicities were rare and seen in 6.5% of patients. The 
most common were fever, diarrhea and bacterial infection (all in less than 6% of the 
patients treated). Neurologic events were seen in this population, although most were 
Grade 2 or less. Grade 3 or 4 seizures or confusion occurred in 4.8 and 4% of patients, 
respectively. Grade 1 and 2 toxicities including abdominal pain and headache were 
frequent. Fever and injection site reactions were also common.27 
 
DFMO has been studied extensively in adults with cancer. A Phase 1 trial (n=22) evaluated 
oral DFMO as a single agent at doses ranging from 3 to 21 g/m2/day divided every 
6 hours.32 GI and hematologic side effects were seen. Nausea, diarrhea and anorexia were 
seen in about 65% of patients but were graded as moderate; only 1 patient discontinued 
DFMO due to GI symptoms. Anorexia was more significant and common at the highest 
dose level of 21 g/m2/day. The dose limiting toxicity was reversible thrombocytopenia seen 
in patients who had received prior chemotherapy. Plasma DFMO concentrations with this 
dosing reached low mM concentrations sufficient to inhibit ODC activity in vitro. The 
recommended single agent Phase 2 dose was 9,000 mg/m2/day (=300 mg/kg/day, orally) 
divided every 6 hours for patients previously treated with chemotherapy.32  
A Phase 2 study of DFMO for patients with colorectal or small cell lung cancer tested this 
dose level (9,000 mg/m2/day) in a 21-day (out of 28 days) or 28-day continuous regimen.34, 
35 The former schedule was associated with reduced toxicity and better tolerability.35 A 
Phase 1/2 study for patients with metastatic breast carcinoma also identified 
9,000 mg/m2/day (divided three times a day) as the MTD of DFMO given orally for 
14 days followed by a 14-day rest period.34 This regimen was well tolerated with only two 
patients experiencing Grade 3 diarrhea. No other Grade 3 or higher toxicities were 
observed. Hematologic toxicity was mild (Grade 1-2 anemia, Grade 1 thrombocytopenia) 
and no transfusions were required. No significant ototoxicity was seen. Only a single 
patient, who received 18 cycles of DFMO, developed asymptomatic 5-10 dB loss at high 
frequencies.34 No objective responses were seen on either trial.34, 35  
In a Phase 2 trial for patients with malignant glioma, DFMO was given at 
10,800 mg/m2/day divided every 8 hours for 14 days out of 21 days.28 Grade 3 or 4 diarrhea 

  
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was seen in 4 patients (4%) and was controlled with supportive care or by dividing the 
daily dose over 4-6 times per day. Grade 3 ototoxicity was noted in 12 of 86 patients and 
was more common in older patients and those exposed to loud noises. Twenty patients 
(45%) with anaplastic glioma achieved stable disease or better with four patients (9%) 
demonstrating partial response and 9 (20%) experiencing minor response. Six (17%) 
patients with GBM experienced stable disease or better with 2 (5.5%) each achieving 
partial response and minor response.28 
 
DFMO has been studied in combination with chemotherapy and radiation therapy. In a 
phase 1/2 study of DFMO with chemotherapy, 70 adult patients were treated with either 
standard carcinoma chemotherapy regimens (32 patients) or DFMO in combination with 
standard chemotherapy regimens. DFMO was given orally at a dose of 5,100 mg/m2/day 
divided 
three 
times 
a 
day. 
Chemotherapy 
regimens 
included 
tamoxifen, 
cyclophosphamide-methotrexate-5-fluorouricil (5-FU), cyclophosphamide-vincristine-
methotrexate-5FU, doxorubicin-cyclophosphamide with or without cis-platinum.36 There 
were no significant differences in hematological toxicities, however, while transient GI 
toxicities (anorexia, nausea, vomiting, diarrhea) were slightly more common among 
patients treated with DFMO, these were mainly mild, reversible, and were not dose-
limiting. Ototoxicity was dose-limiting with 19% of patients having severe hearing loss 
(55-80dB); 16% of patients discontinued DFMO therapy for this reason. 36 
 
Several randomized trials studied the addition of DFMO to radiotherapy or post-radiation 
chemotherapy regimens for newly diagnosed patients with high-grade gliomas.29-31 Patients 
with glioblastoma multiforme (GBM) (n=231) were randomized to receive either standard 
or hyperfractionated radiation with or without concomitant oral DFMO at 5,400 mg/m2/day 
continuously for 1 week prior throughout radiation therapy.31 The DFMO regimens were 
well tolerated. Fatigue and GI toxicity were seen more frequently, but most toxicities were 
Grade 1 or Grade 2. Grade 3 ototoxicity was seen in 3 of 116 patients who received 
continuous DFMO. There was no improvement in survival compared to radiation alone 
(standard or hypofractionated).31 Two randomized trials added oral DFMO at 
9,000 mg/m2/day to post-radiation chemotherapy (procarbazine, lomustine and vincristine; 
PCV) for either GBM or anaplastic astrocytoma (AA) patients.29, 30 In both trials, a total of 
259 patients (134 GBM, 125 AA) were randomized to receive PCV with oral DFMO given 
for 14 days out of 28 days. Two patients with AA had Grade 3 sensorineural hearing loss 
and no ototoxicity above Grade 2 tinnitus was reported in patients with GBM. GI toxicity 
was more common in the DFMO arm, with diarrhea occurring only in the DFMO+PCV 
arm (6% v. 0%). No improvement in survival was seen with the addition of DFMO for 
GBM patients but improved progression-free survival was observed in AA patients who 
received DFMO (6.3 yrs v. 5.1 yrs).29, 30 
2.4 
Pediatric Studies 
The first report of DFMO in children with cancer was reported in 1981 when 8 children 
with relapsed/refractory ALL received either methylglyoxal bisguanylhydrazone (MGBG, 
an Amd1 inhibitor) or MGBG and DFMO combined. DFMO was dosed at 3,000 to 
15,000 mg/m2/day over 3-5 days. No toxicity was reported in these 8 patients and half of 
patients had responses, defined by complete clearance of peripheral blasts.37 DFMO has 
been evaluated as a single metronomic agent for one cycle followed by administration in 
combination with etoposide in a multi-center Phase 1 trial in patients with 
relapsed/refractory neuroblastoma.38 Doses of 500-1500 mg/m2 PO twice daily were very 
well tolerated and no DLTs were observed.38  

  
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The NANT N1201 Phase 1 study evaluated the combination of DFMO with celecoxib, 
cyclophosphamide and topotecan.39 It included a 7-day lead-in with DFMO (three times 
per day) and celecoxib (250 mg/m2/dose orally BID) on Days 1-7. Cyclophosphamide 
(250 mg/m2/dose IV) and topotecan (0.75 mg/m2/dose IV) were given once daily for 5 days 
on Days 8-12. DFMO was continued on Days 8-21 and celecoxib was continued on 
Days 8-28 to complete one cycle. DFMO was dose escalated from 3,000 mg/m2/day, 
divided TID, to 9000 mg/m2/day, divided TID. Twenty-four patients were accrued to this 
study with a median age of 6.8 years. Seven patients had MYCN amplified tumors, 13 had 
MYCN non-amplified tumors, and in 4 cases MYCN status was unknown. Twelve patients 
(50%) had tumor-involved bone marrow at study entry. Patients received 124 total cycles 
(range, 1-17). 
 
The 4-drug combination was generally well tolerated at all dose levels.39 The combination 
of DFMO at dose level 3A (6,750 mg/m2/day divided 3 times a day) in combination with 
cyclophosphamide (250 mg/m2/dose daily x 5 days) and topotecan (0.75 mg/m2/dose daily 
x 5 days) and celecoxib (250 mg/m2 daily) was defined as the recommended Phase 2 dose. 
This dose of DFMO will be used in this study. Observed toxicities were primarily 
hematologic and fever related. There were three Cycle-1 DLTs over 4 dose levels 
(hematologic, in the setting of tumor progression; anorexia; transaminase elevation). One 
patient had Grade 3 hearing loss which was reversible and did not recur with retreatment. 
Three (12.5%) patients had Grade 3 diarrhea but none were DLTs. The observed objective 
response rate [complete response (CR) + partial response (PR)] was 13%. The 
CR+PR+minor response (MR) rate was 26%, and the CR+PR+MR+stable disease (SD) 
rate was 69%. Median OS on this trial was 36.2 months, PFS was 13.3 months, and time-
to-progression of 19.8 months, at the most recent analysis.39 
 
2.5 
Dosing Rationale 
In this trial, DFMO will be dosed orally. The bioavailability of orally administered DFMO 
ranges from 50-60% in multiple studies.26 The dose of DFMO to be used for this trial 
(6,750 mg/m2/day divided 3 times a day orally) was the recommended phase 2 dose 
determined on the NANT consortium N2012-01 trial of DFMO in combination with 
cyclophosphamide, topotecan and celecoxib. The half-life of DFMO is 3-4 hours when 
delivered orally, therefore, a TID dosing regimen provides continuously higher plasma 
concentrations to optimize systemic polyamine depletion. DFMO will be given at this dose 
during therapy.  
 
Starting with Amendment 2A, DFMO will be given on a discontinuous basis, allowing for 
a 7-day break without DFMO administration in each cycle, similar to the dosing used in 
the NANT N2012-01 trial. Four of the first eight patients enrolled on the DFMO containing 
arm (Regimen B) of this study with available ototoxicity data developed documented Grade 3 
hearing loss from their baseline. Hearing loss is a known toxicity of DFMO and is typically 
reversible. Prior studies have shown that the risk of DFMO-associated ototoxicity is decreased 
when the DFMO is administered in an intermittent fashion, with a 7-14 day break per cycle. 
At similar or higher dosing compared to that used in ANBL1821, the incidence of Grade 3 or 
higher hearing loss with interrupted dosing was less than 5%40, 30, 29 Similarly, in the 
NANT2012-01 trial, DFMO dosed at 3000-9000 mg/m2/day for 21 days out of a 28-day cycle 
resulted in only 1 of 24 patients experiencing new Grade 3 hearing loss. This hearing loss was 
reversible and did not recur with re-treatment. 39 The NANT2012-01 trial was conducted in a 
relapsed NBL population similar to that of ANBL1821 supporting that intermittent dosing of 

  
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DFMO may decrease the risk for significant ototoxicity. Therefore, given the incidence of 
hearing loss seen initially on this study with continuous dosing, this trial will now include a 
7-day break in DFMO dosing to decrease the chances of additional hearing loss. Additionally, 
DFMO will be held at first detection of significant hearing loss.  
 
DFMO PK data for lower DFMO doses in the NMTRC phase 1 study was linear between 
1,000 and 3,000 mg/m2/day with mean Cmax ranging from 40 μM to 120 μM.38  On  the NANT 
N2012-01 trial, mean Cmin was measured at about 20 μM, 90 μM, 135 μM and 130 μM at dose 
levels of 3,000; 4,500; 6,750 and 9,000 mg/m2/day, respectively.39  The estimated Cmax (2-3 
times Cmin with these PK parameters) would therefore be > 270 μM at 6,750 mg/m2/day 
DFMO, the dose to be studied here. This is above the DFMO exposure threshold at which 
in vitro studies demonstrate effects on protein translation, and at which in vivo studies 
demonstrate anti-tumor activity and immunomodulatory effects on the TME.7 
 
In this trial, DFMO will be combined with the backbone regimen of irinotecan and 
temozolomide with dinutuximab, which has been shown to be tolerable on the ANBL1221 
study.3 The irinotecan/temozolomide regimen has fewer hematologic toxicities compared 
to cyclophosphamide/topotecan used in the previous NANT trial that combined DFMO 
with chemotherapy.3, 41 This will likely decrease delays in treatment in a heavily pre-treated 
population. To limit unexpected or severe toxicities, this trial will closely monitor for 
increased toxicity on the DFMO arm compared to the standard arm consisting of 
dinutuximab, irinotecan, temozolomide and sargramostim, with specific attention to 
DFMO-related toxicities, including diarrhea and hearing loss. Starting with Amendment 4, 
patients will receive up to 6 cycles of protocol therapy due to changes in drug supply.  
 
2.6 
Rationale for Correlative Studies 
2.6.1 
Rationale for studying immune cell subsets and cytokine profiles 
Despite the early success of the dinutuximab/chemotherapy combination in 
relapsed and refractory neuroblastoma, less than half of all patients assigned to this 
regimen had an objective response, and biomarkers of response to this chemo-
immunotherapy regimen, as well as DFMO, remain to be identified. The effects of 
DFMO on NK cell number and function are currently unknown, however prior 
work supports NK cell activation as a potential mechanism of activity.16  As the 
effects of DFMO on key effector cells regulating antibody dependent cellular 
cytotoxicity (ADCC) deserve further investigation, peripheral blood mononuclear 
cells (PBMCs) will be collected to assess immune cell subsets during course 1 of 
therapy, with a focus on NK fractions. The planned 7-day single agent lead-in with 
DFMO provides the opportunity to gain specific information about immune cell 
subsets prior to DFMO treatment, after 7 days of daily DFMO, and prior to chemo-
immunotherapy. This trial will allow for the exploration of such biomarkers in a 
controlled fashion given that the DFMO with chemo-immunotherapy is being 
compared to chemo-immunotherapy alone. 
 
 
An understanding of the baseline status and the nature of changes in activity of 
immune effector cells in response to immune modulating drugs will be important 
for the design of future passive immunotherapy regimens for patients with 
neuroblastoma, specifically, the number of NK and NK-T cells, T cell subsets and 
expression of NK activation and inhibitory receptors present in patient blood and 
the influence that DFMO therapy has on these subsets. Preclinical data support a 

  
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role for arginine-polyamine signaling in maintaining a tumor-permissive and 
immune-hostile microenvironment.15 DFMO regulates this process in favor of 
reinstating anti-tumor immune response through depleting arginine-regulated 
immune cell suppression.15, 19 Therefore, DFMO may also regulate the immune 
system to enhance antibody dependent cell-mediated cytotoxicity (ADCC) that is 
critical for dinutuximab effects. Cytokines released by cancer cells or by cells of 
the tumor microenvironment have a multitude of effects that can either promote 
tumor cell growth or can potentiate the effect of immunotherapy.42 It is clear that 
the polyamine/arginine pathway suppresses the “inflammatory” host state in favor 
of tumor growth.19, 21, 43 Thus understanding the changes in cytokine repertoires 
during the single agent DFMO therapy week and during administration of DFMO 
with chemo-immunotherapy may identify critical immune biomarkers that are 
augmented or expressed with the addition of DFMO and positively contribute to 
therapy response. 
 
2.6.2 
Rationale for analysis of GD2 levels in bone marrow 
The ganglioside composition of neuroblastoma cells was studied decades ago,44 
yet much remains to be learned regarding the relationship between the presence of 
gangliosides on neuroblastoma cells (particularly GD2) and response to anti-GD2 
based therapy. Lack of GD2 positivity has been observed in 13% of neuroblastoma 
specimens obtained from children with INSS Stage 4 disease at diagnosis.45 Assays 
to assess GD2 presence in real-time are lacking and utilization of an FFPE block 
has been hampered by loss of antigen. Dr. C. Patrick Reynolds has developed a bi-
color flow cytometry assay to detect and quantify GD2 positive neuroblastoma 
tumor cells in bone marrow aspirates.46 This allows for sorting of GD2+ and GD2- 
cells from bone marrow aspirates for further research analysis, such as genomics. 
Determining GD2 expression in bone marrows may elucidate mechanisms of 
chemo-immunotherapy resistance as it pertains to differences in cell surface 
antigen expression for primary and metastatic sites. Determining changes in GD2 
expression in bone marrows over time may also provide insight into mechanisms 
of therapy response and resistance, as well as DFMO and chemotherapy effects 
specifically on GD2 tumor cell expression. 
 
2.6.3 
Rationale for evaluating the effects of DFMO on pain  
The randomized design of this study provides a unique opportunity to explore how 
patient reported outcomes (PROs), or proxy report for young patients, differ with 
the addition of DFMO. Patient and proxy reported outcomes, including pain, are 
increasingly important tools which can be used to support the superiority of a 
treatment arm in randomized studies. GD2 expression in normal tissues is 
restricted to cerebellar neurons, skin melanocytes and peripheral pain fibers.47 A 
well-known side effect of dinutuximab is reversible peripheral pain, necessitating 
the use of intravenous pain medication, often narcotics, during the dinutuximab 
infusion.48-51 Given the role of ODC1 in normal physiology associated with 
environmental signals including touch,52-54 this pathway has been investigated for 
its potential impact on allodynia (pain due to a stimuli which does not normally 
induce pain, such as touch). Silva et al. reported that allodynia and edema induced 
by Freund’s adjuvant injection in paws of rats induced expression and activity of 
ODC155 and that injection of the ODC1 product putrescine or other polyamines 
induced allodynia and edema in the absence of other stimuli. DFMO 

  
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administration decreased allodynia and edema induced by adjuvant in an animal 
model of inflammation-induced pain.55 
 
Preliminary studies evaluating rat models of allodynia demonstrate that DFMO 
may reduce dinutuximab induced pain sensation (personal communication, Dr. 
Alice Yu). Furthermore, pro-inflammatory cytokines have been linked to 
neuropathic pain and the immunomodulatory effects of DFMO may influence such 
cytokine levels.56 Therefore, the association between inflammatory serum cytokine 
levels (IL1, IL6, TNF-alpha, IFN-gamma, etc.), pain, and DFMO therapy merit 
evaluation. This exploratory aim is to examine the change in pain during 
dinutuximab infusion in the patients on the DFMO arm compared to the control 
arm as determined by the Faces Pain Scale. Patients over the age of 5, and proxy 
for those under the age of 5, will complete the Faces Pain Scale-Revised on Day 1 
of chemotherapy with irinotecan and temozolomide, and then daily during the 
dinutuximab infusion. This will be measured during Cycles 1, 2, 4, and 6. Patients 
enrolled prior to Amendment 4 will also have the Faces Pain Scale-Revised 
collected during Cycle 12 of therapy. The Faces Pain Scale-Revised is a simple 
visual scale validated to provide real-time pain assessment in the pediatric and 
adolescent and young adult (AYA) population.57 It has been recommended as the 
superior PRO measure for pain in pediatric populations based on its excellent 
psychometric properties and responsiveness to change.58 The scale scores pain 
based on a visual cue on a scale of 0 to 10. Pain will also be assessed by measuring 
the amount of intravenous narcotic administered during the dinutuximab infusion. 
Patients will also be evaluated for differences in pro-inflammatory cytokine levels 
during dinutuximab infusion. 
 
2.6.4 
Potential use of banked specimens for future research 
The goal of this study is to define the impact of polyamine depletion by DFMO on 
cancer cell survival and response to chemo-immunotherapy, specifically 
dinutuximab/irinotecan/temozolomide. This trial represents a unique opportunity 
to collect and bank clinically-annotated specimens from patients treated with 
chemo-immunotherapy alone or in the setting of polyamine depletion. These 
valuable specimens will serve as a unique resource for exploratory scientific 
projects. Future investigation of these specimens may include determination of 
tumor MYCN expression, ODC1 expression and promotor genotypes, as well as 
urine polyamine markers, and correlation to response to identify predictive 
biomarkers.  
 
Stored biological specimens will be available for further and novel research upon 
initial findings, general technical advances, and newly acquired knowledge of the 
underlying biology of these tumors. These clinically-annotated tumor, blood, and 
urine specimens will be available to external investigators interested in studying 
effects of polyamine depletion and chemo-immunotherapy in neuroblastoma and 
will provide opportunities for interdisciplinary and collaborative basic research. 
 
2.7 
Importance of trial and impact on future clinical practice 
Survival of patients with relapsed high-risk neuroblastoma remains poor despite multi-
modality therapy. Moreover, despite improvement in overall survival for high-risk 
neuroblastoma, an unacceptable percentage of patients experience early disease 

  
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progression or have disease that is refractory to current induction therapy. It is therefore 
critical to integrate agents that target specific biologic pathways critical to neuroblastoma 
survival. DFMO has shown activity against neuroblastoma in both in vitro and in vivo 
animal models and has been shown to be safe and tolerable in combination with 
chemotherapy in pediatric Phase 1 trials. This will be the first attempt to add an immune 
modifying agent to dinutuximab in combination with chemotherapy. This study will serve 
as a foundation for future study of such a combination as part of frontline Induction therapy 
in this important pediatric disease.  
 
 
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 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.1.2 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients. 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 

  
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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 
for Local Context (SSW) 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 
email 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 in order for the processing 
of the IRB/REB approval record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form 
FDA 1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional 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); 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 Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 

  
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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.  
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the registration system in 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 user name and 
password.  
2) In order to make a reservation, the patient must have an OPEN patient 
number. Click on the ‘Slot Reservation’ tab to create an OPEN patient 
number, under ‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient. 
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter 
the COG Patient ID, and choose the required stratum (if applicable) in 
order to obtain a reservation. 
 
Refer to the ‘Slot Reservation Site User Guide’ posted under the ‘Help’ tab in 
OPEN for detailed instructions: 
https://www.ctsu.org/open/Site_Resources/Training/Users_Manual/CTSU-
OPEN-SlotReservationSiteUserGuide.pdf 
 
3.1.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or the 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:  Must be on an LPO 
roster, ETCTN corresponding roster, or participating organization roster 

  
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with the role of Registrar. Registrars must hold a minimum of an Associate 
Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars 
must hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the 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 HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may 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. 
 
To access OPEN, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead protocol 
organization (LPO) or participating organization roster. Registrars must hold a 
minimum of an AP registration type.  If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval.  If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes. 

  
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• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.5 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than ten (10) calendar days after the date of study 
enrollment. It is strongly recommended that patients do not start treatment on a 
Friday or weekend. Patients who are started on protocol therapy on a Phase 2 
study prior to study enrollment will be considered ineligible.  
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 
3.1.6 
Patient Stratification 
Patients will be randomized 1:1 to Regimen A (irinotecan/temozolomide/ 
dinutuximab) or Regimen B (DFMO + irinotecan/temozolomide/dinutuximab), 
with stratification according to the following 4 factors: 
 
• 
Disease category (measurable vs. evaluable) 
• 
Prior anti-GD2 therapy (prior exposure to anti-GD2 antibody vs. no prior 
exposure to anti-GD2 antibody) 
• 
Prior DFMO therapy (prior exposure to DFMO vs. no prior exposure to 
DFMO) 
• 
MYCN status (amplified vs. non-amplified vs. unknown) 
 
Please refer to Appendix II for a flowchart for determining the appropriate stratum. 
 
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.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 

  
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obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy. Imaging studies, echocardiogram, and bone marrow 
evaluations, if applicable, must be obtained within 3 weeks prior to start of protocol 
therapy (repeat the tumor imaging, echocardiogram, and/or bone marrows if 
necessary). 
 
3.2.1 
Age 
Patients ≥ 1 year of age at the time of enrollment are eligible for this study. 
 
3.2.2 
Diagnosis  
3.2.2.1 
Histologic Diagnosis: 
Patients must have had histologic verification of neuroblastoma or 
ganglioneuroblastoma or demonstration of neuroblastoma cells in the 
bone marrow with elevated urinary catecholamines [i.e. > 2 x upper 
limit of normal (ULN)], at the time of initial diagnosis. 
 
3.2.2.2 
Active Disease: 
For the purposes of this study, aggressive multidrug chemotherapy is 
defined as chemotherapy including 2 or more agents that must include 
an alkylating agent and a platinum-containing compound as intended to 
treat high-risk disease. The doses of chemotherapy must be comparable 
to those used in frontline high-risk neuroblastoma therapies (examples 
include 
A3973, 
ANBL0532, 
ANBL09P1, 
ANBL12P1, 
and 
ANBL1531). Patients must have ONE of the following:  
1) First episode of recurrent high-risk disease following completion of 
aggressive multi-drug frontline high-risk therapy.  
2) First episode of progressive high-risk disease during aggressive 
multi-drug frontline high-risk therapy.  
3) Primary resistant/refractory disease (less than partial response by 
INRC) detected at the conclusion of at least 4 cycles of aggressive 
multidrug induction chemotherapy on or according to a high-risk 
neuroblastoma protocol (examples include A3973, ANBL0532, 
ANBL09P1, ANBL12P1, ANBL1531, etc.).  
 
3.2.2.3 
Documentation of Disease:  
Patients must have at least ONE of the following at the time of 
enrollment: 
1) Measurable tumor on MRI or CT scan. Measurable is defined as 
≥ 10 mm in at least one dimension on spiral/helical CT that is MIBG 
avid or demonstrates increased FDG uptake on PET scan.  
2) MIBG-avid lesion detected on MIBG scan with positive uptake at a 
minimum of one site. This site must represent disease recurrence 

  
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after completion of therapy, progressive disease on therapy, or 
refractory disease during induction.  
3) Patients with resistant/refractory soft tissue disease that is not MIBG 
avid or does not demonstrate increased FDG uptake on PET scan 
must undergo biopsy to document the presence of viable 
neuroblastoma. Biopsy is not required for patients who have a new 
site of soft tissue disease (radiographic evidence of disease 
progression) regardless of whether progression occurs while 
receiving therapy or after completion of therapy. 
4) Patients with bone marrow disease only will be eligible if they have 
more than 5% disease involvement (documented neuroblastoma 
cells) in at least one sample from bilateral bone marrow biopsies. 
 
Note: Patients with elevated catecholamines (i.e. > 2 x ULN) only are 
NOT eligible for this study. 
 
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.  
 
See https://members.childrensoncologygroup.org/prot/reference_materials.asp 
under Standard Sections for Protocols. 
 
3.2.4 
Prior Therapy 
3.2.4.1 
Primary refractory/resistant patients must have received at least 4 cycles 
of frontline high-risk chemotherapy. Frontline therapy may also have 
included surgery, chemotherapy, autologous SCT +/- MIBG, 
immunotherapy, radiotherapy, and retinoids but must NOT have 
received second line therapy for resistant/refractory, relapsed, or 
progressive disease. Patients who received intensified therapy for poor 
induction response or refractory disease (e.g. MIBG) will be considered 
to have received second line therapy and will not be eligible. 
 
3.2.4.2 
Myelosuppressive chemotherapy: At least 14 days must have elapsed 
since completion of myelosuppressive therapy. 
 
3.2.4.3 
Biologic (anti-neoplastic agents): Anti-cancer agents not known to be 
myelosuppressive (e.g. not associated with reduced platelet or ANC 
counts): ≥ 7 days after the last dose of agent. See DVL homepage for 
commercial and Phase 1 investigational agent classifications.  
 
Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be recovered 
to Grade ≤ 1. 
 

  
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3.2.4.4 
XRT: No interim time prior to study entry is required following prior RT 
for non-target lesions. However, patients must not have received 
radiation for a minimum of 4 weeks prior to study entry at the site of any 
lesion that will be identified as a target lesion to measure tumor response. 
Lesions that have been previously radiated cannot be used as target 
lesions unless there is radiographic evidence of progression at the site 
following radiation or a biopsy done following radiation shows viable 
neuroblastoma. Palliative radiation while on study is not permitted. 
 
3.2.4.5 
Stem Cell Transplants (SCT): Patients are eligible ≥ 6 weeks after 
autologous stem cell transplants or stem cell infusions (including stem 
cell infusions given as supportive care following 131I-MIBG therapy) as 
long as hematologic and other eligibility criteria have been met.  
 
3.2.4.6 
131I-MIBG therapy: Patients are eligible ≥ 6 weeks after therapeutic 131I-
MIBG provided that all other eligibility criteria are met. 
 
3.2.4.7 
Study specific limitations on prior therapy:  
1. Subjects who have previously received anti-GD2 monoclonal 
antibodies with or without retinoids for biologic therapy are eligible 
unless they have had progressive disease while receiving prior anti-
GD2 therapy or progressed/relapsed within 3 months of receiving 
anti-GD2 therapy. However, eligible patients may NOT have 
received anti-GD2 monoclonal antibodies in combination with 
chemotherapy. 
2. Subjects who have received autologous marrow infusions or 
autologous stem cell infusions that were purged using monoclonal 
antibody linked to beads are eligible. 
3. Subjects who have previously received DFMO are eligible for this 
study provided they have not had progressive disease while receiving 
DFMO or progressed/relapsed within 3 months of completing 
DFMO.  
 
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. 
pegfilgrastim) 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: 
For patients with solid tumors (without marrow involvement) including 
status post SCT: 
- Peripheral absolute neutrophil count (ANC)  750/L 

  
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- Platelet count  75,000/L (transfusion independent) 
 
Patients known to have bone marrow involvement with neuroblastoma 
are eligible provided that minimum ANC and transfusion independent 
platelet count criteria are met (as above). However, these patients are 
not evaluable for hematological toxicity. 
 
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 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR 59 utilizing child length and stature data published 
by the CDC. 
 
3.2.6.3 
Adequate Liver Function Defined As: 
- 
Total bilirubin ≤ 1.5 x ULN for age AND  
- 
SGPT (ALT) ≤ 5.0 x ULN for age (≤ 225 U/L). For the purpose of 
this study, the ULN for SGPT is 45 U/L. 
 
3.2.6.4 
Adequate Cardiac Function Defined As: 
- 
Shortening fraction of  27% by ECHO, or 
- 
Ejection fraction of ≥ 50% by ECHO or gated radionuclide study. 
 
3.2.6.5 
Adequate Pulmonary Function Defined As: 
- 
No evidence of dyspnea at rest, no exercise intolerance, no chronic 
oxygen requirement, and room air pulse oximetry > 94% if there is 
a clinical indication for pulse oximetry. Normal pulmonary function 
tests in patients who are capable of cooperating with testing 
(including DLCO) are required if there is a clinical indication for 
determination. For patients who do not have respiratory symptoms, 
full PFTs are NOT required. 
 
3.2.6.6 
Adequate Central Nervous System Function Defined As: 
- 
Patients with a history of CNS disease must have no clinical or 
radiological evidence of active CNS disease at the time of study 
enrollment 

  
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- 
Patients with seizure disorders may be enrolled if seizures are well 
controlled on anti-convulsants 
- 
CNS toxicity ≤ Grade 2 
 
3.2.7 
Exclusion Criteria 
 
3.2.7.1 
Pregnancy and Breastfeeding 
Men and women of childbearing potential and their partners must agree 
to use adequate contraception while enrolled on this study. Based on the 
established teratogenic potential of alkylating agents, pregnant women 
will be excluded from this study. Because of potential risks to breastfed 
infants due to drug metabolites that could be excreted in breast milk, 
female patients who are lactating must agree to stop breastfeeding or 
will otherwise be excluded from this study. Females of childbearing 
potential must have a negative pregnancy test to be eligible for this 
study. 
 
3.2.7.2 
Patients with only elevated catecholamines (i.e. > 2 x ULN) are NOT 
eligible for this study. 
 
3.2.7.3 
Patients must have been off pharmacologic doses of systemic steroids 
for at least 7 days prior to enrollment. Patients who require or are likely 
to require pharmacologic doses of systemic corticosteroids while 
receiving treatment on this study are ineligible. The only exception is for 
patients known to require 2 mg/kg or less of hydrocortisone (or an 
equivalent dose of an alternative corticosteroid) as premedication for 
blood product administration in order to avoid allergic transfusion 
reactions. The use of conventional doses of inhaled steroids for the 
treatment of asthma is permitted, as is the use of physiologic doses of 
steroids for patients with known adrenal insufficiency. 
 
Patients 
on 
any 
other 
immunosuppressive 
medications 
(e.g. 
cyclosporine, tacrolimus) are not eligible. 
 
3.2.7.4 
Patients must not have received prior treatment with irinotecan and 
temozolomide. 
 
3.2.7.5 
Patients must not have received enzyme-inducing anticonvulsants 
including phenytoin, phenobarbital, or carbamazepine for at least 7 days 
prior to study enrollment. Patients receiving non-enzyme inducing 
anticonvulsants such as gabapentin, valproic acid, or levetiracetam will 
be eligible. (See Appendix III for additional enzyme-inducing 
anticonvulsants and acceptable alternative options.) 
 
3.2.7.6 
Patients who have received drugs that are strong inducers or inhibitors 
of CYP3A4 within 7 days prior to study enrollment are not eligible. See 
Appendix IV for a list of agents. 
 
3.2.7.7 
Patients must not have been diagnosed with myelodysplastic syndrome 
or with any malignancy other than neuroblastoma. 

  
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3.2.7.8 
Patients with symptoms of congestive heart failure are not eligible. 
 
3.2.7.9 
Patients must not have ≥ Grade 2 diarrhea. 
 
3.2.7.10 Patients who are unable to tolerate oral/nasogastric/gastrostomy 
medications will not be eligible for this trial. Additionally, patients with 
significant malabsorption will not be eligible for this trial. 
 
3.2.7.11 Patients must not have uncontrolled infection. 
 
3.2.7.12 Patients with a history of Grade 4 allergic reactions to anti-GD2 
antibodies or reactions that required permanent discontinuation of the 
anti-GD2 therapy are not eligible.  
 
3.2.7.13 Patients with a significant intercurrent illness (any ongoing serious 
medical problem unrelated to cancer or its treatment) that is not covered 
by the detailed exclusion criteria and that is expected to interfere with 
the action of study agents or to significantly increase the severity of the 
toxicities experienced from study treatment are not eligible. 
 
3.2.8 
Regulatory Requirements 
 
3.2.8.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.8.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 

  
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4.0 
TREATMENT PROGRAM 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
Patients with high risk neuroblastoma, either primary resistant/refractory or in first relapse 
or progression, will be randomized to receive one of two arms of therapy: Regimen A 
consisting of dinutuximab, irinotecan, temozolomide and sargramostim (GM-CSF), or 
Regimen B, which will include the addition of DFMO to dinutuximab, irinotecan, 
temozolomide, and GM-CSF. Arms will be balanced with respect to disease category 
(measurable vs. evaluable), prior anti-GD2 therapy, prior DFMO therapy, and MYCN 
amplification status. 
 
Each cycle of therapy will be 21 days in length, with the exception of Regimen B Cycle 1. 
Patients randomized to Regimen B will receive a 7-day DFMO pretreatment phase for 
Days -6 to 0 prior to the start of chemotherapy on Day 1 of Cycle 1 to deplete essential 
polyamines.  
 
Patients enrolled prior to Amendment 4: 
Disease assessments will occur after Cycles 2 and 4. Patients with stable disease or better 
on disease assessments after Cycles 2 and 4 will continue on protocol therapy. After 
Cycle 6, patients who achieve a minor response (MR) or better on disease evaluation will 
continue on protocol therapy. After Cycle 6, patients may remain on study for up to 
17 cycles (approximately 1 year of therapy) as long as they maintain a minor response or 
better on disease assessments performed after every 4th cycle. An end of therapy disease 
evaluation will be performed after Cycle 17 for patients who complete all planned protocol 
therapy.   
 
Patients enrolled on Amendment 4 or later: 
Disease assessments will occur after Cycles 2 and 4. Patients with stable disease or better 
on disease assessments after Cycles 2 and 4 will continue on protocol therapy for a 
maximum of 6 cycles. An end of therapy disease evaluation will be performed after Cycle 
6 for patients who complete all planned protocol therapy.   
 
4.2 
General Guidelines for therapy 
See the Parenteral 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. 
 

  
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For COG Supportive Care Guidelines see: https://childrensoncologygroup.org/index.php/ 
cog-supportive-care-guidelines. 
 
4.2.1 
Central line  
All patients will have a central venous line placed to facilitate administration of 
therapy.  
 
4.2.2 
Diarrhea prophylaxis 
Cefixime (8 mg/kg/day PO once daily) 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. 
 
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. 
 
4.2.3 
Pneumocystis jiroveci pneumonia (PJP) prophylaxis 
Patients must receive PJP prophylaxis during study therapy per institutional 
guidelines. 
 
4.2.4 
Other supportive care 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and 
general supportive care are to be used as necessary. 
 
Use of ototoxic drugs (furosemide, vancomycin, aminoglycosides) should be 
avoided when possible during this therapy.  Reasonable alternatives should be used 
if they exist.  
 
Note: Steroids (dexamethasone) may not be used as an anti-emetic. Single dose of 
aprepitant can be used if necessary for anti-nausea; however, multiple day 
aprepitant regimen may result in moderate CYP3A4 inhibition and should be 
avoided if reasonable alternatives exist. 
 
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 

  
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(hydrocortisone 2 mg/kg or less or an equivalent dose of an alternative 
corticosteroid). The use of steroids during protocol therapy requires clear 
justification and documentation.  
 
4.3.2 
External Beam radiotherapy 
Radiotherapy to localized painful lesions is not permitted on study. 
 
4.3.3 
Surgery 
Surgical resection or debulking of soft tissue disease is allowed any time after 
completion of the post-Cycle 6 disease evaluation. Submission of resected residual 
tumor material per Section 14.2.2.2 is strongly encouraged. 
 
4.3.4 
Cytokines or growth factors (G-CSF, Interferon, etc.) not included in the 
Treatment Plan are prohibited during protocol therapy. 
 
4.3.5 
CYP3A4 active agents  
See Appendix IV for a list of CYP3A4 active agents. 
 
Irinotecan is a substrate for CYP3A4 (major) and CYP2B6 (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 IV) and CYP2B6 (e.g. carbamazepine) 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 IV) should also be avoided 
during protocol therapy, if reasonable alternatives exist. 
 

  
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Regimen A Cycle 1 
4.4 
Regimen A Cycle 1 
0B4.4.1   Therapy Delivery Map –CYCLE 1 
Cycle 1 lasts 3 weeks (21 days).  
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Begin Cycle 2 on Day 22 of Cycle 1 or when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever 
occurs later). See Section 5.0 for dose modifications. This TDM is on 2 pages.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Temozolomide 
(TEMO) 
PO or via NG or 
Gtube 
For patients ≥ 0.5 m2: 
100 mg/m2/dose 
 
For patients < 0.5 m2:  
3.3 mg/kg/dose 
 
See dosing table in 
Appendix VI. 
Days 1 - 5 
Max dose = 200 mg 
Round doses to the nearest 5 mg when using 
capsules. 
 
Administer at least 1 hour prior to IRIN 
administration. 
 
Temozolomide is dosed based on body 
surface area for patients whose BSA is at 
least 0.5 m2. For patients with BSA < 0.5 m2, 
dosing is based on body weight (kg).  
Irinotecan (IRIN) 
IV over 90 minutes 
50 mg/m2/dose 
Days 1 - 5 
Administer at least 1 hour after 
temozolomide, see Section 4.4.3. 
Dinutuximab (DIN) 
IV over 10 hours* 
17.5 mg/m2/dose 
Days 2 - 5 
* Infusion duration may be extended up to 
20 hours if needed. 
 
Start immediately following NS bolus and 
irinotecan.  
 
See Section 4.4.3 for detailed administration 
guidelines, including premedications and 
monitoring during the infusion. 
Sargramostim  
(GM-CSF) 
SubQ (preferred) 
or IV over 2 hours 
250 mcg/m2/dose 
Days 6 - 12 
See Section 4.4.3 for administration 
guidelines. 
 
 
 
 
Ht _________ cm 
Wt 
 _________kg BSA _________m2 
Date Due 
Date 
Given 
Day 
TEMO 
____mg 
IRIN 
____mg 
 DIN 
_____ mg 
GM-CSF 
____mcg 
Studies 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
 
1 
______mg 
_____mg 
 
 
a-o 
 
 
2 
______mg 
_____mg 
_____mg 
 
d, o 
 
 
3 
______mg 
_____mg 
_____mg 
 
d, o 
 
 
4 
______mg 
_____mg 
_____mg 
 
d, o 
 
 
5 
______mg 
_____mg 
_____mg 
 
d, o 
 
 
6 
 
 
 
____mcg 
n 
 
 
7 
 
 
 
____mcg 
 
 
 
8 
 
 
 
____mcg 
c, d, e  
 
 
9 
 
 
 
____mcg 
 
 
 
10 
 
 
 
____mcg 
 
 
 
11 
 
 
 
____mcg 
 
 
 
12 
 
 
 
____mcg 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
c, d, e 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
Begin Cycle 2 on Day 22 or when peripheral counts recover with ANC ≥ 750/µL and 
platelets ≥ 75,000/µL (whichever occurs later).  
 
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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Regimen A Cycle 1 
4.4.2 
Required Observations in Regimen A Cycle 1 
 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
 
a. History, physical exam with vital signs, performance status* 
b. Height, weight, BSA* 
c. CBC with differential and platelets (patients who experience Grade 4 neutropenia 
should have CBCs checked at least twice per week until recovery to Grade 3)* 
d. Electrolytes, BUN, creatinine, calcium, magnesium, phosphorus, albumin*  
e. ALT, total bilirubin* 
f. Pregnancy test (obtain for females of childbearing potential) 
g. ECHO or MUGA  
h. Audiogram or BAER – May be obtained within 3 weeks prior to the start of 
protocol therapy. 
i. Bilateral bone marrow aspirates and biopsies 
j. Cross sectional tumor imaging of original primary site and any non-osseous sites 
of disease involvement at study entry (MRI or CT) (submit for central review as 
soon as scan is obtained; see Section 15.1 for imaging details for patients without 
measurable disease) 
k. 
123I-MIBG scan (submit for central review as soon as scan is obtained)  
l. Curie score profile (patients with MIBG avid disease; see Appendix IX for 
worksheet) (submit for central review as soon as scan is obtained) 
m. FDG-PET scan for patients with 123I-MIBG non-avid disease (submit for central 
review as soon as scan is obtained)  
n. Specimens for correlative studies. Post-dinutuximab specimens should be 
collected at a single time point between Day 6 and Day 9. See Section 14 and 
Appendix X for details. 
o. Faces Pain Scale Revised – can be done anytime on Day 1 of therapy. On 
Days 2-5 of therapy, should be performed at least 4 hours after the 
dinutuximab infusion has begun. See Section 14.1.3 for additional detail. 
 
*These baseline studies must be repeated on Day 1 if not performed within 72 hours 
of Day 1. 
 
This listing only includes evaluations necessary to address the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
Page 2 of 2 

  
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Regimen A Cycle 1 
4.4.3 
Treatment Details for Regimen A Cycle 1 (3 weeks = 1 cycle)  
 
Drug doses should be calculated based on the BSA using height and weight 
obtained within 1 week prior to the beginning of each cycle. 
 
Suggested administration schedule for chemotherapy and dinutuximab 
(Days 2-5): 
• 
At hour 0: patient should receive oral temozolomide. 
• 
At hour 1: patient should start IV irinotecan over 90 minutes, and on days 
patient is receiving dinutuximab infusion (Days 2-5 of each cycle), start 
IVF bolus of normal saline (10-20 mL/kg) over 1 hour. 
• 
At hour 2.5: on days patient is receiving dinutuximab infusion (Days 2-5 
of each cycle), start dinutuximab infusion. 
 
 
Temozolomide: PO daily (NG or G-tube administration is allowed) 
Days: 1-5 
Dose: Round doses to the nearest 5 mg when using capsules. See dosing table in 
Appendix VI. 
For patients ≥ 0.5 m2: 100 mg/m2/dose 
For patients < 0.5 m2: 3.3 mg/kg/dose 
MAX dose = 200 mg 
 
Substitution of IV Temozolomide is not permitted. 
 
Sequencing: when giving with irinotecan, administer temozolomide first and wait 
1 hour before giving irinotecan.  
 
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 to prevent nausea and vomiting. When using temozolomide 
capsules, the dose should be rounded to the nearest 5 mg (round 2.5 mg down, see 
Appendix VI). 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 min, the dose should 
not be repeated. 
 
Administration of oral 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 

  
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Regimen A Cycle 1 
needed for the full course must be dispensed at one time. See Section 6.5 for 
additional details and examples.  
 
Irinotecan: IV over 90 minutes daily 
Days: 1-5 
Dose: 50 mg/m2/dose (regardless of BSA) 
Note: Irinotecan should be administered at least 1 hour after the temozolomide has 
been given.  
 
Higher incidence of cholinergic symptoms has been reported with more rapid 
infusion rates.  
 
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 and the training module on 
the COG website. It is recommended that these be available on the inpatient unit 
to facilitate treatment decisions should these symptoms occur. 
 
Refer to Section 4.4.4 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 1 hour. 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 must be no longer than 20 hours, even if the full dose 
of dinutuximab antibody has not been delivered. Antibody administration should 
not be given beyond the specified schedule regardless of whether doses were 
modified or held per guidelines in Section 5.0. 
 

  
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Regimen A Cycle 1 
Please note the maximum infusion time from initiation of dinutuximab is 
20 hours even if the total dose has not been administered in that timeframe. 
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 mcg/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 
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.  
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
4.4.4 
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 20 mL/kg IV over 1 hour 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. 
• 
Ranitidine 1 mg/kg/dose (maximum 50 mg) IV 20 minutes prior to 
dinutuximab infusion and scheduled q8h or equivalent H2 antagonist e.g. 
famotidine IV. 
• 
Acetaminophen PO/IV: 15 mg/kg/dose (maximum 1000 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 
• 
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. May use hydromorphone or 
fentanyl in patients with known indications for use of hydromorphone or 
fentanyl. If the patient tolerates the dinutuximab infusion without 
difficulty, may consider removing the continuous opioid infusion rate in 
between dinutuximab doses (when dinutuximab is not infusing). 
• 
Recommended starting dose of analgesics:  

  
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Regimen A Cycle 1 
▪ 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 mcg/kg/hr with bolus doses of 
0.25 mcg/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. 
 
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/sex/height of patient), tachycardia, tachypnea, fever  
b. Pain requiring an increase in narcotic infusion rate 
c. Urticaria, bronchospasm, peripheral/sensory neurotoxicity, new 
persistent cough 
 
 
 
4.4.5 
Additional guidance 
• 
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. The routine use 
of diuretics during Days 2-5 is contraindicated unless clinically required (i.e. 
pulmonary capillary leak with respiratory compromise). Use of furosemide 
should be avoided when feasible due to ototoxicity concerns. 

  
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Page 42 
Regimen A Cycle 1 
 
• 
Corticosteroid therapy should be used only for life-threatening conditions (i.e. 
treatment of increased intracranial pressure in patients with CNS tumors, 
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 IVIG is discouraged. 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 22 or when peripheral counts 
recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later).  
 
 

  
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Regimen A Cycle 2 and Subsequent Cycles 
4.5 
Regimen A Cycle 2 and Subsequent Cycles 
0B4.5.1   Therapy Delivery Map –CYCLE 2 and Subsequent Cycles 
Each cycle lasts 3 weeks (21 days).  
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Begin each cycle on Day 22 of the previous cycle or when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL 
(whichever occurs later). See Section 5.0 for dose modifications. This TDM is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Temozolomide 
(TEMO) 
PO or via NG or 
Gtube 
For patients ≥ 0.5 m2: 100 mg/m2/dose  
 
For patients < 0.5 m2: 3.3 mg/kg/dose  
 
See dosing table in Appendix VI. 
Days 1 - 5 
Max dose = 200 mg 
Round doses to the nearest 5 mg 
when using capsules. 
 
Administer at least 1 hour prior 
to IRIN administration. 
 
Temozolomide is dosed based on 
body surface area for patients 
whose BSA is at least 0.5 m2. For 
patients with BSA < 0.5 m2, dosing 
is based on body weight (kg).  
Irinotecan (IRIN) 
IV over 90 minutes 
50 mg/m2/dose 
Days 1 - 5 
Administer at least 1 hour after 
temozolomide, see Section 4.5.3. 
Dinutuximab (DIN) 
IV over 10 hours* 
17.5 mg/m2/dose 
Days 2 - 5 
* Infusion duration may be 
extended up to 20 hours if needed. 
 
Start immediately after completion 
of NS bolus and irinotecan 
infusions. 
 
See Section 4.5.3 for detailed 
administration guidelines, including 
premedications and monitoring 
during the infusion. 
Sargramostim  
(GM-CSF) 
SubQ (preferred) or 
IV over 2 hours 
250 mcg/m2/dose 
Days 6 - 12 
See Section 4.5.3 for administration 
guidelines. 
 
 
 Cycle # ________ 
Ht _________ 
cm 
Wt 
 _________kg 
BSA _________m2 
Date Due 
Date 
Given 
Day 
TEMO 
____mg 
IRIN 
____mg 
 DIN 
_____ mg 
GM-CSF 
____mcg 
Studies 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
Cycle 2 
Subsequent 
cycles 
 
 
1 
______mg 
_____mg 
 
 
a-e, l, m 
a-e, m 
 
 
2 
______mg 
_____mg 
_____mg 
 
d, m 
d, m 
 
 
3 
______mg 
_____mg 
_____mg 
 
d, m 
d, m 
 
 
4 
______mg 
_____mg 
_____mg 
 
d, m 
d, m 
 
 
5 
______mg 
_____mg 
_____mg 
 
d, m 
d, m 
 
 
6 
 
 
 
____mcg 
 
 
 
 
7 
 
 
 
____mcg 
 
 
 
 
8 
 
 
 
____mcg 
c 
c 
 
 
9 
 
 
 
____mcg 
 
 
 
 
10 
 
 
 
____mcg 
 
 
 
 
11 
 
 
 
____mcg 
 
 
 
 
12 
 
 
 
____mcg 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
c 
c 
 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
f-k 
f-k 
 
 
22 
Begin next cycle on Day 22 or when peripheral counts recover with 
ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later).  
 
 
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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Regimen A Cycle 2 and Subsequent Cycles 
4.5.2 
Required Observations in Regimen A Cycle 2 and Subsequent Cycles 
 
a. History, physical exam with vital signs, performance status 
b. Height, weight, BSA 
c. CBC with differential and platelets. Patients who experience Grade 4 neutropenia 
should have CBCs checked at least twice per week until recovery to Grade 3. If 
patients remain on study for > 4 cycles and cytopenias are not observed, CBCs 
should be obtained at the start of subsequent cycles and as clinically indicated. 
d. Electrolytes, BUN, creatinine, calcium, magnesium, phosphorus, albumin 
e. ALT, total bilirubin 
f. Audiogram or BAER (use same mode of testing as baseline). Obtain at the end 
of Cycle 2 and Cycle 6. 
g. Bilateral bone marrow aspirates and biopsies. Obtain at the end of Cycles 2, 4, 
6, and every fourth cycle& thereafter for patients with bone marrow 
involvement at baseline (study enrollment) or patients with any prior history 
of bone marrow involvement. Obtain at the end of Cycles 2 and 6 for all 
patients, including those without bone marrow involvement at baseline (study 
enrollment) and those without any prior history of bone marrow involvement.* 
h. Cross sectional tumor imaging of original primary site and any non-osseous sites 
of disease involvement at study entry (MRI or CT) (submit for central review as 
soon as scan is obtained after Cycles 2, 4, and 6). Obtain at the end of Cycles 2, 
4, 6, and every fourth cycle& thereafter. Patients with no measurable or non-
measurable soft tissue disease (i.e., MIBG avid bone lesions or bone marrow 
involvement only) at baseline are only required to obtain appropriate cross-
sectional imaging (CT and/or MRI) at baseline and at the end of Cycles 2 and 6 
(see Section 15.1 for imaging details).* 
i. 
123I-MIBG scan (submit for central review as soon as scan is obtained after 
Cycles 2, 4, and 6). Obtain at the end of Cycles 2, 4, 6, and every fourth cycle& 
thereafter.* 
j. Curie score profile (patients with MIBG avid disease; see Appendix IX for 
worksheet) (submit for central review as soon as scan is obtained after Cycles 2, 
4, and 6). Obtain at the end of Cycles 2, 4, 6, and every fourth cycle& thereafter.  
k. FDG-PET scan for patients with 123I-MIBG non-avid disease (submit for central 
review as soon as scan is obtained after Cycles 2, 4, and 6). Obtain at the end of 
Cycles 2, 4, 6, and every fourth cycle& thereafter. * 
l. Specimens for correlative studies (see Section 14 and Appendix X for specimen 
requirements). On Day 1 of Cycle 2, specimens should be collected prior to 
initiation of therapy.  
m. Faces Pain Scale Revised – can be done anytime on Day 1 of therapy. On 
Days 2-5 of therapy, should be performed at least 4 hours after the 
dinutuximab infusion has begun. Obtain for Cycles 2, 4, 6, and 12. See Section 
14.1.3 for additional detail. 
 
*Imaging and bilateral bone marrow aspirates and biopsies may be performed within 
1 week prior to the start of the next planned cycle of therapy.  
& Patients enrolled on study prior to Amendment 4 only. 
 
This listing only includes evaluations necessary to address the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Page 2 of 3 

  
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Regimen A Cycle 2 and Subsequent Cycles 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
Page 3 of 3 

  
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Regimen A Cycle 2 and Subsequent Cycles 
 
4.5.3 
Treatment Details for Regimen A Cycle 2 and Subsequent Cycles (3 weeks = 
1 cycle)  
 
Drug doses should be calculated based on the BSA using height and weight 
obtained within 1 week prior to the beginning of each cycle. 
 
Suggested administration schedule for chemotherapy and Dinutuximab 
(Days 2-5): 
• 
At hour 0: patient should receive oral temozolomide. 
• 
At hour 1: patient should start IV irinotecan over 90 minutes, and on days 
patient is receiving dinutuximab infusion (Days 2-5 of each cycle), start 
IVF bolus of normal saline (10-20 mL/kg) over 1 hour. 
• 
At hour 2.5: on days patient is receiving dinutuximab infusion (Days 2-5 
of each cycle), start dinutuximab infusion.  
 
 
Temozolomide: PO daily (NG or G-tube administration is allowed) 
Days: 1-5 
Dose: Round doses to the nearest 5 mg when using capsules. See dosing table in 
Appendix VI. 
For patients ≥ 0.5 m2: 100 mg/m2/dose 
For patients < 0.5 m2: 3.3 mg/kg/dose 
MAX dose = 200 mg 
 
Substitution of IV Temozolomide is not permitted. 
 
Sequencing: when giving with irinotecan, administer temozolomide first and wait 
1 hour before giving irinotecan.  
 
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 to prevent nausea and vomiting. When using temozolomide dose 
capsules, the dose should be rounded to the nearest 5 mg (round 2.5 mg down, see 
Appendix VI). 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 oral temozolomide should be documented; missed doses should 
be noted on therapy delivery map and/or in accordance with institutional 
policy/procedures 
 

  
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Regimen A Cycle 2 and Subsequent Cycles 
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 Section 6.5 for 
additional details and examples.  
 
Irinotecan: IV over 90 minutes daily 
Days: 1-5 
Dose: 50 mg/m2/dose (regardless of BSA) 
Note: Irinotecan should be administered at least 1 hour after the temozolomide has 
been given.  
 
Higher incidence of cholinergic symptoms has been reported with more rapid 
infusion rates.  
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) for special 
precautions and suggestions for patient monitoring 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 and the training module on 
the COG website. It is recommended that these be available on the inpatient unit 
to facilitate treatment decisions should these symptoms occur. 
 
Refer to Section 4.5.4 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 1 hour. 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 must be no longer than 20 hours, even if the full dose 
of dinutuximab antibody has not been delivered. Antibody administration should 

  
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Regimen A Cycle 2 and Subsequent Cycles 
not be given beyond the specified schedule regardless of whether doses were 
modified or held per guidelines in Section 5.0. 
 
Please note the maximum infusion time from initiation of dinutuximab is 
20 hours even if the total dose has not been administered in that timeframe. 
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 mcg/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 
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.  
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
4.5.4 
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: NS 20 mL/kg IV over 1 hour 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. 
• 
Ranitidine 1 mg/kg/dose (maximum 50 mg) IV 20 minutes prior to 
dinutuximab infusion and scheduled q8h or equivalent H2 antagonist e.g. 
famotidine IV. 
• 
Acetaminophen PO/IV: 15 mg/kg/dose (maximum 1000 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 
• 
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. May use hydromorphone or 
fentanyl in patients with known indications for use of hydromorphone or 
fentanyl. If the patient tolerates the dinutuximab infusion without 

  
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Regimen A Cycle 2 and Subsequent Cycles 
difficulty, may consider removing the continuous opioid infusion rate in 
between dinutuximab doses (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 
0.002mg/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 mcg/kg/hr with bolus doses of 
0.25 mcg/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. 
 
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/sex/height of patient), tachycardia, tachypnea, fever  
b. Pain requiring an increase in narcotic infusion rate 
c. Urticaria, bronchospasm, peripheral/sensory neurotoxicity, new 
persistent cough 
 
 
 
4.5.5 
Additional guidance 
• 
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. The routine use 

  
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Regimen A Cycle 2 and Subsequent Cycles 
of diuretics during Days 2-5 is contraindicated unless clinically required (i.e. 
pulmonary capillary leak with respiratory compromise). Use of furosemide 
should be avoided when feasible due to ototoxicity concerns. 
 
• 
Corticosteroid therapy should be used only for life-threatening conditions (i.e. 
treatment of increased intracranial pressure in patients with CNS tumors, 
symptomatic bronchospasm, stridor unresponsive to other measures or life-
threatening allergic reactions). Corticosteroids will impair the immune 
activation 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 IVIG is discouraged. 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. 
 
 

  
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Regimen B Cycle 1 
4.6 
Regimen B Cycle 1 
4.6.1   Therapy Delivery Map –CYCLE 1 
Cycle 1 lasts 4 weeks (28 days). This cycle includes a lead-in of 7 days of DFMO 
(Days -6 to 0) prior to 21 days of chemotherapy. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
 
Begin Cycle 2 on Day 22 of Cycle 1 or when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL 
(whichever occurs later). See Section 5.0 for dose modifications. This TDM is on 3 pages. 
  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Eflornithine 
(DFMO) 
IND# 141913 
PO or via NG or 
Gtube 
2250 mg/m2/dose x 
3 doses/day 
 
See dosing table in 
Appendix XII 
Days -6 to +7 
and  
Days 15 - 21 
Round doses to the nearest 500 mg 
(see dosing table in Appendix XII). 
 
Note: During Days 1-5, consider 
giving one of the 3 times daily 
eflornithine doses and temozolomide 
close together in order to minimize 
potential for emesis and redosing. 
Temozolomide 
(TEMO) 
PO or via NG or 
Gtube 
For patients ≥ 0.5 m2: 
100 mg/m2/dose 
 
For patients < 0.5 m2: 
3.3 mg/kg/dose 
 
See dosing table in 
Appendix VI. 
Days 1 - 5 
Max dose = 200 mg 
Round doses to the nearest 5 mg when 
using capsules. 
 
Administer at least 1 hour prior to 
IRIN administration. 
 
Temozolomide is dosed based on body 
surface area for patients whose BSA is 
at least 0.5 m2. For patients with 
BSA < 0.5 m2, dosing is based on body 
weight (kg).  
Irinotecan (IRIN) 
IV over 
90 minutes 
50 mg/m2/dose 
Days 1 - 5 
Administer at least 1 hour after 
temozolomide, see Section 4.6.3. 
Dinutuximab (DIN) 
IV over 10 hours* 
17.5 mg/m2/dose 
Days 2 - 5 
* Infusion duration may be extended 
up to 20 hours if needed. 
 
Start immediately after completion of 
NS bolus and irinotecan infusions. 
 
See Section 4.6.3 for detailed 
administration guidelines, including 
premedications and monitoring. 
Sargramostim  
(GM-CSF) 
SubQ (preferred) 
or IV over 2 hours 
250 mcg/m2/dose 
Days 6 - 12 
See Section 4.6.3 for administration 
guidelines. 
 
 
 
Page 1 of 3 

  
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Regimen B Cycle 1 
 
0B4.6.1   Therapy Delivery Map –CYCLE 1 
Cycle 1 lasts 4 weeks (28 days). This cycle includes a lead-in of 7 days of 
DFMO (Days -6 to 0) prior to 21 days of chemotherapy. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
 
 
 
Ht _________ 
cm 
Wt 
 _________kg 
BSA _________m2 
Date Due 
Date 
Given 
Day 
DFMO 
____mg 
TEMO 
____mg 
IRIN 
____mg 
 DIN 
_____ mg 
GM-CSF 
____mcg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered 
below 
 
 
 
-6 
______mg 
 
 
 
 
a – o 
 
 
-5 
______mg 
 
 
 
 
 
 
 
-4 
______mg 
 
 
 
 
 
 
 
-3 
______mg 
 
 
 
 
 
 
 
-2 
______mg 
 
 
 
 
 
 
 
-1 
______mg 
 
 
 
 
 
 
 
0 
______mg 
 
 
 
 
 
 
 
1 
______mg 
______mg 
_____mg 
 
 
a, c, d, e, n, o 
 
 
2 
______mg 
______mg 
_____mg 
_____mg 
 
d, o 
 
 
3 
______mg 
______mg 
_____mg 
_____mg 
 
d, o 
 
 
4 
______mg 
______mg 
_____mg 
_____mg 
 
d, o 
 
 
5 
______mg 
______mg 
_____mg 
_____mg 
 
d, o 
 
 
6 
______mg 
 
 
 
____mcg 
n 
 
 
7 
______mg 
 
 
 
____mcg 
 
 
 
8 
 
 
 
 
____mcg 
c, d, e 
 
 
9 
 
 
 
 
____mcg 
 
 
 
10 
 
 
 
 
____mcg 
 
 
 
11 
 
 
 
 
____mcg 
 
 
 
12 
 
 
 
 
____mcg 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
______mg 
 
 
 
 
c, d, e 
 
 
16 
______mg 
 
 
 
 
 
 
 
17 
______mg 
 
 
 
 
 
 
 
18 
______mg 
 
 
 
 
 
 
 
19 
______mg 
 
 
 
 
 
 
 
20 
______mg 
 
 
 
 
 
 
 
21 
______mg 
 
 
 
 
 
 
 
22 
Begin Cycle 2 on Day 22 or when peripheral counts recover with 
ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later).  
 
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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Regimen B Cycle 1 
4.6.2 
Required Observations in Regimen B Cycle 1 
 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
 
a. History, physical exam with vital signs, performance status* 
b. Height, weight, BSA* 
c. CBC with differential and platelets (patients who experience Grade 4 neutropenia 
should have CBCs checked at least twice per week until recovery to Grade 3)* 
d. Electrolytes, BUN, creatinine, calcium, magnesium, phosphorus, albumin* 
e. ALT, total bilirubin* 
f. Pregnancy test (obtain for females of childbearing potential) 
g. ECHO or MUGA  
h. Audiogram or BAER – May be obtained within 3 weeks prior to the start of 
protocol therapy. 
i. Bilateral bone marrow aspirates and biopsies 
j. Cross sectional tumor imaging of original primary site and any non-osseous sites 
of disease involvement at study entry (MRI or CT) (submit for central review as 
soon as scan is obtained; see Section 15.1 for imaging details for patients without 
measurable disease) 
k. 
123I-MIBG scan (submit for central review as soon as scan is obtained) 
l. Curie score profile (patients with MIBG avid disease; see Appendix IX for 
worksheet) (submit for central review as soon as scan is obtained) 
m. FDG-PET scan for patients with 123I-MIBG non-avid disease (submit for central 
review as soon as scan is obtained) 
n. Specimens for correlative studies. Post-dinutuximab specimens should be 
collected at a single time point between Day 6 and Day 9. See Section 14 and 
Appendix X for details. 
o. Faces Pain Scale Revised – can be done anytime on Days -6 and 1 of therapy. 
On Days 2-5 of therapy, should be performed at least 4 hours after the 
dinutuximab infusion has begun. See Section 14.1.3 for additional detail. 
 
* These baseline studies must be repeated on Day -6 if not performed within 72 hours 
of Day -6. 
 
This listing only includes evaluations necessary to address the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
Page 3 of 3 

  
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Regimen B Cycle 1 
4.6.3 
Treatment Details for Regimen B Cycle 1 (4 weeks = 1 cycle)  
 
Drug doses should be calculated based on the BSA using height and weight 
obtained within 1 week prior to the beginning of each cycle. 
 
Suggested administration schedule for eflornithine, chemotherapy and 
dinutuximab (Days 2-5): 
• 
At hour 0: patient should receive oral eflornithine (DFMO) and oral 
temozolomide. Medications should be given separately, not mixed. 
• 
At hour 1: patient should start IV irinotecan over 90 minutes, and on days 
patient is receiving dinutuximab infusion (Days 2-5 of each cycle), start 
IVF bolus of normal saline (10-20 mL/kg) over 1 hour. 
• 
At hour 2.5: on days patient is receiving dinutuximab infusion (Days 2-5 
of each cycle), start dinutuximab infusion.  
 
Eflornithine (DFMO): PO daily (NG or Gtube administration is allowed) 
Days: -6 through +7 and 15 - 21 
Dose: 2250 mg/m2/dose TID (6750 mg/m2/day). See dosing table in Appendix XII 
 
Note: During Days 1-5, consider giving one of the 3 times daily eflornithine doses 
and temozolomide close together in order to minimize potential for emesis and 
redosing. 
 
The eflornithine dose should be rounded to the nearest 500 mg (0.5 g). Please see 
Appendix XIII for eflornithine administration recommendations. Please provide 
these instructions to patient families. 
 
If emesis occurs within 20 minutes of taking a dose of eflornithine, then the dose 
should be repeated once. If emesis occurs after 20 min, the dose should not be 
repeated. 
 
Administration of oral eflornithine should be documented; missed doses should be 
noted on therapy delivery map and/or in accordance with institutional 
policy/procedures. 
 
Temozolomide: PO daily (NG or Gtube administration is allowed) 
Days: 1-5 
Dose: Round doses to the nearest 5 mg when using capsules. See dosing table in 
Appendix VI. 
For patients ≥ 0.5 m2: 100 mg/m2/dose 
For patients < 0.5 m2: 3.3 mg/kg/dose 
MAX dose = 200 mg 
 
Substitution of IV Temozolomide is not permitted. 
 
Sequencing: when giving with irinotecan, administer temozolomide first and wait 
1 hour before giving irinotecan.  
 
Absorption is affected by food and therefore, consistency of administration with 
respect to food is suggested. Preferably, administer on an empty stomach (at least 

  
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Regimen B Cycle 1 
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 to prevent nausea and vomiting. When using temozolomide 
capsules, the dose should be rounded to the nearest 5 mg (round 2.5 mg down, see 
Appendix VI). 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 min, the dose should not be 
repeated. 
 
Administration of oral 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 Section 6.5 for 
additional details and examples.  
 
Irinotecan: IV over 90 minutes daily 
Days: 1-5 
Dose: 50 mg/m2/dose (regardless of BSA) 
Note: Irinotecan should be administered at least 1 hour after the temozolomide has 
been given.  
 
Higher incidence of cholinergic symptoms has been reported with more rapid 
infusion rates.  
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) for special 
precautions, suggestions for patient monitoring, and hydration pre- and post-
cyclophosphamide (or hydrate according to institutional guidelines) 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 and the training module on 

  
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Regimen B Cycle 1 
the COG website. It is recommended that these be available on the inpatient unit 
to facilitate treatment decisions should these symptoms occur. 
 
Refer to Section 4.6.4 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 1 hour. 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 must be no longer than 20 hours, even if the full dose 
of dinutuximab antibody has not been delivered. Antibody administration should 
not be given beyond the specified schedule regardless of whether doses were 
modified or held per guidelines in Section 5.0. 
 
Please note the maximum infusion time from initiation of dinutuximab is 
20 hours even if the total dose has not been administered in that timeframe. The 
total dose given in 20 hours should be recorded.   
 
Sargramostim: Subcutaneous injection (preferred) or IV over 2 hours 
Days: 6 through 12 
Dose: 250 mcg/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 
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.  
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
4.6.4 
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: 

  
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Regimen B Cycle 1 
• 
IV hydration: NS 20 mL/kg IV over 1 hour just prior to each dinutuximab 
infusion. 
o 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. 
o Ranitidine 1 mg/kg/dose (maximum 50 mg) IV 20 minutes prior to 
dinutuximab infusion and scheduled q8h or equivalent H2 antagonist e.g. 
famotidine IV. 
o Acetaminophen PO/IV: 15 mg/kg/dose (maximum 1000 mg) 20 minutes 
prior to each dinutuximab infusion and scheduled q4-6h prn. 
o Consider use of cetirizine for patients with a history of allergic reactions 
o 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. May use hydromorphone or 
fentanyl in patients with known indications for use of hydromorphone or 
fentanyl. If the patient tolerates the dinutuximab infusion without 
difficulty, may consider removing the continuous opioid infusion rate in 
between dinutuximab doses (when dinutuximab is not infusing). 
o 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 mcg/kg/hr with bolus doses of 
0.25 mcg/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. 
 
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.  
 

  
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Regimen B Cycle 1 
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/sex/height of patient), tachycardia, tachypnea, fever  
b. Pain requiring an increase in narcotic infusion rate 
c. Urticaria, bronchospasm, peripheral/sensory neurotoxicity, new 
persistent cough 
 
 
 
4.6.5 
Additional guidance 
• 
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. The routine use 
of diuretics during Days 2-5 is contraindicated unless clinically required (i.e. 
pulmonary capillary leak with respiratory compromise). Use of furosemide 
should be avoided when feasible due to ototoxicity concerns. 
 
• 
Corticosteroid therapy should be used only for life-threatening conditions (i.e. 
treatment of increased intracranial pressure in patients with CNS tumors, 
symptomatic bronchospasm, stridor unresponsive to other measures or life-
threatening allergic reactions). Corticosteroids will impair the immune 
activation 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 IVIG is discouraged. 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. 
 
 
Following completion of this cycle, Cycle 2 starts on Day 22 or when peripheral 
counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs 
later).  
 
See Section 5.0 for Dose Modifications based on Toxicities.

  
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Regimen B Cycle 2 and Subsequent Cycles 
 
4.7 
Regimen B Cycle 2 and Subsequent Cycles 
0B4.7.1   Therapy Delivery Map –CYCLE 2 and Subsequent Cycles 
Each cycle lasts 3 weeks (21 days).  
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Begin each cycle on Day 22 of the previous cycle or when peripheral counts recover with ANC ≥ 750/µL and 
platelets ≥ 75,000/µL (whichever occurs later). See Section 5.0 for dose modifications. This TDM is on 3 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Eflornithine 
(DFMO) 
 
IND# 141913 
PO or via NG 
or Gtube 
2250 mg/m2/dose x 
3 doses/day 
 
See dosing table in 
Appendix XII 
Days 1- 7 
and 
Days 15 - 21 
Round doses to the nearest 500 mg 
(see dosing table in Appendix XII). 
 
Note: During Days 1-5, consider 
giving one of the 3 times daily 
eflornithine doses and temozolomide 
close together in order to minimize 
potential for emesis and redosing. 
Temozolomide 
(TEMO) 
PO or via NG 
or Gtube 
For patients ≥ 0.5 m2: 
100 mg/m2/dose 
 
For patients < 0.5 m2: 
3.3 mg/kg/dose 
 
See dosing table in 
Appendix VI. 
Days 1 - 5 
Max dose = 200 mg 
Round doses to the nearest 5 mg when 
using capsules. 
 
Administer at least 1 hour prior to 
IRIN administration. 
 
Temozolomide is dosed based on body 
surface area for patients whose BSA is 
at least 0.5 m2. For patients with 
BSA < 0.5 m2, dosing is based on body 
weight (kg).  
Irinotecan (IRIN) 
IV over 
90 minutes 
50 mg/m2/dose 
Days 1 - 5 
Administer at least 1 hour after 
temozolomide, see Section 4.7.3. 
Dinutuximab (DIN) 
IV over 
10 hours* 
17.5 mg/m2/dose 
Days 2 - 5 
*Infusion duration may be extended 
up to 20 hours if needed. 
 
Start immediately after completion of 
NS bolus and irinotecan infusions. 
 
See Section 4.7.3 for detailed 
administration guidelines, including 
premedications and monitoring during 
the infusion. 
Sargramostim  
(GM-CSF) 
SubQ 
(preferred) or 
IV over 2 hours 
250 mcg/m2/dose 
Days 6 - 12 
See Section 4.7.3 for administration 
guidelines. 
 
 
 
 
 
Page 1 of 4 

  
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Regimen B Cycle 2 and Subsequent Cycles 
0B4.7.1   Therapy Delivery Map –CYCLE 2 and Subsequent Cycles 
Each cycle lasts 3 weeks (21 days).  
____________________________ 
Patient COG ID number 
________________________ 
DOB  
 
 
 
 Cycle # ________ 
Ht _________ 
cm 
Wt 
 _________kg 
BSA _________m2 
Date Due 
Date 
Given 
Day 
DFMO 
____mg 
TEMO 
____mg 
IRIN 
____mg 
 DIN 
_____ mg 
GM-CSF 
____mcg 
Studies 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
Cycle 2 
Subsequent 
cycles 
 
 
1 
______mg 
______mg 
_____mg 
 
 
a-e, l, m 
a-e, m 
 
 
2 
______mg 
______mg 
_____mg 
_____mg 
 
d, m 
d, m 
 
 
3 
______mg 
______mg 
_____mg 
_____mg 
 
d, m 
d, m 
 
 
4 
______mg 
______mg 
_____mg 
_____mg 
 
d, m 
d, m 
 
 
5 
______mg 
______mg 
_____mg 
_____mg 
 
d, m 
d, m 
 
 
6 
______mg 
 
 
 
____mcg 
 
 
 
 
7 
______mg 
 
 
 
____mcg 
 
 
 
 
8 
 
 
 
 
____mcg 
c 
c 
 
 
9 
 
 
 
 
____mcg 
 
 
 
 
10 
 
 
 
 
____mcg 
 
 
 
 
11 
 
 
 
 
____mcg 
 
 
 
 
12 
 
 
 
 
____mcg 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
15 
______mg 
 
 
 
 
c 
c 
 
 
16 
______mg 
 
 
 
 
 
 
 
 
17 
______mg 
 
 
 
 
 
 
 
 
18 
______mg 
 
 
 
 
 
 
 
 
19 
______mg 
 
 
 
 
 
 
 
 
20 
______mg 
 
 
 
 
 
 
 
 
21 
______mg 
 
 
 
 
f-k 
f-k 
 
 
22 
Begin next cycle on Day 22 or when peripheral counts recover with 
ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later).  
 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
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4.7.2 
Required Observations in Regimen B Cycle 2 and Subsequent Cycles 
 
a. History, physical exam with vital signs, performance status 
b. Height, weight, BSA 
c. CBC with differential and platelets (patients who experience Grade 4 neutropenia 
should have CBCs checked at least twice per week until recovery to Grade 3). If 
patients remain on study for > 4 cycles and cytopenias are not observed, CBCs 
should be obtained at the start of subsequent cycles and as clinically indicated 
d. Electrolytes, BUN, creatinine, magnesium, phosphorus, albumin 
e. ALT, total bilirubin 
f. Audiogram or BAER (use same mode of testing as baseline). Obtain at the end 
of Cycle 2 and end of every 2nd cycle thereafter. 
g. Bilateral bone marrow aspirates and biopsies. Obtain at the end of Cycles 2, 4, 
6, and every fourth cycle& thereafter for patients with bone marrow 
involvement at baseline (study enrollment) or patients with any prior history 
of bone marrow involvement. Obtain at the end of Cycles 2 and 6 for all 
patients, including those without bone marrow involvement at baseline (study 
enrollment) and those without any prior history of bone marrow involvement.* 
h. Cross sectional tumor imaging of original primary site and any non-osseous sites 
of disease involvement at study entry (MRI or CT) (submit for central review as 
soon as scan is obtained after Cycles 2, 4, and 6). Obtain at the end of Cycles 2, 
4, 6, and every fourth cycle& thereafter. Patients with no measurable or non-
measurable soft tissue disease (i.e., MIBG avid bone lesions or bone marrow 
involvement only) at baseline are only required to obtain appropriate cross-
sectional imaging (CT and/or MRI) at baseline and at the end of Cycles 2 and 6 
(see Section 15.1 for imaging details).* 
i. 
123I-MIBG scan (submit for central review as soon as scan is obtained after 
Cycles 2, 4, and 6). Obtain at the end of Cycles 2, 4, 6, and every fourth cycle& 
thereafter.* 
j. Curie score profile (patients with MIBG avid disease; see Appendix IX for 
worksheet) (submit for central review as soon as scan is obtained after Cycles 2, 
4, and 6). Obtain at the end of Cycles 2, 4, 6, and every fourth cycle& thereafter. 
k. FDG-PET scan for patients with 123I-MIBG non-avid disease (submit for central 
review as soon as scan is obtained after Cycles 2, 4, and 6). Obtain at the end of 
Cycles 2, 4, 6, and every fourth cycle& thereafter.* 
l. Specimens for correlative studies (see Section 14 and Appendix X for specimen 
requirements). On Day 1 of Cycle 2, specimens should be collected prior to 
initiation of therapy.  
m. Faces Pain Scale Revised – can be done anytime on Day 1 of therapy. On 
Days 2-5 of therapy, should be performed at least 4 hours after the 
dinutuximab infusion has begun. Obtain for Cycles 2, 4, 6, and 12. See Section 
14.1.3 for additional detail. 
 
*Imaging and bilateral bone marrow aspirates and biopsies may be performed within 
1 week prior to the start of the next planned cycle of therapy. 
& Patients enrolled on study prior to Amendment 4 only. 
 
This listing only includes evaluations necessary to address the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
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Regimen B Cycle 2 and Subsequent Cycles 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
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Regimen B Cycle 2 and Subsequent Cycles 
 
4.7.3 
Treatment Details for Regimen B Cycle 2 and Subsequent Cycles (3 weeks = 
1 cycle)  
 
Drug doses should be calculated based on the BSA using height and weight 
obtained within 1 week prior to the beginning of each cycle. 
 
Suggested administration schedule for eflornithine, chemotherapy and 
dinutuximab (Days 2-5): 
• 
At hour 0: patient should receive oral eflornithine (DFMO) and oral 
temozolomide. Medications should be given separately, not mixed. 
• 
At hour 1: patient should start IV irinotecan over 90 minutes, and on days 
patient is receiving dinutuximab infusion (Days 2-5 of each cycle), start 
IVF bolus of normal saline (10-20 mL/kg) over 1 hour. 
• 
At hour 2.5: on days patient is receiving dinutuximab infusion (Days 2-5 
of each cycle), start dinutuximab infusion.  
 
Eflornithine (DFMO): PO daily (NG or Gtube administration is allowed) 
Days: 1 – 7 and 15 - 21 
Dose: 2250 mg/m2/dose TID (6750 mg/m2/day). See dosing table in Appendix XII 
 
Note: During Days 1-5, consider giving one of the 3 times daily eflornithine doses 
and temozolomide close together in order to minimize potential for emesis and 
redosing. 
 
The eflornithine dose should be rounded to the nearest 500 mg (0.5 g). Please see 
Appendix XIII for eflornithine administration recommendations. Please provide 
these instructions to patient families. 
 
If emesis occurs within 20 minutes of taking a dose of eflornithine, then the dose 
should be repeated once. If emesis occurs after 20 min, the dose should not be 
repeated. 
 
Administration of oral eflornithine should be documented; missed doses should be 
noted on therapy delivery map and/or in accordance with institutional 
policy/procedures. 
 
Temozolomide: PO daily (NG or Gtube administration is allowed) 
Days: 1-5 
Dose: Round doses to the nearest 5 mg when using capsules. See dosing table in 
Appendix VI. 
For patients ≥ 0.5 m2: 100 mg/m2/dose 
For patients < 0.5 m2: 3.3 mg/kg/dose 
MAX dose = 200 mg 
 
Substitution of IV Temozolomide is not permitted. 
 
Sequencing: when giving with irinotecan, administer temozolomide first and wait 
1 hour before giving 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 to prevent nausea and vomiting. When using temozolomide 
capsules, the dose should be rounded to the nearest 5 mg (round 2.5 mg down, see 
Appendix VI). 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 min, the dose should not be 
repeated. 
 
Administration of oral 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 Section 6.5 for 
additional details and examples.  
 
Irinotecan: IV over 90 minutes daily 
Days: 1-5 
Dose: 50 mg/m2/dose (regardless of BSA) 
Note: Irinotecan should be administered at least 1 hour after the temozolomide has 
been given.  
 
Higher incidence of cholinergic symptoms has been reported with more rapid 
infusion rates. To avoid extravasation; the use of a central line is suggested. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) for special 
precautions, and suggestions for patient monitoring 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 and the training module on 

  
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Regimen B Cycle 2 and Subsequent Cycles 
the COG website. It is recommended that these be available on the inpatient unit 
to facilitate treatment decisions should these symptoms occur. 
 
Refer to Section 4.7.4 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 1 hour. Bolus should be given 
concurrently with irinotecan infusion. On Days 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 must be no longer than 20 hours, even if the full dose 
of dinutuximab antibody has not been delivered. Antibody administration should 
not be given beyond the specified schedule regardless of whether doses were 
modified or held per guidelines in Section 5.0. 
 
Please note the maximum infusion time from initiation of dinutuximab is 
20 hours even if the total dose has not been administered in that timeframe. 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 mcg/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 
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.  
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
4.7.4 
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: 

  
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Regimen B Cycle 2 and Subsequent Cycles 
• 
IV hydration: NS 20 mL/kg IV over 1 hour 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. 
• 
Ranitidine 1 mg/kg/dose (maximum 50 mg) IV 20 minutes prior to 
dinutuximab infusion and scheduled q8h or equivalent H2 antagonist e.g. 
famotidine IV. 
• 
Acetaminophen PO/IV: 15 mg/kg/dose (maximum 1000 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 
• 
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. May use hydromorphone or 
fentanyl in patients with known indications for use of hydromorphone or 
fentanyl. If the patient tolerates the dinutuximab infusion without 
difficulty, may consider removing the continuous opioid infusion rate in 
between dinutuximab doses (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 
0.02mg/kg/hr with bolus doses of 0.01mg/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 mcg/kg/hr with bolus doses of 
0.25 mcg/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. 
 
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.  
 

  
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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/sex/height of patient), tachycardia, tachypnea, fever  
b. Pain requiring an increase in narcotic infusion rate 
c. Urticaria, bronchospasm, peripheral/sensory neurotoxicity, new 
persistent cough 
 
 
 
4.7.5 
Additional guidance 
• 
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. The routine use 
of diuretics during Days 2-5 is contraindicated unless clinically required (i.e. 
pulmonary capillary leak with respiratory compromise). Use of furosemide 
should be avoided when feasible due to ototoxicity concerns. 
 
• 
Corticosteroid therapy should be used only for life-threatening conditions (i.e. 
treatment of increased intracranial pressure in patients with CNS tumors, 
symptomatic bronchospasm, stridor unresponsive to other measures or life-
threatening allergic reactions). Corticosteroids will impair the immune 
activation 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 IVIG is discouraged. 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. 
 

 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
In addition to dose modifications, this section provides information regarding management 
of toxicities known to be associated with protocol therapy. 
 
In the sections below, when protocol therapy is to be discontinued, all protocol therapy should 
be discontinued. If treating clinicians elect to continue to administer dinutuximab, irinotecan 
and temozolomide, this can be done as part of clinical care but will not be considered protocol 
therapy. 
 
NOTE: If eflornithine is stopped for any reason (e.g. toxicity or, for patients enrolled prior 
to Amendment 4, tumor resection after Cycle 6 disease evaluation) and then resumed at same 
or lower dose, at least 5 days of the resumed/decreased dose of eflornithine should be given 
prior to starting Day 1 of the next cycle of chemotherapy. The resumed/decreased dose should 
be given for a total of 12 days. Please HOLD eflornithine for 24 hours prior to tumor 
resection.   
 
If a subsequent cycle is delayed by ≤ 7 days for any event that is unlikely related to eflornithine 
(e.g. timing adjustments, count recovery, or toxicity not attributed to eflornithine), the patient 
should continue eflornithine until the next cycle begins. If a subsequent cycle is delayed > 7 days 
for any event that is unlikely related to eflornithine, the patient should stop taking eflornithine until 
he/she meets eligibility to start the subsequent cycle. Once the patient is eligible to start the next 
cycle, 5 days of eflornithine (Day -4 to Day 0) should be given prior to starting Day 1 of the next 
cycle of chemoimmunotherapy.  
 
5.1 
Dose Modifications for Hematologic Toxicity 
Patients must meet hematologic criteria for study entry and at the start of each treatment 
cycle. 
 
5.1.1 
Dose-limiting neutropenia 
Patients who experience neutropenia that causes a delay of ≥ 14 days between 
treatment cycles in the absence of other toxicity requiring dose modification should 
have the temozolomide dose reduced by 25% for subsequent cycles (see dose 
reduction nomogram in Appendix VII). If patient experiences neutropenia that 
causes a delay of ≥ 14 days between treatment cycles after this dose reduction, 
protocol therapy should be discontinued. 
 
5.1.2 
Dose-limiting thrombocytopenia 
For patients who experience thrombocytopenia that causes a delay of ≥ 14 days 
between treatment cycles with or without other hematologic toxicities, the dose of 
temozolomide should be reduced by 25% for subsequent cycles (see dose reduction 
nomogram in Appendix VII). If patient experiences thrombocytopenia that causes 
a delay of ≥ 14 days between treatment cycles after this dose reduction, protocol 
therapy should be discontinued.  
 
5.1.3 
Delayed recovery of platelets and neutrophils 
Patients who do not meet criteria to start the next treatment cycle (see Section 4.5.1 
or 4.7.1) 21 days after the planned subsequent cycle start date (i.e. there is a 
≥ 3 week delay in start of next cycle) must be removed from protocol therapy.  

 
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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.  
 
NOTE: If eflornithine is stopped for any reason and then resumed at same or lower 
dose, at least 5 days of the resumed/decreased dose of eflornithine should be given 
prior to starting Day 1 of the next cycle of chemotherapy. 
 
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 and appropriate use of prophylactic antibiotics, the dose of 
irinotecan should be reduced by 25% for subsequent cycles (i.e. irinotecan 
dose 37.5 mg/m2). 
• 
If diarrhea persists despite maximal use of anti-diarrheal medications and 
appropriate use of prophylactic antibiotics for Grade 3 diarrhea > 7 days and 
Grade 4 diarrhea > 3 days after the completion of irinotecan, hold the 
eflornithine (DFMO) until diarrhea resolves to Grade 1. Then restart at prior 
dose. 
• 
If Grade 4 therapy-associated diarrhea recurs without an infectious etiology 
despite reducing the dose of irinotecan by 25%, the dinutuximab dose (Arm A) 
or both the dinutuximab and eflornithine doses (Arm B) should also be 
decreased by 25% for subsequent cycles (i.e. dinutuximab dose 
13.13 mg/m2/day and eflornithine dose 5 g/m2/day divided TID). 
• 
If Grade 4 diarrhea recurs despite maximal use of anti-diarrheals, prophylactic 
antibiotics, and the dose reductions, the patient should come off protocol 
therapy. 
 
5.2.2 
Dose modifications for nausea and vomiting 
• 
For patients with Grade 4 regimen-related nausea and vomiting and for 
patients with Grade 3 regimen-related nausea and vomiting > 7 days in 
duration who did not receive appropriate anti-emetic therapy, adjustments in 
the anti-emetic regimen should be made during the next cycle 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; for temozolomide see dose reduction nomogram 
in Appendix VII). 
• 
If severe regimen-related nausea and vomiting recurs despite the dose 
reduction, the patient should come off protocol therapy. 
 
5.2.3 
Dose modifications for dehydration 
• 
If dehydration is related to diarrhea or nausea/vomiting, the guidance in 

 
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Section 5.2.1 or 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 temozolomide see dose reduction 
nomogram in Appendix VII).  
• 
If ≥ Grade 3 regimen-related dehydration recurs and persists for > 3 days 
despite the dose reduction, the patient should come off protocol therapy. 
 
5.2.4 
Dose modifications for elevations in ALT, AST, or GGT 
• 
If elevations in ALT, AST or GGT occur such that values are > 20x ULN for 
any duration of time OR > 10x ULN but < 20x ULN and persisting for 
> 7 days, the dose of dinutuximab should be reduced by 25% for subsequent 
cycles (i.e. dinutuximab dose 13.13 mg/m2). For the purposes of this trial the 
ULN for ALT is defined as 45 U/L; institutional ULN values for AST and 
GGT should be used.  
• 
If elevations of this magnitude involving same liver enzyme(s) recur despite 
the first dose reduction, the dose of temozolomide (Arm A) or eflornithine and 
temozolomide (Arm B) should be reduced by 25% for subsequent cycles (i.e. 
for temozolomide see dose reduction nomogram in Appendix VII; eflornithine 
dose 5 g/m2). If the dose limiting elevations of the same liver enzyme(s) recur 
despite the temozolomide/eflornithine dose reduction, the patient should come 
off protocol therapy. 
• 
An elevation in ALT that causes a delay of ≥ 14 days between treatment cycles 
will also require a 25% reduction in the dose of dinutuximab for all subsequent 
cycles (i.e. dinutuximab dose 13.13 mg/m2). If a delay of ≥ 14 days between 
treatment cycles recurs due to elevation in ALT despite the dose reduction, the 
patient should come off protocol therapy. 
 
5.2.5 
Dinutuximab 
specific 
dose 
modifications 
and 
toxicity 
management 
recommendations 
5.2.5.1 
Treatment of dinutuximab-induced 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. In the absence of poor perfusion, end organ dysfunction or acidemia, 
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. For patients with moderate hypotension in the absence of 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 

 
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iv. Consider use of Trendelenberg position 
 
d. If hypotension persists after the above measures have been taken: 
i. Reassess perfusion and end organ function 
ii. Follow PALS algorithm if indicated 
iii. Repeat NS bolus OR 
iv. Consider use of albumin if albumin < 3 gm/dL 
v. Consider use of PRBCs if Hb < 10 gm/dL 
vi. Consider use of platelets if count <50,000/µL 
vii. Consider transfer to intensive care setting  
 
e. If hypotension persists following 2 volume boluses, give an 
additional bolus and prepare to administer pressors 
i. Epinephrine or norepinephrine is preferred over dopamine if 
possible 
 
f. 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. The 
dinutuximab may be restarted on same day if it is possible to 
do so within 20 hours of the start of the day’s infusion. If blood 
pressures are stable for 2 hours, the infusion may be given at 
full rate for that day and subsequent days. If the patient again 
experiences hypotension requiring multiple volume boluses 
(e.g. > 40 mL/kg) when dinutuximab is given at full rate but 
tolerates the 50% infusion rate, the remaining days’ doses of 
dinutuximab should be given at the 50% rate of infusion. If 
> 20 hours have elapsed since the start of the infusion, restart 
dinutuximab the following day. 
▪ 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 remaining days’ doses of dinutuximab should 
be given at the 50% rate of infusion. 
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 

 
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▪ 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 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 should 
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 

 
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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 
▪ 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 should be discontinued. 
o For patients with bronchospasm or angioedema that 
does not require systemic epinephrine but whose 
hypotension 
requires 
more 
extensive 
volume 
resuscitation, guidance in Section 5.2.5.1 should be 
followed. 
 

 
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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 
• 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 should discontinue protocol therapy 
 
5.2.5.4 
Management of renal insufficiency (unrelated to hypotension) 
• Consider the possibility of renal hypoperfusion in the context of 
borderline hypotension; administer volume if appropriate 
• If the patient’s creatinine is elevated to ≥ 2 x the upper limit of normal 
for age/gender (see table in Section 3.2.6.2) and elevation persists 
despite optimized fluid management, hold 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 

 
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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 should discontinue protocol therapy. 
 
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 should 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 should 
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 should 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, 

 
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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 should discontinue protocol 
therapy. 
• For Grade 2 serum sickness, antihistamines should be prescribed. 
 
5.2.5.10 Management of neurotoxicity 
• Patients who develop Grade 4 neurotoxicity should discontinue 
protocol therapy. 
• Dinutuximab should be discontinued for the remainder of the current 
cycle of therapy for patients who develop Grade 3 sensory 
neuropathy or Grade 3 motor neuropathy. If abnormalities resolve by 
start of next cycle of therapy, the patient may receive 50% dose of 
dinutuximab (i.e. dinutuximab dose 8.75 mg/m2). If symptoms do not 
completely resolve or recur with dinutuximab then the patient should 
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 mcg/m2). 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. 
 

 
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5.2.7 
Eflornithine (DFMO) specific dose modifications and toxicity management 
recommendations 
5.2.7.1 
Hearing Loss  
Potential eflornithine-related hearing loss will be identified by 
audiologic assessment and defined as ≥ 15 dB increase from baseline 
in hearing threshold at two contiguous frequencies between 500 and 
3000 Hz. If this hearing deterioration is detected, eflornithine will be 
held for the remainder of the cycle and for one additional full cycle, and 
the audiologic testing should be repeated at the end of the entire dose 
holding period. If hearing sensitivity returns to pre-therapy baseline (or 
within 5dB of baseline), they will resume eflornithine at same dose. If 
hearing remains diminished as described above in comparison with pre-
enrollment baseline, the eflornithine dose will be reduced by 25% (i.e. 
eflornithine of 5 g/m2/day as in Appendix XII) during the next cycle. 
Patients who have eflornithine held more than once for hearing loss, but 
return to baseline after hold, will have the eflornithine dose reduced by 
25% for subsequent cycles. Patients who are receiving eflornithine at the 
lowest dose level (3750 mg/m2/day) for hearing loss and have recurrent 
or progressive hearing loss despite dose reduction will stop protocol 
therapy. 
 
5.2.7.2 
Diarrhea occurring during single agent eflornithine lead-in (Days -6 to 1)  
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 eflornithine is stopped for any reason and then resumed at a lower 
dose, at least 5 days of the decreased dose of eflornithine should be given 
prior to starting Day 1 of the next cycle of chemotherapy, per Section 
5.2. 
 
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, the eflornithine dose should be held until diarrhea 
has resolved to Grade 1 or less and then restarted with a 25% reduction 
of the original dose (i.e. eflornithine of 5 g/m2/day). 
 
If Grade 4 therapy-associated diarrhea recurs again without an infectious 
etiology and despite maximal use of anti-diarrheal medications, the 
eflornithine dose should be held again until diarrhea has resolved to 
Grade 1 or less and then decreased by an additional 25% (i.e. eflornithine 
of 3.75 g/m2/day). 
 
If Grade 4 diarrhea recurs during single agent lead-in despite maximal 
use of anti-diarrheals, and the dose reductions, the patient should come 
off protocol therapy. 
 
 
 

 
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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/
CommercialAgentsMonographs.pdf) and is provided under Standard Sections for Protocols at: 
https://cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials. 
 
6.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

 
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6.2 
DINUTUXIMAB 
 
 
 
 
 
 
(04/30/19) 
(Unituxin, MoAb 14.18, chimeric; human/murine anti-GD2 monoclonal antibody; 
chimeric anti-GD2; chimeric mAb 14.18; ch14.18) NSC# 764038 
 
Source and Pharmacology: 
Dinutuximab (ch14.18, UTC) is an anti-GD2 monoclonal antibody composed of the variable 
region heavy and light chain genes of the murine mAb 14.G2a and the human constant 
region genes for heavy chain IgG1 and light chain kappa. Dinutuximab exerts its antitumor 
effect by binding specifically to the disialoganglioside GD2, an antigen found in human 
tumors of neuroectodermal origin such as melanoma and neuroblastoma. This chimeric 
antibody has been shown to lyse melanoma and neuroblastoma cells through the process 
of antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. 
By targeting the GD2 antigen on the cell surface, dinutuximab may also prevent attachment 
of circulating malignant cells to the extracellular matrix. Additionally, dinutuximab 
mediates lysis of several melanoma and neuroblastoma cell lines in a dose dependent 
manner in the presence of potent mediators of ch14.18-dependent cytotoxicity, such as 
human peripheral blood mononuclear cells and granulocytes. This is most profound with 
neutrophils, especially in the presence of recombinant human granulocyte-macrophage 
colony-stimulating factor. 
 
The PK profile of dinutuximab has been determined in adults with melanoma and children 
with neuroblastoma. Although the plasma clearance for both groups of patients follow a 
two-compartment model, circulating antibody is cleared from the plasma at a much faster 
rate in children than adults (mean t½β = 66.6 ± 27.4 hours in children versus 123 ± 29 hours 
and 181 ± 73 hours in two adult trials, respectively). Maturation of the hepatic and renal 
systems with age is thought to impact on drug metabolism and elimination and could 
account for these differences. In general, the mAb half-life following the first course of 
treatment was longer than the half-lives following subsequent courses in a given patient. 
 
Patient care implications: 
Based on its mechanism of action, dinutuximab may cause fetal harm when administered 
to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise 
females of reproductive potential to use effective contraception during treatment, and for 
two months after the last dose of dinutuximab.  
 
It is not known if dinutuximab is excreted in breast milk. IgG molecules are excreted in 
breast milk. Due to the potential for serious adverse reactions in the nursing infant, breast-
feeding is not recommended. 

 
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Toxicity:  
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Dinutuximab (MoAb 14.18, chimeric, NSCs 623408 and 764038) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. Frequency is provided based on 359 
patients. Below is the CAEPR for dinutuximab (MoAb 14.18, chimeric).  
 
 
Version 2.9, January 10, 201960 
 
 Adverse Events with Possible  
 Relationship to dinutuximab 
 (CTCAE 5.0 Term) 
 [n= 359] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
 
Disseminated intravascular 
coagulation 
 
 
 
 
Hemolytic uremic syndrome61 
 
CARDIAC DISORDERS 
 
 
 
Cardiac arrest 
 
 
 
Sinus bradycardia 
 
 
Sinus tachycardia 
 
 
EYE DISORDERS 
 
 
 
Eye disorders - Other (eye 
disorders)62  
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
 
Diarrhea 
 
 
 
Nausea 
 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Edema limbs 
 
 
Fever 
 
 
 
 
Generalized edema 
 
 
Pain 
 
 
 
 
 
Sudden death NOS 
 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction 
 
 
 
 
Anaphylaxis 
 
 
Serum sickness 
 
 

 
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 Adverse Events with Possible  
 Relationship to dinutuximab 
 (CTCAE 5.0 Term) 
 [n= 359] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
INFECTIONS AND INFESTATIONS 
 
 
 Infection63 
 
 
 
 
Myelitis64 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
 
Infusion related reaction 
 
INVESTIGATIONS 
 
 
Alanine aminotransferase increased  
 
 
Aspartate aminotransferase 
increased 
 
 
 
Creatinine increased 
 
 
Investigations - Other 
(elevated c-reactive 
proteins) 
 
 
 
 
Lymphocyte count decreased 
 
 
 
Neutrophil count decreased 
 
 
 
Platelet count decreased 
 
 
 
White blood cell decreased 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
 
 Hyperkalemia 
 
 
 
 Hypoalbuminemia 
 
 
 
 Hypocalcemia 
 
 
 
 Hypokalemia 
 
 
 
 Hyponatremia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Back pain 
 
 
 
Pain in extremity 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Neuralgia 
 
 
 
 
Peripheral motor neuropathy 
 
 
Peripheral sensory neuropathy65 
 
 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
 
RENAL AND URINARY DISORDERS 
 
 
Proteinuria 
 
 
 
 
Renal and urinary disorders - 
Other (atonic urinary bladder)6 
 
 
Urinary retention65 
 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Bronchial obstruction 
 
 

 
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 Adverse Events with Possible  
 Relationship to dinutuximab 
 (CTCAE 5.0 Term) 
 [n= 359] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Cough 
 
 
 
 
Dyspnea 
 
 
 
Hypoxia 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Pruritus 
 
 
Rash maculo-papular 
 
 
 
 
Urticaria 
 
 
VASCULAR DISORDERS 
 
 
Capillary leak syndrome 
 
 
 
Hypertension 
 
 
 
Hypotension 
 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail.  
 
2There have been rare instances of atypical hemolytic uremic syndrome in the absence of documented 
infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension. 
 
3Neurological disorders of the eye including blurred vision, diplopia, cycloplegia, mydriasis, photophobia, 
optic nerve disorder, eyelid ptosis, and fixed pupils have been observed.  
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5Myelitis expressed as transverse myelitis has occurred in patients treated with dinutuximab. Symptoms 
may include weakness, paresthesia, sensory loss, or incontinence. 
 
6Acute urinary retention occurs during therapy and is thought to be due to fluid shifts and narcotic 
administration that accompany dinutuximab administration.  Atonic urinary bladder results in chronic 
urinary retention (CUR) that requires intermittent urethral catheterization days to weeks following 
dinutuximab administration.  
 
 
Adverse events reported on dinutuximab trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that dinutuximab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(thrombotic microangiopathy [e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic 
syndrome [HUS]); Bone marrow hypocellular; Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Cardiac disorders - Other (gallop on exam); Cardiac disorders - Other (N-
terminal BNP); Chest pain - cardiac; Heart failure; Left ventricular systolic dysfunction; Mobitz (type) II 

 
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atrioventricular block; Myocardial infarction; Palpitations; Pericardial effusion; Supraventricular 
tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain; Hearing impaired 
ENDOCRINE DISORDERS - Endocrine disorders - Other (transient hypoaldosteronism); 
Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Papilledema; Periorbital edema; Scleral disorder 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Cheilitis; Colitis; Constipation; 
Duodenal obstruction; Dysphagia; Enterocolitis; Esophageal stenosis; Esophageal ulcer; Esophagitis; 
Gastrointestinal disorders - Other (bleeding, NOS); Gastrointestinal disorders - Other (esophageal 
stricture); Gastrointestinal disorders - Other (ischemic bowel); Gastrointestinal disorders - Other 
(pneumatosis intestinalis); Gastroparesis; Hemorrhoidal hemorrhage; Ileus; Intra-abdominal hemorrhage; 
Lower gastrointestinal hemorrhage; Mucositis oral; Oral pain; Rectal hemorrhage; Stomach pain; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; 
Edema face; Edema trunk; Fatigue; General disorders and administration site conditions - Other (cold and 
clammy); General disorders and administration site conditions - Other (vascular leak syndrome); 
Hypothermia; Injection site reaction; Localized edema; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (cholestasis) 
IMMUNE SYSTEM DISORDERS - Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alkaline phosphatase increased; 
Blood bilirubin increased; Cardiac troponin I increased; Cholesterol high; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; Fibrinogen decreased; GGT increased; INR increased; 
Lipase increased; Lymphocyte count increased; Urine output decreased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; 
Hyperglycemia; 
Hypermagnesemia; 
Hypernatremia; 
Hypertriglyceridemia; 
Hypoglycemia; 
Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Bone 
pain; Chest wall pain; Muscle weakness lower limb; Myalgia; Neck pain 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Depressed level of consciousness; 
Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Headache; Hydrocephalus; 
Meningismus; Movements involuntary; Nystagmus; Oculomotor nerve disorder; Paresthesia; Seizure; 
Somnolence; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Delirium; Hallucinations; Insomnia; 
Irritability; Personality change; Restlessness 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Glucosuria; 
Hematuria; Renal and urinary disorders - Other (acute renal insufficiency); Renal and urinary disorders - 
Other (urethritis); Renal hemorrhage 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Hematosalpinx; Ovarian hemorrhage; 
Pelvic pain; Penile pain; Prostatic hemorrhage; Spermatic cord hemorrhage; Testicular hemorrhage; 
Uterine hemorrhage; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Apnea; Atelectasis; Bronchospasm; Laryngeal edema; Laryngopharyngeal dysesthesia; 
Laryngospasm; Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumonitis; Pulmonary edema; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (tachypnea); Stridor; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Erythema multiforme; Hyperhidrosis 
VASCULAR DISORDERS - Flushing 
 
Note: dinutuximab in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 

 
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Formulation and Stability: 
Dinutuximab is provided as a sterile solution in single-dose vials containing 17.5 mg/5 mL 
(3.5 mg/mL) in 20 mM Histidine, 150 mM NaCl, 0.05% Tween 20 at pH 6.8. Intact vials 
should be stored in the refrigerator at 2ºC to 8ºC (36°F to 46°F); do not freeze. Do not 
shake. Keep the vial in the outer carton to protect from light. Solutions diluted for infusion 
should be stored at 2°C to 8°C (36°F to 46°F). Initiate infusion within 4 hours of 
preparation. Discard diluted solution 24 hours after preparation. 
 
Must be diluted prior to infusion. Withdraw the required dinutuximab volume and inject 
into a 100 mL bag of NS. Mix by gentle inversion; do not shake. Discard unused vial 
contents. Initiate infusion within 4 hours of preparation. Do not use if cloudy, discolored 
(pronounced), or contains particulates. The use of a filter during preparation is not required. 
The final prepared product of dinutuximab in NS is stable at room temperature for 24 hours 
when diluted to a concentration between 0.044 mg/mL and 0.56 mg/mL; however, the final 
dosage form should be prepared immediately prior to administration as there is a maximum 
infusion time of 20 hours.  
 
Guidelines for Administration:  
See Treatment, Dose Modifications and/or Supportive Care sections of the protocol.  
 
Administer as an IV infusion only (the minimum dinutuximab infusion time is 10  hours 
up to a maximum of 20 hours); do not administer as an IV push or bolus. Administer 
NS 10 mL/kg IV over 1 hour just prior to each dinutuximab infusion. Premedicate with 
analgesics, an antihistamine, and an antipyretic prior to administration. Infuse in an 
environment equipped to monitor for and manage infusion reactions. Interrupt infusion for 
toxicity. Monitor patients closely for signs and symptoms of an infusion reaction during 
and for at least 4 hours following completion of each dinutuximab infusion. 
 
Supplier: 
Commercially available. See package insert for further information. 
 
CANADIAN SITES: 
Commercially available through McKesson Canada. 
 
AUSTRALIA AND NEW ZEALAND SITES: 
United Therapeutics will provide dinutuximab via expanded access program to the COG 
sites in Australia and New Zealand that had ANBL0032 study open in the past. 
Dinutuximab can only be used in accordance with the United States prescribing 
information. IDIS Managed Access will be utilized for this program. Prescribers can order 
dinutuximab for new patient starts by requesting a copy of updated IDIS patient access 
form at global@idispharma.com 
 
 
6.3 
IRINOTECAN 
 
 
 
 
 
 
(12/18/18) 
[CPT-11, Camptothecin-11,7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-
camptothecin), Camptosar®], NSC #616348 
 
Source and Pharmacology: 
Irinotecan is a semisynthetic water-soluble analog of camptothecin (a plant alkaloid 
isolated from Camptotheca acuminata). Irinotecan is a prodrug that requires conversion, 

 
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by the carboxylesterase enzyme to the topoisomerase-I inhibitor, SN-38 in order to exert 
anti-tumor activity. SN-38 is approximately 1000 times more potent than irinotecan. 
Camptothecins interact specifically with the enzyme topoisomerase I which relieves 
torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its 
active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation 
of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan 
is due to double-strand DNA damage produced during DNA synthesis when replication 
enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either 
irinotecan or SN-38. Renal excretion is a minor route of elimination of irinotecan. The 
majority of the drug is metabolized in the liver. SN-38 is conjugated to glucuronic acid and 
this metabolite has no anti-tumor activity. The extent of conversion of SN-38 to its 
glucuronide has been inversely correlated with the risk of severe diarrhea, because the other 
major route of SN-38 excretion is biliary excretion by canalicular multispecific organic 
anion transporter (cMOAT) which presumably leads to mucosal injury. In addition, APC 
and NPC are oxidative metabolites of irinotecan dependent on the CYP3A4 isoenzyme. 
After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations 
decline in a multiexponential manner, with a mean terminal elimination half-life of about 
6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is 
about 10 to 20 hours. Irinotecan is 30% to 68% bound to albumin and SN-38 is 
approximately 95% bound to albumin. 
 
 
Toxicity: 
Incidence 
Toxicities 
Common 
(>20% of 
patients)  
• Anemia 
• Thrombocytopenia 
• Neutrophil count decreased 
• White blood cell count decreased 
• Nausea 
• Vomiting 
• Constipation 
• Anorexia 
• Fever 
• Asthenia 
• Cholinergic symptoms: (rhinitis, increased salivation, miosis, lacrimation, 
diaphoresis, flushing, and intestinal hyperperistalsis that can cause 
abdominal cramping and diarrhea) 
• Alopecia 
• Bilirubin increased 
• Mucositis 
• Dyspnea 
• Cough 
• Weight loss 
• Pain 
Occasional 
(4-20% of 
patients)  
• Abdominal fullness 
• Flatulence 
• Vasodilation 
• Hypotension 

 
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• Dehydration 
• Edema 
• AST increased 
• Alkaline phosphatase increased 
• Ascites 
• Jaundice 
• Febrile neutropenia 
• Infection 
• Headache 
• Dizziness 
• Chills 
• Insomnia 
• Rash 
• Dyspepsia 
• Somnolence 
• Thromboembolic events 
• Pneumonia 
Rare 
(≤ 3% of 
patients)  
• Anaphylaxis 
• Bradycardia 
• Disorientation/confusion 
• Colitis 
• Renal failure (secondary to severe dehydration) 
• Ileus 
• Pancreatitis 
• Pneumonitis (L) 
Pregnancy & 
Lactation 
Fetal toxicities and teratogenic effects of irinotecan have been noted in animals 
at doses similar or less than those used in humans. Toxicities include: decreased 
skeletal ossification, multiple anomalies, low birth weight and increased fetal 
mortality. It is not known if irinotecan is excreted into breast milk but it is 
excreted into rat milk. 
(L) Toxicity may also occur later 
 
Formulation & Stability: 
Each mL of irinotecan injection contains 20 mg irinotecan (on the basis of the trihydrate 
salt), 45 mg sorbitol, and 0.9 mg lactic acid. When necessary, pH has been adjusted to 3.5 
(range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan is available in 
single-dose amber glass vials in 40 mg (2 mL), 100 mg (5 mL), 300 mg (15 mL), and 
500 mg (25 mL). Store at controlled room temperature 15°-30°C (59°-86°F). Protect from 
light. It is recommended that the vial (and backing/plastic blister) should remain in the 
carton until the time of use.  
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
IV Administration: Irinotecan must be diluted prior to infusion. Irinotecan should be 
diluted in D5W, (preferred) or NS to a final concentration range of 0.12-2.8 mg/mL. The 
solution is physically and chemically stable for up to 24 hours at room temperature 
(approximately 25°C) and in ambient fluorescent lighting. Solutions diluted in D5W and 
stored at refrigerated temperatures (approximately 2°-8°C), and protected from light are 

 
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physically and chemically stable for 48 hours. Refrigeration of admixtures using NS is not 
recommended due to a low and sporadic incidence of visible particulates. Care should be 
taken to avoid extravasation; the use of a central line is suggested. 
 
Supplier: 
Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
 
6.4 
SARGRAMOSTIM 
 
 
 
 
 
 
(06/26/18) 
(Granulocyte Macrophage Colony Stimulating Factor, rhu GM-CSF, rGM-CSF, GM-CSF, 
Leukine®) NSC #613795 
 
 
 
 
 
 
Source and Pharmacology: 
Sargramostim (recombinant human GM-CSF) is a glycoprotein produced in yeast (S. 
cerevisiae) by recombinant DNA technology. rGM-CSF is a hematopoietic growth factor 
which supports survival, clonal expansion, and differentiation of hematopoietic progenitor 
cells. rGM-CSF induces partially committed progenitor cells to divide and differentiate in 
the granulocyte-macrophage pathways. rGM-CSF stimulates the production of monocytes, 
granulocytes, erythrocytes, and sometimes, megakaryocytes in the bone marrow. It also 
induces mature neutrophil and monocytes to increase phagocytosis, superoxide generation, 
ADCC, tumoricidal killing and cytokine production (IL-1 and tumor necrosis factor). 
Recombinant human GM-CSF is a glycoprotein of 127 amino acids characterized by three 
primary molecular masses of 15500, 16800, and 19500 daltons. The amino acid sequence 
differs from the natural sequence by a substitution of leucine at position 23 and the CHO 
moiety may be different from the native protein. After subcutaneous administration of 
sargramostim, peak levels were obtained in 1-4 hours and were detectable at therapeutic 
levels for 12-16 hours post injection. The elimination t½ ranges from 1.5-2.7 hours after SubQ 
or IV administration. 
 
Toxicity: 
 
Common 
Happens to 21-100 children out of 
every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-
2 days of 
receiving drug 
Headache, malaise, fatigue, rash, 
pruritus, bone pain, myalgia, 
arthralgia, fever, chills 
Abdominal pain, weakness, 
anorexia, nausea, local injection 
reactions 
Anaphylaxis, “first dose 
reaction” (hypoxia, dyspnea, 
hypotension, fever, tachycardia, 
diaphoresis, flushing, back 
pain), vomiting, diarrhea, 
phlebitis, SVT, pericardial 
effusion 
Prompt: 
Within 2-
3 weeks, prior 
to the next 
course 
 
Weight gain 
In high doses: capillary leak 
syndrome: (pleural effusion, 
peripheral edema, ascites, 
weight gain, hypotension), 
pneumonitis, peripheral edema, 
elevation of creatinine, bilirubin 
and hepatic enzymes in patients 
with pre-existing renal or 
hepatic dysfunction 
Delayed: 
 
Thrombocytopenia  
 

 
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Any time later 
during therapy 
Unknown 
Frequency 
and Timing:  
Fetal and teratogenic toxicities: It is not known whether sargramostim can cause fetal harm or affect 
reproduction capacity when administered to a pregnant woman. It is unknown whether the drug is 
excreted in breast milk. 
 
Formulation and Stability: 
Sargramostim is available as a lyophilized sterile, white, preservative free powder with 
250 mcg (1.4 million International Units) per vial. The sargramostim reconstituted 
lyophilized vial contains 40 mg/mL mannitol, USP; 10 mg/mL sucrose, NF; and 
1.2 mg/mL tromethamine, USP, as excipients. Store refrigerated at 2-8°C (36-46°F). 
Do not freeze or shake. 
 
Guidelines for Administration: 
See Treatment and Dose Modifications and Supportive Care sections of the protocol. 
 
Reconstitute lyophilized powder for injection with 1 mL SWFI or 1 mL Bacteriostatic 
Water for Injection. Use SWFI without benzyl alcohol for neonates, infants, and 
children < 2 years of age or patients with hypersensitivity to benzyl alcohol. During 
reconstitution, direct the diluent at the side of the vial and gently swirl the contents to avoid 
foaming during dissolution. Avoid excessive or vigorous agitation; do not shake. 
Reconstituted solutions prepared with Bacteriostatic Water for Injection (0.9% benzyl 
alcohol) or the liquid preserved solution may be stored for up to 20 days following the first 
entry into the vial at 2°-8°C (36°-46°F). Discard reconstituted solution after 20 days have 
elapsed. Reconstituted solutions prepared with SWFI (without preservative) should be 
administered as soon as possible and within 6 hours following reconstitution. 
 
Use sargramostim for subcutaneous injection without further dilution. Perform dilution for 
IV infusion in NS. If the final concentration is < 10 mcg/mL, add albumin (human) at a 
final concentration of 0.1% to the saline prior to addition of sargramostim to prevent 
adsorption to the components of the drug delivery system. For a final concentration of 0.1% 
albumin (human), add 1 mg albumin (human) per 1 mL NS. For example, for a final 
volume of 50 mL NS, add 50 mg (or 1 mL) of 5% albumin [human]. Intravenous dilutions 
are stable for up to 48 hours at room temperature or refrigerated but should be used within 
6 hours due to microbiological concerns. Do not use an in-line membrane filter for 
IV infusion.  
 
Supplier: 
Commercially available. See package insert for more detailed information. 
 
CANADIAN SITES 
Sargramostim is not commercially available in Canada. Sites may purchase and import the 
USA commercial supply of Lyophylized Leukine® distributed by Partner Therapeutics via 
an International Distributor (Pharma Exports LLC; 
 
 
 
 
 
 
 under the authority of the protocol’s No Objection Letter (NOL). 
 
The Canadian Senior Medical Officer (SMO)’s office is responsible for coordinating the 
“Fax Back” approval with Health Canada’s Biologics and Genetic Therapies Directorate 
for all lots for use in Canada on behalf of all Canadian sites. A list of approved lot numbers 
is posted on the C17 website (www.c17.ca) under the protocol titled Sargramostim. If an 

 
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unapproved lot is received from the distributor, quarantine the lot and contact the COG 
Canada Regulatory Affairs Office at c17@albertahealthservices.ca. 
 
Canadian sites must keep a drug accountability log (DAL) and must record Lot #’s and 
expiry dates of shipments received and doses dispensed. Sites may use their own DAL as 
long as it complies with all elements of ICH GCP and Health Canada’s Division 5 of the 
Food and Drugs Act. Each site is responsible for the procurement (import +/- purchase) of 
sargramostim. Sites may import and manage a single clinical trial supply for multiple 
protocols as long as each protocol has an NOL and the protocol the patient is registered on 
is recorded on the DAL. 
 
 
6.5 
TEMOZOLOMIDE 
 
 
 
 
 
(08/26/20) 
(Temodar, Temodal) NSC #362856 
 
Source and Pharmacology: 
An orally or intravenously administered alkylating agent, a second generation 
imidazotetrazine. A prodrug of MTIC, temozolomide spontaneously decomposes to MTIC 
at physiologic pH.  
 
The cytotoxic effects of MTIC are manifested through alkylation (methylation) of DNA at 
the O6, N7 guanine positions which lead to DNA double strand breaks and apoptosis. 
Temozolomide is noncell cycle specific. 
 
Temozolomide is rapidly and completely absorbed after oral administration with a peak 
plasma concentration (Cmax) achieved in a median Tmax of 1 hour. Food reduces the rate and 
extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased 
by 32% and 9%, respectively, and median Tmax increased by 2-fold (from 1-2.25 hours) 
when temozolomide was administered after a modified high-fat breakfast. A 
pharmacokinetic study comparing oral and intravenous temozolomide in patients with 
primary CNS malignancies showed that at 150 mg/m2 dose temozolomide IV and oral 
capsules are bioequivalent with respect to both Cmax and AUC of temozolomide and MTIC. 
Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is 
weakly bound to human plasma proteins; the mean percent bound of drug-related total 
radioactivity is 15%. Temozolomide is spontaneously hydrolyzed at physiologic pH to the 
active species, MTIC and to temozolomide acid metabolite. Cytochrome P450 enzymes 
play only a minor role in the metabolism of temozolomide and MTIC. About 38% of the 
administered temozolomide total radioactive dose is recovered in the urine. Overall 
clearance of temozolomide is about 5.5 L/hr/m2. Temozolomide is rapidly eliminated, with 
a mean elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic 
dosing range of 75 to 250 mg/m2/day. A population analysis did not demonstrate any 
influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, 
ondansetron, H2 receptor antagonists, or phenobarbital on the clearance of orally 
administered temozolomide.  
 

 
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The table below lists the anticipated toxicity profile of temozolomide (oral): 
Incidence 
Toxicities 
Common 
(>20% of patients) 
Constipation, nausea, vomiting, , anorexia, alopecia, headache, seizure, fatigue 
Occasional 
(4-20% of patients) 
Peripheral edema, skin rash, pruritus, xeroderma, erythema of skin, diarrhea, dysphagia, 
dizziness, ataxia, hemiparesis, asthenia, fever, stomatitis, abdominal pain, dysgeusia, 
weight gain, platelet count decreased, white blood cell count decreased, lymphocyte 
count decreased, urinary incontinence or frequency, cough, dyspnea, infection, anxiety, 
depression, insomnia, gait disturbance, amnesia, paresthesia, drowsiness, visual 
disturbances, back pain, arthralgia/myalgia  
Rare 
(≤ 3% of patients) 
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, 
hyperbilirubinemia, transaminitis, injection site reaction (IV formulation), interstitial 
pneumonitis, pancytopenia (may be prolonged), myelodysplastic syndrome, leukemia 
secondary to oncology chemotherapy, infections and infestations – other: Pneumocystis 
pneumonia, pulmonary fibrosis, anaphylaxis, allergic reaction, hepatotoxicity, 
cholestasis, anemia, aplastic anemia  
Pregnancy & 
Lactation 
Pregnancy Category D 
Adequate, well-controlled studies have not been conducted in humans. Women of 
childbearing potential should be advised against becoming pregnant while taking 
temozolomide and for at least 6 months following the end of therapy. Temozolomide 
administration to rats and rabbits at 3/8 and 3/4 the human dose resulted in the 
development of malformations of the external organs, soft tissues, and skeleton. These 
animal studies also demonstrated embryolethality (increased resorptions) at similar 
doses. There is no information available regarding the transmission of temozolomide 
during lactation; women should avoid breastfeeding while receiving temozolomide. 
 
Formulation and Stability: 
Temozolomide capsules are available in six different strengths (5, 20, 100, 140, 180, 
250 mg). The capsules vary in size, color, and imprint according to strength. In the US, 
capsules are packaged in 5-count and 14-count bottles. In other countries temozolomide 
may be packaged in 5-count, 14-count or 20-count bottles. Temozolomide capsules are 
stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). 
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
There is a potential for medication errors involving temozolomide capsules resulting in 
drug overdosages, which may have been caused by dispensing/taking the wrong number 
of capsules per day and/or product usage exceeding the prescribed dosing schedule. 
 
When dispensing, it is extremely important that prescribing and dispensing include clear 
instructions on which capsules, and how many of each capsule(s) are to be taken per day. 
Only dispense what is needed for the course, and clearly indicate how many days of dosing 
the patient will have and how many days are without temozolomide dosing. When 
counseling patients, it is important for each patient/parent to understand the number of 
capsules per day and the number of days that they take temozolomide. It is also important 
for the patient/parent to understand the number of days that they will be off the medication.  
 
Each strength of temozolomide must be dispensed in a separate vial or in its original 
container (e.g., bottle or sachet). Based on the dose prescribed, determine the number of 

 
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each strength of temozolomide capsules needed for the full course as prescribed by the 
physician. For example, 275 mg/day for 5 days would be dispensed as five 250 mg 
capsules, five 20 mg capsules, and five 5 mg capsules. Label each container with the 
appropriate number of capsules to be taken each day. Dispense to the patient/parent, 
making sure each container lists the strength (mg) per capsule and that he or she 
understands to take the appropriate number of capsules of temozolomide from each bottle 
or vial to equal the total daily dose prescribed by the physician. Institutions that have the 
capability to dispense temozolomide as daily doses in a blister pack may do so, taking 
specific precautions to ensure that the appropriate dose is provided and that the patient is 
educated to understand the daily dosing regimen. 
 
For children unable to swallow the capsules whole, the oral capsules may be formulated into 
a suspension. To prepare a 10 mg/mL suspension triturate the contents of ten 100 mg 
capsules (1000 mg), 500 mg povidone K-30 and 25 mg anhydrous citric acid dissolved in 1.5 
mL purified water in a glass mortar to form a uniform paste. To the paste add 50 mL of Ora-
Plus® by adding a small amount, mixing, and then adding the balance. Transfer to a glass 
graduated cylinder. Add Ora-Sweet® or Ora-Sweet® SF to a total volume of 100 mL by 
rinsing the mortar with small amounts of the syrup (Ora-Sweet® or Ora-Sweet® SF). Rinse 
at least four times. Package in an amber plastic prescription bottle. The packaged suspension 
should be stored in the refrigerator at 2-8C (36-46F) for no more than 2 weeks after 
preparation. The suspension should be shaken well before each use. Procedures for proper 
handling and disposal of cytotoxic drugs should be used when preparing the suspension.66  
 
Extemporaneous temozolomide 10 mg/mL suspension can also be prepared using 100 mg 
temozolomide capsules mixed in Ora-Mix SF®. Open contents of the required number of 100 
mg temozolomide capsules into a mortar and add Ora-Mix SF® until a paste forms. Add more 
vehicle until a liquid is formed (for each 100 mg capsule add 10 mL of Ora-Mix SF®). 
Transfer desired volume to a glass or polyethylene terephthalate bottle. Label the container, 
assigning a beyond-use-date of 30 days, for storage under refrigeration only.67 
 
Alternatively, the capsules can be opened and mixed with apple sauce or juice, which should 
be used immediately after mixing or must be used in 2 hours after mixing (refer to Appendix 
VIII). 
 
Supplier: 
Commercially available. See package insert for further information. 
 

 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
7.1 
End of Therapy & Follow-up 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
STUDIES TO BE 
OBTAINED 
End of 
Therapy 
Disease 
Progression 
Follow up 
Year 1 
Year 1 
Year 1 
Years 2 -5 
30 days 
6 months* 
12 months* 
Annually*  
History 
X 
 
 
 
 
 
Physical Exam with VS 
X 
 
 
 
 
 
Ht, Wt, BSA 
X 
 
 
 
 
 
Performance Status 
X 
 
 
 
 
 
CBC, differential, 
platelets 
X 
 
 
 
 
 
Electrolytes, BUN, 
Creatinine 
X 
 
 
 
 
 
ALT, total bilirubin, 
albumin 
X 
 
 
 
 
 
CT/MRI1 
X2 
X 
 
 
 
 
MIBG (or FDG-PET if 
123I-MIBG non-avid 
disease) 
X2 
X 
 
 
 
 
Bilateral bone marrow 
aspirates and biopsies 
X2 
X 
 
 
 
 
Audiogram 
X 
 
X3 
 
X 
 
Disease status 
X 
 
X 
X 
X 
X 
Toxicity/Significant 
events 
X 
 
X 
X 
X 
X 
Survival/Vital status 
X 
 
X 
X 
X 
X 
 
* +/- 2 months 
1. 
Cross-sectional imaging should be of the original primary site and any non-osseous 
disease sites present at study enrollment or at time of progression. 
2. 
For patients who experienced their first response (MR, PR, CR) at the time of the 
end therapy evaluation, a complete confirmatory disease evaluation should be performed 
at least 4 weeks after the end of therapy evaluation.  
3. 
If the patient underwent an audiogram within 28 days prior to end of therapy (ie, 
at the end of the previous cycle), the end of therapy audiogram should be done 30 days 
+/- 7 days from the end of therapy date. 
 

 
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7.2 
Research Studies for which Patient Participation is Required or Optional 
See Section 14.0 for Special Studies requirements. Required studies are detailed in Section 
14.1 and optional studies (including specimens for biobanking) 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-ANBL1821 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) 
Stable disease after 6 cycles of protocol therapy for patients enrolled prior to Amendment 
4. 
c) 
Intolerance of study therapy or unacceptable toxicity due to protocol therapy (see 
Section 5.0). 
d) 
Refusal of further protocol therapy by patient/parent/guardian. 
e) 
Completion of the maximum allowable number of cycles of therapy (see Section 4.1). 
f) 
Physician determines it is in patient’s best interest. 
g) 
Second malignant neoplasm (SMN). 
h) 
Patients who do not meet criteria to start the next treatment cycle within 21 days after 
the planned subsequent cycle start date (i.e. there is a ≥ 3 week delay in start of next 
cycle). 
i) 
Pregnancy. 
j) 
Repeat eligibility studies (if required) are outside the parameters required for eligibility 
(see Section 3.2). 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for 
Off Study (see below). Follow-up data will be required unless patient is taken off study. 
 
8.2 
Off Study Criteria 
a) 
Death. 
b) 
Lost to follow-up. 
c) 
Patient enrollment onto another COG study with tumor therapeutic intent (e.g. at time 
of progression or subsequent relapse). 
d) 
Withdrawal of consent for any further data submission. 
e) 
The fifth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size and Study Duration 
The proposed randomized Phase 2 study will require enrollment of 90 eligible patients, 
45 assigned to each regimen. Enrollment may proceed up to 95 patients to allow up to 5% 
potentially ineligible patients. 

 
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Expected accrual for this study would be similar to the accrual rate of 42 patients/year 
observed on the ANBL1221 expansion cohort at non-Australian and New Zealand sites as the 
patient population and eligibility are very similar. We anticipate that given the positive results 
of ANBL1221 and the reality that this backbone has become widely used for first relapse, 
there should be similar accrual rates for this trial. Assuming this rate, the trial would take about 
2.3 years to complete accrual of up to 95 patients. The study will require an additional 12 
months for completion of therapy and toxicity evaluation for a total study duration of 
approximately 3.3 years. 
 
The sample size may be increased if accrual is fast: specifically, if 30 months after the study 
commencement the average accrual rate over the previous 3 months is above an annual rate 
of 41 patients per year, then the study may be amended (blindly to the interim outcome data) 
and accrual increased to 148 eligible patients. In this case, enrollment may proceed up to 
155 patients to allow up to 5% potentially ineligible patients. Assuming an accrual rate of 
42 patients/year (this rate would be amended if needed based on observed accrual rate), the 
trial would take about 3.7 years to complete accrual and a total study duration of ~4.7 years. 
The amendment would be submitted after the 30-month time point so that the study will not 
need to be closed to accrual as a result of the increase in the target accrual. 
 
9.2 
Study Design 
This will be a prospective, randomized phase 2 trial to determine whether the addition of 
DFMO to the dinutuximab/irinotecan/temozolomide backbone improves the response rate 
compared to the backbone alone. Patients will be randomized 1:1 to Regimen A 
(irinotecan/temozolomide/dinutuximab) or Regimen B (DFMO + irinotecan/temozolomide/ 
dinutuximab), stratified by disease category (measurable vs. evaluable), prior anti-GD2 
therapy (prior exposure to anti-GD2 antibody vs. no prior exposure to anti-GD2 antibody), 
prior DFMO therapy (prior exposure to DFMO vs. no prior exposure to DFMO), and MYCN 
status (amplified vs. non-amplified vs. unknown). We will monitor for differences in the 
response rate between the two regimens for early indication of futility and efficacy. 
 
9.3 
Methods of Analysis 
9.3.1 
Primary Endpoint 
The primary endpoint will be the proportion of eligible patients who are 
responders. Responders are defined as patients who achieve a minor response 
(MR) or better, per the revised International Neuroblastoma Response Criteria 
(INRC),68 as their best overall response by the end of 6 cycles as determined by 
central review. With Amendment 4, patients with a response of MR, PR, or CR 
that is qualified by “Not Fully Evaluated (NFE)” will be included as responders. 
See Section 10.2.3 and Appendix XIV for definition of NFE. Patients with 
progressive disease (PD) prior to attaining a ≥ MR will be considered non-
responders. If a patient becomes a responder and later has PD or later goes off 
protocol therapy, then the patient will be counted as a responder. Eligible patients 
without any response assessment will be considered non-responders. All eligible 
patients will be considered evaluable for response. All analyses of response will 
be conducted as intent-to-treat. 
 
Patients enrolled prior to Amendment 4: Patients will be assessed for response 
after every 2 cycles for the first 6 cycles, then after every 4 cycles for up to 11 

 
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additional cycles. Patients with stable disease or better during the first 4 cycles will 
be permitted to continue protocol therapy. However, after 6 cycles, patients not 
demonstrating a response [complete response (CR), partial response (PR), or MR] 
will be removed from protocol therapy. The decision to remove patients without 
response after 6 cycles is based on data from ANBL1221, where the majority of 
responders to I/T/DIN were found to have objective responses after 2 cycles but 
some patients did not achieve their best response until later cycles. Data including 
the expanded cohort of patients treated with I/T/DIN on ANBL1221 indicate that 
12 of 22 responders (54.5%) experienced their best response after Cycle 2, with 
the remaining 10 of 22 (45.5%) responders achieving their best response by Cycle 
6.3 
 
Patients enrolled on Amendment 4 or later: Patients will be assessed for 
response after every 2 cycles and may receive a maximum of 6 cycles of protocol 
therapy. Patients with stable disease or better during the first 4 cycles will be 
permitted to continue protocol therapy. All patients will go off protocol therapy 
regardless of response after 6 cycles. 
 
9.3.1.1 
Power Calculations 
With enrollment of 90 eligible patients (45 to each regimen), this design 
has 80% power to detect a 20% difference in response rate [40% under the 
null for Regimen A (as observed on the ANBL1221 including the 
expanded cohort of patients assigned to the I/T/DIN arm), 60% under the 
alternative for Regimen B] and type I error of 20%, using a one-sided 
continuity-corrected test of proportions with pooled variance. 
 
If the study is amended and the sample size is increased to 148 eligible 
patients (74 on each regimen) due to fast accrual, a 15% difference in 
response rate will be targeted [40% under the null for Regimen A, 55% 
under the alternative for Regimen B]. This design has 80% power and type 
I error of 20%, using a one-sided continuity-corrected test of proportions 
with pooled variance and interim monitoring for efficacy with a one-sided 
O'Brien-Fleming rule. 
 
9.3.2 
Secondary Endpoints 
Progression-free survival (PFS) and overall survival (OS) will be assessed for 
patients receiving dinutuximab, irinotecan, and temozolomide with and without 
the addition of DFMO. For PFS, time to event will be calculated from the time of 
randomization to the occurrence of relapse, progressive disease, or death. For OS, 
death will be the only event considered and time to death will be calculated from 
the time of randomization. Patients without a PFS event or death will be censored 
at the time of last follow-up. 
 
9.3.3 
Monitoring for Futility or Efficacy of Regimen B 
Monitoring for futility or efficacy of the DFMO arm will be performed. There 
would be cause to stop the trial early if the response rate on Regimen B appears to 
be insufficiently efficacious or superior to Regimen A. The response rates will be 
monitored after 2 cycles to decrease the amount of time the study must be closed 
for interim analysis. ANBL1221 data showed that most patients that responded on 

 
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the I/T/DIN arm did so early, with 16 of the 22 patients with confirmed responses 
demonstrating partial response or better after the first 2 cycles. With Amendment 
4, the interim analysis will be done using overall response, or if overall response 
was coded as Not Done due to a missing component of the disease evaluation, the 
response at soft tissue and bone sites will be used as the overall response at the end 
of Cycle 2.  
 
Futility monitoring will be performed per Ellenberg and Eisenberger (1985):69 if 
at half the sample size the observed response rate after 2 cycles for Regimen B is 
less than that for Regimen A, accrual will be halted and the DSMC will consider 
permanently stopping accrual. Due to the potential for a drug supply issue, the 
futility analysis will be performed sooner, after accrual of 40 patients rather than 
at half the sample size of 45 patients. The futility rule will be executed once, using 
data from the first 40 eligible patients enrolled. This two-stage rule has been shown 
to lead to a reduction in the expected sample size if Regimen B is ineffective, with 
minimal loss in power.70 
 
A one-sided O'Brien-Fleming group-sequential boundary will be used to monitor 
for efficacy of Regimen B if the sample size is increased to 148 eligible patients. 
Interim monitoring will be performed at 50% of the expected information (N=74, 
37 eligible patients per regimen), and 100% information. The critical p-values 
(upper boundary z-score) for the interim looks (maintaining an overall significance 
level of 20%) are 0.0699 (1.4763) at the first look, with the final analysis 
performed at a significance level of 0.1803 (0.9141). 
 
If the futility and efficacy monitoring rules are not triggered, accrual will continue 
as planned, and the one-sided continuity-corrected test of proportions with pooled 
variance will be applied. 
 
9.3.4 
Assessment of Study Objectives 
The primary study aim (1.1.1) will be assessed by a one-sided continuity-corrected 
test of proportions with pooled variance to compare the response rates after 
6 cycles in the two regimens, and the futility and efficacy monitoring rules (Section 
9.3.3). The response rate by the end of 6 cycles will be calculated on each regimen, 
including placement of a 95% confidence interval. If a patient is a responder and 
later has PD or goes off protocol therapy, then the patient will be counted as a 
responder. If the response rate on Regimen B is significantly better, then it will be 
considered a therapeutic regimen worthy of further testing in patients with newly-
diagnosed high-risk neuroblastoma. In addition, the response rate by the end of 6 
cycles (based on confirmed responses) will also be calculated for each regimen, 
with responders defined as patients who achieve a confirmed minor response or 
better per the revised INRC68 as their best overall response by the end of 6 cycles 
as determined by central review. 
 
To address secondary objective 1.2.1, Kaplan-Meier curves of PFS and OS will be 
generated by regimen and compared using log-rank tests. PFS and OS will also be 
evaluated separately in the cohorts of patients enrolled prior to and post-
Amendment 4 given the reduction in maximum cycles of therapy from 17 to 6 
cycles. 
 

 
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To assess secondary aim 1.2.2, toxicities (Grade ≥ 3) experienced on Regimen B 
will be descriptively summarized.   
 
Exploratory aim 1.3.1 will be assessed by exploring the relationship between 
response (responder vs. non-responder) after 6 cycles on Regimen B with serum 
cytokine levels (IL1, IL6, TNF-alpha, IFN-gamma, etc.), tumor resident immune 
cells (NK cells, TAMS, TILS), and critical immune cell suppressing proteins 
(B7H3, PDL-1) using Fisher's exact test for categorical and Wilcoxon rank-sum 
test for continuous factors. 
 
To address exploratory objective 1.3.2, GD2 levels in tumor cells from bone 
marrow samples will be correlated with response (responder vs. non-responder) 
after 6 cycles using Fisher’s exact test for categorical and the Wilcoxon rank-sum 
test for continuous factors. 
 
To assess exploratory aim 1.3.3, the occurrence of pain on each regimen as 
reported by patient report and opiate use will be descriptively summarized. 
Descriptive and summary statistics will be used to describe the scores from the 
Faces Pain Scale-Revised during the dinutuximab infusion and on Day 1 with 
irinotecan and temozolomide alone for each arm separately. Confidence intervals 
will be constructed for the mean and frequency estimates. The Day 1 patient 
reported outcome data are expected to be similar between the 2 regimens, while 
differences during or after completion of treatment may be observed. 
 
9.4 
Evaluability for Response  
All eligible patients will be considered evaluable for response. 
 
9.5 
Evaluability for Toxicity  
All eligible patients will be evaluable for toxicity from the time of their first treatment with 
eflornithine, irinotecan, temozolomide, or dinutuximab. 
 
The study committee will review ototoxicity data closely during monthly committee meetings. 
If a difference in the incidence of hearing loss of >15% in eligible patients treated on the 
interrupted schedule enacted with Amendment 2A is detected among patients on the DFMO-
containing Regimen B as compared to Regimen A, the study committee will notify the DSMC 
and CTEP and discuss potentially suspending accrual and further modifying the DFMO dose 
and/or schedule. In this context, hearing loss is defined as “an increase of 15dB or more from 
baseline in hearing threshold at two contiguous frequencies between 500-3000Hz” as this is 
the criterion for which DFMO is held for hearing loss. 
 
9.6 
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 

 
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American 
Indian/ 
Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
3 
0 
0 
3 
Native 
Hawaiian 
or 
Other 
Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
8 
5 
0 
0 
13 
White 
18 
29 
5 
10 
62 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
26 
37 
5 
10 
78 
 
 
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 
2 
0 
0 
2 
Native 
Hawaiian 
or 
Other 
Pacific 
Islander 
1 
1 
0 
0 
2 
Black or African 
American 
0 
0 
0 
0 
0 
White 
4 
7 
2 
0 
13 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
5 
10 
2 
0 
17 
 
This distribution was derived from ANBL1221. 
 
 
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. 
 
Please note: ‘CTCAE v5.0’ is understood to represent the most current version of CTCAE 
v5.0 as referenced on the CTEP website (i.e., v5.0 and all subsequent iterations prior to 
version 6.0). 
 

 
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10.2 
Response Criteria for Patients with Solid Tumors 
This study will use the revised International Neuroblastoma Response Criteria (INRC) for 
disease assessment.68 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 
10.2.1.1 Evaluable for toxicity: All eligible patients will be evaluable for toxicity 
from the time of their first treatment with eflornithine, or irinotecan, 
temozolomide or dinutuximab. 
 
10.2.1.2 Evaluable for response: All eligible patients will be considered evaluable 
for response. These patients will have their response classified according 
to the definitions stated below.  
 
10.2.2 Disease Parameters 
10.2.2.1 Measurable disease:  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or 
≥ 10 mm with calipers by clinical exam. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area will 
be considered measurable if they demonstrate clear evidence of 
progression after completion of radiation. 
 
10.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed as per RECIST 1.1 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. 
 
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, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 

 
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Note: Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
10.2.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be 
selected. 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. The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
10.2.2.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
10.2.2.6 Bone lesions: Osteomedullary disease will be assessed using 123I-MIBG 
scans or FDG-PET scans. Technetium bone scans are no longer used as 
part of the revised INRC and are not included as part of disease 
reassessments during this trial. The extent of tracer avid disease will be 
evaluated using the Curie scoring system (see Appendix IX 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. 
10.2.2.7 Bone marrow disease: Bilateral bone marrow aspirates and trephine 
biopsies are required at disease assessment time points (baseline and end 
of Cycles 2, 4, 6 and every 4th cycle thereafter if bone marrow 

 
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involvement at study enrollment or any history of bone marrow disease; 
end of Cycles 2 and 6 for those patients without bone marrow 
involvement at study enrollment and without any history of bone marrow 
involvement). 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.).71 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 
1Not 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 SITES5 
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 a 
reference the absolute score for bone lesions from time 
of enrollment4,6) 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 new bone site that is MIBG avid and that was not seen on 
the immediate prior scan;   
• 
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 enrollment4, 7 
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. 

 
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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. 
4 MIBG-SPECT or MIBG-SPECT/CT may be used for scoring purposes but the same 
imaging methodology should be used for all evaluations. 
5 Criteria 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.   
6 Relative Curie score when assessing patient for partial response: [Current Curie score for 
bone sites] / [Curie score for bone sites at enrollment]. 
7 Relative 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 
In determining overall response, Not Fully Evaluated (NFE) will be used when at 
least one component of response evaluation was not required and not performed for 
one or more of the 3 components required for overall response (this will be 
annotated CR, PR, MR, or SD).  
 
If a component was not performed and was required by protocol, that component 
will be determined to be Not Done (ND) and the overall response will be Not Done. 
 
 
 

 
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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. 
For CR, PR, MR, SD – if one or more component evaluations were not required at that 
disease evaluation timepoint AND they were not performed at the timepoint in question– 
that response will be annotated as Not Fully Evaluated (NFE).   
 
*Patients who enroll with marrow-only disease who have a marrow response of Minimal 
Disease will also be coded as having an overall response of Stable Disease.   
 
See Appendix XIV for additional information regarding overall response assessment 
 
10.2.4 Duration of Response 
10.2.4.1 Duration of overall response: The duration of overall response is 
measured from the time measurement criteria are met for CR, PR, or MR  
(whichever is first recorded, even if annotated as NFE) until the first date 
that recurrent or progressive disease is objectively documented (taking 
as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented. 
 
10.2.4.2 Duration of stable disease: Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 
10.2.5 Progression-Free Survival (PFS) 
For PFS, time to event will be calculated from the time of randomization to first 
occurrence of relapse, progressive disease, or death. Patients without a PFS event 
will be censored at the time of last follow-up. 
 

 
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10.2.6 Response Review 
All patients will have central review of imaging after Cycles 2, 4, and 6 to evaluate 
for response. See Section 15.2 for central review imaging guidelines and 
submission requirements. 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Certain adverse events must be 
reported in an expedited manner to allow for timelier monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated 
with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Application (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply. 
• 
Concurrent administration: When an investigational agent is used in 
combination with a commercial agent, the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration: When a study includes an investigational agent 
and a commercial agent on the same study arm, but the commercial agent is 
given for a period of time prior to starting the investigational agent, 
expedited reporting of adverse events that occur prior to starting the 
investigational agent would follow the guidelines for commercial agents. 
Once therapy with the investigational agent is initiated, all expedited 
reporting of adverse events follow the investigational agent reporting 
guidelines. 
 

 
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11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, NCI requires that AEs be 
submitted according to the timeframes in the AE reporting tables assigned to the protocol, 
using the CTEP Adverse Event Reporting System (CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
11.4 
Special Situations for Expedited Reporting  
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting tables in this protocol.  
 
11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 
occurs at any time following treatment with an agent under an NCI, COG, or 
industry sponsor IND/IDE since these are considered to be serious AEs. 
 
11.4.3 Death 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: A disorder characterized by cessation of life during the first 
28 days of life.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5.  

 
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o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should 
be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.4.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (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) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.4.5 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. 
 
11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form, available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (310) 640-9193. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.4.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy needs 

 
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to be reported in an expedited manner via CTEP-AERS as Grade 3 
“Pregnancy, 
puerperium 
and 
perinatal 
conditions 
- 
Other 
(pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. 
 
Pregnancy needs to be followed until the outcome is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.4.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any 
Pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
11.4.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring during 
the first 28 days after birth”, should be reported expeditiously as Grade 
4, 
“Death 
neonatal” 
under 
the 
“General 
disorders 
and 
administration” SOC, when the death is the result of a patient 
pregnancy or pregnancy in partners of men on study. Do NOT report 
a neonatal death resulting from a patient pregnancy or pregnancy in 
partners of men on study as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
11.5 
Reporting Requirements for Specialized AEs 
11.5.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (e.g. elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.5.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 

 
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11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.6 
Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is listed as 
expected. The exception or acceptable reporting procedures will be specified in the 
protocol. The protocol specific guidelines supersede the NCI Adverse Event Reporting 
Guidelines. These special situations are listed under the CTEP-AERS reporting Table A 
for this protocol. 
 
11.7 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.   
 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
The reporting methods described below are specific for clinical trials evaluating 
agents for which the IND is held by COG, an investigator, or a pharmaceutical 
company. It is important to note that these procedures differ slightly from those used 
for reporting AEs for clinical trials for which CTEP holds the IND. 
 
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 web site at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
An expedited AE report must be submitted electronically via CTEP-AERS at: 
https://eapps-ctep.nci.nih.gov/ctepaers.  
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 

 
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within 7 calendar days of the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 
an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention requires expedited reporting within 24 hours via e-mail to the COG 
CTEP-AERS Coordinator and Study Chair.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention requires expedited reporting 
within 24 hours via e-mail to the COG CTEP-AERS Coordinator and Study Chair.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
Fax or email supporting documentation for AEs related to investigational agents to 
COG: Fax # (310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: 
COG AERS Coordinator.  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 

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

 
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11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
For Regimen A and Regimen B:  
• 
Grade 1-2 dehydration or Grade 3 dehydration ≤ 3 days duration does not 
require expedited reporting 
• 
Grade 1-3 irritability does not require expedited reporting 
• 
Grade 1-3 urine output decreased does not require expedited reporting 
• 
Grade 1-2 decrease in vision or Grade 3 decrease in vision that resolves within 
7 days of onset does not require expedited reporting 
• 
Grade 1-3 capillary leak does not require expedited reporting 
• 
Grade 1-3 anemia does not require expedited reporting 
• 
Grade 1-3 white blood cell or neutrophil count decrease do not require 
expedited reporting 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated 
pathway 
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this study. 
Commercial reporting requirements are provided in Table B.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy with a Commercial Agent or Within 30 Days1 
 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent, regardless of attribution.  Any death that occurs more than 30 days after the last 
dose of treatment with a commercial agent that can be attributed (possibly, probably, 
or definitely) to the agent and is not due to cancer recurrence must be reported via 
CTEP-AERS. 
 
 
11.12 Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 

 
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Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all toxicities 
reported via CTEP-AERS and all Grade 3 and higher Adverse Events.  
 
 
12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted quarterly to CTEP 
by electronic means. Reports are due January 31, April 30, July 31 and October 31. CDUS 
reporting is not a responsibility of institutions participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (e.g. termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
 
 

 
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13.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
No pathology review is planned for this study. 
 
 
14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
If the patient consents to banking, any specimens left over after the required and optional 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. 
 
14.1 
Required Studies 
All patients who provide consent will be eligible for all special studies on ANBL1821. 
 
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)  
• 
Cycle 1, Day 1 (Regimen B only) 
• 
Cycle 1, post-completion of dinutuximab (collect a single sample 
between Day 6 and Day 9) 
• 
Cycle 2, Day 1 (prior to initiation of Cycle 2 therapy) 
 
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 as collected. Sites should plan 
ahead to avoid Friday or Saturday sample collection. Sample 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 

 
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14.1.1.4 Specimen Shipping 
These specimens will be shipped 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: 
 
 
 
  
 
 
 
 
 
 
 
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 
DFMO and the DFMO/chemo-immunotherapy combination. 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.  
 

 
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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. 
 
 
Samples are requested at the following time points: 
• 
Pre-therapy (between study enrollment and start of therapy)  
• 
Cycle 1, Day 1 (Regimen B only) 
• 
Cycle 1, post-completion of dinutuximab (collect a single sample 
between Day 6 and Day 9) 
• 
Cycle 2, Day 1 (prior to initiation of Cycle 2 therapy) 
 
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.  
 
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 2, Day 1 sample is drawn 
and processed. 
 
Specimens should be 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. 
 

 
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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 DFMO or chemo-immunotherapy combination 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 
 
14.1.3 Patient Reported Outcomes of Pain 
Patients or their proxy for those under the age of 5 years, must complete the Faces 
Pain Scale-Revised. The Faces Pain Scale-Revised is a simple visual scale 
validated to provide a real-time (current) pain assessment in the pediatric 
population.57 The scale scores pain based on a visual cue on a scale of 0 to 10.  
 
14.1.3.1 Timing 
Administer the Faces Pain Scale Revised at any time on Day -6 (Cycle 1 
of Regimen B only) and Day 1 of therapy with irinotecan and 
temozolomide alone, and then on Days 2-5 of therapy at least 4 hours 
after the dinutuximab infusion has begun. It will be administered during 
Cycles 1, 2, 4, 6 for all patients and Cycle 12 of therapy for patients 
enrolled prior to Amendment 4. 
 
14.1.3.2 Assessments 
The assessments will be performed by the nurse caring for the patient at 
the appropriate time-points described above. The data will be entered in 
RAVE. The total daily intravenous narcotic dose will also be entered in 
RAVE. 
 
14.2 
Optional Studies 
The following correlative studies are optional, but strongly encouraged. All patients will 
be eligible for all special studies on ANBL1821. 
 
14.2.1 GD2 Biomarkers 
14.2.1.1 Specimen Schedule and Requirements 
Send 3-5 mL of bone marrow aspirates in heparinized (lithium heparin 
or sodium heparin) tube whenever they are obtained for disease 
evaluation. 
 

 
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14.2.1.2 Specimen Processing and Storage 
No processing required, bone marrow aspirate samples will be sent fresh 
to the laboratory of Dr. C. Patrick Reynolds. 
 
14.2.1.3 Specimen Labeling 
Heparinized tube must be labeled with: 
• The patient’s COG ID number 
• Specimen type 
• Collection Time Point (e.g. Cycle 2, Day 21) 
• Collection date 
 
14.2.1.4 Specimen Shipping 
The heparinized bone marrow should be sent in aseptic secure 
containers, at 4°C or room temperature but in an insulated Styrofoam 
container (provided by the institution) to prevent temperature 
fluctuations. Please ship overnight to: 
 
 
  
 
 
  
 
 
Saturday deliveries will be accepted. Please contact the laboratory by 
email or phone when shipping for arrival on weekends or holidays. 
For questions about sample processing and shipping, please contact Dr. 
Reynolds’ lab directly.  
 
14.2.1.5 Methodology 
For bone marrow aspirates, a multi-color flow cytometry with directly 
labeled dinutuximab as well as antibodies (HSAN + 459) that bind to 
neuroblastoma (but not to marrow or blood cells) is used to detect all 
neuroblastoma cells and accurately quantify the amount of dinutuximab 
bound and the percent of neuroblastoma cells binding to it. These studies 
will be overseen by Dr. C. Patrick Reynolds at Texas Tech University 
Health Sciences Center. 
 
14.2.2 Specimens for Biobanking 
If the patient has consented to banking of material for future research then tumor 
tissue, urine, and 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. 
 

 
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14.2.2.1 Whole Blood Collection 
5 mL of whole blood should be collected (2.5 mL in a PAXgene DNA 
tube and 2.5 mL in a PAXgene RNA tube). 
 
If consent for specimen biobanking is signed, please contact the CCTDC 
immediately after patient enrollment to obtain PAXgene tubes.  
 
Phone:  404-727-2342 
Email:  CCTDC@emory.edu 
 
Collection Time 
A single blood sample should be obtained prior to the start of therapy on 
ANBL1821. The WBC count on the day of the blood draw should be 
> 1,000/mm
3 (sufficient for DNA extraction). 
 
Specimen Handling 
Gently invert the PAXgene tubes 8-10 times after collection. Keep the 
tubes at room temperature for 2 – 72 hours and then freeze upright in a 
wire rack (NOT Styrofoam holder) for 24 hours at -20°C and then 
transfer to -70°C or -80°C freezer until ready to batch ship.  If a -70°C 
or a -20°C freezer is unavailable, then freeze on dry ice and ship frozen 
to BPC on the day of collection.  
 
Labeling 
Label each tube with the following information:  
• 
COG patient ID number 
• 
BPC number 
• 
Specimen type (blood) 
• 
Date and time of collection 
 
Shipping 
See Section 14.3.2 for details on ordering a specimen procurement kit 
and shipping frozen specimens to the Biopathology Center. 
 
14.2.2.2 Tissue Collection 
Please submit representative frozen tumor tissue, as well as matching 
paraffin embedded tumor tissue, as described below. Frozen tissue is 
preferred over paraffin embedded tissue. 
 
Collection Time 
Tumor tissue samples are requested at the following time points: 
• 
Most recent relapsed tissue biopsy performed before study 
enrollment. For patients who have refractory or progressive 
disease, most recent tissue biopsy prior to study registration (2nd 
look surgery is acceptable). Initial diagnostic tissue is not 
acceptable unless no other tissue is available to be submitted. 
Please notify study chair if submitting diagnostic tissue. 
• 
Any time patient undergoes biopsy (or resection) of either primary 
or metastatic tumor while on study.  

 
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• 
Any soft tissue biopsy done post-completion of ANBL1821 
therapy and prior to the start of any other therapy. 
 
Specimen Handling 
• 
Snap Frozen Tumor Tissue 
Snap freeze tissue within 15 minutes after surgery for optimal 
preservation – immediately frozen in vapor phase liquid nitrogen 
or isopentane/dry ice. Cut at least one specimen from the primary 
tumor and metastatic areas into maximum 1 gram aliquots. Place 
each aliquot of tissue in a labeled cryovial and snap freeze in vapor 
phase liquid nitrogen (do not submerge) or on dry ice. 
 
• 
Paraffin Embedded Tumor Tissue 
Paraffin tissue blocks or slides can be stored at room temperature. 
 
Submit the following materials: 
• 
2 H and E stained slides of tumor from each block 
• 
10 unstained slides (5 micron) from the most 
representative blocks (not necessary to send slides from 
every block)  
• 
Additional paraffin embedded blocks not required for 
diagnosis or institutional quality control (optional) 
 
Labeling 
Label the frozen tissue specimens with the following information:  
• 
COG patient ID number 
• 
BPC number 
• 
Specimen type (P for primary, M for metastatic, or BM for bone 
marrow) 
• 
Collection time point 
• 
Date collected 
 
Label the blocks or slides with the following information:  
• 
COG patient ID number 
• 
Specimen type (P for primary, M for metastatic, or BM for bone 
marrow) 
• 
Date collected 
• 
Blocks and slides must also be labeled with the surgical pathology 
ID and block number from the corresponding pathology report 
 
Shipping 
See Section 14.3.1 for details on shipping blocks or slides. See Section 
14.3.2 for details on ordering a specimen procurement kit and shipping 
frozen specimens to the Biopathology Center. 
 

 
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14.2.2.3 Urine Collection 
15 mL of urine should be collected (minimum 5 mL) by clean-catch 
technique and transferred to a 2 mL clean screw-cap vials. 
Approximately 10 vials will be needed for each time point.  
 
Collection Time 
Urine samples are requested at the following time points: 
• 
Pre-therapy (between study enrollment and start of therapy)  
• 
Cycle 1, Day 1 (Regimen B only) 
• 
Cycle 1, post-completion of dinutuximab (collect a single sample 
between Day 6 and Day 9) 
• 
Cycle 2, Day 1 (prior to initiation of Cycle 2 therapy) 
 
Specimen Handling 
Urine-containing vials should be frozen at -80°C within 30 minutes of 
collection (or the specimen can be placed on dry ice for up to 4 hours 
prior to freezing).  
 
Labeling 
Label the tubes with the following information:  
• 
COG patient ID number 
• 
BPC number 
• 
Date and time of sample collection 
• 
Time point (include treatment cycle, day of cycle) 
• 
Source of material (urine) 
 
Shipping 
Urine samples should be batched for individual patients and shipped 
frozen on dry ice to the Biopathology Center as described in Section 
14.3.2. 
 
14.2.2.4 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 Blocks/Slides 
FFPE blocks or unstained paraffin tissue slides should be sent to the COG 
Biopathology Center (BPC) at room temperature using the submitting institution’s 
courier account.  
 

 
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An ANBL1821 BPC specimen transmittal form must be completed in RAVE, 
printed and sent with the specimen. In addition, the corresponding pathology report 
must be included with the shipment. 
 
Blocks/slides should not be shipped for Saturday delivery. See Section 14.3.3 for 
shipping address. 
 
14.3.2 Frozen Specimens  
Send 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 Biopathology Center (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://ricapps.nationwidechildrens.org/KitManagement/). 
 
An ANBL1821 BPC specimen transmittal form must be completed in RAVE, 
printed and sent with the specimen. When tissue is submitted, the corresponding 
pathology report must also be included in the shipment.  
 
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. 
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) and pathology report (when applicable) 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. 
 

 
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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 Biopathology Center 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. 
 
 
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 
Timing of Imaging 
To document tumor, standard CT, MRI, and MIBG (FDG PET/CT or PET/MRI scan if 
tumor is not MIBG avid) scans must be performed at the following time points: 
• 
within 3 weeks prior to the start of protocol therapy 
• 
end of Cycles 2*, 4 and 6*, then for patients enrolled prior to Amendment 4 
every 4th cycle thereafter 
• 
end of therapy* 
• 
at relapse/progression 
* Patients with no soft tissue (non-osseous) disease at baseline (i.e., MIBG avid bone lesions 
or bone marrow involvement only) are only required to undergo appropriate cross-sectional 
imaging (CT and/or MRI) of primary tumor site at the end of Cycles 2, 6, and end of therapy 
only. Additionally, CT and/or MRI are required for confirmatory imaging at least 4 weeks 
after first response is documented for those patients who do not continue on protocol therapy. 
This is in addition to MIBG (FDG PET/CT or PET/MRI scan if tumor is not MIBG avid) 
performed at all disease evaluation time points. 
 
Note: Patients with any soft tissue disease (either measurable or non-measurable) at baseline 
are required to have CT/MRI, and MIBG (FDG PET/CT or PET/MRI scan if tumor is not 
MIBG avid) scans at all disease evaluation time points.  

 
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15.2 
Imaging Required for Confirmation of Response Status 
The pertinent imaging studies (CT/MRI and MIBG or FDG PET/CT or PET/MRI) of all 
patients after Cycles 2, 4, and 6 will be centrally reviewed. Additionally, central review of 
confirmatory imaging performed at least 4 weeks after first response was documented for 
those patients who do not continue on protocol therapy will be performed. 
 
Central review will be performed by the Diagnostic Imaging Specialists of the Study 
Committee. They will review baseline scans and scans after Cycles 2, 4, and 6 for all 
patients. Radiology scans and corresponding reports will be sent to the IROC Rhode Island 
(formerly QARC). The results of the central review will not be returned to the institution. 
 
For all patients after Cycles 2, 4, 6, and any patients with confirmatory response 
imaging after stopping protocol therapy, , the following must be submitted for central 
review: 
 
Baseline, End of Cycles 2, 4, and 6 imaging and confirmatory response imaging (if 
applicable see Section 7.1) Scans: 
• 
CT/MRI 
• 
MIBG scan 
• 
Curie Scoring Summary Sheet (submit via RAVE; see Appendix IX) 
• 
FDG PET/CT or PET/MRI scan if tumor is not MIBG avid 
• 
Copies of the reports for the scans submitted 
 
Scans and corresponding reports should be submitted to IROC as soon as they are 
obtained. 
 
For PET/CT or PET/MRI scan guidelines please refer to the NCI guidelines for the 
recommended set of procedures for the acquisition and analysis of 18F-FDG PET/CT or 
PET/MRI scans of patients participating in NCI-sponsored diagnostic and therapeutic 
clinical trials, which can be found at the following link:  
https://imaging.cancer.gov/programs_resources/reports_publications/publications/clinical
_trials_guidelines.htm72  
 
15.3 
Image Submission  
Submission of Diagnostic Imaging data in digital DICOM format is required. These files 
should be submitted electronically via TRIAD, sFTP or Dicommunicator. Information for 
TRIAD is below. Information for obtaining an sFTP account and submission instructions can 
be found at www.QARC.org. Follow the link labeled digital data. Sites using 
Dicommunicator may submit imaging via that application.  
 
Submission by CD is discouraged. Only when electronic submission is not possible, the 
imaging may be burned to a CD and mailed to IROC RI. Multiple studies for the same patient 
may be submitted on one CD; however, please submit only one patient per CD. Contact IROC 
RI with questions or for additional information. The required Diagnostic Imaging reports 
should be submitted electronically with the DICOM files. 
 
If submitted via CD send to: 
IROC Rhode Island QA Center 

 
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Building B, Suite 201 
640 George Washington Highway 
Lincoln, Rhode Island 02865-4207 
 
For questions regarding data submission please contact: 
E-mail to DataSubmission@QARC.org  
Phone:   (401) 753-7600 
 
TRIAD is the American College of Radiology’s (ACR) image exchange application. TRIAD 
provides sites participating in clinical trials a secure method to transmit DICOM, DICOM RT 
and other digital files. The TRIAD software anonymizes, encrypts and validates the images 
as they are transferred. 
 
Site staff who will submit images through TRIAD will need to be registered with the Cancer 
Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and Access 
Management (IAM) account. Please refer to CTEP Registration Procedures of the protocol 
for instructions on how to request a CTEP-IAM account.  
 
To submit images, the site TRIAD user must be on the listed on the enrolling site’s roster in 
CTSU and be assigned the 'TRIAD site user' role. Users should contact their site’s CTSU 
Administrator or Data Administrator to request assignment of the TRIAD site user role.  
 
After a user receives a CTEP-IAM account with the proper user role, he/she will need to have 
the TRIAD application installed on his/her workstation to be able to submit the image files. 
TRIAD 
installation 
documentation 
can 
be 
found 
by 
following 
this 
link: 
https://triadinstall.acr.org/triadclient/.   
 
This process can be done in parallel to obtaining your CTEP-IAM account username and 
password.  
 
For support with the TRIAD application, please send an e-mail to TRIAD-
Support@ACR.org. 
 
 
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).  
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU 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 at 1-866-651-2878 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: 
• 
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 

 
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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. 
 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link on the 
DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on the 
DQP. A protocol must have the Calendar functionality implemented in Rave by the Lead Protocol 
Organization for delinquent form details and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding questions about Rave Calendaring 
functionality.   
 
 
 
 

 
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Does patient 
have 
measurable 
disease?
YES
Did patient 
have prior 
anti-GD2 
therapy?
NO
Did patient 
have prior 
DFMO 
therapy?
NO
MYCN status:
Amplified → Stratum 1
Non-amplified → Stratum 2
Unknown/Unable to be 
determined → Stratum 3
YES
MYCN status:
Amplified → Stratum 4
Non-amplified → Stratum 5
Unknown/Unable to be 
determined → Stratum 6
YES
Did patient 
have prior 
DFMO 
therapy?
NO
MYCN status:
Amplified → Stratum 7
Non-amplified → Stratum 8
Unknown/Unable to be 
determined → Stratum 9
YES
MYCN status:
Amplified → Stratum 10
Non-amplified → Stratum 11
Unknown/Unable to be 
determined → Stratum 12
NO
Did patient 
have prior 
anti-GD2 
therapy?
NO
Did patient 
have prior 
DFMO 
therapy?
NO
MYCN status:
Amplified → Stratum 13
Non-amplified → Stratum 14
Unknown/Unable to be 
determined → Stratum 15
YES
MYCN status:
Amplified → Stratum 16
Non-amplified → Stratum 17
Unknown/Unable to be 
determined → Stratum 18
YES
Did patient 
have prior 
DFMO 
therapy?
NO
MYCN status:
Amplified → Stratum 19
Non-amplified → Stratum 20
Unknown/Unable to be 
determined → Stratum 21
YES
MYCN status:
Amplified → Stratum 22
Non-amplified → Stratum 23
Unknown/Unable to be 
determined → Stratum 24
APPENDIX II: PATIENT STRATIFICATION FLOWCHART 
 

 
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APPENDIX III:  UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-
ENZYME INDUCING ANTICONVULSANTS 
 
 
 
 
 
 
 
 
 
 
Recommended Non-enzyme inducing 
anticonvulsants 
 
Clonazepam 
Diazepam 
Ethosuximide 
Ezogabine 
Gabapentin 
Lacosamide 
Lamotrigine 
Levetiracetam  
Lorazepam 
Perampanel 
Tiagabine 
Topiramate 
Valproic Acid 
Zonisamide 
 
Unacceptable Enzyme inducing anticonvulsants 
 
Carbamazepine 
Felbamate 
Phenobarbital 
Fosphenytoin 
Phenytoin 
Primidone 
Oxcarbazepine 
 

 
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APPENDIX IV:  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 
felodipine5 
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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Page 134 
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 
telaprevir 

 
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Page 135 
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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Page 136 
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. Patients will also be instructed to contact their physician if any diarrhea 
occurs. Patients will be given loperamide based on body weight.  
 
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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Page 137 
LOPERAMIDE DOSING RECOMMENDATIONS FOR LATE DIARRHEA 
(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 (one-half teaspoonful of the 1 mg/5 mL oral solution) after the first 
loose bowel movement, followed by 0.5 mg (one-half teaspoonful of the 
1 mg/5 mL oral solution) every 3 hours.  During the night, the patient may take 
0.5 mg (one-half teaspoonful of the 1 mg/5 mL oral solution) every 4 hours. Do 
not exceed 4 mg per day (20 mL or 4 teaspoonfuls) per day. 
≥ 13 kg to < 20 kg 
Take 1 mg (1 teaspoonful of the 1 mg/5 mL oral solution or one-half tablet) after 
the first loose bowel movement, followed by 1 mg (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 (one teaspoonful of the 1 mg/5 mL oral solution or one-
half tablet) every 4 hours.  Do not exceed 6 mg per day (30 mL or 
6 teaspoonfuls) per day. 
≥ 20 kg to < 30 kg 
Take 2 mg (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 tablet) after the 
first loose bowel movement, followed by 1 mg (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 (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 tablet) 
every 4 hours. Do not exceed 8 mg per day (40 mL or 8 teaspoonfuls) per day. 
≥ 30 kg to < 43 kg 
Take 2 mg (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 tablet) after the 
first loose bowel movement, followed by 1 mg (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 (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 tablet) 
every 4 hours. Do not exceed 12 mg per day (60 mL or 12 teaspoonfuls) per day. 
Over 43 kg 
Take 4 mg (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 (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 (4 teaspoonfuls of the 1 mg/5 mL oral solution 
or 2 capsules or tablets) every 4 hours. Do not exceed 16 mg per day (80 mL or 
16 teaspoonfuls) per day. 
 
 
 

 
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Page 138 
APPENDIX VI:  TEMOZOLOMIDE DOSING (100 mg/m2) NOMOGRAM 
Temozolomide is dosed based on body surface area for patients whose BSA is at least 0.5 m2. For 
these patients, doses are rounded to the nearest 5 mg. For patients with BSA < 0.5 m2, dosing is based 
on body weight (kg).  
 
For patients with a BSA < 0.5 m2: Use 3.3 mg/kg. 
 
Examples: For a patient with BSA= 0.3 m2 and weight= 5 kg, the calculated dose = 5 kg x 3.3 mg/kg = 
16.5 mg  
 
Temozolomide oral suspension is compounded to a concentration of 10 mg/mL. When temozolomide 
suspension is used, consider rounding doses to the nearest 1 mg (0.1 mL) for doses ≤ 22.5 mg and to the 
nearest 2 mg (0.2 mL) for doses > 22.5 mg for deliverability. In the example above, the dose can be rounded 
to 16 mg (1.6 mL).  
 
For a patient with BSA= 0.66 m2 the calculated dose is 0.66 m2 x 100 mg/m2 = 66 mg/day; 
administered dose = 65 mg temozolomide/day. 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
0.2-0.49 
3.3 mg/kg 
3.3 mg/kg 
0.50-0.52 
50-52 
50 
0.53-0.57 
53-57 
55 
0.58-0.62 
58-62 
60 
0.63-0.67 
63-67 
65 
0.68-0.72 
68-72 
70 
0.73-0.77 
73-77 
75 
0.78-0.82 
78-82 
80 
0.83-0.87 
83-87 
85 
0.88-0.92 
88-92 
90 
0.93-0.97 
93-97 
95 
0.98-1.0 
98-100 
100 
1.01-1.05 
100-105 
105 
1.06-1.14 
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 VII:  TEMOZOLOMIDE REDUCED (75 mg/m2) DOSING NOMOGRAM 
Temozolomide is dosed based on body surface area for patients whose BSA is at least 0.5 m2. For 
these patients, doses are rounded to the nearest 5 mg. For patients with BSA < 0.5 m2, dosing is based 
on body weight (kg).  
 
For patients with a BSA < 0.5 m2: Use 2.5 mg/kg.  
 
Examples: For a patient that is 0.3 m2 and weighs 5 kg, the calculated dose is 5 kg x 2.5 mg/kg = 12.5 mg  
 
Temozolomide oral suspension is compounded to a concentration of 10 mg/mL. When temozolomide 
suspension is used, consider rounding doses to the nearest 1 mg (0.1 mL) for doses ≤ 22.5 mg and to the 
nearest 2 mg (0.2 mL) for doses > 22.5 mg for deliverability. In the example above, the dose can be rounded 
to 12 mg (1.2 mL). 
 
For a patient with a BSA of 0.66 m2, the calculated dose = 49.5 mg/dose; administered dose = 
50 mg temozolomide/dose. 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
0.2-0.49 
2.5 mg/kg 
2.5 mg/kg 
0.50-0.56 
38-42 
40 
0.57-0.63 
43-47 
45 
0.64-0.70 
48-52 
50 
0.71-0.76 
53-57 
55 
0.77-0.83 
58-62 
60 
0.84-0.90 
63-67 
65 
0.91-0.96 
68-72 
70 
0.97-1.03 
73-77 
75 
1.04-1.10 
78-82 
80 
1.11-1.16 
83-87 
85 
1.17-1.23 
88-92 
90 
1.24-1.30 
93-97 
95 
1.31-1.36 
98-102 
100 
1.37-1.43 
103-107 
105 
1.44-1.50 
108-112 
110 
1.51-1.56 
113-117 
115 
1.57-1.63 
118-122 
120 
1.64-1.70 
123-127 
125 
1.71-1.76 
128-132 
130 
1.77-1.83 
133-137 
135 
1.84-1.90 
138-142 
140 
1.91-1.96 
143-147 
145 
≥ 1.97 
148-152 
150 

 
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Page 140 
APPENDIX 
VIII: 
INSTRUCTIONS 
FOR 
TEMOZOLOMIDE 
PREPARATION, 
ADMINISTRATION AND SAFE HANDLING 
Patient Name: ___________________________        Cycle#: _____         Date Range: _______________ 
Temozolomide is an oral medicine for the treatment of cancer. 
This information sheet will help you prepare, administer, store, 
and dispose of the medicine. Please read the information 
before preparing and giving the medicine. If you have any 
questions, please contact:_______________ 
 
 
WHAT DO I NEED?  
 
 
Your Temozolomide dose is: ________mg 
• You should use the following number of capsules for 
each dose): 
 
Number of temozolomide capsules per dose 
5 mg 
20 mg 
100 mg 
140 mg 
180 mg 
250 mg 
 
 
 
 
 
 
 
• Give each dose by mouth one time each morning for 5 
days in a row. 
• You should take the temozolomide on the following 
days:_________________________ 
 
Supplies: 
• Temozolomide capsules (see the table above) 
• Disposable pad or paper towels  
• Disposable gloves and mask and a pair of goggles (eye 
protection) 
• Disposable cup and disposable spoon 
• A container to collect waste (zip top plastic bag or 
medical waste bag or container) 
• A small amount of applesauce or apple juice  
o 
Two teaspoons (10 mL) should be enough. A 
single-serving container of applesauce may be 
used, but the patient must be able to eat the entire 
contents of the container to ensure the full dose is 
taken.  
o 
Food should be cool or close to room temperature 
when administered; do not use hot or boiling food 
 
 
HOW DO I STORE THE MEDICINE AND WASTE?  
 
Store the medication in the original bottle away from food 
and out of the reach of children or pets. Store the waste 
container out of the reach of children or pets. Return the 
container to the clinic during your next visit. 
 
 
 
WHAT SAFETY MEASURES SHOULD I TAKE? 
 
If the medicine gets into eyes, hold eyelids open while 
flushing with water for at least 15 minutes.  If you spilled the 
medicine on your skin, remove contaminated clothing.  Wash 
area with soap and large amount of water.  Seek medical 
attention if the skin becomes red, irritated, or if you are 
concerned.  Call your doctor or nurse immediately 
at:____________________________________________ 
and/or contact the Poison Center at 1-800-222-1222. 
 
HOW DO I PREPARE THE MEDICINE?  
 
 
CAUTION: If you are pregnant, could become pregnant, or are breast-
feeding, DO NOT prepare or administer this medicine. 
 
1. Choose a quiet working space away from food, windows, 
fans or heat ducts. 
2. Clean the working space with damp paper towels. 
3. Wash your hands with soap and water; dry them well. 
4. Put on disposable gloves, disposable mask, and a pair of 
goggles or eye protection. 
5. Place a disposable pad or paper towel on the clean working 
space and place all supplies on the pad or paper towel.  
6. Fill a cup with a small amount of apple juice or applesauce 
(or use pre-filled applesauce cup). 
7. Open each capsule required for the daily dose over the cup 
with the apple juice or applesauce. 
• Hold one capsule over the center of the cup.  
• To open, pinch both ends of one capsule with gentle 
pressure. Slowly rotate one end in small, back and forth 
movements while holding the other end steady until the 
capsule sections begin to separate. 
• Gently separate the ends so the powder falls into the 
center of the food. Look inside each end of the capsule. 
Tap and shake each end of the capsule until all 
medicine powder is out of the capsule. 
• Repeat the steps above for each capsule needed. 
8. The medicine will not dissolve completely if mixing in apple 
juice. Keep extra apple juice on hand to add to any remaining 
powder left at the bottom of the cup.  If you need more apple 
juice or applesauce, remove your gloves before touching the 
main container. Wear new gloves before adding the 
additional apple juice or applesauce to the medicine to 
prevent contaminating the main container with any powder 
that may be on your gloves. 
9. Give the medicine mixture to the patient immediately. 
 
 
HOW DO I TAKE/GIVE THE MEDICINE? 
 
• Take/give an anti-nausea medicine 30-60 minutes before the 
temozolomide only if instructed to do so by your doctor.  
• Take/give temozolomide 1 hour before irinotecan. 
• Take/give temozolomide at around the same time each day 
with or without food. On days where you have special blood 
tests drawn, take both medicines on an empty stomach, at 
least 2 hours after food. 
• When you are finished, place all used supplies in a plastic 
zip top bag or the waste container that was provided to you 
by your doctor, nurse, or pharmacist.  
• If the dose is vomited within 30 minutes, the dose should be 
repeated. If the dose is vomited more than 30 minutes after 
the dose, do not repeat the dose. If the patient is unable to 
take a dose, or a dose is accidentally missed, place the 
remaining medicine from this dose in the waste container, 
seal, and contact your doctor or nurse for instructions. 

 
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Page 141 
APPENDIX IX: CURIE SCORING SUMMARY SHEET (Submit this sheet via RAVE) 
 
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 2 
 
End of Cycle 4 
 
End of Cycle 6  
 
End of Cycle 10 
 
 
End of Cycle 14 
 
End of Cycle 17 
 
Relapse/Progression 
Other (specify) 
Note: For patients enrolled with Amendment 4 or later, the End of Cycle 6 timepoint will be the end of 
therapy. Please do not fill out End of Cycles 10, 14, and 17 as those timepoints are not relevant.  
 
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) 
 
 

 
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10 
Soft Tissue 
 
 
TOTAL 
Total scores from Regions 1 - 10 
 
Figure 1. 

  
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APPENDIX X:  BIOLOGIC CORRELATIVE LAB STUDIES 
 
Time Point 
Sample Type 
Tube Type / Sample Prep 
Notes 
Ship to 
Section 
Number 
Most recent 
biopsy performed 
before study 
registration 
Biopsy of primary or metastatic site 
Snap-frozen tumor material and 
paraffin-embedded tumor tissue 
OPTIONAL 
Banking 
BPC 
14.2.2.2 
Time point 
Sample 
Type 
Volume 
per tube 
Quantity 
Tube Type / Sample Prep 
Notes  
Ship to 
Section 
Number 
Any time bone 
marrow aspirate 
or tumor tissue is 
obtained  
Biopsy of primary or metastatic site 
Snap-frozen tumor material and 
paraffin-embedded tumor tissue 
OPTIONAL 
Banking 
BPC 
14.2.2.2 
Bone 
marrow 
aspirate 
3-5 mL 
1 tube 
Heparinized tube 
OPTIONAL; 
Send fresh 
overnight 
GD2 Biomarkers 
Reynolds 
14.2.1 
Pre-therapy 
 
Blooda, b 
2.5 mL 
2 tubes 
PAXgene RNA tube 
PAXgene DNA tube 
OPTIONAL 
Banking 
BPC 
14.2.2.1 
Urine 
15 mL 
 
Clean-catch; transfer to sterile 
screw-cap vials 
OPTIONAL; 
Freeze within 
30 minutes 
Banking 
BPC 
14.2.2.3 
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 
Cycle 1, Day 1 
(Regimen B only)  
Urine 
15 mL 
 
Clean-catch; transfer to sterile 
screw-cap vials 
OPTIONAL; 
Freeze within 
30 minutes 
Banking 
BPC 
14.2.2.3 
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 
Cycle 1, post-
completion of 
dinutuximab 
(collect a single 
sample between 
Day 6 and Day 9)c 
Urine 
15 mL 
 
Clean-catch; transfer to sterile 
screw-cap vials 
OPTIONAL; 
Freeze within 
30 minutes 
Banking 
BPC 
14.2.2.3 
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 
Cycle 2, Day 1 
Urine 
15 mL 
 
Clean-catch; transfer to sterile 
screw-cap vials 
OPTIONAL; 
Freeze within 
30 minutes 
Banking 
BPC 
14.2.2.3 
Blood 
5 mL 
2 tubes 
Sodium heparin (Green top) 
tube 
REQUIRED; 
Ship same day 
Immune Phenotyping 
Emory 
14.1.1 

  
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a. If consent for blood biobanking is signed, please contact the Emory CCTDC, immediately after 
patient enrollment to obtain PAXgene tubes (see Section 14.2.2.1 for contact information)  
b. A single blood sample is requested from each patient consenting to optional banking. This sample 
should be obtained prior to the start of therapy. The WBC count on the day of the blood draw should 
be > 1,000/mm
3 
c. Collect all specimens at this time point post-completion of dinutuximab 
 
 
Blood 
5 mL 
1 tube 
Sodium heparin (Green top) 
tube 
REQUIRED; 
Process for plasma 
Cytokine Analysis 
Emory 
14.1.2 
Time point 
Sample Type 
Tube Type / Sample Prep 
Notes  
Ship to 
Section 
Number 
Any soft tissue 
collected post-
completion of 
ANBL1821 therapy 
and prior to start 
of any other 
therapy. 
Soft tissue tumor 
Snap-frozen tumor material and 
paraffin-embedded tumor tissue 
 
OPTIONAL 
Banking 
BPC 
14.2.2.2 

  
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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: EFLORNITHINE (DFMO) DOSING TABLES 
 
DOSE LEVEL – 6750 mg/m2/day (6.75 g/m2/day) divided TID 
BSA range (m2) 
Dose 1 (g) 
Dose 2 (g) 
Dose 3 (g) 
Total daily 
dose (g) 
lower 
upper 
0.35 
0.40 
1 
1 
0.5 
2.5 
0.41 
0.47 
1 
1 
1 
3 
0.48 
0.55 
1.5 
1 
1 
3.5 
0.56 
0.62 
1.5 
1.5 
1 
4 
0.63 
0.69 
1.5 
1.5 
1.5 
4.5 
0.70 
0.77 
2 
1.5 
1.5 
5 
0.78 
0.84 
2 
2 
1.5 
5.5 
0.85 
0.92 
2 
2 
2 
6 
0.93 
1.03 
2.5 
2 
2 
6.5 
1.04 
1.21 
2.5 
2.5 
2.5 
7.5 
1.22 
1.43 
3 
3 
3 
9 
1.44 
1.66 
3.5 
3.5 
3.5 
10.5 
1.67 
1.88 
4 
4 
4 
12 
1.89 
and above  
4.5 
4.5 
4.5 
13.5 
 
 
DOSE LEVEL – 5000 mg/m2/day (5 g/m2/day) divided TID 
BSA range (m2) 
Dose 1 (g) 
Dose 2 (g) 
Dose 3 (g) 
Total daily 
dose (g) 
lower 
upper 
0.35 
0.47 
1 
0.5 
0.5 
2 
0.48 
0.55 
1 
1 
0.5 
2.5 
0.56 
0.63 
1 
1 
1 
3 
0.64 
0.77 
1.5 
1 
1 
3.5 
0.78 
0.84 
1.5 
1.5 
1 
4 
0.85 
0.92 
1.5 
1.5 
1.5 
4.5 
0.93 
1.03 
2 
1.5 
1.5 
5 
1.04 
1.21 
2 
2 
1.5 
5.5 
1.22 
1.43 
2.5 
2 
2 
6.5 
1.44 
1.66 
2.5 
2.5 
2.5 
7.5 
1.67 
and above 
3 
3 
3 
9 
 
 
 

  
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Page 147 
 
DOSE LEVEL – 3750 mg/m2/day (3.75 g/m2/day) divided TID 
BSA range (m2) 
Dose 1 (g) 
Dose 2 (g) 
Dose 3 (g) 
Total daily 
dose (g) 
lower 
upper 
0.35 
0.47 
0.5 
0.5 
0.5 
1.5 
0.48 
0.63 
1 
0.5 
0.5 
2 
0.64 
0.77 
1 
1 
0.5 
2.5 
0.78 
0.84 
1 
1 
1 
3 
0.85 
1.03 
1.5 
1 
1 
3.5 
1.04 
1.21 
1.5 
1.5 
1 
4 
1.22 
1.43 
2 
1.5 
1.5 
5 
1.44 
1.49 
2 
2 
1.5 
5.5 
1.50 
1.88 
2 
2 
2 
6 
1.89 
and above 
2.5 
2.5 
2 
7 
 
 
 

  
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Page 148 
APPENDIX XIII: INSTRUCTIONS FOR PREPARATION AND ADMINISTRATION OF 
EFLORNITHINE (DFMO) 
Take eflornithine (DFMO) solution by mouth or give through an enteral tube (NG or Gtube), without regard to meals. 
If you vomit within 20 minutes of taking a dose, an additional dose can be taken once. If you vomit after 20 minutes of 
taking a dose, the dose should not be repeated. 
 
DFMO is provided as either 0.5 or 1 gram of powdered drug in a single dose sachet. The parent or caregiver will fully 
dissolve the powder in the appropriate amount of sterile or distilled water for each dose (see table below). This provides 
a solution of 100 mg DFMO per 1 mL of solution. When preparing each dose, use a disposable cup and discard the 
cup when the medication has been administered. Administer each dose immediately after dissolution. A delay of 
up to 30 minutes between dissolution and administration is acceptable. 
 
Dilution table to achieve 100 mg/mL solution: 
Eflornithine 
Dose (g) 
Number of 
0.5 g sachets 
Number of 
1 g sachets 
Amount of 
sterile/distilled 
water 
0.5 
1 
0 
5 mL 
1 
0 
1 
10 mL 
1.5 
1 
1 
15 mL 
2 
0 
2 
20 mL 
2.5 
1 
2 
25 mL 
3 
0 
3 
30 mL 
3.5 
1 
3 
35 mL 
4 
0 
4 
40 mL 
4.5 
1 
4 
45 mL 
 
To improve the taste of DFMO solution, an additional liquid can be added to the 100 mg/mL solution. The amount of 
liquid to be used can be decided by the patient and/or family but typically would include adding juice equal to 2 times 
the volume of DFMO. For example, a dose of 45 mLs of eflornithine (= 4.5 g) would be added to 90 mLs (= 3 ounces) 
of juice. 
 
RECOMMENDED juices for this purpose include lemonade, apple juice, cranberry or grape juice (in order of 
preference). 
 
Juices to be AVOIDED when administering DFMO include grapefruit juice, orange juice and tomato juice (including 
V8 juice). 
 
DFMO should be taken IMMEDIATELY after it is dissolved, rather than storing it for later use.  
 
Enteral Tube Administration: DFMO should be given via enteral tube (NG or Gtube) the same way other medications 
are given. Pause the feeds if running, flush the tube with water, administer the medication, flush the tube again with 
water, and restart feeds. The tube should be flushed with water before and after each medication administration.  
 
Please note: 
• 
Gloves should be worn when preparing DFMO solution.  
• 
Pregnant women should not prepare the medication.  
• 
If DFMO sachet is ripped or broken and the powder gets on skin, wash the exposed area with soap and 
water. Inform your study doctor or nurse if this occurs.  
• 
If DFMO sachet powder or mixed solution is spilled on the counter or other surface, use a damp paper 
towel to clean up the area. Then use Clorox to clean the area and dispose of the paper towels when finished.  
 
 

  
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Page 149 
 
APPENDIX XIV: 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 
NI 
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 
NI 
NI 
SD 
SD 
SD 
NI 
SD 
SD 
SD 
SD 
SD 
SD 
NI 
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 

  
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Page 150 
No response evaluation performed for any of the 3 components that were involved at study entry or explicitly required as 
a component of disease evaluation at that timepoint during study 
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. NFE: Not Fully Evaluated; when at least one component of response 
evaluation was not required AND not performed at that timepoint for one or more of the 3 response components of overall response (this will 
annotate CR, PR, MR, or SD). 
 

  
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Page 151 
APPENDIX XV: 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. 
 
 
Some drugs, food, and supplements may interact with irinotecan. Examples include: 
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 
 
 
 

  
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Page 152 
 
Some drugs, food, and supplements may interact with temozolomide.  Examples include: 
 
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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Page 153 
 
APPENDIX XVI: YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY ANBL1821 
(for children from 7 through 12 years of age) 
 
A trial to compare 2 ways to treat children with Neuroblastoma (NBL) that  
is not responding to treatment or has come back after treatment 
 
1. We have been talking with you about your illness, neuroblastoma (NBL). NBL is a kind of cancer 
that grows in the soft issue in your body. It can grow in different parts of the body. After doing 
tests, we have found that you have this type of cancer. You have had treatment for this cancer 
already but the cancer did not go away or has come back after treatment. 
 
2. We are asking you to take part in a research study because you have NBL that is not responding 
to treatment or has come back after treatment. A research study is when doctors work together to 
try out new ways to help people who are sick.  
 
3. All children who are part of this study will be treated with chemotherapy. Some children who are 
part of this study will be treated with chemotherapy and the drug eflornithine (also called 
DFMO). Chemotherapy is a type of medicine that destroys cancer cells. Study doctors would like 
to learn if your cancer responds to treatment with DFMO. 
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is a better 
chance of getting rid of the cancer for as long as possible. But we do not know for sure if there is 
any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that the study treatment may not work as 
well as other therapies. Also, the study treatment may cause more side effects than other 
therapies. Your doctors will watch you for signs of any side effects. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We want to learn more about how people respond to treatment with DFMO. In order to take part 
in this study, you must take part in two tests to help us learn about DFMO. Extra blood will be 
collected 3-4 times during your treatment and a nurse will ask about any pain you may have on 
this study. 
 
We are also asking your permission to collect extra bone marrow, tumor tissue, and urine and use 
them for research studies. We would take extra when we collect bone marrow, tumor tissue, and 
urine for regular tests. You can still take part in this study even if you do not agree to let us 
collect the extra samples for research. 
 
 
 
 

  
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Page 154 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ANBL1821 
(for teens from 13 through 17 years of age) 
 
A trial to compare 2 ways to treat patients with NBL that  
is not responding to treatment or has come back after treatment 
 
1. We have been talking with you about your illness, neuroblastoma (NBL). NBL is a type of cancer 
that grows in the soft issue in your body. It can grow in different parts of the body. After doing 
tests, we have found that you have this type of cancer.  
 
2. We are asking you to take part in a research study because you have NBL that is recurrent or 
refractory. Recurrent means that the cancer has come back after treatment. Refractory means that 
the cancer has not responded to treatment. A research study is when doctors work together to try 
out new ways to help people who are sick.  
 
3. All children who are part of this study will be treated with chemotherapy. Some children who are 
part of this study will be treated with chemotherapy and the drug eflornithine (also called 
DFMO). Chemotherapy is a type of medicine that destroys cancer cells. Study doctors would like 
to learn if your cancer responds to treatment with DFMO. 
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is a better 
chance of getting rid of your cancer for as long as possible. But we don’t know for sure if there is 
any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that the study treatment may be less 
effective than other therapy options. It is also possible that the study treatment may cause more 
side effects than other therapies. Your doctors will monitor you closely for signs of any side 
effects. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We want to learn more about how people respond to treatment with DFMO. In order to take part 
in this study, you must take part in two tests to help us learn about DFMO. Extra blood will be 
collected 3-4 times during your treatment and a nurse will ask about any pain you may have on 
this study. 
 
We are also asking your permission to collect extra bone marrow, tumor tissue, and urine and use 
them for research studies. We would take extra when we collect bone marrow, tumor tissue, and 
urine for regular tests. You can still take part in this study even if you do not agree to let us 
collect the extra samples for research. 
 
 

  
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Page 155 
REFERENCES 
 
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2. 
Pinto NR, Applebaum MA, Volchenboum SL, et al.: Advances in Risk Classification and 
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3. 
Mody R, Naranjo A, Van Ryn C, et al.: Irinotecan-temozolomide with temsirolimus or 
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30. 
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31. 
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32. 
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Croghan MK, Aickin MG,Meyskens FL: Dose-related alpha-difluoromethylornithine ototoxicity. 
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39. 
Hogarty M, Flynn A, Liu K, et al.: NANT 2012-01: Phase 1 Study of DFMO and Celecoxib with 
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Abeloff MD, Rosen ST, Luk GD, et al.: Phase II trials of alpha-difluoromethylornithine, an 
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Treat Rep 70:843-5, 1986 
41. 
London WB, Frantz CN, Campbell LA, et al.: Phase II randomized comparison of topotecan plus 
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42. 
Pistoia V, Bianchi G, Borgonovo G, et al.: Cytokines in neuroblastoma: from pathogenesis to 
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43. 
Sinha P, Clements VK,Ostrand-Rosenberg S: Reduction of myeloid-derived suppressor cells and 
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44. 
Schengrund CL, Repman MA,Shochat SJ: Ganglioside composition of human neuroblastomas. 
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