A Pilot Induction Regimen Incorporating Chimeric 14.18 Antibody (ch14.18, Dinutuximab) (NSC# 764038) and Sargramostim (GM-CSF) for the Treatment of Newly Diagnosed High-Risk Neuroblastoma
Phase: PHASE2
Conditions: Ganglioneuroblastoma, High Risk Neuroblastoma
Sponsor: National Cancer Institute (NCI)

  
 
i 
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, M.S. 
crabtreed@email.chop.edu 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
October 24, 2019 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
The study committee for ANBL17P1, A Pilot Induction Regimen Incorporating Chimeric 
14.18 Antibody (ch14.18, dinutuximab) (NSC# 764038) and Sargramostim (GM-CSF) for 
the Treatment of Newly Diagnosed High-Risk Neuroblastoma, has provided Amendment 2 
for CTEP review. This amendment is being submitted to remove aldesleukin from post-
consolidation therapy as instructed in the ANBL17P1 safety memo posted on 08/23/2019. 
 
The ANBL17P1 study committee looks forward to approval of this amendment. Please 
contact me with any questions or concerns. 
 
Sincerely, 
 
 
Edwin Ha, Protocol Coordinator (for) 
Sara Federico, MD, ANBL17P1 Study Chair 
Peter Adamson, MD, Children’s Oncology Group Chair 
 

 
ii 
 
 
CIRB SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In response to CIRB stipulations, the following specific revision has been made to the protocol. 
Additions are in boldfaced font and deletions in strikethrough font. 
 
 
# 
Section 
Page(s) 
Change 
1. 
4.9.6 
89 
We have corrected the typographical error illustrated below:  
Enter Cycle # _______ (1 , 3 or   - 5) 
 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the 
protocol. Additions are in boldfaced font and deletions in strikethrough font. 
 
# 
Section 
Page(s) 
Change 
1. 
Title Page & 
Throughout 
1 
The protocol version date and amendment number have been updated. 
2. 
Table of Contents 3-6 
The table of contents has been updated and repaginated. 
3. 
Study Committee 
9 
The COG research coordinator and protocol coordinator have been 
updated. 
4. 
Study Committee 
10 
Removed aldesleukin from the list of agents for the study. 
5. 
Schema 
12 
The schema was revised based on the new post-consolidation 
regimen, which utilizes one treatment schedule for the first 5 cycles 
of post-consolidation. The previous cycles 2 and 4 of post-
consolidation, which contained aldesleukin, has been removed. 
6. 
2.8 
19-20 
Background information and rationale has been provided regarding 
the removal of aldesleukin from post-consolidation therapy. All 
subsequent background sections were renumbered. 
7. 
4.1 
35 
The phrase “as per ANBL0032” was removed in reference to the post-
consolidation regimen, as the updated Post-Consolidation regimen is 
not the same regimen as in ANBL0032. 
8. 
4.1.5 
38 
Minor administrative edits were made in the post-consolidation 
summary to reflect changes to the post-consolidation regimen. 
9. 
4.9.5 
88 
References to aldesleukin in the additional guidance for post-
consolidation were removed. 

 
iii 
 
# 
Section 
Page(s) 
Change 
10. 4.9.6 
89 
The following changes have been made to the Cycles 1 – 5 therapy 
delivery map: 
• 
The TDM was revised so the first 5 cycles of post-
consolidation will now utilize one therapy delivery map. 
Cycles 2 and 4 will follow the same observation schedule as 
Cycle 5.  
• 
The duration of the first 5 cycles of post-consolidation have 
been extended from 24 days to 28 days for ease of 
scheduling. The additional 3 days (Days 25- 28) will be rest 
days. 
• 
Certain correlative study timepoints have been moved based 
on the changes to the post-consolidation regimen. 
• 
For the end of Cycle 3 disease evaluation, labs were removed 
from the evaluation so that only imaging and bone marrow 
biopsies are required. 
11. 4.9.7 
90 
The days that the end of Cycle 3 disease evaluation could be 
performed was updated to reflect the 28-day cycle. 
12. 4.10 
93-95 
The previous therapy delivery map for post-consolidation Cycles 2 
and 4, which contained aldesleukin, has been removed from the 
protocol.   
13. 4.10 
93 
Section numbers subsequent to 4.9 in the treatment section have been 
renumbered accordingly. 
14. 5.3 
98-100 
Under renal toxicity dose modifications, in addition to nuclear 
medicine GFR and creatinine clearance, an estimated GFR is being 
added as an option to assess GFR, as serum creatinine increases 
of > 2x the baseline value can often occur. 
15. 5.11 
5.13 
108-111 
112-113 
References to aldesleukin in the dose modification section were 
removed from the protocol. Other parts of the dose modifications 
were reworded for clarity. 
16. 5.11 
108-111 
The term cytokines was replaced with the term sargramostim for 
specificity. 
17. Throughout 
Section 5.0  
Throughout 
Section numbers subsequent to 5.11 in the dose modification section 
have been renumbered accordingly based on the removal of the 
aldesleukin-containing dose modifications. 
18. 5.13.2 
113 
We have included a statement which allows for institutional standards 
to be used for dose modifying dinutuximab and sargramostim in post-
consolidation. 

 
iv 
 
# 
Section 
Page(s) 
Change 
19. 6.2 
122 
The aldesleukin monograph was removed from the drug information 
section. 
20. Throughout 
Section 6.0 
Throughout 
Section numbers subsequent to 6.1 in the drug information section 
have been renumbered accordingly based on the removal of the 
aldesleukin monograph. 
21. 15.1.3 
15.1.6 
188 
192 
Due to the changes in the post-consolidation regimen, the days for 
which optional specimens are being obtained are being altered slightly 
to match the change to the post-consolidation cycle lengths. 
22. Appendix IV 
232 
Aldesleukin has been removed from the possible drug interactions 
appendix. 
23. Appendix V 
238 
Based on the changes to Section 15, minor edits have been made for 
consistency in the summary of optional correlative studies table. 
24. Appendix VI 
240 
The term cytokines was replaced with the term sargramostim for 
specificity and references to aldesleukin were removed. 
 
 

 
 
 
 
Page 1 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
ANBL17P1 
 
A Pilot Induction Regimen Incorporating Chimeric 14.18 Antibody (ch14.18, dinutuximab) 
(NSC# 764038) and Sargramostim (GM-CSF) for the Treatment of Newly Diagnosed High-
Risk Neuroblastoma  
 
NCI Supplied Agent: Chimeric 14.18 Antibody (ch.14.18, dinutuximab) (NSC#764038)  
IND sponsor: DCTD, NCI 
 
A Limited Institution Pilot Study. Participation is limited to the following COG institutions: 
 
St. Jude Children’s Research Hospital, Memphis, TN 
Dana-Farber Cancer Institute, Boston, MA 
Children’s Hospital of Los Angeles, Los Angeles, CA 
Primary Children’s Hospital, Salt Lake City, UT 
Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 
Children’s National Medical Center, Washington, DC 
Columbia University/Herbert Irving Cancer Center, New York, NY 
Starship Children’s Hospital, Auckland, New Zealand 
The Children’s Hospital at Westmead, Westmead, NSW, Australia 
Royal Children’s Hospital, Parkville, VIC, Australia 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH MEANS A 
SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO 
DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED 
BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE 
INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE PROCEDURES IN 
THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, 
AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL 
CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST 
LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
STUDY CHAIR 
 
Sara M. Federico, MD 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place, MS260 
Memphis, TN 38105 
Phone: (901) 595-2220 
Fax: 
(901) 521-9005 
E-mail: sara.federico@stjude.org
Activated: 
01/14/19 
Version Date:  
10/24/19 
Closed: 
      
Amendment  
#2 

 
 
 
ANBL17P1 
 
Version Date: 10/24/19 
 
Page 2 
 
 
CONTACT INFORMATION 
 
To 
submit 
site 
registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
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) which 
can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
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 Web page of the CTSU Member Web site located at 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 user log on with 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 RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) contact 
the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence 
will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 ANBL17P1 
 
Version Date: 10/24/19 
 
Page 3 
 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
7 
ABSTRACT 
11 
EXPERIMENTAL DESIGN SCHEMA 
12 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
13 
1.1 
Primary Aim 
13 
1.2 
Secondary Aim 
13 
1.3 
Exploratory Aims 
13 
2.0 
BACKGROUND 
13 
2.1 
Introduction/Rationale for Development 
13 
2.2 
Rationale for GD2-directed Therapy 
14 
2.3 
Rationale for GD2-directed Therapy Plus Chemotherapy 
15 
2.4 
Rationale for Standard Induction Chemotherapy 
17 
2.5 
Rationale for ch14.18 (dinutuximab) Dosage and Schedule during Induction 
Therapy 
18 
2.6 
Rationale for the Addition of Granulocyte Macrophage Colony-Stimulating 
Factor (GM-CSF) to Induction Cycles 3 – 5 
18 
2.7 
Rationale for the Tandem ASCT 
18 
2.8 
Removal of Aldesleukin from Post-Consolidation Therapy (post-Amendment 2)
 
19 
2.9 
Correlative and Exploratory Studies 
20 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
27 
3.1 
Study Enrollment 
27 
3.2 
Patient Eligibility Criteria 
31 
4.0 
TREATMENT PLAN 
35 
4.1 
Overview of Treatment Plan 
35 
4.2 
Induction Cycle 1 
39 
4.3 
Induction Cycle 2 
43 
4.4 
Induction Cycle 3 
47 
4.5 
Induction Cycle 4 
56 
4.6 
Induction Therapy Cycle 5 
67 
4.7 
Consolidation HSCT #1 
76 
4.8 
Consolidation HSCT #2 
81 
4.9 
Post-Consolidation Therapy 
85 
4.10 
Post-Consolidation Therapy Cycle 6 
93 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
96 
5.1 
Hematologic Toxicities during Induction therapy 
96 
5.2 
Hematuria during Induction therapy 
97 
5.3 
Renal Toxicity during Induction Therapy 
98 
5.4 
Cardiac Toxicity during Induction Therapy 
100 
5.5 
Liver Toxicities during Induction therapy 
102 
5.6 
Other Gastrointestinal Toxicity during Cycles 1-5 of Induction Therapy 
103 
5.7 
Neurologic Toxicity during Induction Therapy 
104 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 ANBL17P1 
 
Version Date: 10/24/19 
 
Page 4 
 
5.8 
Hypothyroidism during Induction Therapy 
105 
5.9 
Allergic reactions during Induction Therapy 
105 
5.10 
Other toxicities associated with Induction therapy 
108 
5.11 
Ch14.18 (dinutuximab)-associated toxicities during post-Consolidation 
108 
5.12 
Sargramostim (GM-CSF)-associated toxicities during post-Consolidation therapy
 
112 
5.13 
Ch14.18 (dinutuximab + sargramostim-associated toxicities during post-
Consolidation therapy 
112 
5.14 
Isotretinoin (ISOT)-associated toxicities during post-Consolidation therapy 
114 
6.0 
DRUG INFORMATION 
116 
6.1 
CHIMERIC MONOCLONAL ANTIBODY 14.18 
116 
6.2 
CARBOPLATIN 
122 
6.3 
CISPLATIN 
123 
6.4 
CYCLOPHOSPHAMIDE INJECTION 
125 
6.5 
DEXRAZOXANE 
127 
6.6 
DOXORUBICIN 
129 
6.7 
ETOPOSIDE – INJECTION 
131 
6.8 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ 
133 
6.9 
ISOTRETINOIN 
135 
6.10 
MELPHALAN 
139 
6.11 
MESNA – INJECTION 
142 
6.12 
PEGFILGRASTIM, PEGFILGRASTIM-JMDB, PEGFILGRASTIM-CBQV 143 
6.13 
SARGRAMOSTIM 
145 
6.14 
THIOTEPA 
147 
6.15 
TOPOTECAN 
149 
6.16 
VINCRISTINE SULFATE 
150 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
153 
7.1 
End of Therapy and Follow-up 
153 
7.2 
Research Studies for which Patient Participation is Optional 
153 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
154 
8.1 
Criteria for Removal from Protocol Therapy 
154 
8.2 
Off Study Criteria 
154 
9.0 
STATISTICAL CONSIDERATIONS 
155 
9.1 
Sample Size and Study Duration 
155 
9.2 
Study Design 
155 
9.3 
Methods of Analysis 
156 
9.4 
Evaluability for Response 
162 
9.5 
Evaluability for Toxicity 
162 
9.6 
Gender and Minority Accrual Estimates 
162 
10.0 
EVALUATION CRITERIA 
163 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
163 
10.2 
Response Criteria 
163 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
168 
11.1 
Purpose 
168 
11.2 
Determination of Reporting Requirements 
168 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 ANBL17P1 
 
Version Date: 10/24/19 
 
Page 5 
 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
168 
11.4 
Special Situations for Expedited Reporting 
169 
11.5 
Reporting Requirements for Specialized AEs 
171 
11.6 
Exceptions to Expedited Reporting 
172 
11.7 
Reporting Requirements - Investigator Responsibility 
172 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
172 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
174 
11.10 
Protocol Specific Additional Instructions and Reporting Exceptions 
175 
11.11 
Reporting of Adverse Events for Commercial Agents – CTEP-AERS 
Abbreviated Pathway 
176 
11.12 
Routine Adverse Event Reporting 
176 
12.0 
RECORDS AND REPORTING 
176 
12.1 
CDUS 
177 
12.2 
Data and Safety Monitoring Committee 
177 
12.3 
CRADA/CTA 
177 
13.0 
SURGICAL GUIDELINES 
179 
13.1 
Surgical Rationale 
179 
13.2 
Pre-Operative Management 
179 
13.3 
Specimen/Sampling Requirements at Diagnosis 
179 
13.4 
Specimen/Sampling Requirements at Definitive Surgery 
180 
13.5 
Operative Management 
180 
13.6 
Management of Surgical Complications 
182 
13.7 
Special Techniques 
183 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
183 
14.1 
Rapid Central Pathology Review 
183 
14.2 
Retrospective Central Review of Bone Marrow Samples 
184 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
185 
15.1 
Optional Studies 
185 
15.2 
Shipping Instructions for Specimens Submitted to the Biopathology Center 
196 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
198 
16.1 
Cross Sectional Imaging Studies 
198 
16.2 
123I-MIBG Scintigraphy 
199 
16.3 
[18F]–Fluorodeoxyglucose (18FDG)-PET Scintigraphy 
200 
16.4 
Tumor Measurement 
201 
16.5 
Curie Scoring 
201 
16.6 
Submission of Scans for Central Review 
202 
17.0 
RADIATION THERAPY GUIDELINES 
204 
17.1 
Indications for Radiation Therapy 
206 
17.2 
Timing of Radiation Therapy 
206 
17.3 
Emergency Radiation 
207 
17.4 
Equipment and Methods of Delivery and Verification 
208 
17.5 
Target Volume Definitions 
210 
17.6 
Target Dose 
215 
17.7 
Treatment Technique 
217 
17.8 
Organs at Risk 
218 
17.9 
Dose Calculations and Reporting 
219 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 ANBL17P1 
 
Version Date: 10/24/19 
 
Page 6 
 
17.10 
Quality Assurance Documentation 
220 
17.11 
Definitions of Deviations in Protocol Performance 
221 
18.0 
HEMATOPOIETIC TRANSPLANT GUIDELINES 
223 
18.1 
Catheter Use 
223 
18.2 
PBSC Mobilization 
223 
18.3 
PBSC Collection Guidelines 
224 
18.4 
PBSC Analyses 
224 
18.5 
Cryopreservation of PBSC Products 
224 
18.6 
Autologous Stem Cell Rescue 
225 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
226 
APPENDIX II: INTERNATIONAL NEUROBLASTOMA RISK GROUP (INRG) STAGING 
SYSTEM80,81 
229 
APPENDIX III: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
230 
APPENDIX IV: POSSIBLE DRUG INTERACTIONS 
232 
APPENDIX V: SUMMARY OF OPTIONAL CORRELATIVE STUDIES 
237 
APPENDIX VI: EMERGENCY MANAGEMENT OF CH14.18 (DINUTUXIMAB) 
TOXICITIES 
240 
APPENDIX VII: OVERALL RESPONSE CRITERIA 
241 
APPENDIX VIII: INTERNATIONAL NEUROBLASTOMA RISK GROUP (INRG) IMAGE 
DEFINED RISK FACTORS 
242 
APPENDIX IX: YOUTH INFORMATION SHEETS 
243 
REFERENCES 
245 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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Version date: 10/24/19 
 
Page 7 
 
STUDY COMMITTEE 
 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Sara M. Federico, MD 
Rochelle Bagatell, MD 
Oncology 
Hematology/Oncology 
St. Jude Children’s Research Hospital 
Children's Hospital of Philadelphia 
262 Danny Thomas Place, MS260 
Division of Oncology 
Memphis, TN 38105 
CTRB 4022 
Phone: (901) 595-2220  
3501 Civic Center Blvd 
Fax: 
(901) 521-9005 
Philadelphia, PA 19104 
E-mail: sara.federico@stjude.org 
Phone: (267) 426-9737 
 
Fax: 
(267) 425-0311 
STUDY VICE CHAIR 
Email: bagatellr@email.chop.edu 
Wayne Furman, MD 
 
Oncology 
Joy Bartholomew, APRN 
St. Jude Children’s Research Hospital 
Nursing 
262 Danny Thomas Place, MS260 
Hematology/Oncology 
Memphis, TN 38105 
Children’s Mercy Hospitals and Clinics 
Phone: (901) 595-2403  
2401 Gillham Road 
Fax: 
(901) 521-9005 
Kansas City, MO 64108 
E-mail: wayne.furman@stjude.org 
Phone: (816) 234-3297 
 
Fax: 
(816) 855-1726 
STUDY VICE CHAIR 
E-mail: joyb@cmh.edu 
Suzanne Shusterman, MD 
 
Oncology 
Steve Braunstein, MD 
Dana-Farber/Harvard Cancer Center 
Radiation Oncology 
450 Brookline Avenue SW 350 
UCSF Medical Center – Mission Bay 
Boston, MA 02215 
Radiation Oncology 
Phone: (617) 632-4901  
505 Parnassus Ave. L75 
Fax: 
(617) 632-5710 
San Francisco, CA 94143 
E-mail: suzanne_shusterman@dfci.harvard.edu 
Phone: (415) 353-3448 
 
E-mail: steve.braunstein@ucsf.edu 
STUDY STATISTICIAN 
 
Arlene Naranjo, PhD 
Ami V. Desai, MD 
Children’s Oncology Group - Data Center (Gainesville) 
Hematology/Oncology 
University of Florida – Dept of Biostatistics 
University of Chicago Comprehensive Cancer Center 
6011 NW 1st Place 
5841 South Maryland Ave. MC4060 
Gainesville, FL 32607 
Chicago, IL 60639 
Phone: (352) 273-0577 
Phone: (773) 834-3943 
Fax: 
(352) 392-8162 
Fax: 
(773) 702-9881 
E-mail: anaranjo@cog.ufl.edu 
Email: adesai12@peds.bsd.uchicago.edu 
 
 
STUDY COMMITTEE MEMBERS 
 
Shahab Asgharzadeh, MD 
 
Hematology/Oncology 
 
Children’s Hospital of Los Angeles 
 
4650 Sunset Blvd. #57 
 
Los Angeles, CA 90027 
 
Phone: (323) 660-2450 x 5101 
 
E-mail: shahab@chla.usc.edu 
 
 
 
 
 
 

  
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Page 8 
STUDY COMMITTEE MEMBERS 
STUDY COMMITTEE MEMBERS 
Julie Gastier-Foster, PhD 
Julie Ruggieri Park, MD 
Laboratory Medicine 
Hematology/Oncology 
Nationwide Children’s Hospital 
Seattle Children's Hospital 
700 Children’s Drive, CO988A 
M/S MB.8.501, PO Box 5371 
Columbus, OH 43205 
Seattle WA 98145 
Phone: (614) 722-2866 
Phone: (206) 987-2106 
Fax: 
(614) 722-2887 
Fax: 
(206) 987-3946 
Email: Julie.Gastier-Foster@nationwidechildrens.org 
E-mail: julie.park@seattlechildrens.org 
 
 
Daphne Haas-Kogen, MD 
Hiroyuki Shimada, MD 
Dana-Farber/Harvard Cancer Center 
Pathology 
Radiation Oncology 
Children's Hospital of Los Angeles 
450 Brookline Ave. D1622 
Department of Pathology 
Boston, MA 02215 
4650 Sunset Boulevard, MS 43 
Phone: (617) 632-2291  
Los Angeles, CA 90027 
Fax: 
(617) 632-2290 
Phone: (323) 361-2377 
E-mail: Dhaas-kogan@lroc.harvard.edu 
Fax: 
(323) 361-8005 
 
Email: hshimada@chla.usc.edu 
Meredith S. Irwin, MD  
 
Hematology/Oncology 
Barry Lynn Shulkin, MD 
Hospital for Sick Children 
Diagnostic Imaging 
555 University Avenue 9th Floor 
Saint Jude Children's Research Hospital 
Toronto, ON M5G 1X8 
262 Danny Thomas Place, MS 220 
Canada 
Memphis, TN 38105-3678 
Phone: (416) 813-7654 x302912 
Phone: (901) 595-3347 
Fax: 
(416) 813-5327 
Fax: 
(901) 595-3981 
Email: meredith.irwin@sickkids.ca 
Email: barry.shulkin@stjude.org 
 
 
Jason Anthony Jarzembowski, MD, PhD 
Paul Sondel, MD, PhD 
Children’s Hospital of Wisconsin 
Hematology/Oncology 
Pathology 
University of Wisconsin Hospital and Clinics 
9000 W. Wisconsin Avenue 
4159 WIMR Bldg. 
Milwaukee, WI 53201 
111 Highland Avenue 
Phone: (414) 266-2526 
Madison, WI 53792 
Fax: 
(414) 266-2779 
Phone: (608) 263-9069 
E-mail: jjarzemb@mcw.edu 
Fax: 
(608) 263-4226 
 
Email: pmsondel@humonc.wisc.edu 
Araz Marachelian, MD 
 
Pediatric Hematology/Oncology 
Tamarah Jeannette Westmoreland, MD, PhD 
Children’s Hospital of Los Angeles 
Surgery 
4650 Sunset Blvd. #307 
Nemours Children’s Hospital 
Los Angeles, CA 90027 
13535 Nemours Parkway 
Phone: (323) 644-8573 
Orlando, FL 32827 
Fax: 
(323) 660-7128 
Phone: (407) 650-7622 
Email: amarachelian@chla.usc.edu 
Email: tamarah.westmoreland@nemours.org 
 
 
 
 
 
 
 
 
 

  
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STUDY COMMITTEE MEMBERS 
RESEARCH COORDINATOR 
Gregory A. Yanik, MD 
Mariquis Stargel 
Hematology/Oncology 
Children's Oncology Group - Operations Center 
C S Mott Children's Hospital 
222 E. Huntington Drive, Suite 100 
Dept of Peds, BMT Program 
Monrovia, CA 91016 
5303 CCGC, SPC-5914 
Phone:  (626) 241-1614 
1500 E. Medical Center Drive 
Fax:  
(626) 445-4334 
Ann Arbor MI 48109-5914 
E-mail: mstargel@childrensoncologygroup.org 
Phone:  (734) 764-8630 
 
Fax:  
(734) 936-8788 
PROTOCOL COORDINATOR 
E-mail: gyanik@med.umich.edu 
Edwin Ha 
 
Children’s Oncology Group 
Nancy Sommers, PharmD 
222 E. Huntington Drive, Suite 100 
Pharmacy 
Monrovia, CA 91016 
Children’s Hospitals and Clinics of Minnesota 
Phone:  (626) 241-1502 
2525 Chicago Avenue South 
Fax:  
(626) 445-4334 
Minneapolis, MN 55404 
E-mail: eha@childrensoncologygroup.org 
Phone: (612) 813-7259 
 
Fax: 
(612) 813-6365 
 
Email: nancy.sommers@childrensmn.org 
 
 
 
Alice Lin-Tsing Yu, MD, PhD 
 
Hematology/Oncology 
 
Rady Children’s Hospital – San Diego 
 
200 West Arbor Drive (8447) 
 
San Diego, CA 92103-8447 
 
Phone: (619) 543-2438 
 
Fax: 
(858) 246-0019 
 
Email: aliceyu@ucsd.edu 
 
 
 
Marguerite T. Parisi, MD 
 
Radiology 
 
Seattle Children’s Hospital 
PO Box 5371 
Seattle, WA 98145 
Phone: (206) 987-2134 
Fax: 
(206) 987-2730 
Email: meg.parisi@seattlechildrens.org 
 
Christopher L. Tinkle, MD, PhD 
Radiation Oncology 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place, MS210 
Memphis, TN 38105 
Phone: (901) 595-8735  
Fax: 
(901) 595-8735 
E-mail: Christopher.tinkle@stjude.org 
 
 

  
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AGENT 
 
NSC # 
Supplier 
Ch14.18 (Dinutuximab) 
 
764038 
CTEP 
Carboplatin 
 
241240 
Commercial 
Cisplatin 
 
119875 
Commercial 
Cyclophosphamide 
 
26271 
Commercial 
Dexrazoxane 
169780 
Commercial 
Doxorubicin 
 
123127 
Commercial 
Etoposide 
 
141540 
Commercial 
Filgrastim 
 
614629 
Commercial 
Isotretinoin 
 
329481 
Commercial 
Melphalan 
 
8806 
Commercial 
Mesna 
 
113891 
Commercial 
Pegfilgrastim 
 
725961 
Commercial 
Sargramostim 
 
613795 
Commercial 
Thiotepa 
 
6396 
Commercial 
Topotecan 
 
609699 
Commercial 
Vincristine 
 
67574 
Commercial 
 
 
 
 
 
 
IND Sponsor: DCTD, NCI 
 
 
 
SEE SECTION 15.0 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 
 
Intensification of Consolidation therapy with tandem autologous stem cell transplants and the addition of post-
Consolidation immunotherapy targeting the disialoganglioside GD2 present on neuroblastoma cells have led to 
improved event-free survival rates for patients with high-risk neuroblastoma. However, a substantial number of 
children still experience disease progression during Induction therapy, show evidence of persistent metastatic 
disease, or relapse after completion of treatment. The need for innovative therapies for children with high-risk 
neuroblastoma remains critical. Recent studies conducted in patients with recurrent or refractory neuroblastoma 
have demonstrated objective clinical responses following treatment with the combination of an anti-GD2 
monoclonal antibody (mAb) plus chemotherapy and GM-CSF. This protocol will evaluate whether the addition 
of the anti-GD2 mAb, ch14.18 (dinutuximab), and GM-CSF to standard Induction chemotherapy Cycles 3 to 5 
for patients with newly-diagnosed neuroblastoma is safe and tolerable. Secondary endpoints will include disease 
response and survival. Embedded biologic correlative studies will further evaluate tumor and host response to 
the proposed therapy. 
 
 
 
 
 
 
 
 

  
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EXPERIMENTAL DESIGN SCHEMA 
 
 
Generic Drug Name/Regimen 
Abbreviation 
Carboplatin/Etoposide/Melphalan 
CEM 
Cisplatin 
CDDP 
Cyclophosphamide 
CPM 
Ch14.18 (Dinutuximab) 
DIN 
Doxorubicin 
DOXO 
Etoposide 
ETOP 
Isotretinoin 
ISOT 
Sargramostim 
GM-CSF 
Thiotepa/Cyclophosphamide 
TC 
Topotecan 
TOPO 
Vincristine 
VCR 
Induction Cycles 1 & 2 
TOPO/CPM 
Stem Cell Harvest 
Induction Cycle 3 
CDDP/ETOP/DIN/GM-CSF 
Induction Cycle 4 
VCR/DOXO/CPM/DIN/GM-CSF 
Surgery* 
Induction Cycle 5 
CDDP/ETOP/DIN/GM-CSF 
Primary Site 
Disease Evaluation 
Complete Disease 
Evaluation 
Consolidation HSCT #1 
TC 
Consolidation HSCT #2 
CEM 
Consolidation Local XRT 
Complete Disease 
Evaluation 
Post-Consolidation Cycles 1-5 
ISOT/DIN/GM-CSF 
Post-Consolidation Cycle 6 
ISOT 
Complete Disease 
Evaluation 
Progressive Disease:  
Off Protocol Therapy  
Progressive Disease:  
Off Protocol Therapy  
Disease Evaluation 
after Cycle 3 
Progressive Disease:  
Off Protocol Therapy  
*If clinically indicated, surgery may take place after the fifth cycle of Induction. 

  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Aim 
1.1.1 To assess the feasibility and tolerability of administering ch14.18 (dinutuximab) and 
sargramostim (GM-CSF) in combination with a multi-agent chemotherapy regimen 
during Cycles 3-5 of the Induction phase for patients with newly-diagnosed high-risk 
neuroblastoma. 
 
1.2 
Secondary Aim 
1.2.1 To describe the response rates, event-free survival (EFS) and overall survival (OS) for 
patients receiving the combination of standard Induction chemotherapy and ch14.18 
(dinutuximab) followed by tandem transplant, radiation therapy, and post-Consolidation 
immunotherapy. 
 
1.3 
Exploratory Aims 
1.3.1 To describe the clinical relevance of naturally occurring anti-glycan antibodies in 
patients receiving ch14.18 (dinutuximab). 
1.3.2 To describe the clinical relevance of natural killer (NK) receptor NKp30 isoforms in 
patients receiving ch14.18 (dinutuximab). 
1.3.3 To describe the association between host factors, including human anti-chimeric 
antibodies (HACA), and response to protocol therapy. 
1.3.4 To describe the immune environment (gene expression; immune effector cells, activities 
and signaling molecules; immune target expression) during and following treatment. 
1.3.5 To describe the association between levels of circulating GD2, and tumor cell GD2 
expression with response to therapy. 
 
 
2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
High-risk neuroblastoma  
In spite of recent improvements in therapy, outcomes for patients with high-risk neuroblastoma 
remain poor. For patients enrolled on COG A3973, the estimated 5-year EFS was only 38%.1 
In COG ANBL0032, the addition of an anti-GD2 monoclonal antibody (dinutuximab) to the 
post-Consolidation phase of therapy was evaluated. In this study, patients with high-risk 
neuroblastoma who had not experienced disease progression during Induction or Consolidation 
therapy were randomized to receive either ch14.18 (dinutuximab) combined with cytokines and 
isotretinoin or isotretinoin alone. The patients that received immunotherapy plus isotretinoin 
had a 2-year post-randomization EFS of 66% (± 5%) versus 46% (± 5%) in those that received 
single agent isotretinoin.2 In ANBL0532, Consolidation therapy was intensified; patients were 
randomized to receive either high-dose chemotherapy followed by autologous stem cell 
transplant (ASCT) or two sequential cycles of high dose chemotherapy with ASCT (tandem 
ASCT). Patients who received a tandem ASCT had a significantly improved 3-year post-
randomization EFS of 63% (± 5%) compared to 49% (± 5%) for patients assigned to a single 
transplant.3 While intensification of Consolidation therapy and the addition of post-
Consolidation immunotherapy have both improved EFS for high-risk patients, a substantial 
number of children still experience disease progression during Induction therapy, show 

  
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evidence of persistent metastatic disease, or relapse after the completion of treatment. Thus, the 
need for innovative therapies for children with high-risk neuroblastoma remains critical. 
 
This pilot study represents the culmination of decades of studies evaluating the role of GD2-
directed therapy in patients with high-risk neuroblastoma. The trial will evaluate the feasibility 
and tolerability of administering concurrent anti-GD2 monoclonal antibody ch14.18 
(dinutuximab) with GM-CSF and chemotherapy in Cycles 3-5 of the Induction phase of 
treatment for patients with newly-diagnosed high-risk neuroblastoma. If delivery of the 
combined therapy is feasible and results in improved outcomes, this pilot study will provide the 
basis for a definitive Phase 3 clinical trial to determine whether the addition of anti-GD2 
immunotherapy during Induction improves survival in children with newly diagnosed high-risk 
neuroblastoma. If the results are positive, this could alter clinical practice by establishing a new 
Induction standard of care. 
 
Importantly, the rate of development of HACA in patients treated with ch14.18 (dinutuximab) 
during Induction will also be studied during this pilot trial. These results will be instrumental in 
guiding the development of a future Phase 3 study. To aid in identification of patients most 
likely to benefit from the GD2-directed immunotherapy, potential biomarkers of response will 
also be evaluated. The exploratory work that will be completed during this trial could provide 
the basis for prospective validation of biomarkers in a larger Phase 3 clinical trial.  
 
2.2 
Rationale for GD2-directed Therapy  
2.2.1 
Pre-Clinical Studies 
The disialoganglioside GD2 is expressed on neuroblastoma cells, but its expression in 
normal human tissues is restricted to neurons, skin melanocytes and peripheral pain 
fibers.4-6 Because of this pattern of expression, anti-GD2 monoclonal antibodies are an 
attractive form of targeted immunotherapy for children with neuroblastoma. Over the 
past 3 decades, antibodies directed against GD2 have been studied extensively. Early 
studies were performed using the murine IgG3 monoclonal antibody 3F84,5 and murine 
IgG2a, 14G2a.7,8 3F8 has been shown to mediate very efficient antitumor antibody 
dependent cell-mediated cytotoxicity (ADCC) in vitro in the presence of GM-CSF.9 
However, murine antibody therapy can be accompanied by development of a human 
anti-mouse antibody response (HAMA), which results in the formation of neutralizing 
antibodies. This can be particularly problematic in patients who have not received high 
dose chemotherapy or undergone myeloablative treatment within 90 days preceding 
murine antibody treatment.10 To address this challenge, alternative antibody constructs 
have been developed. Ch14.18 (dinutuximab) consists of the variable regions of murine 
IgG3 b 14.18 and the constant regions of human IgG1-κ. Pharmacokinetic and 
immunological studies have shown that ch14.18 (dinutuximab) has a longer plasma 
half-life and less immunogenicity when compared to the murine antibody, making it 
potentially more effective.11,12 Preclinical studies performed both in vitro and in vivo 
indicate that its anti-neuroblastoma activity involves complement dependent 
cytotoxicity (CDC) and ADCC when ch14.18 (dinutuximab) is used alone13 or in 
combination with GM-CSF.14 
 
2.2.2 
Clinical Studies using anti-GD2 Antibodies 
The murine anti-GD2 antibody 3F8 was tested in a Phase 1 trial in patients with 
neuroblastoma, and in a Phase 2 trial in combination with GM-CSF. The 2 agent 
combination appeared to have efficacy, especially in patients with bone marrow 

  
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disease.15 Phase 1 and 2 clinical trials of ch14.18 (dinutuximab) or 14G2a, alone or 
combined with cytokines such as GM-CSF or IL-2 respectively, also showed signals of 
activity in patients with neuroblastoma.11,16 Subsequent clinical trials have 
demonstrated a significant decrease in risk of relapse and an improvement in survival 
for patients with high risk neuroblastoma who are in remission after initial multi-
modality therapy. An early analysis of results from a German study of single agent 
ch14.18 (dinutuximab) administered to patients > 1 year of age with Stage 4 
neuroblastoma showed no difference in the rate of recurrence when compared to 
patients who did not receive the antibody.17 However, analysis of data with longer 
follow up time revealed a statistically significant improvement in EFS for those patients 
who received ch14.18 (dinutuximab).18 A randomized Phase 3 study (COG 
ANBL0032) of Post-consolidation ch14.18 (dinutuximab) combined with GM-CSF, 
interleukin 2 and isotretinoin compared with single agent isotretinoin was stopped early 
because the EFS of patients treated with the antibody containing regimen was clearly 
superior to that of patients treated with isotretinoin alone.19  
 
The clinical evaluation of various anti-GD2 monoclonal antibodies in children with 
neuroblastoma initially focused on treatment of minimal residual disease. However, 
several studies conducted in adults with cancer suggest that monoclonal antibodies can 
be effectively combined with chemotherapy to treat patients, including those with 
measurable disease.20-27 These studies provided a rationale for the development of 
chemo-immunotherapy regimens for patients with neuroblastoma. 
 
2.3 
Rationale for GD2-directed Therapy Plus Chemotherapy 
Preclinical studies  
Preclinical studies show that anti-GD2 antibodies may enhance the effects of chemotherapy in 
small cell lung cancer cell lines and in a neuroblastoma cell line. Yoshida et al. demonstrated 
that an anti-GD2 monoclonal antibody enhanced apoptotic effects of specific chemotherapeutic 
agents against a small cell lung cancer cell line.28 In a neuroblastoma cell line, Kowalczyk et al. 
demonstrated that the anti-GD2 monoclonal antibody (mAb), 14G2a, had additive cell killing 
when combined with carboplatin and synergistic cell killing when combined with doxorubicin 
and topotecan.29 In addition to synergistic effects of anti-GD2 mAbs with chemotherapy, there 
is also evidence that the anti-GD2-specific antibodies can suppress tumor growth, independent 
of the immune system involvement by directly inducing apoptosis in lung cancer cells30 and 
suppressing growth in melanoma xenografts31 and a neuroblastoma cell line.29 
 
Clinical studies 
In the clinical setting, investigators have demonstrated that the addition of an anti-GD2 mAb 
plus chemotherapy is safe and feasible, and that this combination results in clinically meaningful 
responses. The St. Jude Children’s Research Hospital pilot study GD2NK evaluated the 
combination of a humanized anti-GD2 mAb, hu14.18K322A, with cytokines and alternating 
chemotherapy combinations (cyclophosphamide plus topotecan, irinotecan plus temozolomide 
and ifosfamide plus carboplatin and etoposide) in patients with recurrent or refractory 
neuroblastoma.32 Administration of this therapy in a cohort of 13 patients was feasible and well-
tolerated. Moreover, 8 of 13 (63%) had an objective response and the time to progression was 
delayed compared to historical controls.32  
 
Based on these data, a Phase 2 clinical trial, NB2012, was designed to evaluate the response of 
combined anti-GD2 mAb (hu14.18K322A) with cytokines during Induction and Consolidation 
chemotherapy for patients with newly-diagnosed high-risk disease. An interim analysis 

  
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(performed after the first 20 patients) confirmed that the delivery of combined Induction 
chemotherapy plus hu14.18K322A in newly diagnosed patients is feasible and well-tolerated.33 
Additional patients were therefore enrolled. As reported at ASCO 2017, of 42 evaluable patients 
with newly-diagnosed high-risk neuroblastoma treated on NB2012 who completed the first 2 
courses of chemotherapy plus hu14.18K322A, 32 achieved a response of ≥ PR (76.2%; 95% 
C.I. 61.3 – 87.9%).34 This nearly doubled the response rate following 2 cycles of Induction 
therapy achieved by a historical control group that received the same chemotherapy regimen 
without the addition of mAb (p=0.05).33,35 Further, none of the patients treated on NB2012 
developed disease progression during Induction compared with the 10-15% who experienced 
disease progression on recent COG high-risk neuroblastoma trials.1,36,37 All of the patients on 
NB2012 were able to proceed to Consolidation therapy (with a single BuMel ASCT) and 
subsequently to post-Consolidation immunotherapy. Only five percent of the patients 
discontinued treatment due to personal choice, unrelated to toxicities attributable to therapy.  
 
The COG trial ANBL1221 evaluated response in patients with recurrent or refractory 
neuroblastoma following treatment with the combination of ch14.18 (dinutuximab) and 
chemotherapy. This trial was a 2-arm “pick the winner” study in which patients were 
randomized to treatment with irinotecan and temozolomide combined with either temsirolimus 
or ch14.18 (dinutuximab) and GM-CSF. Among 18 patients randomized to receive 
irinotecan/temozolomide/temsirolimus, 1 PR was observed (5.6%, 95% confidence interval 
(CI): [0.0%, 16.1%]). Among 17 patients randomized to receive irinotecan/temozolomide/ 
ch14.18 (dinutuximab)/GM-CSF, 9 (53%, 95% CI: [29.2%, 76.7%]) had objective responses (4 
PR, 5 CR) including responses in 5/10 patients with relapsed/progressive disease and 4/7 with 
refractory disease. The combination of irinotecan with temozolomide and ch14.18 
(dinutuximab) met the protocol-defined criteria for selection as the combination meriting further 
study.38 After a 53% response rate was noted in the initial cohort of 17 patients assigned to 
irinotecan/temozolomide/ch14.18 (dinutuximab)/GM-CSF on the randomized portion of the 
study, the study was amended to allow greater confidence in the response estimate. Preliminary 
data indicate an overall response rate (CR + PR) of ~40% (95% CI: [26.5%, 52.8%]) in an 
intention to treat analysis including all patients on the trial who were assigned to irinotecan, 
temozolomide and ch14.18 (dinutuximab). Of the 53 patients assigned to the regimen, 17 during 
the randomization and 36 during study expansion, 21 experienced objective responses, 
including 11 CR and 10 PR. Taken together, these data provide a compelling basis for further 
evaluation of the anti-GD2 monoclonal antibody, ch14.18 (dinutuximab), given with Induction 
chemotherapy in children with newly diagnosed high-risk neuroblastoma. 
 
Rationale for concurrent administration of ch14.18 (dinutuximab) and chemotherapy  
Collectively, the 3 clinical studies previously described provide evidence that an anti-GD2mAb 
can be safely administered with chemotherapy in patients with bulky neuroblastoma. As noted, 
in the recurrent setting, 13 patients (many with significant tumor burden) safely received 
chemotherapy plus hu14.18K322A on a trial conducted at St. Jude (GD2NK) and 51 patients 
safely received chemotherapy plus ch14.18 (dinutuximab) with expansion of the COG trial 
(ANBL1221). In patients with newly diagnosed high-risk neuroblastoma, more than 40 patients 
have safely received hu14.18K322A combined with 6 cycles of Induction chemotherapy. 
Importantly, all of these newly-diagnosed patients have been able to receive Consolidation and 
post-Consolidation therapy. In total, over 100 patients with neuroblastoma have safely received 
anti-GD2mAb plus GM-CSF and chemotherapy. 
 
One concern regarding the administration of ch14.18 (dinutuximab) during Induction is the 
potential for the development of HACA, which could interfere with delivery of ch14.18 
(dinutuximab) during post-Consolidation therapy. Therefore, development of HACA will be 

  
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closely monitored. Analysis of data from COG ANBL0032, in which patients received ch14.18 
(dinutuximab) during post-Consolidation, revealed a low incidence of neutralizing HACA [only 
4.4% among patients who received ch14.18 (dinutuximab)] in the post-Consolidation setting. 
In addition, in the preliminary analyses of data regarding patients receiving a similar anti-GD2 
mAb (hu14.18K322A in the St. Jude NB2012 trial), no patients have developed a neutralizing 
human anti-human antibody (HAHA) at any point during therapy.  
 
Unpublished data from NB2012 indicate that exposure to hu14.18K322A during Induction does 
not cause an increase in detectable HAHA responses. At an interim analysis, twenty-two 
patients on NB2012 had samples evaluated for all 6 Induction cycles and 20 of these also had 
samples evaluated for all post-Consolidation cycles. HAHA was documented in 1 patient after 
Cycle 4 Induction. However, serum levels of hu14.18K322A were also detectable, thereby 
arguing against the development of a neutralizing antibody. HAHA was undetectable for all 
subsequent evaluations of this patient, including during post-Consolidation therapy. No other 
patients had a detectable HAHA at any time during therapy. Thus, of 22 evaluable patients 
assayed during Induction, only 1 (5%) showed a HAHA response, and 0 (0%) had a neutralizing 
response. Furthermore, for the 20 patients assessed during post-Consolidation, 0 (0%) had a 
detectible HAHA response.  
 
Hu14.18K322A is a humanized (rather than chimeric) antibody, and therefore may be less 
immunogenic than a chimeric antibody. Importantly, single agent administration of 
hu14.18K322A antibody to patients with relapsed or refractory neuroblastoma resulted in 
HAHA development (>0.7 O.D.) in 15 of 37 (40%) patients.39 However, the identification of 
HAHA in only 5% of patients treated on NB2012 suggests that the concurrent administration of 
chemotherapy with anti-GD2 antibody may mitigate the risk of developing a neutralizing 
antibody. Indeed, it is possible that frontline chemo-immunotherapy may be “tolerizing” 
patients and may help to avoid neutralizing antibody responses. Since this is the first time 
ch14.18 (dinutuximab) will be given in conjunction with induction chemotherapy it is critical 
to determine the incidence of HACA development during the ANBL17P1 trial. Based on the 
results summarized above, we hypothesize that the ANBL17P1 regimen is unlikely to cause a 
meaningful increase in HACA (or neutralizing HACA) compared to that seen in ANBL0032. 
Collection of HACA data on the uniformly treated ANBL17P1 cohort will be necessary prior 
to evaluation of this treatment in a frontline Phase 3 trial. 
 
2.4 
Rationale for Standard Induction Chemotherapy  
The Induction chemotherapeutic regimen and schedule used for this study are identical to the first 
5 cycles administered in COG ANBL09P1 and ANBL12P1, as well as the planned 5-cycle 
Induction regimen that will be administered in ANBL1531. Patients in the POG 9340 series of trials 
who received 5 cycles of Induction had similar response rates compared to patients who received 
7 cycles of Induction.40 Investigators from Memorial Sloan Kettering Cancer Center compared the 
end-Induction complete response (CR) and very good partial response (VGPR) rates for patients 
receiving 5 or 7 cycles of Induction therapy. In both study groups, the response rates were 
approximately 80%.41 Further, rates of stable or progressive disease were similar between the 2 
groups and there was a decrease rate of secondary leukemia in patients receiving 5 rather than 7 
cycles of Induction.42 In ANBL12P1 the end-Induction response rate following 5 cycles of 
chemotherapy was 82%, which is similar to the end-Induction response rate of 80% following 6 
cycles of chemotherapy on ANBL0532.43 Therefore, this study will use a 5-cycle Induction 
regimen. 
  

  
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2.5 
Rationale for ch14.18 (dinutuximab) Dosage and Schedule during Induction Therapy 
Ch14.18 (dinutuximab) (17.5 mg/m2/dose) will be administered during Induction Cycles 3-5. 
Similar to ongoing studies evaluating the concurrent administration of anti-GD2 mAb and 
chemotherapy, ch14.18 (dinutuximab) will be given on Days 2-5 of Cycles 3, 4, and 5. Standard 
pre-medications, as outlined below, will be administered to limit allergic reactions. The initial 
infusion of ch14.18 (dinutuximab) will start out slowly and the rate will be increased if the 
infusion is well tolerated. The infusion rate is identical to the infusion rate used in ANBL1221.38 
 
Ch14.18 (dinutuximab) will not be given during Induction Cycles 1 and 2 to avoid excessive 
toxicity in patients with newly diagnosed high-risk disease who are frequently systemically ill 
and/or have pleural or peritoneal fluid collections that may complicate their ability to tolerate 
the known capillary leak syndrome that can accompany ch14.18 (dinutuximab).19 In addition, a 
delay in initiation of ch14.18 (dinutuximab) until Induction Cycle 3 (the time point for 
peripheral blood stem cell collection for the majority of patients) will allow for immune 
reconstitution following myeloablative Consolidation chemotherapy with a stem cell product 
that is not primed for HACA response. This is expected to decrease the potential development 
of HACA that could preclude administration or decrease the effectiveness of ch14.18 
(dinutuximab) during post-Consolidation therapy.  
 
Throughout ANBL17P1, samples will be obtained to assess HACA formation, and results of 
this testing will be compared to data from ANBL0032. This information will be critical to 
planning future randomized clinical trials using chemo-immunotherapy.  
 
2.6 
Rationale for the Addition of Granulocyte Macrophage Colony-Stimulating Factor (GM-
CSF) to Induction Cycles 3 – 5 
GM-CSF (250 mcg/m2/dose subQ) will replace G-CSF during Cycles 3-5 of Induction therapy. 
Administration of GM-CSF during Cycles 3-5 will serve two purposes. It will both decrease the 
duration of chemotherapy-induced neutropenia and will augment antibody-dependent cell 
mediated cytotoxicity (ADCC).44-46 Unlike the administration schedule defined by ANBL0032, 
GM-CSF administration during Induction will start on Day 6 or 7, occurring after administration 
of ch14.18 (dinutuximab) and chemotherapy. This schedule and dose of GM-CSF has been used 
in three other clinical trials of chemo-immunotherapy for patients with high-risk or 
relapsed/refractory neuroblastoma (St. Jude trials GD2NK and NB2012; COG-ANBL1221). In 
all 3 trials, GM-CSF was initiated 24-48 hours after the completion of chemotherapy. The 
rationale for sequential delivery during Induction therapy is related to the concern that GM-
CSF, when combined with simultaneous myelosuppressive chemotherapy, may potentiate 
additional myelosuppression by driving division of myeloid precursors and make them more 
sensitive to the cytotoxic agents.47 Daily sub-cutaneous administration of GM-CSF will 
continue post-nadir until the absolute neutrophil count (ANC) is greater than or equal to 
2000/mm3 or until criteria have been met to begin the next cycle of therapy. GM-CSF will be 
stopped at least 24 hours prior to initiating the next cycle of chemotherapy. 
 
2.7 
Rationale for the Tandem ASCT 
COG ANBL0532 was designed to test the hypothesis that intensification of the Consolidation phase 
of therapy using tandem cycles of myeloablative chemotherapy would improve 3-year EFS of 
children with high-risk NBL. The tandem regimen used on ANBL0532 was successfully piloted in 
the 
ANBL00P1 
study.36 
This 
trial 
demonstrated 
the 
feasibility 
of 
administering 
thiotepa/cyclophosphamide (TC) followed by carboplatin/etoposide/melphalan (CEM) in the 
cooperative group setting. Among 41 eligible patients, 33 (80%) underwent the first cycle of 

  
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myeloablative therapy and 26 (63%) underwent both cycles. Stopping rules for transplant-related 
mortality were not met, and complications of therapy, including hematologic, gastrointestinal, and 
infectious toxicities, were as expected.36 A total of 652 eligible patients were enrolled on 
ANBL0532; 355 underwent randomization to either single (CEM) or tandem (TC, CEM) ASCT.43 
As noted above, the 3-year EFS from time of randomization for patients assigned to CEM was 49% 
(± 5%) compared to 63% (± 5%) for patients assigned to tandem ASCT. The 3-year EFS from time 
of diagnosis was 51%. The proportion of patients that went on to immunotherapy did not differ 
between the two arms of the study, and the difference in 3 year EFS in the two groups remained 
significant among those treated with immunotherapy (55% ± 5% for single vs 74% ± 5% for 
tandem transplant).43 In light of these data, tandem ASCT has been adopted as the COG 
recommended consolidation regimen for patients with high-risk neuroblastoma.  
 
2.8 
Removal of Aldesleukin from Post-Consolidation Therapy (post-Amendment 2) 
Based on the landmark results of the COG ANBL0032 trial, post-consolidation therapy 
including dinutuximab together with granulocyte-monocyte colony stimulating factor (GM- 
CSF) and interleukin-2 (IL-2) combined with isotretinoin has been considered a component of 
standard frontline treatment for children with high-risk neuroblastoma.2 The toxicities 
associated with this regimen have been attributed to the combination of dinutuximab and both 
cytokines, though capillary leak syndrome and serious allergic reactions have been noted to be 
more common during IL-2-containing cycles compared to GM-CSF containing cycles.2 
 
To evaluate the contribution of IL-2 to survival outcomes and toxicity, the International Society 
of Pediatric Oncology Europe Neuroblastoma (SIOPEN) group conducted a trial in which 
patients were randomized to receive either dinutuximab derived from Chinese hamster ovary 
cells (dinutuximab beta) alone or dinutuximab beta with subcutaneous IL-2.48 In an intention-
to-treat analysis, no differences in 3-year event-free survival (EFS) or cumulative incidence of 
relapse/progression were detected between patients treated with or without IL-2, nor was a 
difference in 5-year overall survival (OS) detected.48 Patients assigned to receive IL-2 had 
higher rates of fever, pain, allergic reaction, capillary leak syndrome, hematologic toxicity, 
neurotoxicity, and GI toxicity. Only 62% of patients randomized to the IL-2 + dinutuximab beta 
arm received the planned therapy while 87% of patients assigned to dinutuximab beta alone 
received the planned therapy.48 Therefore, while the results raised questions regarding the 
relative contribution of IL-2 to this post-consolidation regimen, concern regarding the lack of 
receipt of assigned therapy suggested that further study of IL-2 as a component of post-
consolidation therapy was necessary.  
 
SIOPEN subsequently conducted a trial designed to reduce treatment-related toxicity overall so 
that a larger portion of patients would be expected to receive planned therapy. Dinutuximab beta 
(10 mg/m2/day) was delivered over 10 days as a continuous infusion to all patients. For those 
assigned to the IL-2-containing arm, a reduced dose of subcutaneous IL-2 (3 million IU/m2/day) 
was administered. During this trial, similar portions of patients on each arm completed 
therapy.49 Rates of Grade 3 or higher fever and pain were reported among patients assigned to 
the IL-2-containing therapy. Among evaluable patients, response rates and 2-year EFS/OS in 
the two arms did not differ significantly. Based on these results, SIOPEN has made the 
determination to eliminate IL-2 from standard post-consolidation therapy.49 
 
Additional data also support the removal of IL-2 from dinutuximab beta-containing therapy. 
SIOPEN demonstrated in a randomized Phase 2 trial in patients with relapsed/refractory 
neuroblastoma that response rate, EFS and OS were similar among patients assigned to 
dinutuximab beta as a long-term infusion with or without the addition of subcutaneous IL-2.50 

  
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In this study, rates of Grade 3 or higher fever, allergic reaction, hematological toxicity and 
neurotoxocity were higher in patients randomized to the IL-2 containing arm.  
 
In addition, unpublished data suggest that treatment with dinutuximab and GM-CSF may result 
in elevation of soluble IL-2 receptor levels in the absence of IL-2 administration, potentially 
obviating the need for IL-2 administration to activate NK cells and promote antibody dependent 
cellular cytotoxicity. (Paul Sondel, personal communication) 
 
While differences exist between administration of anti-GD2 antibody and IL-2 in COG and 
SIOPEN trials, the COG Neuroblastoma Committee has concluded that the available data 
demonstrate a lack of clear benefit of IL-2 and show a higher rate of toxicity associated with 
IL-2-containing regimens. Therefore, patients on ANBL17P1 will no longer receive IL-2 as a 
component of post-consolidation therapy. Instead, GM-CSF will be administered will all five 
dinutuximab-containing post-consolidation cycles. This change was implemented as part of an 
urgent groupwide memo posted on August 23, 2019. 
 
2.9 
Correlative and Exploratory Studies 
The correlative studies included in this trial are critical to identify potential biomarkers of 
activity and toxicity that will warrant validation in the context of a subsequent, a larger Phase 3 
trial. Historically, cytotoxic chemotherapeutic regimens are evaluated with pharmacokinetic 
(PK) and pharmacodynamic (PD) studies to determine how drugs affect and are processed by 
the body, with the goal to identify the most appropriate doses that maximize efficacy and 
minimize toxicity. For immunotherapy and chemoimmunotherapy, the toxicity, efficacy and 
selected doses are not solely informed by PK or PD studies. Instead, it is imperative to measure 
the immune response and identify immune markers that may permit optimization of 
chemoimmunotherapy treatment. Identification of immune markers may play a critical role in 
the future selection of patients who are more likely to respond to upfront chemoimmunotherapy. 
Findings from the proposed correlative studies may serve as a foundation for the development 
of integrated biomarker studies in a larger Phase 3 trial. 
 
This is the first trial to evaluate these markers in patients with newly diagnosed high-risk 
neuroblastoma who will receive immunotherapy with Induction chemotherapy. The analyses of 
the relationships between immune markers and response will primarily be descriptive given the 
small sample size. Many of these studies are time sensitive and/or the analytes are unstable and 
must therefore be processed and performed directly by the investigator(s) conducting the 
studies. The scientific basis for the correlative studies is provided below. 
 
2.9.1 
Rationale for studying naturally occurring anti-glycan antibodies 
Ch14.18 (dinutuximab) is produced in a rodent cell line that contains the glycans 
galactose alpha-1,3-galactose (alpha-gal) and Neu5Gc. These glycans are found in most 
mammals but are missing in humans. All humans have naturally occurring antibodies 
to non-human glycans, including anti-alpha-gal and anti-Neu5Gc.51 When ch14.18 
(dinutuximab) is administered to a patient, the patient may experience an allergic 
reaction. Levels of anti-alpha-gal have been correlated with allergic reactions to the 
drug cetuximab (Erbitux), a chimeric antibody against the EGF receptor that is 
extensively modified with the glycans alpha-gal and Neu5Gc.52 Thus, it is possible that 
the presence and/or levels of antibodies to these non-human glycans may correlate with 
allergic reactions to ch14.18 (dinutuximab). Additionally, the levels of anti-glycan 
antibodies may increase after serial courses of ch14.18 (dinutuximab) have been 

  
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administered. The presence and/or level(s) of antibodies to non-human glycans may 
affect the blood levels of ch14.18 (dinutuximab) and ultimately impact the response to 
therapy.  
 
Pre-treatment blood samples from patients treated with ch14.18 (dinutuximab) during 
post-Consolidation on ANBL0032 and ANBL0931 demonstrated high levels of anti-
alpha-gal and anti-Neu5Gc antibodies. (Alice Yu, personal communication, 2018). 
These levels were measured over the course of treatment [continued exposure to 
ch14.18 (dinutuximab)] and were found to decrease over time. Notably, in patients who 
received ch14.18 (dinutuximab), lower levels of both anti-alpha-gal and anti-Neu5Gc 
antibodies at the end of therapy were significantly associated with an improved EFS.53 
In patients with recurrent/refractory neuroblastoma treated with chemo-immunotherapy 
on ANBL1221 (n=14), the anti-glycan levels measured at the beginning and end of 
therapy were stable, but were lower than those detected at the last time point of 
ANBL0032 (Day 118 of Course 5), (Alice Yu personal communication, 2018). The 
significance of this is unknown, but merits further study. There was no association 
between anti-glycan levels and EFS in patients treated on ANBL1221; however power 
was limited due to the small sample size.  
 
ANBL17P1 represents a unique opportunity to evaluate antiglycan levels present in 
patients with newly diagnosed high-risk neuroblastoma and to evaluate the relationship 
between antiglycan levels and response to therapy. The predictive value of this 
biomarker may be dependent on the timing of ch14.18 (dinutuximab) delivery and/or 
the combination of ch14.18 (dinutuximab) with chemotherapy. Anti-alpha-gal and anti-
Neu5Gc antibodies will be collected prior to treatment and at varying time points during 
Induction and post-Consolidation therapy; associations between anti-glycan levels, 
ch14.18 (dinutuximab) half-life, treatment response and toxicity will be evaluated. 
 
2.9.2 
Rationale for NK cell receptor NKp30 isoform 
The natural killer (NK) cell receptor NKp30 is selectively expressed by all human NK-
cells and plays an important role in triggering NK-mediated cytotoxicity. NKp30 is also 
involved in the cross-talk between NK and dendritic cells. The three NKp30 splice 
variants54 have been shown to be of prognostic significance in gastrointestinal stromal 
tumor (GIST), a malignancy that expresses NKp30 ligands and is treated with NK-
stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST 
show distinct transcriptional patterns of functionally different NKp30 isoforms. In 
patients with GIST, predominant expression of the immunosuppressive NKp30c 
isoform (compared to the immunostimulatory NKp30a and NKp30b isoforms) was 
associated with the following: 1) reduced survival, 2) decreased NKp30-dependent 
tumor necrosis factor-α (TNF-α), IL-10 and CD107a release, and 3) defective secretions 
of interferon-γ (IFN-γ) and interleukin-12 (IL-12) in the NK-DC cross-talk that could 
be restored by blocking IL-10.55 A French study reported an association between high 
levels of the immunosuppressive Nkp30c-isoform and inferior outcome in patients with 
high-risk neuroblastoma, (PFS p-value= 0.01). No impact of the Nkp30a-isoform was 
noted.56  
 
Since NK cytotoxicity plays a major role in tumor immunity and specifically in anti-
GD2-mediated neuroblastoma cell kill, the impact of NKp30 isoforms may be more 
pronounced in patients receiving ch14.18 (dinutuximab). On ANBL1221, NKp30 
isoforms were evaluated in 14 patients with refractory/recurrent neuroblastoma who 

  
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received chemoimmunotherapy. Three of the 14 patients evaluated had the 
immunosuppressive (NKp30c) isoform. This small sample size precluded correlative 
analysis. The prognostic significance of NKp30 isoforms is still unknown, but further 
study of NKp30c status may permit identification of patients who will or will not 
respond to chemoimmunotherapy. Therefore, patient samples obtained on ANBL17P1 
will quantify NKp30 isoforms present during Induction and post-Consolidation. Results 
will be correlated with response. 
 
2.9.3 
Rationale for studying the association between host factors and response to protocol 
therapy 
2.9.3.1 
Rationale for KIR/KIR-L genotyping 
Killer-Immunoglobulin-like Receptors (KIR) recognize specific HLA 
molecules, regulate function of human NK cells and control their self-
tolerance. The interactions between KIR on donor NK cells and KIR ligands 
(KIR-L) on recipient tissues influence anti-tumor efficacy in the setting of 
allogeneic hematopoietic stem cell transplantation, and influence the 
antitumor effects of autologous transplantation. Since the genes encoding 
KIR and KIR-L are inherited independently, it is possible for an individual 
to be KIR-receptor ligand mismatched with oneself. In a COG Phase 2 study 
of 38 patients with relapsed/refractory neuroblastoma receiving humanized 
anti-GD2 linked to IL-2, 7 of 24 mismatched patients experienced either 
complete response or improvement in disease status after immunocytokine 
therapy, while there was no response or comparable improvement in disease 
status in 14 patients who were matched (p = 0.03).57 In the larger Phase 3 
ANBL0032 study, KIR status (including the “all KIR-ligands present” 
genotype, inhibitory KIR2DL2 with its ligand (HLA-C1) and inhibitory 
KIR3DL1 with its ligand (HLA-Bw4)) was associated with improved 
outcome if patients received immunotherapy.58 Taken together, these data 
suggest that patients with KIR receptor-ligand mismatch may experience a 
better clinical response to immunotherapy with an anti-GD2 antibody than 
patients without a mismatch. Further investigation of KIR/KIR-ligand 
genotypes may clarify their role in cancer immunotherapy and may enable 
KIR-KIR-ligand genotyping to be used prospectively to identify patients who 
are likely to benefit from chemoimmunotherapy. Therefore, at a single 
timepoint, KIR and KIR-ligand genotyping will be performed on 
ANBL17P1. 
 
2.9.3.2 
Rationale for Fc receptor genotyping 
In general, the anti-tumor activities of unconjugated monoclonal antibodies 
require the contribution of either complement or Fcγ receptor (FcγR)-
expressing effector cells in order to achieve tumor cell killing. However, 
because most tumor cells, including neuroblastoma, express increased 
amounts of complement-inhibiting proteins that protect the cells against lysis 
by complement, antibody-dependent cell-mediated cytotoxicity (ADCC) is 
considered the key antitumor mechanism of therapeutic antibodies in vivo. 
Most natural killer (NK) cells, certain subpopulations of T lymphocytes, as 
well as monocytes and granulocytes are capable of mediating ADCC against 
antibody-coated targets via their expression of FcγR for IgG. The FcγR genes 
display polymorphisms that greatly influence the affinity of IgG for the Fcγ 

  
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receptor. NK cells bearing the FcγRIIIa-158V/V allele mediate ADCC more 
effectively than those with F/F allele. Similarly, for FcγRIIA, the high-
affinity H allele at position 131 results in greater affinity of FcγRIIa for IgG, 
whereas the low-affinity R allele correlates with decreased binding. In 
patients with lymphoma, Fc receptor polymorphisms have been reported to 
influence the response to rituximab whereby patients with the high affinity 
alleles have a better outcome.59,60 While not uniformly reported for all 
analyses, most studies of FcγR genotypes in clinical trials of mAbs that 
mediate ADCC have shown similar associations of better outcome for 
patients with the high affinity alleles (i.e. as for trastuzumab).61  
 
In the setting of neuroblastoma, in a small COG Phase 2 study of 38 patients 
treated with hu14.18-IL-2 (an immunocytokine linking anti-GD2 mAb to 
IL-2), there was evidence for an association between FcRIIA genotype and 
response was seen.57 No association was seen for FcRIIIA in that study. 
However, because only 2 patients had the high affinity genotype, there was 
inadequate statistical power to identify a significant association. Unpublished 
FcR genotype analyses have been performed for 174 neuroblastoma patients 
treated on COG ANBL0032, a randomized Phase 3 trial of ch14.18 
(dinutuximab) + GM-CSF and IL-2.19 When analyzed separately, there was 
no significant association of outcome with FcRIIA status, nor with FcRIIIA 
status (Alice Yu and Mitchell Diccianni, personal communication, 2018). 
FcγR expressing cells were also measured in patients with relapsed/refractory 
neuroblastoma who were treated on a German Phase 2 trial of ch14.18 
(dinutuximab)-beta, given as a 10 day continuous infusion with IL-2.62 In that 
report, Seibert et al found no significant association between outcome 
between either FcR2A or FcRIIIA status individually. However, when an 
algorithm that included both genotypes together was used, the favorable 
combined genotype showed a significant association with outcome (p = 
0.008).62 Thus, there is a need to further evaluate the potential predictive 
nature of FcR genotype for neuroblastoma patients receiving anti-GD2-based 
immunotherapy. 
 
More recently the FcγRIIc molecules have been shown to influence ADCC. 
Polymorphisms at this locus can influence expression vs. lack of expression 
(function vs. lack of function) of this FcγRIIc (expressed on NK cells, 
neutrophils and monocytes/macrophages) and can mediate ADCC. The 
Sondel lab has shown that an algorithm incorporating polymorphism data for 
FcγRIIa, FcγRIIIa and FcγRIIc is more powerful than analyses of individual 
FcR loci or than an algorithm that combines only FcγRIIa, FcγRIIIa.63 Using 
this algorithm, the authors found an association between FcR genotype and 
therapeutic response in an IL-2 immunotherapy trial for adults with renal cell 
carcinoma.64 Because ch14.18 (dinutuximab) is very effective in mediating 
ADCC, its efficacy in neuroblastoma may be associated with Fc receptor 
genotype.  
 
In ANBL17P1 we hypothesize that the strength of the ADCC-immunologic 
effect of combining ch14.18 (dinutuximab) with chemotherapy will be 
greater than that observed during prior trials in which dinutuximab was 
administered without chemotherapy. Further, we hypothesize that the greater 

  
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immunotherapeutic effect will augment the ability to detect an association of 
FcR genotype with therapeutic response. Finally, the 3-gene algorithm, that 
includes FcγRIIc63, will be used to test for an association with outcome 
(response and survival). This method has never been used to analyze data on 
neuroblastoma trials and may identify a potential biomarker of disease 
response.  
 
2.9.3.3 
Rationale for HACA and PATA testing 
Human anti-chimeric antibody (HACA) can develop following exposure to 
ch14.18 (dinutuximab). The identification of a detectible HACA response is 
not necessarily of functional significance. In some studies, the presence of 
anti-therapeutic antibodies (such as HAMA or HACA) have been associated 
with clinical benefit. However, this is not uniformly demonstrated, and the 
mechanistic connection to this observation remains uncertain. Some studies 
have generated data suggesting that the presence of HAMA or HACA may 
be a marker (or potentially a factor in the process) of induction of an 
endogenous host anti-tumor immune response. Even so, most agree that the 
presence of a neutralizing HAMA or HACA is antagonistic to the desired in 
vivo function of the mAb. For this reason, we will seek to identify HACA 
levels that are neutralizing. 
While many in vitro assays can detect whether a HACA+ specimen can 
neutralize an anti-GD2 mAb in vitro, their relevance in vivo remains 
unproven. For this reason, COG investigators have used an “in vivo 
neutralization” approach. Once a HACA response is detected, if subsequent 
courses of ch14.18 (dinutuximab) are associated with a peak ch14.18 
(dinutuximab) level <10% of that predicted, then the HACA response is 
considered to demonstrate “in vivo neutralization”. Of 136 COG patients 
evaluated in ANBL0032, only 11 had detectible HACA and only 6 (4.4%) 
showed evidence of in vivo neutralization. In ANBL17P1 we will determine 
the incidence of overall HACA and in vivo neutralizing HACA during 
Induction cycles (in which patients receive ch14.18 (dinutuximab) with 
chemotherapy), and during post-Consolidation therapy (in which patients 
receive ch14.18 (dinutuximab) with cytokines).  
Analysis of samples from a Phase 1 trial of a humanized anti-GD2 antibody 
(hu14.18K322A) conducted at St. Jude Children’s Research Hospital39 has 
shown that sera obtained prior to therapy from 9 of 38 patients with relapsed 
or refractory neuroblastoma contained Pre-existing Anti-Therapeutic 
Antibodies (PATA) that reacted against the anti-GD2 antibody. Notably, 
these patients had no prior exposure to any monoclonal antibody. Initial 
analyses of the immunologic reactivity pattern of the sera from these 9 
PATA+ patients revealed that these PATA are not anti-idiotypic antibodies 
against the therapeutic hu14.18K322A mAb. Unexpectedly, these PATA 
bound to other human IgG1 mAbs (rituximab, trastuzumab), pooled human 
IgG (Gammagard), and also to the anti-GD2 chimeric antibody ch14.18 
(dinutuximab). However, they did not bind to the parental mouse anti-GD2 
mAb (14.G2a). The presence of PATA may be linked to patient outcome. Of 
the 38 initially evaluable patients with relapsed or refractory disease, only 4 
were known to be in remission or without progression 2.5 years following 

  
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treatment. All 4 of these patients were among the 9 found to have PATA (p= 
0.002). (Paul Sondel, personal communication, 2017) This preliminary 
observation requires further study, however it suggests that these PATA 
recognize a shared IgG1 epitope (also known as an antibody-allotype65 that is 
found on most human IgG1 antibodies, but is “foreign” to the 9 PATA+ 
patients who may have been immunized via exposure to allo-IgG1 in prior 
transfusions). PATA/anti-alloantibodies may augment the efficacy of tumor 
reactive therapeutic antibodies and may represent some of the antibody 
reactivity identified in prior “human anti-chimeric antibody (HACA)” assays. 
An understanding of the role of PATA/anti-allotype biology may aid in the 
selection of patients for GD2-directed immunotherapy. The association 
between results of testing for the presence HACA, anti-idiotype and 
PATA/anti-allotype antibody [not directed against the ch14.18 (dinutuximab) 
idiotype] with response to study therapy will be examined.  
 
2.9.4 
Rationale for studying the immune environment during and following treatment 
2.9.4.1 Rationale for immune function studies 
Understanding the state of the immune effector cells may be crucial to the 
design of future passive immunotherapies for cancer. Specifically, the number 
of NK and NK-T cells, T cell subsets and expression of NK activation and 
inhibitory receptors present in patient blood may have an association with 
clinical responses to immunotherapies, including ch14.18 (dinutuximab). In 
ANBL0032, a pre-immunotherapy expression of NK markers including KIR, 
CD161 and NKp44 was associated with outcome, suggesting that patients with 
NK populations expressing these markers may be most responsive to the 
actions of ch14.18 (dinutuximab). This raises the possibility that these NK 
markers may represent a predictive biomarker of response to ch14.18 
(dinutuximab). However, the number of patient samples available for marker 
analysis in ANBL0032 was small, and it is not known whether marker levels 
prior to Induction will be predictive of outcome. Thus, samples will be obtained 
prior to Induction, and prior to Consolidation therapy on ANBL17P1 to further 
study these issues as part of the process of biomarker evaluation and 
development.  
 
For children with neuroblastoma, cytokine levels and changes in these levels 
throughout 
treatment 
may 
correlate 
with 
therapeutic 
response 
to 
immunotherapy. Cytokines can be released by cancer cells or by cells of the 
tumor microenvironment and have a multitude of effects that either promote 
tumor cell growth or potentiate the effect of immunotherapy.66 Cytokines have 
been associated with outcome in patients with cancer. In particular, elevated 
IL-6 levels at diagnosis have been associated with poor outcome in numerous 
cancers including neuroblastoma.67,68 In ANBL0931, a study of post-
Consolidation immunotherapy in patients with high-risk neuroblastoma, 15 
cytokines/chemokines were measured throughout treatment. Samples were 
obtained during each cycle of immunotherapy. Results showed that patients 
developed significant increases (p < 0.001) in serum levels of IL-6, IL1ra, IFN-
ɣ, IL-10, TNFα, IL5, IL17A, CXCL9, IL15 and nitric oxide when compared to 
baseline levels. However, a low pretreatment (baseline) level of CXCL9 was 
the only cytokine level that was associated with an improved event free survival 
(p = 0.05). Therefore, samples will be obtained on ANBL17P1 to evaluate the 

  
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levels of CXCL9 at baseline and throughout treatment to determine if CXCL9 
levels may be predictive of response. Additionally, since investigators 
identified that the rs1800795 IL-6 promoter SNP is an independent prognostic 
factor for EFS and OS in high-risk neuroblastoma, and since rs1800795 SNP 
has been shown to correlate with the production on IL-6,68 IL-6 levels will also 
be measured at baseline and throughout therapy, and correlation with response 
to therapy will be assessed.  
 
2.9.4.2 Rationale for analysis of gene expression studies 
Expression of immune response related genes may be predictive of ADCC and 
anti-tumor effect in patients treated with ch14.18 (dinutuximab) in combination 
with Induction chemotherapy. Deep sequencing analyses to identify alterations 
in expression of genes related to circulating immune cells may provide 
biological insights and identify biomarkers for response. RNA sequencing 
(RNASeq) will be performed on blood samples obtained at baseline and during 
treatment to evaluate the expression of a panel of genes related to immune 
function (including cell surface receptors, proteases, cytokines and cytokine 
receptors, cell cycle and protein kinases, etc.) and non-immune genes. New 
algorithms (e.g. CIBERSORT) have emerged that allow estimation of immune 
cell presence in tumor and blood through deconvolution of RNAseq expression 
profiles. This technology will be used to assess gene expression from whole 
blood in children being treated with chemo-immunotherapy. 
 
2.9.5 
Rationale for studying the association between, levels of circulating GD2, and GD2 
tumor cell expression with response to therapy 
 
The ganglioside composition of neuroblastoma cells was studied decades ago;69 yet 
much remains unknown about the relationship between the presence of gangliosides on 
neuroblastoma cells (particularly GD2) and response to anti-GD2 based therapy. 
Because serial tumor sampling is not possible in young children receiving 
neuroblastoma therapy, methods for detection of GD2 shed from the surface of 
neuroblastoma cells have been developed. A high performance liquid chromatography 
(HPLC)/tandem mass spectrometry (MS/MS) assay for enhanced detection of GD2 in 
plasma and serum has been validated. Median circulating GD2 concentration in serum 
from 40 children with high-risk neuroblastoma was >30-fold higher than the median 
circulating GD2 concentration in 40 normal controls, and circulating GD2 was elevated 
in all 40 samples from patients with high-risk neuroblastoma. In ANBL17P1, 
circulating GD2 concentrations will be measured at baseline and throughout therapy; 
levels will be correlated with response and outcome. 
 
Circulating GD2 could bind to ch14.18 (dinutuximab) and block its therapeutic effect. We 
will estimate the fraction of circulating ch14.18 (dinutuximab) that is bound to GD2 (r) 
based on the measured circulating GD2 concentration and the previously reported KA 
(association constant) for ch14.18 (dinutuximab) of 3.5 x 108 M-1. The r value will be 
compared in responders and non-responders to determine if antibody binding to circulating 
GD2 influences response. Demonstrating that circulating GD2 can serve as a clinical tumor 
biomarker for neuroblastoma and a surrogate clinical trial endpoint for future clinical trials 
could have a substantial impact on the care of children with neuroblastoma and the design, 
conduct and efficiency of future trials. GD2 expression in tumor samples will be evaluated 

  
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using immunocytochemical (IC) analysis of touch preps of tumors at diagnosis and relapse. 
Immunocytochemical touch preps of bone marrow biopsies and smear slides of bone 
marrow aspirates obtained at diagnosis and at disease evaluation time points will also be 
evaluated. The GD2 IC test will utilize both concurrent staining of Phox2b and GD2 to 
qualitatively assess GD2 expression. The assay has been successfully tested on formalin 
fixed specimens (S. Asgharzadeh, H. Shimada, personal communication, 2018). 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Study Enrollment 
ANBL17P1 will only be open to enrollment at the following 10 institutions: 
 
• 
St. Jude Children’s Research Hospital, Memphis, TN 
• 
Dana-Farber Cancer Institute, Boston, MA 
• 
Children’s Hospital of Los Angeles, Los Angeles, CA 
• 
Primary Children’s Hospital, Salt Lake City, UT 
• 
Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 
• 
Children’s National Medical Center, Washington, DC 
• 
Columbia University/Herbert Irving Cancer Center, New York, NY 
• 
Starship Children’s Hospital, Auckland, New Zealand 
• 
The Children’s Hospital at Westmead, Westmead, NSW, Australia 
• 
Royal Children’s Hospital, Parkville, VIC, Australia 
 
While ANBL17P1 is open and accruing at these trial centers, patients at these centers should 
not enroll onto protocol ANBL1531 until ANBL17P1 is closed to accrual. 
 
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. 
 

  
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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. Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including 
but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
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. 
 
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. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to 
the RSS in an automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRBManager to indicate their 
intent to open the study locally. The CIRB’s approval of the SSW is then communicated 
to the CTSU Regulatory Office. In order for the SSW approval to be processed, the 
Signatory Institution must inform the CTSU which CIRB-approved institutions aligned 
with the Signatory Institution are participating in the study. Other site registration 
requirements (ie, laboratory certifications, protocol-specific training certifications, or 
modality credentialing) must be submitted to the CTSU Regulatory Office or 
compliance communicated per protocol instructions. 
 
3.1.3 
Reservation Requirements 
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 the Oncology Patient Enrollment 

  
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Network (OPEN). Prior to discussing protocol entry with the patient, all site staff must 
use the CTSU OPEN Slot Reservation System to ensure that a slot on the protocol is 
available to the patient. Once a slot- reservation confirmation is obtained, site staff may 
then proceed to enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM 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 ‘SITE – Slot Reservation Quick Reference’ guide posted under the ‘Help’ 
tab in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_QuickRefe
rence_SiteUserGuide_102612.pdf&ftype=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. 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. 
• 
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. 
 

  
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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 
Enrollment on APEC14B1 or ANBL00B1 
Patients must be enrolled on APEC14B1 (if open for the classification of NBL 
patients) or ANBL00B1 prior to enrollment on ANBL17P1.  
 
• 
It is strongly recommended that sites submit tissue on APEC14B1 ((if open 
for the classification of NBL patients) or ANBL00B1 and commence the 
process of enrollment as soon as a diagnosis of high-risk neuroblastoma is 
suspected. 
 
3.1.6 
Timing 
Patients must be enrolled onto APEC14B1 (if open for the classification of NBL 
patients) or ANBL00B1 prior to the time of enrollment on ANBL17P1. Once enrolled 
on APEC14B1 or ANBL00B1, biology results will be entered by the Neuroblastoma 
Reference Lab when available for viewing by the institution. Shortly thereafter, the 
Neuroblastoma Tracking Center will perform the Risk Group Analysis based upon the 
age, stage, and biology results. Risk group assignment will then be made available to 
the institution. In emergency situations (or if in the opinion of the treating physician, it 
is in the patient’s best interest) consent can be obtained and the patient can be enrolled 
on both APEC14B1 or ANBL00B1 and ANBL17P1 on the same day if the patient is 
considered to have high risk neuroblastoma by virtue of BOTH stage (INRG Stage M) 
and age (>547 days) prior to submission of biology results by the Neuroblastoma 
Reference Lab.  
 
For the majority of patients on this study, age > 547 days and the presence of metastatic 
disease are the key criteria for eligibility. For such patients, enrollment is expected to 
take place within 5 days of starting therapy.  
 
• 
For patients with localized disease for whom tumor MYCN status is required to 
determine eligibility, but in whom the index of suspicion for high risk disease 
is high and emergency therapy is clinically indicated, therapy as per 
ANBL17P1 may be initiated. However, consent for ANBL17P1 must be 
obtained prior to start of therapy. Enrollment must take place when MYCN 
amplification has been documented and no later than fourteen (14) calendar 
days from the beginning emergent ANBL17P1 protocol therapy.  
• 
For clinically stable patients initially thought to have non-high risk disease but 
subsequently found to have MYCN amplified tumor, study enrollment must 
occur after recovery from a maximum of one (1) cycle of intermediate risk 
chemotherapy and prior to the start of ANBL17P1 protocol therapy.  
• 
For clinically stable patients > 547 days of age who were initially diagnosed 
with INRG L1 or L2 disease but who progress to Stage M, enrollment must 
take place within 4 weeks of progression to Stage M and prior to the start of 
ANBL17P1 protocol therapy. 
• 
Likewise, clinically stable patients initially diagnosed with MYCN amplified 
INRG L1 disease who develop progression to Stage M must be enrolled within 
4 weeks of progression and prior to the start of ANBL17P1 therapy. 

  
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Patients ≤ 547 days in age with INRG Stage M disease and patients of any age with 
INRG L2 or MS disease will only be eligible for this study if documentation of MYCN 
amplification is entered via APEC14B1 or ANBL00B1. While tracking center 
confirmation of risk group assignment is not required prior to consent and enrollment 
on ANBL17P1, results of MYCN testing through APEC14B1 or ANBL00B1 are 
required for these patients. 
 
When ANBL17P1 enrollment is completed prior to the start of protocol therapy, the 
date protocol therapy is projected to start must be no later than five (5) calendar days 
after enrollment. In the event that an investigator determines that emergency therapy is 
required, protocol therapy may start before enrollment on ANBL17P1. However, 
consent for ANBL17P1 must be obtained prior to start of therapy AND enrollment must 
take place as soon as possible. 
 
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. 
Timing of imaging and assessment of bone marrow status is also indicated in the 
eligibility section below.  
 
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived. All clinical and laboratory data required for determining eligibility of a patient 
enrolled on this trial must be available in the patient's medical/research record which will 
serve as the source document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
must be no older than seven (7) days at the start of therapy. Laboratory tests need not be 
repeated if therapy starts within seven (7) days of obtaining labs to assess eligibility. If a 
post-enrollment lab value is outside 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: 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, with the exception of 123I-MIBG or PET 
scans, and bone marrow aspirates/biopsies must be obtained within 2 weeks prior to start 
of protocol therapy (repeat if necessary). 
 
Note: Baseline 123I-MIBG scans (and PET scans if the subject is found to have MIBG non-
avid disease) must be performed within 14 days prior to or within 14 days after of the start 
of Cycle 1. Baseline audiogram or BAER must also be obtained before the end of Cycle 2. 
 
See Section 4.2 for required studies to be obtained prior to starting protocol therapy. 
 
3.2.1 
Enrollment on ANBL00B1 or APEC14B1 
Patients must be enrolled on ANBL00B1 or APEC14B1 prior to enrollment on 
ANBL17P1. 
 

  
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3.2.2 
Age 
≤ 30 years of age at the time of initial diagnosis. 
 
3.2.3 
Diagnosis 
Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) 
verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone 
marrow with elevated urinary catecholamine metabolites. The following disease groups 
are eligible: 
 
• 
Patients with INRG Stage M disease are eligible if found to have either of the 
following features:  
a) MYCN amplification (> 4-fold increase in MYCN signals as compared to 
reference signals), regardless of age or additional biologic features; OR  
b) Age > 547 days regardless of biologic features;  
 
• 
Patients with INRG Stage MS disease with MYCN amplification  
 
• 
Patients with INRG Stage L2 disease with MYCN amplification  
 
 
• 
Patients > 547 days of age initially diagnosed with INRG Stage L1, L2 or MS 
disease who progress to Stage M without prior chemotherapy may enroll within 
4 weeks of progression to Stage M.  
 
• 
Patients ≥ 365 days of age initially diagnosed with MYCN amplified INRG Stage 
L1 disease who progress to Stage M without systemic therapy may enroll within 
4 weeks of progression to Stage M. 
 
See Appendix II for INRG Staging System. 
 
3.2.4 
Prior Therapy 
Patients initially recognized to have high-risk disease must have had no prior systemic 
therapy (other than topotecan/cyclophosphamide initiated on an emergent basis and 
within allowed timing as described in Section 3.1.6). 
 
Patients observed or treated with a single cycle of chemotherapy per a low or 
intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or 
similar) for what initially appeared to be non-high risk disease but subsequently found 
to meet the criteria in Section 3.2.3 will also be eligible. 
 
Patients who receive localized emergency radiation to sites of life-threatening or 
function-threatening disease prior to or immediately after establishment of the 
definitive diagnosis will be eligible. 
 
3.2.5 
Organ Function Requirements 
3.2.5.1 Adequate renal function defined as: 
Creatinine clearance (CrCl) or radioisotope GFR  70 mL/min/1.73 m2 or a 
serum creatinine based on age/sex as follows: 
 
 

  
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Age 
Maximum Serum 
Creatinine (mg/dL) 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR70 utilizing child length and stature data published by the CDC. 
 
3.2.5.2 Adequate liver function defined as: 
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and 
• SGPT (ALT) < 10 x ULN. For the purposes of this study, ULN for ALT is 
45 IU / L. 
 
3.2.5.3 Adequate cardiac function defined as: 
• Shortening fraction of ≥ 27% by echocardiogram, or 
• Ejection fraction of ≥ 50% by echocardiogram or radionuclide angiogram.  
 
3.2.5.4 Ability to tolerate PBSC Collection 
No known contraindication to PBSC collection. Examples of contraindications 
might be a weight or size less than the collecting institution finds feasible, or a 
physical condition that would limit the ability of the child to undergo apheresis 
catheter placement (if necessary) and/or the apheresis procedure. 
 
3.2.6 
Exclusion Criteria 
3.2.6.1 Patients >18 months of age with INRG Stage L2, MYCN non-amplified, 
regardless of additional biologic features. 
 
3.2.6.2 Patients with bone marrow failure syndromes. 
 
3.2.6.3 Patients that are ≥ 12 and ≤ 18 months of age with INRG Stage M and all 3 
favorable biologic features (i.e., non-amplified MYCN, favorable pathology, 
and DNA index > 1) are not eligible. 
 
3.2.6.4 Patients on immunosuppressive medications (e.g. tacrolimus, cyclosporine, 
corticosteroids for reasons other than prevention/treatment of allergic reactions, 
adrenal replacement therapy, etc.) are not eligible. 
 
3.2.6.5 Pregnancy and Breast Feeding 
3.2.6.5.1 Female patients who are pregnant are ineligible since fetal toxicities and 
teratogenic effects have been noted for several of the study drugs. A 
pregnancy test is required for female patients of childbearing potential. 
 

  
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3.2.6.5.2 Lactating females who plan to breastfeed their infants. 
 
3.2.6.6  Sexually active patients of reproductive potential who have not agreed to use 
an effective contraceptive method during study therapy and for two months 
after the last dose of ch14.18 (dinutuximab) are not eligible. 
 
3.2.7 
Regulatory Requirements  
3.2.7.1 All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.7.2 All institutional, FDA, and NCI requirements for human studies must be met. 
 

  
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4.0 
TREATMENT PLAN 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations 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 newly-diagnosed high-risk neuroblastoma will receive three standard phases of 
treatment including: Induction, Consolidation, and post-Consolidation therapy. The research 
portion of this study includes the addition of ch14.18 (dinutuximab) with sargramostim (GM-
CSF) to Cycles 3-5 of the Induction phase of therapy. The ch14.18 (dinutuximab) used 
throughout this protocol will be provided by CTEP under an IND. Do not use commercial 
supply. 
 
Induction therapy will consist of 5 cycles of chemotherapy, similar to treatment given on 
ANBL12P1 and ANBL1531. Following Induction Cycle 2 of chemotherapy (topotecan and 
cyclophosphamide), peripheral blood stem cells will be harvested. Patients will then receive the 
remaining 3 cycles of Induction chemotherapy with the addition of ch14.18 (dinutuximab) on 
Days 2-5 and sargramostim (GM-CSF) beginning 24 – 48 hours after the completion of ch14.18 
(dinutuximab). Ch14.18 (dinutuximab) will be withheld from Induction until an adequate PBSC 
product (minimum of 4 x 106 CD34+ cells/kg) is obtained for Consolidation therapy. Induction 
chemotherapy Cycles 3 and 5 will include cisplatin and etoposide, Cycle 4 will include 
vincristine, doxorubicin, and cyclophosphamide. Surgical resection of the primary tumor will 
be undertaken after the fourth cycle of chemotherapy as on ANBL09P1, ANBL12P1 and 
ANBL1531. If clinically indicated (e.g. surgeon’s preference), it is permissible for surgery to 
take place after the fifth cycle. 
 
Patients with stable disease or better tumor response at the end of Induction will proceed to 
Consolidation. Consolidation therapy will consist of two sequential cycles of high dose 
chemotherapy with autologous stem cell rescue. Conditioning for the first cycle will consist of 
thiotepa and cyclophosphamide and the second will consist of modified CARBOplatin, 
etoposide, and melphalan as per ANBL0532. Upon recovery from the second cycle, patients 
will undergo external beam radiation to the primary tumor bed and sites of persistent metastatic 
disease detected at the end of Induction. Following a disease evaluation at the end of 
Consolidation, patients with stable disease or better will go on to receive ch14.18 
(dinutuximab)-based post-Consolidation therapy (see Section 4.1.5).  
 
For COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines under Standard 
Sections for Protocols. 
 
4.1.1 
General guidelines for therapy 
 
4.1.1.1 Central line 
All patients will have a central venous line placed to facilitate administration 
of Induction chemotherapy. Appropriate devices for peripheral blood stem cell 
harvest, delivery of high dose chemotherapy with stem cell rescue, and 

  
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administration of immunotherapy will be used per institutional standard 
practice. 
 
Due to the requirement for multiple supportive care medications concurrent 
with ch14.18 (dinutuximab) administration, the number of lumens available for 
venous access should be carefully considered. Many centers use 2 central 
lumens routinely; institutional standards should be followed. Due to 
compatibility issues, it is possible that additional (peripheral) access may be 
required in patients needing narcotics other than morphine (e.g. 
hydromorphone or fentanyl).  
 
4.1.1.2 Stem cell harvest 
Patients will undergo PBSC harvest after Induction Cycle 2 REGARDLESS of 
bone marrow status. See Section 18.0 for additional information. The PBSC 
product will not be manipulated prior to cryopreservation. All patients must 
have a PBSC collection that is sufficient for tandem autologous stem cell 
rescue. 
 
The goal for stem cell collection is therefore 10 - 20 x 106 CD 34 + cells / kg 
divided into 3 separate aliquots. Ch14.18 (dinutuximab) should not be started 
prior to confirmation of adequate PBSC collection. See Section 18.2 for 
guidance regarding the approach to patients from whom adequate PBSC 
collection is not obtained after Cycle 2. Interventions to maximize PBSC 
harvest are strongly recommended given that ch14.18 (dinutuximab) will not 
be administered during Induction until an adequate PBSC collection is 
obtained. 
 
4.1.1.3 Clinical disease progression during Cycles 1 and 2 of Induction 
 
There is no required disease evaluation after Cycle 2 of therapy. All patients 
will proceed to Cycle 3 (cisplatin/etoposide/ch14.18 (dinutuximab)/ 
sargramostim) regardless of disease status, including patients with clinical 
disease progression during topotecan/cyclophosphamide. Disease progression 
during the first two cycles of therapy will be noted, but progressive disease 
(PD) will not be a cause for discontinuation of protocol therapy. Furthermore, 
this will NOT be considered an analytic event during evaluation of data relevant 
to the primary study objectives. 
 
4.1.1.4 Resection of the primary tumor 
Patients will undergo surgical resection of the primary tumor after Induction 
chemotherapy Cycle 4 (or Cycle 5 if medically necessary). Response of the 
primary tumor to therapy must be assessed prior to surgical resection. See 
Section 13.0 for further information regarding surgery. Post-operative 
chemotherapy should begin as soon as possible following surgery. Therapy 
should not be delayed by more than one week after surgery unless 
complications arise. If surgery cannot be scheduled after chemotherapy 
Cycle 4, it should occur after chemotherapy Cycle 5.  
 

  
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4.1.2 
Concomitant Therapy 
The following guidance regarding concomitant therapy pertains primarily to the 
Induction phase of treatment. Additional guidance relevant to Consolidation and post-
Consolidation therapy is detailed in the treatment section for those phases of therapy. 
 
4.1.2.1 Chemotherapy or Immunomodulating Agents 
No other cancer chemotherapy or immunomodulating agents (including 
steroids) will be used. Exception: Dexamethasone may be used as an antiemetic 
for short periods of time around chemotherapy administration only if all other 
antiemetic regimens have been maximized and the patient continues to have 
refractory nausea and vomiting. However, dexamethasone should be avoided 
during Induction Cycles 3-5 (during ch14.18 (dinutuximab) therapy) and 
during post-Consolidation. Corticosteroid therapy is also permitted for 
treatment of increased intracranial pressure or spinal cord compression and for 
immediate treatment of transfusion reactions.  
 
4.1.2.2 External Beam Radiation 
External beam radiotherapy is only permitted in emergency situations during 
Induction. Emergency situations are those that have the potential to result in 
loss of function (spinal cord compression, optic nerve compression). 
 
4.1.2.3 CYP3A4 active agents  
See Appendix III for a list of CYP3A4 active agents. The potential for 
interaction between these agents and the following drugs must carefully 
considered: 
 
VinCRIStine, DOXOrubicin, etoposide 
Strong inducers or inhibitors of CYP3A4 should not be administered with 
vinCRIStine, DOXOrubicin and etoposide if reasonable alternatives exist. 
 
4.1.2.4 Nephro- and ototoxic agents  
Administration of loop diuretics (eg, ethacrynic acid, furosemide, and 
bumetanide) and/or aminoglycosides should be avoided if possible during 
CISplatin-containing cycles of chemotherapy. Concurrent usage may increase 
the risk of nephrotoxicity and ototoxicity. 
 
4.1.2.5 Enzyme inducing anticonvulsants  
Enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and 
carbamazepine) should not be given concurrent with administration of 
vinCRIStine. See Appendix IV.  
 
4.1.3 
Induction Therapy 
Patients will receive 5 cycles of chemotherapy. Each chemotherapy cycle lasts 21 days 
(3 weeks). Chemotherapy cycles EXCEPT Cycle 1 may begin when the ANC ≥ 750/µL 
and platelets ≥ 75,000/µL after post-chemotherapy nadir. There are no hematologic 
criteria to begin Cycle 1. See Section 5.0 for specifics regarding criteria to begin 
Induction chemotherapy cycles in the setting of myelosuppression and for dose 

  
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modifications for toxicity. See Section 18.0 for details regarding the PBSC harvest that 
will occur after Induction Cycle 2, and Section 16.0 for details regarding imaging that 
will occur prior to surgical resection and at end of Induction. Refer to Section 13.0 for 
details regarding the surgical resection that will occur after Induction Chemotherapy 
Cycle 4 (or Cycle 5 if medically necessary). Institutional count recovery criteria for 
surgical resection should be followed. 
4.1.4 
Consolidation Therapy  
Consolidation 
therapy 
includes 
tandem 
transplant 
therapy 
(Thiotepa/Cyclophosphamide and modified CARBOplatin/Etoposide/Melphalan; 
TC/CEM). For further information regarding drug doses, schedules and administration, 
please see the Treatment Details in Sections 4.7 and 4.8. It is recommended that 
Consolidation treatment begin between 4 and 6 weeks from the start date of Induction 
chemotherapy Cycle 5. For patients who have surgical resection delayed until after 
Induction chemotherapy Cycle 5, it is recommended that Consolidation start within 
4 weeks from the date of surgery.  
 
Patients with progressive disease at the end of Induction evaluation (after completion 
of Cycle 5) are NOT eligible to continue on to the Consolidation phase of protocol 
therapy. Other eligibility criteria that must be met prior to starting Consolidation are 
listed in Section 4.6.6. 
 
Restaging will not be performed between transplant cycles. Patients who complete the 
prescribed transplant component of therapy will not be required to undergo a disease 
evaluation prior to radiation therapy unless clinically indicated OR unless > 5 sites of 
metastatic disease were seen on the end-Induction MIBG or PET scan. Such patients 
will undergo repeat imaging to direct radiation therapy. See Section 17.0 for further 
information about radiation decision making for this group of patients. 
 
Following completion of transplant and recovery from transplant related acute 
toxicities, patients will receive 21.6 Gy external beam radiation therapy (EBRT) to the 
primary site regardless of presence or absence of residual primary tumor at end 
Induction.  
 
Patients with residual MIBG (if MIBG avid disease) or PET (if MIBG non-avid disease) 
positive metastases detected on end-Induction disease evaluations will receive 21.6 Gy 
EBRT to address up to and including 5 metastatic sites of disease. Patients with > 5 sites 
of residual metastatic disease detectable on end-Induction MIBG or PET scans will 
undergo repeat MIBG or PET scans (using the same modality used previously) upon 
recovery from HSCT #2. See Section 17.5.2.2 for additional information regarding 
radiation for such patients. 
 
Local radiation therapy will begin no earlier than Day +42 following HSCT #2.See 
Section 18.0 for details regarding HSCT and Section 17.0 for details regarding radiation 
therapy.  
 
4.1.5 
Post-Consolidation Summary 
All patients will receive standard post-Consolidation therapy with ISOtretinoin (ISOT) 
for 6 cycles during post-Consolidation therapy. For the first 5 of those cycles, patients 
will also receive ch14.18 (dinutuximab) combined with sargramostim (GM-CSF).  
 

  
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Induction Cycle 1 
 
4.2 
Induction Cycle 1 
4.2.1   Therapy Delivery Map – INDUCTION CYCLE 1 
Cycle 1 lasts 3 weeks (21 days).  
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Begin Cycle 1 of therapy regardless of blood counts. See Section 5.0 for dose modifications. This TDM is 
on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
Cyclophosphamide 
(CPM) 
IV over  
15-30 minutes  
BSA < 0.6 m2: See Dosing Table 
in Section 4.2.3  
BSA ≥ 0.6 m2: 400 mg/m2/dose 
Days 1-5 
 
Topotecan (TOPO) IV over 30 minutes 
BSA < 0.6 m2: See Dosing Table 
in Section 4.2.3  
BSA ≥ 0.6 m2: 1.2 mg/m2/dose 
Days 1-5 
 
Myeloid Growth 
Factor 
Start myeloid growth factor support 24 – 48 hours after the final dose of chemotherapy: e.g.,  
(1) filgrastim or biosimilar 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the 
expected nadir or until the ANC ≥ 750 if it is ≥ Day 21 of the cycle: or, (2) pegfilgrastim 
(0.1 mg/kg SubQ once; maximum dose 6 mg). Filgrastim should be discontinued for at least 
24 hours before the start of the Cycle 2. If pegfilgrastim is used, the next chemotherapy cycle 
should start at least 14 days after pegfilgrastim administration. 
 
 
 
 Ht _________ cm 
Wt 
 _________kg BSA _________m2 
Date 
Due 
Date 
Given 
Day 
CPM 
____mg 
TOPO 
____mg 
Myeloid growth factor used: 
_______ 
Calc. dose___________  
Studies 
 
 
 
Enter calculated dose above 
and actual dose administered 
below 
Start Date 
Stop Date 
 
 
 
1 
______mg 
_____mg 
 
 a-p 
 
 
2 
______mg 
_____mg 
 
  
 
 
3 
______mg 
_____mg 
 
  
 
 
4 
______mg 
_____mg 
 
  
 
 
5 
______mg 
_____mg 
 
  
 
 
6 
 
 
 
 p 
 
 
7 
 
 
 
  
 
 
8 
 
 
 
 b, c 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 b, c 
 
 
 
 
 
 
 
 
 
 
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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Induction Cycle 1 
4.2.2 
Required Observations in Induction Cycle 1 
 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
 
a. Physical exam, height, weight 
b. CBC with differential and platelets 
c. Electrolytes, BUN, creatinine, magnesium, phosphorous 
d. ALT, AST, total bilirubin 
e. Free T4, TSH 
f. Urinalysis 
g. Pregnancy test (obtain for females of childbearing potential) 
h. GFR or creatinine clearance (obtain if serum creatinine is above maximum for 
age and sex) 
i. ECG 
j. ECHO or MUGA 
k. Audiogram or BAER (may be obtained during Cycle 1 or 2 of therapy) 
l. Cross sectional tumor imaging (MRI or CT) (submit for central review) 
m. 123I-MIBG scan – may be obtained during the first or second week of Cycle 1 
(submit for central review) 
n. FDG-PET/CT or PET/MR scan for patients with 123I-MIBG non-avid disease - 
may be obtained during the first or second week of Cycle 1. Submit for central 
review. 
o. Bilateral bone marrow aspirates and biopsies 
p. Specimens for correlative studies (see Section 15 and Appendix V for specimen 
requirements) 
 
 
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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Page 41 
Induction Cycle 1 
4.2.3 
Treatment Details for Induction Cycle 1 (3 weeks = 1 cycle)  
 
Cyclophosphamide: IV over 15-30 minutes  
Days: 1-5 
Dose: For BSA ≥ 0.6 m2 the dose of cyclophosphamide is 400 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of cyclophosphamide in the 
table is expressed as final dose in mg to be administered. 
 
 
 
 
 
 
 
 
 
 
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 
 
Topotecan: IV over 30 minutes  
Days: 1-5 
Dose: For BSA ≥ 0.6 m2 the dose of topotecan is 1.2 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of topotecan in the table is 
expressed as final dose in mg to be administered. 
 
Topotecan 
BSA (m2) 
Dose 
0.25-0.29 
0.32 mg 
0.3-0.34 
0.38 mg 
0.35-0.39 
0.44 mg 
0.4-0.44 
0.5 mg 
0.45-0.49 
0.56 mg 
0.5-0.54 
0.62 mg 
0.55-0.59 
0.68 mg 
 
Myeloid Growth Factors: 
During Induction Cycle 1, cytokine support can include filgrastim or biosimilar or 
pegfilgrastim. Filgrastim or biosimilar should be administered at a dose of 
5 mcg/kg/dose SubQ once daily. Pegfilgrastim should be administered at a dose 
0.1 mg/kg/dose (maximum dose 6 mg) SubQ ONCE according to institutional 
standard guidelines. Choice of myeloid growth factor must be recorded 
appropriately in the therapy delivery maps. Myeloid growth factors should be 
started 24 – 48 hours after the final dose of chemotherapy. If filgrastim or 
biosimilar is used, it should be continued until the ANC ≥ 2000/µL following the 
nadir. Discontinue filgrastim or biosimilar a minimum of 24 hours prior to 
Cyclophosphamide 
BSA (m2) 
Dose 
0.25-0.29 
68 mg 
0.3-0.34 
100 mg 
0.35-0.39 
124 mg 
0.4-0.44 
148 mg 
0.45-0.49 
180 mg 
0.5-0.54 
200 mg 
0.55-0.59 
220 mg 

  
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Induction Cycle 1 
administration of the next chemotherapy cycle. If the ANC has recovered to 
≥ 750/μL by Day 21, but has not yet reached ≥ 2000, discontinue filgrastim and 
proceed to Cycle 2. If pegfilgrastim is used, the next chemotherapy cycle should 
start at least 14 days after pegfilgrastim administration. 
 
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 for Toxicities. 

  
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Induction Cycle 2 
 
4.3 
Induction Cycle 2 
4.3.1 
Therapy Delivery Map – INDUCTION CYCLE 2 
Cycle 2 lasts 3 weeks (21 days).  
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Begin Cycle 2 on Day 22 of Induction Cycle 1 or when peripheral counts recover with ANC ≥ 750/µL and 
platelets ≥ 75,000/µL (whichever occurs later). For instructions regarding discontinuation of myeloid 
growth factor see Section 4.3.3. See Section 5.0 for dose modifications and for modification in timing of 
therapy for patients with delayed count recovery. Peripheral blood stem cells will be harvested as counts 
recover after Cycle 2. See Section 18.0 for information regarding stem cell harvest. This TDM is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
Cyclophosphamide 
(CPM) 
IV over  
15-30 minutes  
BSA < 0.6 m2: See Dosing Table 
in Section 4.3.3  
BSA ≥ 0.6 m2: 400 mg/m2/dose 
Days 1-5 
 
Topotecan (TOPO) IV over 30 minutes 
BSA < 0.6 m2: See Dosing Table 
in Section 4.3.3  
BSA ≥ 0.6 m2: 1.2 mg/m2/dose 
Days 1-5 
 
Myeloid Growth 
Factor 
Start filgrastim or biosimilar 5-10 mcg/kg/dose SubQ daily 24 – 48 hours after the final dose 
of chemotherapy. Follow Section 18.2 and institutional guidelines for use of growth factors 
prior to stem cell apheresis. Filgrastim should be discontinued at least 24 hours before the 
start of the next cycle. Do NOT administer pegfilgrastim during Cycle 2.  
 
 
 
 Ht _________ cm 
Wt 
 _________kg BSA _________m2 
Date 
Due 
Date 
Given 
Day 
CPM 
____mg 
TOPO 
____mg 
Myeloid growth factor used: 
_______ 
Calc. dose___________  
Studies 
 
 
 
Enter calculated dose above 
and actual dose administered 
below 
Start Date 
Stop Date 
 
 
 
1 
______mg 
_____mg 
 
 a-f 
 
 
2 
______mg 
_____mg 
 
  
 
 
3 
______mg 
_____mg 
 
  
 
 
4 
______mg 
_____mg 
 
  
 
 
5 
______mg 
_____mg 
 
  
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 b, c 
 
 
 
 
 
 
 
 
 
 
15 
PBSC Harvest as counts 
recover 
See Section 18.3 
 
 b, c 
 
 
 
 
 
 
 
 
 
22 
Begin Cycle 3 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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Induction Cycle 2 
4.3.2 
Required Observations in Induction Cycle 2 
 
a. Physical exam, height, weight 
b. CBC with differential and platelets 
c. Electrolytes, BUN, creatinine 
d. ALT, AST, total bilirubin 
e. Urinalysis 
f. Audiogram or BAER: If not obtained during Cycle 1. Must be obtained prior to 
Cycle 3. 
 
 
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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Induction Cycle 2 
4.3.3 
Treatment Details for Induction Cycle 2 (3 weeks = 1 cycle)  
 
Cyclophosphamide: IV over 15-30 minutes  
Days: 1-5 
Dose: For BSA ≥ 0.6 m2 the dose of cyclophosphamide is 400 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of cyclophosphamide in the 
table is expressed as final dose in mg to be administered. 
 
 
 
 
 
 
 
 
 
 
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 
 
Topotecan: IV over 30 minutes  
Days: 1-5 
Dose: For BSA ≥ 0.6 m2 the dose of topotecan is 1.2 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of topotecan in the table is 
expressed as final dose in mg to be administered. 
 
Topotecan 
BSA (m2) 
Dose 
0.25-0.29 
0.32 mg 
0.3-0.34 
0.38 mg 
0.35-0.39 
0.44 mg 
0.4-0.44 
0.5 mg 
0.45-0.49 
0.56 mg 
0.5-0.54 
0.62 mg 
0.55-0.59 
0.68 mg 
 
Myeloid Growth Factors: 
Start myeloid growth factor support once daily after myelosuppressive 
chemotherapy. Pegfilgrastim is NOT permitted during Induction Cycle 2. See 
Section 18 for recommendations regarding use of growth factors and stem cell 
harvest. 
 
Cycle 2 chemotherapy is administered in the same manner as that administered in 
Cycle 1. However, the dose of filgrastim following Cycle 2 may be larger 
(5- 10 mcg/kg/day) in anticipation of apheresis, per institutional guidelines. As 
with Cycle 1, filgrastim will start 24-48 hours after the final dose of chemotherapy. 
Cyclophosphamide 
BSA (m2) 
Dose 
0.25-0.29 
68 mg 
0.3-0.34 
100 mg 
0.35-0.39 
124 mg 
0.4-0.44 
148 mg 
0.45-0.49 
180 mg 
0.5-0.54 
200 mg 
0.55-0.59 
220 mg 

  
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Induction Cycle 2 
Peripheral blood stem cells are to be harvested as counts recover after Cycle 2. See 
Section 18.2 for additional details. 
 
See Section 5.0 for Dose Modifications for Toxicities.

  
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Induction Cycle 3 
4.4 
Induction Cycle 3 
4.4.1 
Induction Therapy Cycle 3: CISplatin, Etoposide, Ch14.18 
(Dinutuximab), and Sargramostim (GM-CSF) 
Cycle 3 lasts 3 weeks (21 days).  
                    
 _______________________
 COG Patient ID Number
 _____________ 
 
DOB 
Start Cycle 3 once peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later). Drugs should 
be given in the order listed below (see Section 4.4.3 for a summary of the schedule). See Section 5.0 for dose modification for organ 
dysfunction. This TDM is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
CISplatin 
(CDDP) 
IV over 1 hour 
BSA < 0.6 m2: See Dosing Table in Section 
4.4.3 
BSA ≥ 0.6 m2: 60 mg/m2/dose 
1-3 
Avoid use of dexamethasone during Cycle 3 of 
Induction therapy. See Section 4.4.3 for hydration and 
antiemetic recommendations. 
Etoposide 
(ETOP) 
IV over 2 hours 
BSA < 0.6 m2: See Dosing Table in Section 
4.4.3 
BSA ≥ 0.6 m2: 200 mg/m2/dose 
1-3 
 
Ch14.18 
(Dinutuximab) 
 
 
 
 
IV over 10 hrs† 
 
†The infusion 
duration may be 
extended up to 
20 hours if 
needed. 
17.5 mg/m2/dose  
See admin guidelines in Section 4.4.3. 
2-5 
Ch14.18 (dinutuximab) should not be started prior 
to confirmation of adequate PBSC collection (see 
Section 18. 2. and 4.4.3). 
 
For premedication and supportive care, see Section 
4.4.4. 
 
Prior to the first dose of ch14.18 (dinutuximab), 
patients should not have dyspnea at rest or an oxygen 
requirement (see Section 4.4.3).  
Sargramostim 
(GM-CSF) 
SubQ  
250 micrograms/m2/dose  
6 or 7 - 
nadir 
Start sargramostim 24-48 hours after the completion of 
Day 5 ch14.18 (dinutuximab). See Section 4.4.3 for 
more details. 
 
Sargramostim should not be started prior to 
confirmation of adequate PBSC collection (see Section 
18.2 and 4.4.3). 
 
If sargramostim and ch14.18 (dinutuximab) are not 
administered, start myeloid growth factor as outlined 
in Section 4.4.3. 
 
 
 
Ht_____cm 
    Wt____kg 
     BSA____m2 
Due Date 
Date 
Given 
Day 
CDDP 
____mg 
ETOP 
____mg 
Ch14.18 
_____mg 
GM-CSF 
____mcg 
Cycle 3 Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
______mg 
_____mg 
 
 
a-d, e if indicated, f 
 
 
2 
______mg 
_____mg 
____mg 
 
c* 
 
 
3 
______mg 
_____mg 
____mg 
 
c* 
 
 
4 
 
 
____mg 
 
c* 
 
 
5 
 
 
____mg 
 
c* 
 
 
6 
 
 
 
____mcg 
b, f 
 
 
7 
 
 
 
____mcg 
 
 
 
8 
 
 
 
____mcg 
b, c 
 
 
9 
 
 
 
____mcg 
 
 
 
10 
 
 
 
____mcg 
 
 
 
11 
 
 
 
____mcg 
 
 
 
12 
 
 
 
____mcg 
 
 
 
13 
 
 
 
____mcg 
 
 
 
14 
 
 
 
____mcg 
 
 
 
15 
 
 
 
____mcg 
b, c 
 
 
16 
 
 
 
____mcg 
 
 
 
17 
 
 
 
____mcg 
 
 
 
18 
 
 
 
____mcg 
 
 
 
19 
 
 
 
____mcg 
 
 
 
20 
 
 
 
____mcg 
 
 
 
21 
 
 
 
____mcg 
 
 
 
22 
Begin the next cycle on Day 22 or when starting criteria are met, whichever occurs later (see Section 4.5.1). 
*Only required on Days 2-5 if ch14.18 (dinutuximab) is administered. See Section 5.0 for Dose Modifications for 
Toxicities and the COG Member website for Supportive Care Guidelines. 
 
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Induction Cycle 3 
4.4.2 
Required Observations in Induction Cycle 3  
 
a. Physical exam, height, weight 
b. CBC with differential and platelets 
c. Electrolytes, BUN, creatinine, magnesium, phosphorus 
d. ALT, AST, total bilirubin 
e. GFR or Creatinine Clearance (obtain if serum creatinine is above maximum for 
age/sex or if serum creatinine increases to > 2 x baseline ) 
f. Correlative studies (see Section 15 and Appendix V for specimen requirements) 
 
 
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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Induction Cycle 3 
4.4.3 
Treatment Details for Induction Therapy for Cycle 3 
Begin therapy as early in the day as possible.  
 
A summary of drug administration schedule for Days 1-5 is below. 
Day 1: 
1. CISplatin will be administered following pre-hydration. 
2. Etoposide will be administered immediately after CISplatin, during post-
CISplatin hydration. 
 
Days 2 & 3: 
1. CISplatin will be administered first, followed by post-hydration. 
2. Etoposide will be administered immediately after CISplatin, during post-
CISplatin hydration. 
3. The ch14.18 (dinutuximab) infusion will be started immediately after 
completion of etoposide, during post-CISplatin hydration. 
 
Days 4 & 5: 
1. The ch14.18 (dintuximab) infusion will be started approximately 24 hours 
after the start of the prior ch14.18 (dinutuximab) dose. 
 
 
CISplatin: IV over 1 hour. Protect from light.  
Days: 1-3 
Dose: For BSA ≥ 0.6 m2 the dose of CISplatin is 60 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of CISplatin in the table is 
expressed as final dose in mg to be administered. 
 
 
 
 
 
 
 
 
 
 
Special precautions: Avoid use of aluminum containing needles or administration 
sets, since aluminum interacts with CISplatin causing black precipitate formation 
and loss of potency. The infusion solution should include at least 0.2% sodium 
chloride. To avoid precipitation, CISplatin solutions should not be refrigerated. 
CISplatin is incompatible with sodium bicarbonate and alkaline solutions. 
Accidental extravasation with solutions that are > 0.5 mg/mL may result in 
significant tissue toxicity. 
 
Medication errors have occurred due to confusion between CISplatin 
(Platinol®) and CARBOplatin (PARAplatin®). 
 
Antiemetics may be used as needed. Dexamethasone and other corticosteroids 
SHOULD NOT BE GIVEN unless clinically indicated. Since dexamethasone is 
CISplatin 
BSA (m2) 
Dose 
0.25-0.29 
10 mg 
0.30-0.34 
14 mg 
0.35-0.39 
18 mg 
0.40-0.44 
22 mg 
0.45-0.49 
26 mg 
0.50-0.54 
30 mg 
0.55-0.59 
34 mg 

  
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Induction Cycle 3 
discouraged [due to administration of ch14.18 (dinutuximab)], recommend 
maximizing antiemetics as suggested below. 
 
Refer to institutional standards or use the following recommended antiemetic 
regimen: 
• Ondansetron 0.15 mg/kg IV q8hrs (max 8 mg/dose); may consider another 5HT3 
antagonist 
• Diphenhydramine 0.5 mg/kg – 1 mg/kg IV q8hr (max 50 mg/dose) – begin 
4 hours after 1st dose of ondansetron  
• Lorazepam 0.04 mg/kg IV q8hr (max 2 mg/dose)  
• Aprepitant 3 mg/kg (max 125 mg/dose) 1 hour prior to chemotherapy on Day 1 
then 2 mg/kg (max 80 mg/dose) on Days 2 and 3. Do not use in patients 
< 6 months of age and/or < 6 kg. 
 
Cisplatin Hydration and Fluid Status Monitoring Recommendations 
Patients may receive aggressive pre- and post-CISplatin hydration IV fluids per 
institutional guidelines. The following IV fluid rate(s) and fluid status monitoring 
are recommended. The routine use of diuretics during Days 2-5 is contraindicated 
unless clinically required (i.e. pulmonary capillary leak with respiratory 
compromise). 
 
Day 1 Pre-Hydration:  
• 
A pre-hydration rate of 125 mL/m2/hr overnight (prior to Day 1) or a rapid 
pre-hydration rate of 150-200 mL/m2/hr for at least 2 hours AND 
• 
Urine output of at least 1.5 mL/kg/hr for patients weighing < 70 kg or 
• 
Urine output of at least 100 mL/hr in patients who weigh ≥ 70 kg  
• 
Continue fluid rate throughout the Day 1 CISplatin infusion.  
 
Day 1 Post-Hydration:  
• 
Following completion of Day 1 CISplatin, continue the fluid rate at 
125 mL/m2/hr 
• 
Continue until 24 hours after the completion of the last (Day 3) CISplatin 
infusion.  
 
Day 4 Post-Hydration (24 hours after the Day 3 CISplatin infusion): 
• 
Decrease the IV fluid rate to 90 mL/m2/hr 
• 
Continue fluids at this rate until the completion of the final ch14.18 
(dinutuximab) infusion.  
• 
Hydration fluids may contain supplemental magnesium, calcium, and 
potassium to decrease acute electrolyte losses associated with CISplatin 
therapy.  
 
Fluid Status Monitoring: 
The patient’s fluid status (intake and output) should be monitored closely while 
receiving therapy. Patients are at risk for capillary leak related to ch14.18 
(dinutuximab). Patients have known decreased urine output during ch14.18 
(dinutuximab) therapy. The routine use of diuretics during Days 2-5 is 
contraindicated unless clinically required (i.e. pulmonary capillary leak with 
respiratory compromise).  
 

  
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Induction Cycle 3 
For post-CISplatin monitoring, it is recommended that electrolytes be monitored 
daily and urine output (UOP) of ≥ 1 mL/kg/hr for patients < 70 kg or ≥ 100 mL/hr 
for patients ≥ 70 kg until 24 hours after the last dose of CISplatin be maintained. 
If the UOP is < 1 mL/kg/hr, may administer a bolus of 10 mL/kg of 0.9% NaCl. If 
the UOP remains < 1 mL/kg/hr, a second bolus of 10 mL/kg of 0.9% NaCl is 
recommended. If the UOP remains low, check electrolytes BID and consider 
administering a dose of mannitol. Given the concerns with ototoxicity and 
nephrotoxicity associated with CISplatin and furosemide, exercise caution and 
check chemistries twice a day if furosemide is administered. 
 
Etoposide: IV over 2 hours  
Days: 1-3 
Dose: For BSA ≥ 0.6 m2 the dose of etoposide is 200 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of etoposide in the table is 
expressed as final dose in mg to be administered. 
 
 
 
 
 
 
 
 
 
 
 
Infuse diluted solution (concentration ≤ 0.4 mg/mL) over 120 minutes; slow rate 
of administration if hypotension occurs. The use of an in-line filter during the 
infusion is suggested.  
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of 
large volumes of D5W due to potential development of hyponatremia.  
 
Stability: Leaching of diethylhexyl phthalate (DEHP) from PVC bags occurred 
with etoposide 0.4 mg/mL in 0.9% NaCl solution. To avoid leaching, prepare the 
etoposide solution as close as possible, preferably within 4 hours, to the time of 
administration or alternatively as per institutional policy. Glass or polyethylene-
lined (non-PVC) containers and polyethylene-lined tubing may be used. 
 
Ch14.18 (dinutuximab): IV over 10 hours* 
Days: 2 through 5 
Dose: 17.5 mg/m2/dose. 
 
Ch14.18 (dinutuximab) should not be started prior to confirmation of 
adequate PBSC collection (see Section 18.2). If an adequate PBSC collection 
(minimum of 4 x 106 CD34+ cells/kg) has not been obtained, then ch14.18 
(dinutuximab) and sargramostim should not be administered. Instead, myeloid 
growth factor will be given after the completion of CISplatin and etoposide as 
described in Cycle 2, see Sections 4.3.1 and 4.3.3. 
 
Etoposide 
BSA (m2) 
Dose 
0.25-0.29 
34 mg 
0.3-0.34 
48 mg 
0.35-0.39 
60 mg 
0.4-0.44 
72 mg 
0.45-0.49 
88 mg 
0.5-0.54 
100 mg 
0.55-0.59 
112 mg 

  
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Induction Cycle 3 
Note: Due to the increased risk of capillary leak and respiratory compromise with 
ch14.18 (dinutuximab) administration, patients should not have dyspnea at rest or 
an oxygen requirement when starting the first dose of ch14.18 (dinutuximab). 
Every effort should be made to give ch14.18 (dinutuximab) as ordered. Treatment 
may be delayed for up to one week for patients who have developed a new 
requirement for supplemental oxygen (due to an intercurrent illness or the like) 
prior to the start of a cycle of ch14.18 (dinutuximab)-containing Induction therapy. 
If the patient continues to have clinically significant respiratory symptoms (such 
as dyspnea or hypoxemia) after the one week delay and the treating team feels that 
the patient is ready to start the next cycle of Induction therapy, then dinutuximab 
should be omitted from that cycle of Induction therapy. Close monitoring of 
patients with prior bulky thoracic disease, pleural effusions or concurrent upper 
respiratory viral infections is recommended as these patients are at risk of 
developing respiratory compromise. Before starting ch14.18 (dinutuximab), 
please obtain a copy of management recommendations for anaphylaxis and 
hypotension (see Appendix VI) and the study training module on the COG website. 
It is recommended that these be available on the inpatient unit to facilitate 
treatment decisions should these symptoms of respiratory compromise occur. 
 
Refer to Section 4.4.4 for premedication and supportive care for the prevention of 
anticipated toxicities associated with ch14.18 (dinutuximab), and for monitoring 
during the ch14.18 (dinutuximab) infusion. Additional information can be found 
in Appendix VI. 
 
On Day 2, start ch14.18 (dinutuximab) immediately following the completion of 
CISplatin and etoposide. Run the ch14.18 (dinutuximab) concurrently with post-
hydration fluids as outlined above. On Days 2 and 3, ch14.18 (dinutuximab) will 
be administered concurrently with a higher rate of post-chemotherapy hydration 
fluids. Once the post-chemotherapy hydration fluids are complete, it is 
recommended that intravenous fluids (IVF) continue at a maintenance rate through 
the completion of the Day 5 ch14.18 (dinutuximab) infusion. The ch14.18 
(dinutuximab) should be started at a rate of 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 ch14.18 (dinutuximab) 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 ch14.18 (dinutuximab) antibody has not been 
delivered. Ch14.18 (dinutuximab) 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 ch14.18 (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 
Days: 6 or 7 through nadir until the ANC is ≥ 2000/L or until counts have 
recovered for the next cycle of therapy 
Dose: 250 micrograms/m2/dose  

  
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Induction Cycle 3 
 
Start sargramostim 24-48 hours after the completion of Day 5 ch14.18 
(dinutuximab). The sargramostim start day may fall on Day 6 or Day 7 of therapy. 
 
If ch14.18 (dinutuximab) is not administered, sargramostim will not be 
administered either. Instead, myeloid growth factor will be given as described in 
Cycle 2, see Sections 4.3.1 and 4.3.3. 
 
Of note, the sargramostim dose will be held if the total white blood 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 blood 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 for Toxicities.  
 
4.4.4 
Premedication and Supportive Care for the prevention of anticipated toxicities 
associated with ch14.18 (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: 
o IV hydration: Post-chemotherapy hydration IVF will run concurrently 
with ch14.18 (dinutuximab) on Days 2 and 3. When post-chemotherapy 
hydration fluids have finished, recommend decreasing IVF to maintenance 
rate. Continue IVF at maintenance rate with Days 4 and 5 ch14.18 
(dinutuximab). Consider administering NS 20 mL/kg IV over 1 hour just 
prior to the ch14.18 (dinutuximab) infusion on Days 4 and 5. 
o Diphenhydramine 1 mg/kg/dose (maximum 50 mg) IV/PO 20 minutes 
prior to ch14.18 (dinutuximab) infusion and scheduled q6h. Hydroxyzine 
PO 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 
ch14.18 (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 ch14.18 (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 ch14.18 (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 ch14.18 
(dinutuximab) infusion without difficulty, may consider removing the 
continuous infusion rate in between ch14.18 (dinutuximab) doses (when 
ch14.18 (dinutuximab) is not infusing). 
o Recommended starting dose of analgesics:  
▪ Morphine 0.1 mg/kg/dose 20 minutes prior to initiation of ch14.18 
(dinutuximab) infusion. At the same time, start a continuous morphine 

  
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Induction Cycle 3 
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 ch14.18 (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 q15 
minutes prn for pain.  
▪ If fentanyl PCA is used, recommend fentanyl 1 microgram/kg 10 
minutes prior to starting ch14.18 (dinutuximab) infusion. At the same 
time, start a continuous fentanyl infusion of 0.5 microgram/kg/hr with 
bolus doses of 0.25 microgram/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 ch14.18 (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 ch14.18 (dinutuximab) infusion: 
• 
Check vital signs every 15 minutes for the first hour; if stable check vitals 
hourly until ch14.18 (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 ch14.18 (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). Given the concerns with ototoxicity and nephrotoxicity 
associated with CISplatin and furosemide, exercise caution and check 
chemistries twice a day if furosemide is administered. 
 

  
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Induction Cycle 3 
• 
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 ch14.18 (dinutuximab) treatment and 1 week after completing ch14.18 
(dinutuximab) therapy. 
 
 
Cytokines or growth factors (G-CSF, Interferon, etc.) not included in the 
Treatment Plan are prohibited during immunotherapy. 

  
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Induction Cycle 4 
4.5 
Induction Cycle 4 
4.5.1 Therapy Delivery Map –INDUCTION CYCLE 4 
Cycle 4 lasts 3 weeks (21 days). This TDM is on 3 pages. 
___________________ 
_______ 
Patient COG ID number 
   DOB  
Begin Cycle 4 on Day 22 of the prior cycle or as soon as the peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever 
occurs later). Drugs should be given in the order listed below (see Section 4.5.3 for a summary of the schedule). See Section 5.0 for dose 
modification for organ dysfunction. Note that surgical resection will take place following recovery from Cycle 4 chemotherapy.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
VinCRIStine 
(VCR) 
IV push over 1 minute or 
infusion via minibag per 
institutional policy. 
BSA < 0.6 m2: See Dosing Table 
Section 4.5.3 
BSA ≥ 0.6 m2: 2 mg/m2/dose 
1 
Maximum dose: 2 mg. 
Dexrazoxane (DXR) 
Slow IV push or infusion 
over 5-15 minutes 
BSA < 0.6 m2: See Dosing Table in 
Section 4.5.3 
BSA ≥ 0.6 m2: 375 mg/m2/dose 
1-2 
Administer immediately before 
DOXO  
DOXOrubicin 
(DOXO) 
Slow IV push or infusion 
over 1-15 minutes 
BSA < 0.6 m2: See Dosing Table in 
Section 4.5.3 
BSA ≥ 0.6 m2: 37.5 mg/m2/dose  
1-2 
Administer within 30 minutes of 
beginning the dexrazoxane infusion 
Mesna 
IV (short or  
continuous infusion) 
BSA < 0.6 m2: See Section 4.5.3  
BSA ≥ 0.6 m2: 400 mg/m2/dose  x 5 
doses / day 
1-2 
See Section 4.5.3. If given as a 
continuous infusion, please indicate in 
documentation.  
Cyclophosphamide 
(CPM) 
IV over 1 hour 
BSA < 0.6 m2: See Dosing Table in 
Section 4.5.3 
BSA ≥ 0.6 m2: 2000 mg/m2/dose  
1-2 
 
Ch14.18 
(dinutuximab) 
 
 
 
 
IV over 10 hrs† 
 
†The infusion duration 
may be extended up to 
20 hours if needed. 
17.5 mg/m2/dose  
See admin guidelines in Section 4.5.3. 
2-5 
Ch14.18 (dinutuximab) should not 
be started prior to confirmation of 
adequate 
PBSC 
collection 
(see 
Section 18. 2. and 4.5.3). 
 
For premedication and supportive 
care, see Section 4.5.4. 
 
Patients should not have dyspnea at 
rest or an oxygen requirement (see 
Section 4.5.3). 
Sargramostim  
(GM-CSF) 
SubQ  
250 micrograms/m2/dose  
6 or 7 
- nadir 
Start sargramostim 24-48 hours after 
the completion of Day 5 ch14.18 
(dinutuximab) (see Section 4.5.3). 
 
Sargramostim should not be started 
prior to confirmation of adequate 
PBSC collection (see Section 18.2 and 
4.5.3).  
 
If sargramostim and ch14.18 
(dinutuximab) are not administered, 
start myeloid growth factor as 
outlined in Section 4.5.3. 
 
This TDM is continued on the next page. 
 
Page 1 of 3 

  
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Induction Cycle 4 
Page 2 of 3 
 
4.5.1 Therapy Delivery Map –INDUCTION CYCLE 4 - Continued 
Cycle 4 lasts 3 weeks (21 days). This TDM is on 3 pages. 
___________________ 
_______ 
Patient COG ID number 
   DOB  
Begin Cycle 4 on Day 22 of the prior cycle or as soon as the peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever 
occurs later). Drugs should be given in the order listed below (see Section 4.5.3 for a summary of the schedule). See Section 5.0 for dose 
modification for organ dysfunction. Note that surgical resection will take place following recovery from Cycle 4 chemotherapy.  
 
Ht _________ 
cm 
Wt 
 _________kg 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
 
DXR 
____mg 
DOXO 
____mg 
Mesna 
 
CPM 
____mg 
 
Ch14.18 
____mg   
GM-CSF 
____mcg  
 
Studies 
___mg 
___mg 
___mg 
___mg 
___mg 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
 
1 
_____mg 
_____mg 
_____mg 
___mg 
___mg 
___mg 
___mg 
___mg 
______mg 
 
 
 
a-e, g 
 
 
2 
 
_____mg 
_____mg 
___mg 
___mg 
___mg 
___mg 
___mg 
 
______mg 
 
____mg 
 
c* 
 
 
3 
 
 
 
 
 
____mg 
 
c* 
 
 
4 
 
 
 
 
 
____mg 
 
c* 
 
 
5 
 
 
 
 
 
____mg 
 
c* 
 
 
6 
 
 
 
 
 
 
____mcg 
b, g 
 
 
7 
 
 
 
 
 
 
____mcg 
 
 
 
8 
 
 
 
 
 
 
____mcg 
b, c 
 
 
9 
 
 
 
 
 
 
____mcg 
 
 
 
10 
 
 
 
 
 
 
____mcg 
 
 
 
11 
 
 
 
 
 
 
____mcg 
 
 
 
12 
 
 
 
 
 
 
____mcg 
 
 
 
13 
 
 
 
 
 
 
____mcg 
 
 
 
14  
 
 
 
 
 
 
____mcg 
 
 
 
15 
 
 
 
 
 
 
____mcg 
b, c, f, g 
 
 
16 
 
 
 
 
 
 
____mcg 
 
 
 
17 
 
 
 
 
 
 
____mcg 
 
 
 
18 
 
 
 
 
 
 
____mcg 
 
 
 
19 
 
 
 
 
 
 
____mcg 
 
 
 
20 
 
 
 
 
 
 
____mcg 
 
 
 
21 
 
 
 
 
 
 
____mcg 
 
 
 
22 
Proceed to surgery after Cycle 4 and obtain correlative studies samples as per Appendix V. Begin Cycle 
5 upon recovery from surgery. If surgery is delayed until after Cycle 5, begin Cycle 5 chemotherapy 
when counts recover (ANC ≥ 750/µL and platelets ≥ 75,000/µL) and obtain correlative studies samples 
pre- and post-surgery 
 
*Only required on Days 2-5 if ch14.18 (dinutuximab) is administered. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines.  

  
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Induction Cycle 4 
 
4.5.2 
Required Observations in Induction Cycle 4 
 
a. Physical exam, height, weight 
b. CBC with differential and platelets 
c. Electrolytes, BUN, creatinine 
d. ALT, AST, total bilirubin 
e. Urinalysis 
f. Cross sectional imaging of primary site (MRI or CT) – perform between Days 15 
and 21 (pre-surgery). 
g. Correlative studies (see Section 15 and Appendix V) 
 
 
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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Induction Cycle 4 
4.5.3 
Treatment Details for Induction Cycle 4  
Begin therapy as early in the day as possible.  
 
A summary of drug administration schedule for Days 1 - 5 is below. 
Day 1: 
1. VinCRIStine should be administered first. 
2. Dexrazoxane should then be administered, followed immediately by 
doxorubicin. 
3. Doxorubicin should be administered within 30 minutes of beginning the 
dexrazoxane infusion. 
4. Mesna should then be administered. The initial dose of mesna may be 
administered 
15 minutes 
before 
or 
at 
the 
same 
time 
as 
cyclophosphamide dose; subsequent doses are given 3, 6, 9, and 
12 hours after the start of cyclophosphamide. 
5. Cyclophosphamide should be administered over 1 hour. 
 
Day 2: 
1. Dexrazoxane should be administered first, followed immediately by 
doxorubicin. 
2. Doxorubicin should be administered within 30 minutes of beginning the 
dexrazoxane infusion. 
3. Mesna should then be administered. The initial dose of mesna may be 
administered 
15 minutes 
before 
or 
at 
the 
same 
time 
as 
cyclophosphamide dose; subsequent mesna doses are given 3, 6, 9, and 
12 hours after the start of cyclophosphamide. 
4. Cyclophosphamide should be administered over 1 hour. 
5. The ch14.18 (dinutuximab) infusion should be started immediately after 
cyclophosphamide is completed and should infuse concurrently with 
post-chemotherapy hydration. 
 
Days 3 - 5: 
1. The dintuximab infusion will be started approximately 24 hours after the 
start of the Day 2 ch14.18 (dinutuximab) dose. Intravenous fluids should 
continue at a maintenance rate throughout the duration of the ch14.18 
(dinutuximab) infusion. 
 
 
 

  
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Induction Cycle 4 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy  
Day: 1 
Dose: For BSA ≥ 0.6 m2 the dose of vinCRIStine is 2 mg/m2/dose. The max 
dose of vinCRIStine is 2 mg. 
 
For BSA < 0.6 m2, please see table below. The dose of vinCRIStine in the table 
is expressed as final dose in mg to be administered. 
 
VinCRIStine 
BSA (m2) 
Dose 
0.25-0.29 
0.32 mg 
0.3-0.34 
0.46 mg 
0.35-0.39 
0.6 mg 
0.4-0.44 
0.72 mg 
0.45-0.49 
0.85 mg 
0.5-0.54 
1 mg 
0.55-0.59 
1.1 mg 
 
Administer vinCRIStine prior to dexrazoxane. 
 
Special precautions: FOR INTRAVENOUS USE ONLY. 
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine 
and vinBLAStine. 
 
Dexrazoxane: Slow IV push or IV given over 5-15 minutes immediately 
prior to administration of DOXOrubicin 
Days: 1 and 2 
Dose: For BSA ≥ 0.6 m2 the dose of dexrazoxane is 375 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of dexrazoxane in the table 
is expressed as final dose in mg to be administered. 
 
Dexrazoxane 
BSA (m2) 
Dose 
0.25-0.29 
66 mg 
0.3-0.34 
92 mg 
0.35-0.39 
120 mg 
0.4-0.44 
140 mg 
0.45-0.49 
160 mg 
0.5-0.54 
180 mg 
0.55-0.59 
200 mg 
 
 

  
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Induction Cycle 4 
 
DOXOrubicin: IV Slow IV push or given over 1-15 minutes immediately 
after dexrazoxane administration. 
Days: 1 and 2 
Dose: For BSA ≥ 0.6 m2 the dose of DOXOrubicin is 37.5 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of DOXOrubicin in the table 
is expressed as final dose in mg to be administered. 
 
DOXOrubicin 
BSA (m2) 
Dose 
0.25-0.29 
6.6 mg 
0.3-0.34 
9.2 mg 
0.35-0.39 
12 mg 
0.4-0.44 
14 mg 
0.45-0.49 
16 mg 
0.5-0.54 
18 mg 
0.55-0.59 
20 mg 
 
IV push/short infusion: Administer after dexrazoxane at a concentration not to 
exceed 2 mg/mL by slow IV push or infusion over 15 minutes. It is suggested 
that DOXOrubicin be administered through the tubing of rapidly infusing 
solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Administer DOXOrubicin after completing the infusion of dexrazoxane but 
within 30 minutes of beginning the dexrazoxane infusion.  
 
Mesna: IV (short or continuous infusion; start after completion of 
vinCRIStine, dexrazoxane, and DOXOrubicin)  
Days: 1-2 
Dose:  
BSA < 0.6 m2: Total dose of mesna per day is equal to the total daily 
cyclophosphamide dose divided into 5 equal doses given at the same time or 
15 min prior to cyclophosphamide and again at  3, 6, 9, and 12 hours from the 
start of cyclophosphamide infusion.  
 
BSA ≥ 0.6 m2: 400 mg/m2/dose x 5 doses per day given at the same time or 
15 min prior to cyclophosphamide and again at  3, 6, 9, and 12 hours from the 
start of cyclophosphamide infusion.  
 
IV short or continuous infusion: For prophylaxis of hemorrhagic cystitis, the 
total daily mesna dose is equal to 100% of the daily cyclophosphamide dose. 
Mesna can be administered in 5 divided doses by short infusion over 15 to 
30 minutes. The initial bolus dose of mesna may be administered 15 minutes 
before or at the same time as cyclophosphamide dose; subsequent doses are 
given 3, 6, 9, and 12 hours after the start of cyclophosphamide.  
  
For example: if cyclophosphamide dose is 1,000 mg, then the total daily mesna 
dose is 1,000 mg; 200 mg of mesna will be given 15 minutes before or with the 
cyclophosphamide dose (Hour 0) and 4 boluses of 200 mg each will be given at 
Hours 3, 6, 9 and 12. 
  

  
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Induction Cycle 4 
This total daily dose of mesna can also be administered as IV continuous 
infusion. The continuous infusion should be started 15-30 minutes before or at 
the same time as cyclophosphamide and finished no sooner than 12 hours after 
the end of the cyclophosphamide infusion.  
 
Cyclophosphamide: IV over 1 hour 
Days: 1 and 2 
Dose: For BSA ≥ 0.6 m2 the dose of cyclophosphamide is 2000 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of cyclophosphamide in the 
table is expressed as final dose in mg to be administered. 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
Hydration 
and 
Fluid 
Status 
Monitoring 
Recommendations: 
Patients may receive pre- and post-cyclophosphamide hydration IV fluids per 
institutional guidelines. The following IV fluid rate(s) and fluid status 
monitoring are recommended. The routine use of diuretics during Days 2-5 is 
contraindicated unless clinically required (i.e. pulmonary capillary leak with 
respiratory compromise). 
 
Day 1 Pre-Hydration:  
• 
A pre-hydration rate of 125 mL/m2/hr for a minimum of two hours AND 
• 
Urine specific gravity ≤ 1.010 prior to the start of cyclophosphamide 
 
Day 1 Post-Hydration:  
• 
Following completion of Day 1 cyclophosphamide, continue the fluid 
rate at 125 mL/m2/hr 
• 
Continue until 24 hours after the completion of the last 
cyclophosphamide infusion.  
 
Day 3 Post-Hydration (24 hours after the Day 2 cyclophosphamide infusion): 
• 
Decrease the IV fluid rate to 90 mL/m2/hr 
• 
Continue fluids at this rate until the completion of the final ch14.18 
(dinutuximab) infusion.  
 
Fluid Status Monitoring: 
The patient’s fluid status (intake and output) should be monitored closely while 
receiving therapy. Patients are at risk for capillary leak related to ch14.18 
(dinutuximab). Patients have known decreased urine output during ch14.18 
(dinutuximab) therapy. The routine use of diuretics during Days 2-5 is 
Cyclophosphamide 
BSA (m2) 
Dose 
0.25-0.29 
360 mg 
0.3-0.34 
480 mg 
0.35-0.39 
600 mg 
0.4-0.44 
720 mg 
0.45-0.49 
880 mg 
0.5-0.54 
1000 mg 
0.55-0.59 
1100 mg 

  
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Induction Cycle 4 
contraindicated unless clinically required (i.e. pulmonary capillary leak with 
respiratory compromise).  
 
For post-cyclophosphamide monitoring, it is recommended that electrolytes be 
monitored daily and urine output (UOP) of ≥ 1 mL/kg/hr for patients < 70 kg or 
≥ 100 mL/hr for patients ≥ 70 kg until 24 hours after the last dose of 
cyclophosphamide be maintained. If the UOP is < 1 mL/kg/hr, may administer 
a bolus of 10 mL/kg of 0.9% NaCl. If the UOP remains < 1 mL/kg/hr, a second 
bolus of 10 mL/kg of 0.9% NaCl is recommended. If the UOP remains low, 
check electrolytes BID and consider administering a diuretic.  
 
Ch14.18 (dinutuximab): IV over 10 hours* 
Days: 2 through 5 
Dose: 17.5 mg/m2/dose. 
 
Ch14.18 (dinutuximab) should not be started prior to confirmation of 
adequate PBSC collection (see Section 18.2). If an adequate PBSC collection 
(minimum of 4 x 106 CD34+ cells/kg) has not been obtained, then ch14.18 
(dinutuximab) and sargramostim should not be administered. Instead, myeloid 
growth factor will be given after completion of vincristine, DOXOrubicin, 
cyclophosphamide therapy as described in Cycle 2, see Sections 4.3.1 and 4.3.3. 
 
Note: Due to the increased risk of capillary leak and respiratory compromise 
with ch14.18 (dinutuximab) administration, patients should not have dyspnea at 
rest or an oxygen requirement when starting the first dose of ch14.18 
(dinutuximab). Every effort should be made to give ch14.18 (dinutuximab) as 
ordered. Treatment may be delayed for up to one week for patients who have 
developed a new requirement for supplemental oxygen (due to an intercurrent 
illness or the like) prior to the start of a cycle of ch14.18 (dinutuximab)-
containing Induction therapy. If the patient continues to have clinically 
significant respiratory symptoms (such as dyspnea or hypoxemia) after the one 
week delay and the treating team feels that the patient is ready to start the next 
cycle of Induction therapy, then dinutuximab should be omitted from that cycle 
of Induction therapy. Close monitoring of patients with prior bulky thoracic 
disease, pleural effusions or concurrent upper respiratory viral infections is 
recommended as these patients are at risk of developing respiratory compromise. 
Before starting ch14.18 (dinutuximab), please obtain a copy of management 
recommendations for anaphylaxis and hypotension (See Appendix VI) 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 of 
respiratory compromise occur. 
 
Refer to Section 4.5.4 for premedication and supportive care for the prevention 
of anticipated toxicities associated with ch14.18 (dinutuximab), and for 
monitoring during the ch14.18 (dinutuximab) infusion. Additional information 
can be found in Appendix VI. 
 
Ch14.18 
(dinutuximab) 
should 
be 
administered 
immediately 
after 
cyclophosphamide has been given, as early in the day as possible. Ch14.18 
(dinutuximab) will be administered concurrently with a higher rate of post-
chemotherapy hydration fluids on Day 2. Once post-chemotherapy hydration 
fluids are complete, it is recommended that intravenous fluids (IVF) continue at 

  
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Induction Cycle 4 
a maintenance rate through the completion of the Day 5 ch14.18 (dinutuximab) 
infusion. The ch14.18 (dinutuximab) should be started at a rate of 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 ch14.18 (dinutuximab) 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 ch14.18 (dinutuximab) antibody has not been 
delivered. Ch14.18 (dinutuximab) 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 ch14.18 
(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 (GM-CSF): Subcutaneous injection 
Days: 6 or 7 through nadir until the ANC is ≥ 2000/μL after the expected nadir 
or until Day 21. May discontinue if ANC >750 on Day 21. 
Dose: 250 mcg/m2/dose  
 
Start sargramostim 24-48 hours after the completion of Day 5 ch14.18 
(dinutuximab). The sargramostim start day may fall on Day 6 or Day 7 of 
therapy. 
 
If ch14.18 (dinutuximab) is not administered, sargramostim will not be 
administered either. Instead, myeloid growth factor will be given as described in 
Cycle 2, see Sections 4.3.1 and 4.3.3. 
 
Of note, the sargramostim dose will be held if the total white blood 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 blood 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.  
 
Following Cycle 4, patients will receive surgery followed by Induction Cycle 5. 
If clinically indicated, it is permissible for surgery to take place after the fifth 
cycle of Induction. 
 
See Section 5.0 for Dose Modifications for Toxicities.  
 
4.5.4 
Premedication and Supportive Care for the prevention of anticipated toxicities 
associated with ch14.18 (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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o IV hydration: Post-chemotherapy hydration IVF will run concurrently 
with Day 2 ch14.18 (dinutuximab). When post-chemotherapy hydration 
fluids have finished, recommend decreasing IVF to maintenance rate. 
Continue IVF at maintenance rate with Days 3, 4 and 5 ch14.18 
(dinutuximab). Consider administering NS 20 mL/kg IV over 1 hour just 
prior to the ch14.18 (dinutuximab) infusion on Days 4 and 5. 
o Diphenhydramine 1 mg/kg/dose (maximum 50 mg) IV/PO 20 minutes 
prior to ch14.18 (dinutuximab) infusion and scheduled q6h. 
Hydroxyzine PO 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 
ch14.18 (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 ch14.18 (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 ch14.18 (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 ch14.18 
(dinutuximab) infusion without difficulty, may consider removing the 
continuous infusion rate in between ch14.18 (dinutuximab) doses [when 
ch14.18 (dinutuximab) is not infusing]. 
o Recommended starting dose of analgesics:  
▪ Morphine 0.1mg/kg/dose 20 minutes prior to initiation of ch14.18 
(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 ch14.18 (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 ch14.18 (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 ch14.18 (dinutuximab) infusion: 
a. Albuterol and oxygen 
b. Epinephrine  

  
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c. Hydrocortisone: Use only for life-threatening reactions (hypotension, 
bronchospasm, angioedema involving the airway) not responsive to 
other measures.  
 
Monitoring during the ch14.18 (dinutuximab) infusion: 
• 
Check vital signs every 15 minutes for the first hour; if stable check 
vitals hourly until ch14.18 (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 ch14.18 (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). Given the concerns with ototoxicity and nephrotoxicity 
associated with furosemide, exercise caution and check chemistries twice a 
day if furosemide is administered. 
 
• 
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 ch14.18 (dinutuximab) treatment and 1 week after completing 
ch14.18 (dinutuximab) therapy. 
 
 
• 
Cytokines or growth factors (G-CSF, Interferon, etc.) not included in the 
Treatment Plan are prohibited during immunotherapy. 
 
 
 

  
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Induction Cycle 5 
4.6 
Induction Therapy Cycle 5 
4.6.1 
Induction Therapy Cycle 5: CISplatin, Etoposide, Ch14.18 
(Dinutuximab), and Sargramostim (GM-CSF) 
This cycle lasts 3 weeks (21 days).  
                    
 _______________________
 COG Patient ID Number
 _____________ 
 
DOB   
Begin Cycle 5 when counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL AND upon recovery from surgery or Day 22 
(whichever occurs later). Drugs should be given in the order listed below (see Section 4.6.3 for a summary of the schedule). See 
Section 5.0 for dose modification for organ dysfunction. This TDM is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
CISplatin 
(CDDP) 
IV over 1 hour 
BSA < 0.6 m2: See Dosing Table in 
Section 4.6.3 
BSA ≥ 0.6 m2: 60 mg/m2/dose 
1-3 
Avoid use of dexamethasone during Cycle 5 
of Induction therapy. See Section 4.6.3 for 
hydration and antiemetic recommendations. 
Etoposide 
(ETOP) 
IV over 2 
hours 
BSA < 0.6 m2: See Dosing Table in 
Section 4.6.3 
BSA ≥ 0.6 m2: 200 mg/m2/dose 
1-3 
 
Ch14.18 
(dinutuximab) 
 
 
 
 
IV over 10 hrs† 
 
†The infusion 
duration may 
be extended up 
to 20 hours if 
needed. 
17.5 mg/m2/dose  
See admin guidelines in Section 4.6.3. 
2 – 5 
For premedication and supportive care, see 
Section 4.6.4. 
 
Prior to the first dose of ch14.18 (dinutuximab), 
patients should not have dyspnea at rest or an 
oxygen requirement (see Section 4.6.3). 
Sargramostim 
(GM-CSF) 
SubQ  
250 micrograms/m2/dose  
6 or 7 
- nadir 
Start sargramostim 24-48 hours after the 
completion of Day 5 ch14.18 (dinutuximab) 
(see Section 4.6.3). 
 
 
 
Ht_____cm 
    Wt____kg 
     BSA____m2 
Due 
Date 
Date 
Given 
Day 
CDDP 
____mg 
ETOP 
____mg 
Ch14.18 
_____mg 
GM-CSF 
____mcg 
Cycle 5 Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
______mg 
_____mg 
 
 
a-d, e if indicated, n 
 
 
2 
______mg 
_____mg 
____mg 
 
c 
 
 
3 
______mg 
_____mg 
____mg 
 
c 
 
 
4 
 
 
____mg 
 
c 
 
 
5 
 
 
____mg 
 
c 
 
 
6 
 
 
 
____mcg 
n 
 
 
7 
 
 
 
____mcg 
 
 
 
8 
 
 
 
____mcg 
b, c 
 
 
9 
 
 
 
____mcg 
 
 
 
10 
 
 
 
____mcg 
 
 
 
11 
 
 
 
____mcg 
 
 
 
12 
 
 
 
____mcg 
 
 
 
13 
 
 
 
mcg 
 
 
 
14 
 
 
 
____mcg 
 
 
 
15 
 
 
 
____mcg 
b, c 
 
 
16 
 
 
 
____mcg 
 
 
 
17 
 
 
 
____mcg 
 
 
 
18 
 
 
 
____mcg 
 
 
 
19 
 
 
 
____mcg 
 
 
 
20 
 
 
 
____mcg 
 
 
 
21 
 
 
 
____mcg 
a - n 
 
 
22 
Begin Consolidation when criteria in Section 4.6.6 are met. 
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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Induction Cycle 5 
4.6.2 
Required Observations in Induction Cycle 5  
 
a. Physical exam, height, weight 
b. CBC with differential and platelets 
c. Electrolytes, BUN, creatinine, calcium, magnesium, phosphorous 
d. ALT, AST, total bilirubin 
e. GFR or creatinine clearance (due at end Induction for all patients; due at start of 
Cycle 5 if serum creatinine is above maximum for age/sex or if serum 
creatinine increases to > 2 x baseline) 
f. Pregnancy test (obtain for females of childbearing potential) 
g. ECG 
h. ECHO or MUGA  
i. Audiogram or BAER 
j. Cross sectional tumor imaging (MRI or CT) (submit for central review) 
k. 
123I-MIBG scan if MIBG-avid disease at baseline (submit for central review) 
l. FDG-PET/CT or PET/MR scan if obtained and positive for disease at baseline 
(submit for central review) 
m. Bilateral bone marrow aspirates and biopsies (submit for central review per 
Section 14.2) 
n. Correlative studies (see Section 15 and Appendix V) 
 
Disease evaluation may be performed after the completion of Induction therapy 
(chemotherapy and resection of the primary tumor), between Day 17 of Cycle 5 
and prior to the start of Consolidation. 
 
 
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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Induction Cycle 5 
4.6.3 
Treatment Details for Induction Therapy for Cycle 5 
Begin therapy as early in the day as possible.  
 
A summary of drug administration schedule for Days 1-5 is below. 
Day 1: 
1. CISplatin will be administered first following pre-hydration. 
2. Etoposide will be administered immediately after CISplatin, during 
post-CISplatin hydration. 
 
Days 2 & 3: 
1. CISplatin will be administered first, followed by post-hydration. 
2. Etoposide will be administered immediately after CISplatin, during 
post-CISplatin hydration. 
3. The ch14.18 (dinutuximab) infusion will be started immediately after 
completion of etoposide, during post-CISplatin hydration. 
 
Days 4 & 5: 
1. The dintuximab infusion will be started approximately 24 hours after the 
start of the prior ch14.18 (dinutuximab) dose. 
 
 
CISplatin: IV over 1 hour. Protect from light.  
Days: 1-3 
Dose: For BSA ≥ 0.6 m2 the dose of CISplatin is 60 mg/m2/dose.  
 
For BSAs < 0.6 m2, please see table below. The dose of CISplatin in the table is 
expressed as final dose in mg to be administered. 
 
 
 
 
 
 
 
 
 
 
Special precautions: Avoid use of aluminum containing needles or 
administration sets, since aluminum interacts with CISplatin causing black 
precipitate formation and loss of potency. The infusion solution should include 
at least 0.2% sodium chloride. To avoid precipitation, CISplatin solutions should 
not be refrigerated. CISplatin is incompatible with sodium bicarbonate and 
alkaline solutions. Accidental extravasation with solutions that are > 0.5 mg/mL 
may result in significant tissue toxicity. 
 
Medication errors have occurred due to confusion between CISplatin 
(Platinol®) and CARBOplatin (PARAplatin®). 
 
Antiemetics 
Antiemetics may be used as needed. Dexamethasone and other corticosteroids 
SHOULD NOT BE GIVEN unless clinically indicated. Since dexamethasone is 
CISplatin 
BSA (m2) 
Dose 
0.25-0.29 
10 mg 
0.30-0.34 
14 mg 
0.35-0.39 
18 mg 
0.40-0.44 
22 mg 
0.45-0.49 
26 mg 
0.50-0.54 
30 mg 
0.55-0.59 
34 mg 

  
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discouraged [due to administration of ch14.18 (dinutuximab)], recommend 
maximizing antiemetics as suggested below. 
 
Refer to institutional standards or use the following recommended antiemetic 
regimen: 
• Ondansetron 0.15 mg/kg IV q8hrs (max 8 mg/dose); may consider other 5HT3 
antagonist 
• Diphenhydramine 0.5 mg/kg – 1 mg/kg IV q8hr (max dose 50 mg/dose) – begin 
4 hours after 1st dose of ondansetron  
• Lorazepam 0.04 mg/kg IV q8hr (max 2 mg/dose)  
• Aprepitant 3 mg/kg (max 125 mg/dose) 1 hour prior to chemotherapy on Day 
1 then 2 mg/kg (max 80 mg/dose) on Days 2 and 3. Do not use in patients 
< 6 months of age and/or < 6 kg 
 
Cisplatin Hydration and Fluid Status Monitoring Recommendations 
Patients may receive aggressive pre- and post-CISplatin hydration IV fluids per 
institutional guidelines. The following IV fluid rate(s) and fluid status 
monitoring are recommended. The routine use of diuretics during Days 2-5 is 
contraindicated unless clinically required (i.e. pulmonary capillary leak with 
respiratory compromise). 
 
Day 1 Pre-Hydration:  
• 
A pre-hydration rate of 125 mL/m2/hr overnight (prior to Day 1) or a 
rapid pre-hydration rate of 150-200 mL/m2/hr for at least 2 hours AND 
• 
Urine output of at least 1.5 mL/kg/hr for patients weighing < 70 kg or 
• 
Urine output of at least 100 mL/hr in patients who weigh ≥ 70 kg  
• 
Continue fluid rate throughout the Day 1 CISplatin infusion.  
 
Day 1 Post-Hydration:  
• 
Following completion of Day 1 CISplatin, continue the fluid rate at 
125 mL/m2/hr 
• 
Continue until 24 hours after the completion of the last (Day 3) CISplatin 
infusion.  
 
Day 4 Post-Hydration (24 hours after the Day 3 CISplatin infusion): 
• 
Decrease the IV fluid rate to 90 mL/m2/hr 
• 
Continue fluids at this rate until the completion of the final ch14.18 
(dinutuximab) infusion.  
• 
Hydration fluids may contain supplemental magnesium, calcium, and 
potassium to decrease acute electrolyte losses associated with CISplatin 
therapy.  
 
Fluid Status Monitoring: 
The patient’s fluid status (intake and output) should be monitored closely while 
receiving therapy. Patients are at risk for capillary leak related to ch14.18 
(dinutuximab). Patients have known decreased urine output during ch14.18 
(dinutuximab) therapy. The routine use of diuretics during Days 2-5 is 
contraindicated unless clinically required (i.e. pulmonary capillary leak with 
respiratory compromise).  
 

  
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For post-CISplatin monitoring, it is recommended that electrolytes be monitored 
daily and urine output (UOP) of ≥ 1 mL/kg/hr for patients < 70 kg or 
≥ 100 mL/hr for patients ≥ 70 kg until 24 hours after the last dose of CISplatin 
be maintained. If the UOP is < 1 mL/kg/hr, may administer a bolus of 10 mL/kg 
of 0.9% NaCl. If the UOP remains < 1 mL/kg/hr, a second bolus of 10 mL/kg of 
0.9% NaCl is recommended. If the UOP remains low, check electrolytes BID 
and consider administering a dose of mannitol. Given the concerns with 
ototoxicity and nephrotoxicity associated with CISplatin and furosemide, 
exercise caution and check chemistries twice a day if furosemide is administered. 
 
Etoposide: IV over 2 hours 
Days: 1-3 
Dose: For BSA ≥ 0.6 m2 the dose of etoposide is 200 mg/m2/dose.  
 
For BSA < 0.6 m2, please see table below. The dose of etoposide in the table is 
expressed as final dose in mg to be administered. 
 
 
 
 
 
 
 
 
 
 
 
Infuse diluted solution (concentration ≤ 0.4 mg/mL) over 120 minutes; slow rate 
of administration if hypotension occurs. The use of an in-line filter during the 
infusion is suggested.  
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use 
of large volumes of D5W due to potential development of hyponatremia.  
 
Stability: Leaching of diethylhexyl phthalate (DEHP) from PVC bags occurred 
with etoposide 0.4 mg/mL in 0.9% NaCl solution. To avoid leaching, prepare 
the etoposide solution as close as possible, preferably within 4 hours, to the time 
of administration or alternatively as per institutional policy. Glass or 
polyethylene-lined (non-PVC) containers and polyethylene-lined tubing may be 
used. 
 
Ch14.18 (dinutuximab): IV over 10 hours* 
Days: 2 through 5 
Dose: 17.5 mg/m2/dose. 
 
Note: Due to the increased risk of capillary leak and respiratory compromise 
with ch14.18 (dinutuximab) administration, patients should not have dyspnea at 
rest or an oxygen requirement when starting the first dose of ch14.18 
(dinutuximab). Every effort should be made to give ch14.18 (dinutuximab) as 
ordered. Treatment may be delayed for up to one week for patients who have 
developed a new requirement for supplemental oxygen (due to an intercurrent 
Etoposide 
BSA (m2) 
Dose 
0.25-0.29 
34 mg 
0.3-0.34 
48 mg 
0.35-0.39 
60 mg 
0.4-0.44 
72 mg 
0.45-0.49 
88 mg 
0.5-0.54 
100 mg 
0.55-0.59 
112 mg 

  
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Induction Cycle 5 
illness or the like) prior to the start of a cycle of ch14.18 (dinutuximab)-
containing Induction therapy. If the patient continues to have clinically 
significant respiratory symptoms (such as dyspnea or hypoxemia) after the one 
week delay and the treating team feels that the patient is ready to start the next 
cycle of Induction therapy, then dinutuximab should be omitted from that cycle 
of Induction therapy. Close monitoring of patients with prior bulky thoracic 
disease, pleural effusions or concurrent upper respiratory viral infections is 
recommended as these patients are at risk of developing respiratory compromise. 
Before starting ch14.18 (dinutuximab), please obtain a copy of management 
recommendations for anaphylaxis and hypotension (see Appendix VI) 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 of 
respiratory compromise occur. 
 
Refer to Section 4.6.4 for premedication and supportive care for the prevention 
of anticipated toxicities associated with ch14.18 (dinutuximab), and for 
monitoring during the ch14.18 (dinutuximab) infusion. Additional information 
can be found in Appendix VI. 
 
On Day 2, start ch14.18 (dinutuximab) immediately following the completion of 
CISplatin and etoposide. Run the ch14.18 (dinutuximab) concurrently with post-
hydration fluids as outlined above. On Days 2 and 3, ch14.18 (dinutuximab) will 
be administered concurrently with a higher rate of post-chemotherapy hydration 
fluids on Days 2 and 3. Once the post-chemotherapy hydration fluids are 
complete, it is recommended that IVF continue at a maintenance rate through the 
completion of the Day 5 ch14.18 (dinutuximab) infusion. The ch14.18 
(dinutuximab) should be started at a rate of 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 ch14.18 (dinutuximab) 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 ch14.18 (dinutuximab) antibody has not been 
delivered. Ch14.18 (dinutuximab) 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 ch14.18 
(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 
Days: 6 or 7 through nadir until the ANC is ≥ 2000/L or until counts have 
recovered for the next cycle of therapy 
Dose: 250mcg/m2/dose  
 
Start sargramostim 24-48 hours after the completion of Day 5 ch14.18 
(dinutuximab). The sargramostim start day may fall on Day 6 or Day 7 of 
therapy. 
 

  
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Induction Cycle 5 
Of note, the sargramostim dose will be held if the total white blood 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 blood 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 for Toxicities.  
 
4.6.4 
Premedication and Supportive Care for the prevention of anticipated toxicities 
associated with ch14.18 (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: 
o IV hydration: Post-chemotherapy hydration IVF will run concurrently 
with ch14.18 (dinutuximab) on Days 2 and 3. When post-chemo 
hydration fluids have finished, recommend decreasing IVF to 
maintenance rate. Continue IVF at maintenance rate with Days 4 and 5 
ch14.18 (dinutuximab). Consider administering NS 20 mL/kg IV over 1 
hour just prior to the ch14.18 (dinutuximab) infusion on Days 4 and 5. 
o Diphenhydramine 1 mg/kg/dose (maximum 50 mg) IV/PO 20 minutes 
prior to ch14.18 (dinutuximab) infusion and scheduled q6h. 
Hydroxyzine PO 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 
ch14.18 (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 ch14.18 (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 ch14.18 (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 ch14.18 
(dinutuximab) infusion without difficulty, may consider removing the 
continuous infusion rate in between ch14.18 (dinutuximab) doses (when 
ch14.18 (dinutuximab) is not infusing). 
o Recommended starting dose of analgesics:  
▪ Morphine 0.1mg/kg/dose 20 minutes prior to initiation of ch14.18 
(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 ch14.18 (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.  

  
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▪ If fentanyl PCA is used, recommend fentanyl 1 mcg/kg 10 minutes 
prior to starting ch14.18 (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 ch14.18 (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 ch14.18 (dinutuximab) infusion: 
• 
Check vital signs every 15 minutes for the first hour; if stable check 
vitals hourly until ch14.18 (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 ch14.18 (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). Given the concerns with ototoxicity and nephrotoxicity 
associated with CISplatin and furosemide, exercise caution and check 
chemistries twice a day if furosemide is administered. 
 
• 
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.  
 

  
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Page 75 
Induction Cycle 5 
• 
The use of IVIG is discouraged. IVIG should not be given within 2 weeks 
of starting ch14.18 (dinutuximab) treatment and 1 week after completing 
ch14.18 (dinutuximab) therapy. 
 
 
• 
Cytokines or growth factors (G-CSF, Interferon, etc.) not included in the 
Treatment Plan are prohibited during immunotherapy. 
 
4.6.6 
Criteria to Start Consolidation Therapy  
It is recommended that Consolidation therapy should begin between 4 and 
6 weeks after the start of Induction chemotherapy Cycle 5. In addition, patients 
must meet the criteria below: 
• End of Induction disease evaluation demonstrating complete response (CR), 
partial response (PR), minor response (MR), or stable disease (SD) (see 
Section 10.2.3). 
• Minimum number of frozen PBSCs remaining (with a back-up recommended 
but not required; see Section 18.3 for collection details). 
o Treatment requires that 2 bags of stem cells (each containing at least 
2 x 106 CD34+ cells/kg based on weight at the start of Consolidation) 
remain available for each patient. A backup containing the same number 
of cells is strongly recommended but not required. 
• ALT < 3 x ULN for age. For the purposes of this study, ULN for SGPT (ALT) 
is 45 IU/L 
• Total bilirubin ≤ 1.5 x ULN for age; if baseline was normal; > 1.0 – 1.5 x 
baseline if baseline was abnormal 
• Shortening fraction ≥ 27% or ejection fraction ≥ 50%, and no clinical 
evidence of congestive heart failure 
• No evidence of dyspnea at rest and no requirement for supplemental oxygen  
• GFR ≥ 60 mL/min/1.73m2 assessed via nuclear blood sampling method or 
iothalamate clearance method 
• No uncontrolled infection 
• Recovery from acute toxicities of final cycle of Induction therapy 
 
Patients unable to meet the criteria to begin Consolidation therapy within 
12 weeks from the start of Cycle 5 of Induction therapy should undergo a disease 
re-evaluation before proceeding to Consolidation when criteria are met. If 
patients are unable to move to Consolidation within 16 weeks from the start of 
Cycle 5 Induction therapy, due to an inability to meet Consolidaton criteria, then 
they will be removed from protocol therapy. 
 

 
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Consolidation HSCT #1 
4.7 
Consolidation HSCT #1 
4.7.1 Consolidation Therapy HSCT#1 
 
 
_______________________
 
COG Patient ID Number 
 
_____________ 
DOB 
 
Begin HSCT#1 once criteria in Section 4.6.6 have been met. See TDM for Cycle 5 Induction for observations due at the end of 
Induction and prior to the start of Consolidation. See Section 4.7.3 for recommended anti-sinusoidal obstruction syndrome (SOS) 
prophylaxis. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Thiotepa  
(TEPA) 
IV over 
2 hours 
300 mg/m2/dose or  
If ≤ 12 kg: 10 mg/kg/dose 
 
Once daily   
 -7, -6 and -5 
Thiotepa can cause significant skin 
toxicity, including sloughing of skin. 
See Section 6.15 
Cyclophosphamide 
(CPM) 
IV over 
1 hour 
1500 mg/m2/dose or 
If ≤ 12 kg: 50 mg/kg/dose 
 
Once daily  
 -5, -4, -3, and -2 
Suggested hydration at 3000 mL/m2/day 
using fluid containing at least 0.45% 
NaCl. Suggest achieving urine specific 
gravity ≤ 1.010 prior to start of 
cyclophosphamide.   
Mesna 
IV (short 
or 
continuous 
infusion) 
300 mg/m2/dose or  
If  ≤ 12 kg: 10 mg/kg/dose 
 
Given prior to the start of 
CPM and again 4 and 8 hours 
after the start of CPM 
 -5, -4, -3, and -2 
See Section 4.7.3. If given as a 
continuous infusion, please indicate in 
documentation.  
Filgrastim  
(G-CSF) or 
biosimilar 
SubQ 
5 micrograms/kg once daily 
until ANC recovery per 
institutional guidelines 
Recommend beginning on 
Day 0 after stem cell 
infusion and continue per 
institutional guidelines  
Do not substitute other colony 
stimulating factors (eg, pegfilgrastim or 
sargramostim). 
 
 
 
Ht _________ 
cm 
Wt _________ 
kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
 
TEPA 
____mg 
 
CPM 
____mg 
 
Mesna 
_____mg 
 
G-CSF: _______mcg  
 
Studies 
 
 
 
Enter calculated dose above and 
actual dose administered below 
Start Date 
Stop Date 
 
 
 
-7 
____mg 
 
 
 
 
a-e 
 
 
-6 
____mg 
 
 
 
 
b, c 
 
 
-5 
____mg 
_____mg 
____mg 
____mg 
____mg 
 
 
b 
 
 
 
 
 
 
-4 
 
_____mg 
____mg 
____mg 
____mg 
 
 
b, c 
 
 
 
 
 
 
-3 
 
_____mg 
____mg 
____mg 
____mg 
 
 
b 
 
 
 
 
 
 
-2 
 
_____mg 
____mg 
____mg 
____mg 
 
 
b, c 
 
 
 
 
 
 
-1 
Rest 
 
 
 
 
 
0 
PBSC Infusion (see Section 18.6) 
 
 
a, b (daily until neutrophil engraftment),  
c (every other day if stable)  
d (twice weekly) 
 
 
 
 
 
 
 
 
 
42 
Proceed to HSCT#2 no less than 6 weeks and prior to 10 weeks from Day 0 of  HSCT# 1 
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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Consolidation HSCT #1 
 
4.7.2 
Required Observations in Consolidation Therapy for HSCT #1 
 
a. Physical exam, weight, and height to be obtained within 1 week prior to 
Day -7 
b. CBC with differential and platelets 
c. Electrolytes, BUN, creatinine 
d. ALT, AST, total bilirubin 
e. Urinalysis 
 
 
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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Consolidation HSCT #1 
4.7.3 
Treatment Details for Consolidation HSCT#1  
 
Thiotepa: IV over 2 hours 
Days: -7 to -5 
Dose: 300 mg/m2/dose (or if ≤ 12 kg, 10 mg/kg/dose)  
 
Thiotepa can cause significant skin toxicity, including sloughing of skin. 
Frequent bathing and linen changes should be done to avoid chemical skin burns. 
See Section 6.15. 
 
Cyclophosphamide: IV over 1 hour 
Days: -5 to -2 
Dose: 1500 mg/m2/dose (or if ≤ 12 kg, 50 mg/kg/dose)  
Suggested hydration at 3000 mL/m2/day using fluid containing at least 0.45% 
NaCl. Suggest achieving urine specific gravity ≤ 1.010 prior to start of 
cyclophosphamide. 
 
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.p
df 
 
Mesna: IV (short or continuous infusion) 
Days: -5 to -2 
Dose: Mesna 300 mg/m2/dose (or if ≤ 12 kg, 10 mg/kg/dose) immediately prior 
to each cyclophosphamide dose and then 4 hours and 8 hours after the start of 
each cyclophosphamide dose. 
 
Mesna can be administered in 3 divided doses by short infusion (as above) 
over 15 to 30 minutes. The initial bolus dose of mesna may be administered 
beginning 15-30 minutes before or at the same time as the cyclophosphamide 
dose; subsequent doses are given 4 and 8 hours after the start of 
cyclophosphamide. 
 
For example: If the cyclophosphamide dose is 1,500 mg, then the total daily 
mesna dose is 900 mg; 300 mg of mesna will be given 15-30 minutes before 
or with the cyclophosphamide dose. Two boluses of 300 mg each will be given 
at Hours 4 and 8 after the start of the cyclophosphamide dose. 
 
Alternatively, mesna can be administered as a continuous infusion 
(900 mg/m2). The continuous infusion should be started 15-30 minutes before 
or at the same time as cyclophosphamide and finished no sooner than 12 hours 
after the end of the cyclophosphamide infusion. 
 
For example: If the cyclophosphamide dose is 1,500 mg, then the total daily 
mesna dose is 900 mg; the 900 mg mesna continuous infusion will start 15-
30 minutes before or at the same time as the cyclophosphamide and be 

 
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Page 79 
Consolidation HSCT #1 
completed no sooner than 12 hours after the end of the cyclophosphamide 
infusion.  
 
Peripheral Blood Stem Cell (PBSC) infusion  
Days: Day 0 
Please see Section 18.6 for PBSC infusion details.  
 
Filgrastim or biosimilar: SubQ  
Days: Recommend beginning on Day 0 after stem cell infusion and continue per 
institutional guidelines 
Dose: 5 micrograms/kg/dose (recommended starting dose)  
Note: Do not substitute other colony stimulating factors (eg, pegfilgrastim or 
sargramostim). 
 
Anti-sinusoidal obstruction syndrome (SOS) prophylaxis: 
The use of ursodiol is strongly recommended during conditioning and 
through engraftment, with dosing per institutional guidelines. Suggested 
ursodiol dosing is 150 mg/m2/dose PO, administered BID (up to 300 mg PO 
BID), beginning on Day -7 and continuing a minimum of 28 days post-
transplant, or until the end of Consolidation. Defibrotide for SOS prophylaxis 
(or SOS therapy) may be used per institutional guidelines.  
 
Please 
see 
COG 
endorsed 
supportive 
care 
guidelines 
(https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines) 
for suggested management of febrile neutropenia, mucositis, chemotherapy 
induced nausea and vomiting (CINV), and antifungal prophylaxis or manage per 
institutional guidelines. The use itraconazole, voriconazole, and posaconazole 
during chemotherapy conditioning should be avoided due to potential interaction 
with cyclophosphamide. 
 
4.7.4 
Criteria to Start Consolidation HSCT #2 (modified CEM) 
No restaging will be performed between transplants unless clinically indicated. 
Patients will proceed to HSCT #2 (modified CEM) no less than 6 weeks and 
prior to 10 weeks from Day 0 of HSCT #1, provided they have recovered from 
acute toxicities of HSCT #1 and meet organ function criteria for HSCT #2.  
 
All patients must have repeat GFR testing after hematologic recovery 
from HSCT #1 and prior to HSCT #2. GFR testing must be performed 
using direct measurement either with a nuclear blood sampling method 
or iothalamate clearance method. If the GFR is < 100 mL/min/1.73m2, 
modified dosing is used as noted below. If the GFR is < 60 mL/min/1.73m2, 
the patient is NOT eligible to receive HSCT #2.  
 
Additional criteria to proceed to HSCT #2 include the following: 
1. Resolution of acute pulmonary or cardiac toxicities developed during 
HSCT#1.  
2. ALT < 3 x ULN. For the purposes of this study, ULN for ALT (SGPT) is 
45 IU/L.  
3. Total bilirubin ≤ Grade 1 (> ULN – 1.5 x ULN if baseline was normal; 
> 1.0 – 1.5 x baseline if baseline was abnormal)  

 
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Page 80 
Consolidation HSCT #1 
4. Shortening fraction  27%, or ejection fraction  50%, no clinical 
congestive heart failure 
5. No evidence of dyspnea at rest and no requirement for supplemental 
oxygen 
6. No uncontrolled infection 
7. No prior history of severe liver dysfunction (such as CTC Grade 4 
bilirubin) or sinusoidal obstruction syndrome (SOS) (formerly veno-
occlusive disease (VOD)) during HSCT#1, defined as: 
CTCAE v5.0 Grade 4 SOS, or Grade 3 SOS PLUS a specific organ failure 
listed below: 
o CTC Grade 4 hepatic failure, OR 
Pulmonary dysfunction: Grade 3 hypoxia necessitating continuous 
oxygen support for >48 hours, ventilator support not clearly attributable 
to another cause, OR 
o 
Renal dysfunction: CTC Grade 3 creatinine, or the need for dialysis 
(CTC Grade 4 acute kidney injury), not clearly attributable to another 
cause. 
8. A minimum of 2 x 106 CD34 cells/kg PBSCs must be available to proceed 
with HSCT #2 
10. No clinical evidence of progressive disease as defined in Section 10.2.3; 
restaging studies between HSCT courses only as clinically indicated. 
11. ANC recovery to ≥ 750/µL after HSCT #1 
12. Platelet count > 20,000/µL (transfusion permitted) 
13. Recovery from other acute toxicities related to HSCT#1 
 
 

 
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Consolidation HSCT #2 
4.8 
Consolidation HSCT #2 
4.8.1 Consolidation HSCT #2.  
 
  
_______________________ 
 
COG Patient ID Number 
 ________________ 
DOB 
Start HSCT#2 once criteria in Section 4.7.4 have been met. See Section 4.8.3 for recommended anti-sinusoidal 
obstruction syndrome (SOS) prophylaxis. This TDM is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
Melphalan (MEL) 
IV over 
30 minutes 
60 mg/m2/dose or 
If ≤ 12 kg: 2 mg/kg/dose 
 
Once daily 
Days -7,  
-6 and -5 
See Section 4.8.3 
Etoposide (ETOP) 
IV over 
24 hours 
GFR ≥ 100 mL/min/1.73m2  
300 mg/m2/dose or  
If ≤ 12 kg: 10 mg/kg/dose 
 
GFR 60-99 mL/min/1.73m2 
200 mg/m2/dose or  
If ≤ 12 kg: 6.7 mg/kg/dose  
 
Once daily 
Days -7,  
-6, -5 and -4 
 
CARBOplatin  
(CARBO) 
IV over 
24 hours 
See Dosing Table in Section 4.8.3   
Days -7,  
-6, -5 and -4 
 
Filgrastim 
(G-CSF) or biosimilar 
SubQ  
5 micrograms/kg once daily until recovery per 
institutional guidelines. 
Recommend 
beginning on Day 
0 after stem cell 
infusion and 
continue per 
institutional 
guidelines 
Do not substitute 
other colony 
stimulating factors 
(eg, pegfilgrastim or 
sargramostim). 
 
 
Ht______cm 
        Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Day 
MEL 
_____mg 
ETOP 
_____mg 
CARBO 
_____mg 
G-CSF: 
________mcg 
Studies 
 
 
 
Enter calculated dose above and 
actual dose administered below 
Start 
Date 
Stop Date 
 
 
 
-7 
___mg 
____mg 
____mg 
 
 
a-f 
 
 
-6 
___mg 
____mg 
____mg 
 
 
b, c 
 
 
-5 
___mg 
____mg 
____mg 
 
 
b 
 
 
-4 
 
____mg 
____mg 
 
 
b, c 
 
 
-3 
 
 
 
 
 
b 
 
 
-2 
 
 
 
 
 
b, c 
 
 
-1 
Rest 
 
 
b 
 
 
0 
PBSC Infusion (See Section 18.6) 
 
 
a, b (daily until neutrophil engraftment),  
c (every other day if stable),  
d (twice weekly if stable)  
 
 
 
 
 
 
 
 
 
42 
Begin radiation therapy no sooner than 42 days post-transplant, 
(see Section 17.0). 
For patients with >5 persistently 
positive metastatic sites on end-
Induction imaging, obtain MIBG or 
PET (as appropriate) for radiation 
planning purposes. 
 
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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Consolidation HSCT #2 
 
4.8.2 
Required Observations in Consolidation Therapy for HSCT #2 
 
a. Physical exam, weight, height to be obtained within one week prior to Day -7  
b. CBC with differential and platelets 
c. Electrolytes, BUN, creatinine 
d. ALT, AST, total bilirubin 
e. Urinalysis 
f. GFR testing: must be performed using direct measurement either with a 
nuclear blood sampling method or iothalamate clearance method. See 
Section 4.7.4. 
 
 
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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Consolidation HSCT #2 
4.8.3 
Treatment Details for Consolidation HSCT #2  
As noted above, if the GFR is < 60 mL/min/1.73m2, the patient is not eligible to 
receive HSCT #2 (see Section 4.7.4). 
 
Melphalan: IV Infuse over 30 minutes. 
Days: -7 to -5 
Dose: 60 mg/m2/dose (or if ≤ 12 kg, 2 mg/kg/dose, not adjusted for renal 
dysfunction) once daily  
 
Stability: Melphalan stability is concentration-dependent once diluted for 
administration. The drug is most stable in NS. See Section 6.11 for agent specific 
preparation and stability information. 
 
Etoposide: IV Infuse diluted solution (concentration ≤ 0.4 mg/mL) over 
24 hours; slow rate of administration if hypotension occurs. The use of an in-line 
filter during the infusion is suggested. 
Days: -7 to -4 
Dose (GFR ≥ 100 mL/min/1.73m2): 300 mg/m2/dose (or if ≤ 12 kg, 
10 mg/kg/dose) continuous infusion once daily  
Dose (GFR 60 to 99 mL/min/1.73m2): 200 mg/m2/dose (or if ≤ 12 kg, 
6.7 mg/kg/dose) continuous infusion once daily  
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use 
of large volumes of D5W due to potential development of hyponatremia.  
 
Stability: Leaching of diethylhexyl phthalate (DEHP) from PVC bags occurred 
with etoposide 0.4 mg/mL in 0.9% NaCl solution. To avoid leaching, prepare 
the etoposide solution as close as possible, preferably within 4 hours, to the time 
of administration or alternatively as per institutional policy. Glass or 
polyethylene-lined (non-PVC) containers and polyethylene-lined tubing may be 
used. 
 
CARBOplatin: IV Administer each dose of CARBOplatin over 24 hours. 
Compatible with both saline- and dextrose-containing fluids. Prepare per 
institutional guidelines. 
Days: -7 to -4 
Dose: According to BSA and GFR per the tables below.  
 
 
CARBOplatin daily dose 
BSA (m2) 
GFR  ≥ 100 
mL/min/1.73 m2 
GFR 91-99 
mL/min/1.73 m2 
GFR 76-90 
mL/min/1.73 m2 
GFR 60-75 
mL/min/1.73 m2 
0.25-0.29 
68 mg 
54 mg 
48 mg 
40 mg 
0.30-0.34 
80 mg 
64 mg 
56 mg 
48 mg 
0.35-0.39 
90 mg 
72 mg 
64 mg 
54 mg 
0.40-0.44 
110 mg 
90 mg 
74 mg 
66 mg 
0.45-0.49 
130 mg 
100 mg 
90 mg 
80 mg 
0.50-0.54 
160 mg 
130 mg 
110 mg 
100 mg 
0.55-0.59 
190 mg 
150 mg 
130 mg 
120 mg 

 
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Consolidation HSCT #2 
 
Patients with prior allergic reactions to platinum compounds may be managed 
with pre-medications such as diphenhydramine 1 mg/kg IV (maximum dose: 
50 mg), ranitidine 1 mg/kg IV (maximum single dose: 50 mg) or equivalent H2 
antagonist e.g., famotidine, and hydrocortisone 1-4 mg/kg IV. 
 
Avoid use of aluminum containing needles or administration sets. Medication 
errors have occurred due to confusion between CISplatin (Platinol®) and 
CARBOplatin (PARAplatin®). 
 
Peripheral Blood Stem Cell (PBSC) infusion (Day 0). Please see Section 18.6 
for PBSC infusion details.  
 
Filgrastim or biosimilar: SubQ  
Dose: 5 micrograms/kg/dose, (recommended starting dose)  
Days: Recommend beginning on Day 0 after stem cell infusion and continue per 
institutional guidelines  
 
Note: Do not substitute other colony stimulating factors (eg, pegfilgrastim or 
sargramostim). 
 
Anti-sinusoidal obstruction syndrome (SOS) prophylaxis: 
The use of ursodiol is strongly recommended during conditioning and through 
engraftment, with dosing per institutional guidelines. Suggested ursodiol 
dosing is 150 mg/m2/dose PO, administered BID (up to 300 mg PO BID), 
beginning on Day -7 and continuing a minimum of 28 days post-transplant, or 
until the end of Consolidation. Defibrotide for SOS prophylaxis (or SOS 
therapy) may be used per institutional guidelines. 
 
Please 
see 
COG 
endorsed 
supportive 
care 
guidelines 
(https://childrensoncologygroup.org/index.php/cog-supportive-care-
guidelines) for suggested management of febrile neutropenia, mucositis, 
chemotherapy induced nausea and vomiting (CINV), and antifungal 
prophylaxis or manage per institutional guidelines. 
 
Note: Upon recovery following HSCT #2, radiation therapy will begin. Please note 
that for patients with >5 persistent tracer-avid metastatic lesions at the end of 
Induction, imaging for radiation planning purposes should be performed after 
HSCT #2. See Section 17.0 for Radiation Therapy Guidelines. CBCs should be 
performed at least weekly for all patients during radiation therapy; additional 
testing may be performed as clinically indicated. 
 
A disease evaluation will be performed after completion of radiation therapy, 
prior to the start of the post-Consolidation phase of treatment. See Appendix V 
for correlative study specimens to be obtained at the start of post-Consolidation 
therapy. 
CARBOplatin daily dose 
BSA (m2) 
GFR  ≥ 100 
mL/min/1.73 m2 
GFR 91-99 
mL/min/1.73 m2 
GFR 76-90 
mL/min/1.73 m2 
GFR 60-75 
mL/min/1.73 m2 
≥ 0.6 
375 mg/m2 
300 mg/m2 
260 mg/m2 
230 mg/m2 

 
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Post-Consolidation Therapy Cycles 1 - 5 
 
4.9 
Post-Consolidation Therapy 
Post-Consolidation therapy will be delivered after completion of external beam radiation as per 
Section 17.0. 
 
4.9.1 
Criteria to Start Post-Consolidation Therapy 
To begin post-Consolidation therapy, at least 1 week must have elapsed since completion of 
external beam radiotherapy. Patients who do not undergo radiotherapy (those with 
unidentifiable primary tumors and no persistent metastatic disease) may begin post-
Consolidation therapy upon recovery from ASCT. Prior to the start of post-Consolidation 
Therapy, patients will undergo a disease evaluation to consist of cross sectional tumor imaging 
(MRI or CT), an 123I-MIBG or PET scan, and bilateral bone marrow aspirates and biopsies.  
 
All patients must start post-Consolidation by Day 200 after HSCT #2 PBSC infusion (or HSCT 
#1 PBSC infusion if patient did not receive HSCT #2) and meet the following criteria to 
proceed, otherwise they will be removed from protocol therapy: 
• 
Stable disease or better on complete disease re-evaluation (CNS imaging not required but 
recommended) 
• 
No sooner than 1 week from completion of external beam radiotherapy 
• 
ANC ≥ 500/µL  
• 
Patients with a history of neuroblastoma metastatic to the central nervous system should 
receive platelet transfusion support to maintain platelet counts  50,000/µL. There is no 
platelet requirement for patients without a history of CNS metastases; platelets should be 
supported as per institutional standards for clinical care 
• 
ALT < 10 x ULN for age. For the purposes of this protocol, the ULN for ALT is 45 IU/L. 
• 
Total bilirubin ≤ 1.5 x ULN for age or > 1.0 – 1.5 x baseline if baseline was abnormal 
• 
Renal function that meets criteria below 
- 
Creatinine clearance or radioisotope GFR  60 mL/min/1.73 m2 or 
- 
A serum creatinine based on age/sex as follows: 
 
 
 
 
 
 
 
 
 
 
 
• 
Cardiac function that meets criteria below 
- 
Shortening fraction of  27% by echocardiogram, or 
- 
Ejection fraction of  50% by ECHO or radionuclide angiogram. 
• 
Adequate respiratory function as reflected in absence of dyspnea at rest and no oxygen 
requirements. If PFTs are performed, FEV1/FVC must be > 60% 
• 
No uncontrolled infection 
• 
Negative pregnancy test in females of childbearing potential 
• 
Patients 
on 
immunosuppressive 
medications 
(e.g. 
tacrolimus, 
cyclosporine, 
corticosteroids for reasons other than prevention/treatment of allergic reactions, adrenal 
replacement therapy, etc) are not eligible. 
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 

 
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Post-Consolidation Therapy Cycles 1 - 5 
 
4.9.2 
Criteria to start Post-Consolidation Cycles 2-5: 
a. ALT < 10x normal provided that the usual causes of transaminitis such as infections, 
tumor progression, or drug toxicity are excluded by appropriate blood and imaging studies 
AND the transaminitis is stable if not improving. 
b. No evidence of serious infection, or infection under control with no active disease and 
negative blood culture 
c. A serum creatinine based on age/sex 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 
 
d. To proceed to post-Consolidation Cycle 4, patients must have no evidence of disease 
progression on the post-Cycle 3 evaluation. For patients with no evidence of marrow 
disease at the start of post-Consolidation therapy, bone marrow aspirates and biopsies may 
be omitted from the post-Cycle 3 evaluation. Patients with marrow involvement at the 
start of post-Consolidation therapy should undergo bone marrow aspirates/biopsies as part 
of the post-Cycle 3 evaluation. 
 
4.9.3 
Criteria to Start ISOtretinoin in Each Cycle 
• 
ALT ≤ 10 x ULN for age. For the purposes of this study, ULN for ALT is 45 IU/L 
• 
Serum triglycerides < 500 mg/dL  
• 
Serum creatinine below the upper limit of normal for age and sex per table above 
 
Observations may be obtained within 7 days prior to start of ISOtretinoin. 
 
4.9.4 
Premedication and Supportive Care for the prevention of anticipated toxicities associated with 
ch14.18 (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: 
o IV hydration: Administer NS 20 mL/kg IV over 1 hour just prior to each ch14.18 
(dinutuximab) infusion. 
o Diphenhydramine 1 mg/kg/dose (maximum 50 mg) IV/PO 20 minutes prior to 
ch14.18 (dinutuximab) infusion and scheduled q6h. Hydroxyzine PO 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 ch14.18 
(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 
ch14.18 (dinutuximab) infusion and scheduled q4-6h prn. 

 
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Post-Consolidation Therapy Cycles 1 - 5 
o May consider ibuprofen 10 mg/kg/dose (maximum 800 mg) PO scheduled q6 in 
patients with adequate platelets and adequate renal function as needed for control of 
persistent fever or pain. 
o Consider use of cetirizine for patients with a history of allergic reactions 
o Use of a patient controlled analgesia device (PCA) during the ch14.18 (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 ch14.18 (dinutuximab) infusion 
without difficulty, may consider removing the continuous infusion rate. 
o Recommended starting dose of analgesics is the maximum dose used for treatment of 
pain associated with previous ch14.18 (dinutuximab) cycles or the following:  
▪ Morphine 0.1 mg/kg/dose 20 minutes prior to initiation of ch14.18 (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 ch14.18 
(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 micrograms/kg 10 minutes prior to 
starting dose of ch14.18 (dinutuximab) infusion. At the same time, start a 
continuous fentanyl infusion of 0.5 micrograms/kg/hr with bolus doses of 
0.25 micrograms/kg/dose q10 minutes prn pain.  
▪ Doses should be titrated as needed in accordance with institutional guidelines. 
o To reduce opiate requirements during ch14.18 (dinutuximab) therapy, gabapentin 
dosing is recommended. To optimize the effect of gabapentin, it should be initiated 1 
week prior to expected start of antibody so that it can be increased to full dose by the 
start of ch14.18 (dinutuximab) administration. Dosing should follow institutional 
standards, however the following dosing may be considered:  
▪ Day 1: 5 mg/kg/dose (max 300 mg/dose) at bedtime 
▪ Day 2: 5 mg/kg/dose (max 300 mg/dose) BID 
▪ Day 3: 5 mg/kg/dose (max 300 mg/dose) TID – patients should be at this dose by 
the time of admission for the first cycle of ch14.18 (dinutuximab) 
▪ Gabapentin doses can be increased further if necessary; institutional guidelines 
should be followed 
 
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.  
 
Fluid shifts and increased insensible volume losses due to fever are commonly seen in patients 
receiving ch14.18 (dinutuximab). In addition to the IV saline bolus given immediately prior 
to the start of ch14.18 (dinutuximab) in patients with a prior history of hypotension-related to 
ch14.18 (dinutuximab), recommend administering IV fluids at maintenance rate while 
receiving the ch14.18 (dinutuximab). Fluids can be adjusted as needed based on intravascular 
volume status.  
 
Have immediately available during the ch14.18 (dinutuximab) infusion: 
a. Albuterol and oxygen 

 
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Post-Consolidation Therapy Cycles 1 - 5 
b. Epinephrine  
c. Hydrocortisone: Use only for life-threatening reactions (hypotension, bronchospasm, 
angioedema involving the airway) not responsive to other measures.  
 
Monitoring during the ch14.18 (dinutuximab) infusion: 
• 
Check vital signs every 15 minutes for the first hour; if stable check vitals hourly until 
ch14.18 (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 
 
 
 
4.9.5 
Additional guidance 
• 
Capillary leak syndrome is an expected side effect of ch14.18 (dinutuximab) therapy. 
Complications of capillary leak syndrome can be mitigated if euvolemia is maintained. 
Close monitoring of heart rate and urine output is required, and fluids should be adjusted 
to compensate for third space losses. Use of furosemide is indicated in cases of pulmonary 
capillary leak but is not required routinely. 
 
• 
Corticosteroid therapy should be used only for life-threatening conditions (i.e. treatment 
of increased intracranial pressure in patients with CNS tumors, bronchospasm or stridor 
unresponsive to other measures or life-threatening allergic reaction). 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 during post-Consolidation therapy is discouraged. If necessary, IVIG 
may be given during the first 100 days post-ASCR because IVIG may interfere with 
ch14.18 (dinutuximab) dependent cellular cytotoxicity. IVIG should not be given within 
2 weeks of starting ch14.18 (dinutuximab) treatment and 1 week after completing ch14.18 
(dinutuximab) therapy; (i.e, if necessary, IVIG may be given on Days 14-17 and 42-45 of 
immunotherapy. 
 
 
• 
Cytokines or growth factors (G-CSF, Interferon, etc.) not included in the Treatment Plan 
are prohibited during immunotherapy. 
 
 
 
 

 
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Post-Consolidation Therapy Cycles 1 - 5 
4.9.6 
Post-Consolidation Therapy Cycles 1 - 5 
4.9.6.1 
Post Consolidation Therapy Cycles 1 - 5: Sargramostim (GM-
CSF), Ch14.18 (Dinutuximab), and ISOtretinoin 
Each cycle lasts 28 days.  
                    
 _______________________
 COG Patient ID Number
 _____________ 
 
DOB   
Start Cycle 1 once criteria in Section 4.9.1 have been met. It is recommended that post-Consolidation cycles begin on a 
Wednesday or Thursday to allow for fresh specimen shipments. This TDM is on 2 pages. 
Start Cycles 2 - 5 once criteria in Section 4.9.2 have been met. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Sargramostim 
(GM-CSF) 
SubQ  
250 
micrograms/m2/dose  
1 – 14 
Administer prior to ch14.18 (dinutuximab) administration. 
Follow GM-CSF with NS bolus (20 mL/kg) over 1 hour on 
Days 4-7. 
See guidelines in Section 4.9.8. 
Ch14.18 
(Dinutuximab)  
 
 
 
IV over 10 hrs† 
17.5 mg/m2/dose  
See admin guidelines 
in Section 4.9.8 
4 – 7 
Start 1 hour after GM-CSF administration (ie, immediately 
following NS bolus). 
† Start at 0.88 mg/m2/hour x 0.5 hour, then 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 if needed. 
ISOtretinoin 
(ISOT) 
PO 
BSA < 0.6 m2: See 
Dosing Table in 4.9.8 
BSA ≥ 0.6 m2: 
80 mg/m2/dose BID 
11–24 
BID dosing. 
See additional starting criteria for ISOtretinoin in Section 4.9.3 
 
Enter Cycle # _______ (1 - 5)  
 
Ht_____cm 
    Wt____kg 
     BSA____m2 
Due 
Date 
Date 
Given 
Day 
GM-CSF 
_____mcg 
Ch14.18 
____mg 
ISOT 
_______mg  _______mg 
Cycle 1 
Studies 
Cycles 2- 5 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
Prior to 
start  
 
 
 
a – m 
a – d, m 
 
 
1 
____mcg 
 
 
 
 
 
 
2 
____mcg 
 
 
 
 
 
 
3 
____mcg 
 
 
 
 
 
 
4 
____mcg 
____mg 
 
b, c, d, m 
b, c, d 
Cycle 2 only: m 
 
 
5 
____mcg 
____mg 
 
c 
c 
 
 
6 
____mcg 
____mg 
 
c 
c 
 
 
7 
____mcg 
____mg 
 
b, c, d, e, 
m 
c, d, e, m 
 
 
8 
____mcg 
 
 
 
 
 
 
9 
____mcg 
 
 
 
 
 
 
10 
____mcg 
 
 
 
 
 
 
11 
____mcg 
 
_______mg            _______mg         
 
 
 
12 
____mcg 
 
_______mg   
_______mg 
 
 
 
 
13 
mcg 
 
mg   
mg 
 
 
 
 
14 
____mcg 
 
_______mg   
_______mg 
 
 
 
 
15 
 
 
_______mg   
_______mg 
 
 
 
 
16 
 
 
_______mg   
_______mg 
 
 
 
 
17 
 
 
_______mg   
_______mg 
 
 
 
 
18 
 
 
_______mg   
_______mg 
 
 
 
 
19 
 
 
_______mg   
_______mg 
 
 
 
 
20 
 
 
_______mg   
_______mg 
 
 
 
 
21 
 
 
_______mg   
_______mg 
 
 
 
 
22 
 
 
_______mg   
_______mg 
 
 
 
 
23 
 
 
_______mg   
_______mg 
 
 
 
 
24 
 
 
_______mg   
_______mg 
 
Cycle 3 only: 
g-j  
 
 
25-28 
Rest Period 
 
 
29 
Begin the next cycle on Day 29 or when starting criteria are met, whichever occurs later (for Cycles 
2 - 5 see Section 4.9.2; for Cycle 6 see Section 4.9.3).  
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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4.9.7 
Required Observations in Post-Consolidation Cycles 1 – 5  
 
a. Physical exam, height, weight 
b. CBC with differential and platelets 
c. Electrolytes, BUN, creatinine 
d. ALT, AST, total bilirubin 
e. Triglycerides, calcium 
f. Free T4, TSH 
g. Cross sectional tumor imaging (MRI or CT). This is required for all patients prior 
to start of post-Consolidation; only required after Cycle 3 for patients with 
residual disease detected at the start of post-Consolidation (only submit the scan 
obtained prior to the start of post-Consolidation for central review) 
h. 
123I-MIBG scan (only submit the scan obtained prior to the start of post-
Consolidation for central review) 
i. FDG-PET/CT or PET/MR scan for patients with MIBG-non-avid disease (only 
submit the scan obtained prior to the start of post-Consolidation for central 
review) 
j. Bilateral bone marrow aspirates and biopsies. This is required for all patients prior 
to start of post-Consolidation; only required after Cycle 3 for patients with 
detectable bone marrow involvement at the start of post-Consolidation (only 
submit the samples obtained prior to start of post-Consolidation for central review 
per Section 14.2) 
k. ECHO  
l. ECG 
m. Correlative studies (see Section 15 and Appendix V) 
 
Disease evaluation may be performed between Days 17 and 28 of Cycle 3 
 
 
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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Post-Consolidation Therapy Cycles 1 - 5 
 
4.9.8 
Treatment Details for Post-Consolidation Therapy for Cycles 1 – 5 
If patient meets criteria for discontinuation of immunotherapy (see Section 5.13.3), treatment 
should be continued with ISOtretinoin unless organ function criteria do not permit 
ISOtretinoin administration. 
 
See guidelines for management of toxicities in Appendix VI. Before starting immunotherapy, 
please obtain a copy of management recommendations for anaphylaxis and hypotension 
available in Appendix VI 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. 
 
See Section 5.0 for Dose Modifications for Toxicities. Information on management of 
toxicities is also included in Section 5.0. 
 
Sargramostim: Subcutaneous injection  
Days: 1 through 14 
Dose: 250 micrograms/m²/dose. 
 
NOTE: Sargramostim should be administered daily prior to ch14.18 (dinutuximab), around 
8:00 – 9:00 AM. Follow sargramostim with 0.9% sodium chloride (NS) bolus (20 mL/kg) over 
1 hour Days 4, 5, 6, and 7.  
 
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.  
 
If criteria for holding sargramostim are met (e.g., see Sections 5.12 and 5.13), then ch14.18 
(dinutuximab) should be administered daily without sargramostim. 
 
Ch14.18 (dinutuximab): IV over 10* hours 
Days: 4, 5, 6 and 7 
Dose: 17.5 mg/m2/dose. 
 
Note: Due to the increased risk of capillary leak and respiratory compromise with ch14.18 
(dinutuximab) administration, patients should not have dyspnea at rest or an oxygen 
requirement when starting the first dose of ch14.18 (dinutuximab). Before starting ch14.18 
(dinutuximab), please obtain a copy of management recommendations for anaphylaxis and 
hypotension (see Appendix VI) 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 4.9.4 for premedication and supportive care for the prevention of anticipated 
toxicities associated with ch14.18 (dinutuximab), and for monitoring during the ch14.18 
(dinutuximab) infusion. Additional information can be found in Appendix VI. 
 
Prior to ch14.18 (dinutuximab) administration (morning start recommended), administer an 
IV bolus of normal saline (20 mL/kg) over 1 hour. Begin antibody infusion one hour after 

 
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Post-Consolidation Therapy Cycles 1 - 5 
completion of sargramostim is administered (i.e. immediately following the bolus of normal 
saline [20 mL/kg]. 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 ch14.18 (dinutuximab) antibody has not been 
delivered. Cytokine and 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 ch14.18 (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. 
 
ISOtretinoin (ISOT): PO BID 
Days: 11-24 
Dose: For BSA ≥ 0.6 m2 the dose of ISOtretinoin is 80 mg/m2/dose rounded to nearest 10 mg 
to accommodate capsule strength. 
 
For BSA < 0.6 m2, please see table below. The dose of ISOtretinoin in the table is expressed 
as final dose in mg to be administered. 
 
NOTE: dose BID. For example, if BSA ≥ 0.6 m2, administer 80 mg/m2/dose BID. The 
total daily dose is 160 mg/m2/day.  
 
ISOtretinoin 
BSA (m2) 
Dose (mg) 
0.25-0.29 
10 mg 
0.3-0.39 
20 mg 
0.4-0.49 
30 mg 
0.5-0.59 
40 mg 
 
NOTE: Capsules can be cut and the contents squeezed into a high fat food such as ice cream 
or peanut butter immediately prior to administration. Capsules can be chewed (best absorbed 
if chewed with high fat food) or the child taught to swallow entire capsules, which is feasible 
and to be encouraged. Under no circumstances should ISOtretinoin be removed from the 
capsules for more than 1 hour prior to administering to the patient (see drug monograph). 
Administration via nasogastric tube or orally via syringe is not encouraged. 
 
See Section 5.0 for Dose Modifications for Toxicities.  

 
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Post-Consolidation Therapy Cycle 6 
 
. 
4.10 
Post-Consolidation Therapy Cycle 6 
 
 
 
Start Cycle 6 when criteria in Section 4.10.3 are met. This cycle lasts 28 days. The TDM for this cycle is on 2 
pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
ISOtretinoin 
(ISOT) 
PO 
BSA < 0.6 m2: See Dosing Table in Section 4.10.3 
BSA ≥ 0.6 m2: 80 mg/m2/dose BID  
15-28 
BID dosing. 
 
Ht_____cm 
 
Wt_______kg  
BSA_______m2 
 
Date Due 
Date Given 
Day 
ISOT  
 
__________mg 
__________mg 
Studies 
 
 
 
Enter calculated dose above and 
dose administered below 
 
 
 
1-14 
Rest Period 
 
 
 
15 
__________mg 
__________mg 
a-f 
 
 
16 
__________mg 
__________mg 
 
 
 
17 
__________mg 
__________mg 
 
 
 
18 
__________mg 
__________mg 
 
 
 
19 
__________mg 
__________mg 
 
 
 
20 
__________mg 
__________mg 
 
 
 
21 
__________mg 
__________mg 
 
 
 
22 
__________mg 
__________mg 
 
 
 
23 
__________mg 
__________mg 
 
 
 
24 
__________mg 
__________mg 
 
 
 
25 
__________mg 
__________mg 
 
 
 
26 
__________mg 
__________mg 
 
 
 
27 
__________mg 
__________mg 
 
 
 
28 
__________mg 
__________mg 
 
 
 
Upon completion of Cycle 6, protocol therapy is complete. For required observations to be obtained 
within 2 weeks of end of therapy, see Section 7.1.  
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care 
Guidelines. 
 
 
 
 
 
4.10.1 
Post-Consolidation Therapy Cycle 6 – ISOtretinoin (ISOT) 
This cycle lasts 28 days.  
 
 
 _________________________ 
COG Patient ID Number 
_________________________
_ 
DOB 
Page 1 of 2 
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Post-Consolidation Therapy Cycle 6 
4.10.2 Required Observations Post-Consolidation Therapy Cycle 6 
 
a. Physical exam, height and weight 
b. CBC with differential and platelets 
c. ALT 
d. Serum triglycerides  
e. Serum creatinine  
f. Correlative studies (see Section 15 and Appendix V) 
 
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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Post-Consolidation Therapy Cycle 6 
4.10.3 Treatment Details for Post-Consolidation Therapy Cycle 6 
 
Prior to beginning treatment on Day 15 of Cycle 6, a patient must have: 
• ALT ≤ 10 x ULN for age. For the purposes of this study, ULN for ALT is 
45 IU/L 
• Serum triglycerides < 500 mg/dL 
• Serum creatinine below the upper limit of normal for age and sex per the table 
below 
 
 
See Section 5.0 for Dose Modification for Toxicities. Section 5.0 also includes 
information for management of toxicities. 
 
ISOtretinoin (ISOT): PO BID 
Days: 15-28 
Dose: For BSA ≥ 0.6 m2 the dose of ISOtretinoin is 80 mg/m2/dose rounded to 
nearest 10 mg to accommodate capsule strength. 
 
For BSA < 0.6 m2, please see table below. The dose of ISOtretinoin in the table is 
expressed as final dose in mg to be administered. 
 
NOTE: dose BID. For example, if BSA ≥ 0.6 m2, administer 80 mg/m2/dose 
BID. The total daily dose is 160 mg/m2/day.  
 
ISOtretinoin 
BSA (m2) 
Dose (mg) 
0.25-0.29 
10 mg 
0.3-0.39 
20 mg 
0.4-0.49 
30 mg 
0.5-0.59 
40 mg 
Note: Capsules can be cut and the contents squeezed into a high fat food such as 
ice cream or peanut butter immediately prior to administration. Capsules can be 
chewed (best absorbed if chewed with high fat food) or teach child to swallow 
entire capsules, which is feasible and to be encouraged. Under no circumstances 
should ISOtretinoin be removed from the capsules for more than 1 hour prior to 
administering to the patient (see drug monograph). Administration via nasogastric 
tube or orally via syringe is not encouraged. 
 
See Section 7.1 for end of therapy evaluations to be conducted within 2 weeks of 
completion of Cycle 6.  
See Section 5.0 for Dose Modifications for Toxicities.  
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 

 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES  
All toxicities should be graded according to the current version of the Common Terminology 
Criteria for Adverse Events. Please note: ‘CTCAE v5.0’ is understood to represent the most current 
version of CTCAE v5.0 as referenced on the CTEP website (ie, v5.02 and all subsequent iterations 
prior to version 6.0). 
 
5.1 
Hematologic Toxicities during Induction therapy  
5.1.1 
Hematopoietic Recovery Following Induction Cycle 1  
If the ANC is <750/L and/or the platelet count is <75,000/L on Day 22 of Cycle 
1, delay Cycle 2 by up to one week. If the ANC is <750/L and/or the platelet 
count is <75,000/L on Day 29 of Cycle 1 and the patient had marrow disease at 
diagnosis, proceed to Cycle 2 without further delay or dose modification.  
 
If the ANC is <750/L and/or the platelet count is <75,000/L on Day 29 of Cycle 
1 and the patient did not have marrow disease at diagnosis, delay chemotherapy, 
follow blood counts according to institutional standards, and proceed to Cycle 2 
upon count recovery. The following dose adjustments should be made based upon 
time to recovery:  
 
• 
If recovery occurs between Day 30-34, proceed to Cycle 2 with full dose 
topotecan and cyclophosphamide. 
• 
If recovery occurs between Day 35-43, reduce the Cycle 2 topotecan and 
cyclophosphamide doses by 25%. 
• 
If recovery occurs after Day 43 reduce the Cycle 2 topotecan and 
cyclophosphamide doses by 50%. 
 
5.1.2 
Hematopoietic Recovery Following Induction Cycle 2  
If the patient has not met hematopoietic recovery criteria on or before Day 35 after 
Cycle 2, perform bone marrow aspirate and biopsy. If the marrow was positive for 
tumor at diagnosis and still contains ≥ 5% tumor at Day 35 of Cycle 2, proceed 
with the next cycle of chemotherapy without alteration in dose, regardless of ANC 
and platelets IF there is evidence of recovering hematopoiesis. If the marrow has 
<5% tumor and/or is severely hypocellular, delay the next cycle of therapy until 
ANC ≥ 750/L and platelets ≥ 75,000/L. Full doses of Cycle 3 chemotherapy 
[cisplatin, etoposide, and ch14.18 (dinutuximab)] should be given upon count 
recovery.  
 
5.1.3 
Hematopoietic Recovery Following Induction Cycle 3  
If the patient has not met hematopoietic recovery criteria on or before Day 35 after 
Cycle 3 chemotherapy, perform bilateral bone marrow aspirates and biopsies. If 
the marrow was positive for tumor at diagnosis and still contains ≥ 5% tumor at 
Day 35 of Cycle 3, see Section 10.2.3 to determine if the definition of disease 
progression has been met. If the patient does not meet criteria for PD, proceed with 
the next cycle of chemotherapy without alteration in dose, regardless of ANC and 
platelets IF there is evidence of recovering hematopoiesis. If the marrow has <5% 
tumor and/or is severely hypocellular, delay the next cycle of therapy until ANC 
≥ 750/L 
and 
platelets 
≥ 75,000/L 
and 
reduce 
the 
doses 
of 

 
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doxorubicin/dexrazoxane and cyclophosphamide to be given in Cycle 4 by 25%. 
Full dose vincristine and ch14.18 (dinutuximab) should be administered. 
 
5.1.4 
Hematopoietic Recovery Following Induction Cycle 4 
If the patient has not met hematopoietic recovery criteria on or before Day 35 after 
Cycle 4 chemotherapy, perform bilateral bone marrow aspirates and biopsies. If 
the marrow contains ≥ 5% tumor at Day 35 of Cycle 4, see Section 10.2.3 to 
determine if the definition of disease progression has been met. If the patient does 
not have progressive disease, proceed with the next cycle of chemotherapy without 
alteration in dose regardless of ANC and platelets IF there is evidence of 
recovering hematopoiesis. If the marrow has <5% tumor and/or is severely 
hypocellular, delay the next cycle of therapy until ANC ≥ 750/L and platelets 
≥ 75,000/L and reduce doses of etoposide and cisplatin to be given in Cycle 5 
by 25%. Full dose ch14.18 (dinutuximab) should be administered. 
 
5.2 
Hematuria during Induction therapy 
5.2.1 
Hematuria during Induction Cycle 1 or 2 
• 
If transient microscopic hematuria (≥ 50 RBCs per high power field 1 or 2 
times) is observed, increase the rate of post-hydration to 200 mL/m2/hour and 
give for 8 hours.  
• 
For persistent microscopic hematuria (≥ 50 RBCs per high power field ≥ 3 
times) or for transient gross hematuria, increase the rate of post-hydration to 
200 mL/m2/hour and continue this for 8 hours. Also add mesna as a continuous 
infusion at 60% of the cyclophosphamide dose to run over 8 hours. 
• 
For 
persistent 
gross 
hematuria 
(3 
or 
more 
episodes 
during 
a 
cyclophosphamide-containing 
cycle 
of 
therapy) 
discontinue 
cyclophosphamide until urine clears to microscopic hematuria. When the urine 
clears, resume cyclophosphamide at 50% of the full dose with post-hydration 
for 24 hours and add mesna as a continuous infusion at 60% of the 
cyclophosphamide dose to be given over 8 hours. Escalate cyclophosphamide 
dose to 75% and 100% of full dose on consecutive remaining days of the 
chemotherapy cycle as tolerated. Consider urology consultation. If gross 
hematuria persists or recurs, discontinue cyclophosphamide for the remainder 
of induction therapy.  
o If 100% of full dose was delivered without recurrent hematuria by the end 
of Cycle 1, full dose cyclophosphamide may be administered at the start 
of Cycle 2, provided that there is no hematuria detected just prior to the 
start of Cycle 2 therapy. If microscopic hematuria is detected prior to the 
start of Cycle 2 therapy, follow guidance for persistent microscopic 
hematuria above. If gross hematuria is detected hold cyclophosphamide 
and consult urology. 
o If 75% of full dose cyclophosphamide was delivered without recurrent 
hematuria by the end of Cycle 1, 75% of full dose should be administered 
at the start of Cycle 2, provided that there is no hematuria detected just 
prior to the start of Cycle 2 therapy. Follow the guidance in the preceding 
bullet if hematuria is detected prior to initiation of Cycle 2. If no hematuria 
is detected after administration of 75% of full dose cyclophosphamide at 

 
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the start of Cycle 2, the dose can be increased to 100% of full dose. If 
hematuria recurs, follow instructions above. 
 
5.2.2 
Hematuria during Induction Cycle 4 
• 
For patients with hematuria during Cycles 1 and/or 2, if Cycle 2 ended without 
cyclophosphamide dose reduction due to hematuria, begin Cycle 4 with full 
prescribed dose. If Cycle 2 ended with a cyclophosphamide dose reduction due 
to hematuria, begin Cycle 4 with the analogous dose reduction (e.g., 75% dose 
cyclophosphamide in Cycle 2 = 300 mg/m2/dose would correspond to 1500 
mg/m2/dose in Cycle 4), prescribe continuous mesna for 12 hours at 100% 
equivalent cyclophosphamide dosing, and post-hydration with 200 mL/m2/hr 
for 24 hours. 
• 
If new transient microscopic hematuria (≥ 50 RBCs per high power field 1 or 
2 times) is observed in Cycle 4, increase the rate of post-hydration to 
200 mL/m2/hour and give for 8 hours. Also give mesna as a continuous 
infusion at 100% of the cyclophosphamide dose over 8 hours. 
• 
For persistent microscopic hematuria (≥ 50 RBCs per high power field 
≥ 3 times) or for transient gross hematuria, increase the rate of post-hydration 
to 200 mL/m2/hour and continue this for 24 hours. Also give mesna as a 
continuous infusion at 100% of the cyclophosphamide dose over 24 hours. For 
persistent gross hematuria (3 or more episodes during a cyclophosphamide-
containing cycle of therapy) discontinue cyclophosphamide if the infusion has 
not been completed. Consider urology consultation. If gross hematuria persists 
or recurs, do not give cyclophosphamide as a substitute for cisplatin/etoposide 
during Induction therapy.  
 
5.3 
Renal Toxicity during Induction Therapy 
5.3.1 
Cisplatin 
No dose reductions in cisplatin will be made for a decrease in the baseline GFR or 
creatinine clearance as long as the value remains ≥ 60 mL/min/1.73m².  
 
5.3.1.1 Renal Toxicity Prior to Cisplatin Cycles 
If the serum creatinine increases by > 2 x the baseline value documented 
in the preceding cycle of therapy prior to a cycle of cisplatin-containing 
chemotherapy, OR increases to greater than maximum serum creatinine 
for age as listed in table below, obtain a nuclear medicine GFR, estimated 
GFR, or creatinine clearance. 
 
 
 
 
 
 
 
 
 
 
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 

 
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If the GFR, estimated GFR, or creatinine clearance is < 60 mL/min/1.73 
m² prior to a cisplatin/etoposide/ch14.18 (dinutuximab) cycle, substitute a 
vincristine/doxorubicin/cyclophosphamide/ch14.18 (dinutuximab) cycle 
for the cisplatin/etoposide/ch14.18 (dinutuximab) cycle and do not give 
ch14.18 (dinutuximab). Make a notation of substitution of chemotherapy 
and omission of ch14.18 (dinutuximab) on the data forms. The intent of 
Induction is to give a total of 2 cycles of cyclophosphamide and topotecan, 
2 cycles of cisplatin/etoposide/ch14.18 (dinutuximab), and one cycle of 
cyclophosphamide/ 
doxorubicin/vincristine/ch14.18 
(dinutuximab). 
Therefore 
if 
a 
substitution 
of 
cyclophosphamide/doxorubicin/vincristine/dinutuximab cycle is made for 
Cycle 
3 
cisplatin/etoposide/ch14.18 
(dinutuximab), 
give 
the 
cisplatin/etoposide/ch14.18 (dinutuximab) cycle later in therapy. Again, 
do 
not 
give 
ch14.18 
(dinutuximab) 
unless 
the 
GFR 
is 
> 60 mL/min/1.73 m². If GFR, estimated GFR or creatinine clearance 
remains < 60 mL/min/1.73 m² when a patient is due for a subsequent cycle 
of cisplatin/etoposide/ch14.18 (dinutuximab), replace this cycle with a 
cycle of cyclophosphamide/doxorubicin/vincristine so that the patient 
receives a total of 5 cycles of induction chemotherapy. If the patient has 
received 2 cycles of topotecan and cyclophosphamide and 2 cycles of 
vincristine/doxorubicin/cyclophosphamide/ch14.18 (dinutuximab), and 
GFR, estimated GFR, or creatinine clearance remains < 60 mL/min/1.73 
m², further cycles of cisplatin therapy will be omitted. In this case, an 
additional cycle of vincristine/doxorubicin/cyclophosphamide should be 
given. Note replacement therapy and/or omission on data forms. 
 
5.3.1.2 Renal Toxicity during Cisplatin Cycles 
If, during a cycle of cisplatin-containing chemotherapy, the serum 
creatinine increases to > 2x the baseline value documented at the 
beginning of the current cycle, or increases to greater than maximum 
serum creatinine for age as listed in table above, then hold remaining 
cisplatin and ch14.18 (dinutuximab) and obtain a nuclear medicine GFR, 
estimated GFR, or creatinine clearance. If the GFR is < 60 mL/min/1.73m² 
omit the remainder of the cisplatin and ch14.18 (dinutuximab) from that 
cycle. If the GFR is > 60 mL/min/1.73m², may resume cisplatin and 
ch14.18 (dinutuximab). 
 
5.3.2 
Etoposide 
If GFR, estimated GFR, or creatinine clearance is < 60 mL/min/1.73 m² prior to 
cisplatin/etoposide/ch14.18 
(dinutuximab) 
cycle, 
substitute 
a 
vincristine/doxorubicin/cyclophosphamide/ch14.18 (dinutuximab) cycle for the 
cisplatin/etoposide/ch14.18 (dinutuximab) cycle and do not give the ch14.18 
(dinutuximab). Follow the instructions in the preceding section regarding 
additional substitutions for persistently decreased renal function.  
 

 
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5.3.3 
Cyclophosphamide, Doxorubicin, Vincristine and Topotecan  
No dose reductions in cyclophosphamide, doxorubicin, vincristine or topotecan are 
necessary for a decrease in creatinine clearance. 
 
5.3.4 
Ch14.18 (Dinutuximab) 
Patients may have decreased urine output, develop peripheral edema, and elevated 
creatinine related to the effects of ch14.18 (dinutuximab). Since capillary leak is a 
common side effect related to ch14.18 (dinutuximab), consider the possibility of 
renal hypoperfusion and administer volume if appropriate. 
 
If, during an Induction cycle of ch14.18 (dinutuximab)-containing therapy, the 
serum creatinine increases to > 2x the baseline value documented at the beginning 
of the current cycle, or increases to greater than maximum serum creatinine for age 
as listed in table above, then hold remaining ch14.18 (dinutuximab) and obtain a 
nuclear medicine GFR, estimated GFR, or creatinine clearance. If the GFR is < 60 
mL/min/1.73m² omit the remainder of the ch14.18 (dinutuximab) from that cycle. 
If the GFR is > 60 mL/min/1.73m², may resume the ch14.18 (dinutuximab). 
 
5.4 
Cardiac Toxicity during Induction Therapy 
5.4.1 
Change in Ejection/Shortening Fraction 
• 
If the patient has had a drop in SF/EF compared to his/her baseline but is not 
symptomatic from a cardiac perspective and has normal LV function 
(SF ≥ 27% or EF ≥ 50%), administer doxorubicin.  
• 
If the patient is not symptomatic from a cardiac perspective and has SF < 27% 
or EF < 50%, delay the doxorubicin-containing cycle and repeat the 
echocardiogram in 1 week. If SF ≥ 27% or EF ≥ 50% on re-check, resume 
doxorubicin.  
• 
For a persistent, asymptomatic decrease in LV function (SF < 27% or 
EF < 50%) that occurs prior to Cycle 4, substitute a cycle of 
cisplatin/etoposide/ch14.18 (dinutuximab) for doxorubicin-containing cycle, 
but do not give ch14.18 (dinutuximab). Make a notation of the substitution and 
omission on data forms. If a cycle of cisplatin/etoposide is substituted for a 
doxorubicin-containing 
cycle, 
give 
the 
cyclophosphamide/doxorubicin/vincristine/ch14.18 (dinutuximab) cycle in 
place of the next cisplatin/etoposide/ch14.18 (dinutuximab) if cardiac function 
improves (SF ≥ 27% or EF ≥ 50%). If cardiac function does not return to 
normal 
prior 
to 
rescheduled 
cyclophosphamide/doxorubicin/vincristine/ch14.18 (dinutuximab), omit the 
doxorubicin/dexrazoxane/ch14.18 
(dinutuximab) 
and 
give 
cyclophosphamide/vincristine. 
• 
If a patient becomes symptomatic, omit doxorubicin/dexrazoxane/ch14.18 
(dinutuximab) from Cycle 4 and administer vincristine/cyclophosphamide.  
 
5.4.2 
Dysrhythmia 
During Induction, if the patient develops Grade ≥ 2 cardiac dysrhythmia (other 
than sinus tachycardia or sinus bradycardia) as defined in the Common Toxicity 
Criteria, delay therapy and repeat the EKG in 1 week. If Grade ≥ 2 toxicity resolves 

 
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to ≤ Grade 1 toxicity, the patient may continue induction therapy without 
chemotherapy dose alterations. 
 
If Grade ≥ 2 toxicity occurs prior to Cycle 4 and persists on the follow up EKG, 
substitute 
cisplatin/etoposide/ch14.18 
(dinutuximab 
[but 
omit 
ch14.18 
(dinutuximab)] 
for 
vincristine/doxorubicin/cyclophosphamide/ch14.18 
(dinutuximab) until the dysrhythmia resolves. Make a notation of chemotherapy 
substitution/omission on the data form. The intent of Induction is to give a total of 
1 cycle of vincristine/doxorubicin/cyclophosphamide/ch14.18 (dinutuximab) and 
2 cycles of cisplatin/etoposide/ch14.18 (dinutuximab), therefore if a 
cisplatin/etoposide 
cycle 
is 
substituted 
for 
vincristine/doxorubicin/cyclophosphamide/ch14.18 
(dinutuximab), 
give 
the 
vincristine/ doxorubicin/cyclophosphamide/ch14.18 (dinutuximab) cycle later in 
therapy. 
If 
dysrhythmia 
symptoms 
occur 
prior 
to 
re-scheduled 
vincristine/doxorubicin/cyclophosphamide/ch14.18 (dinutuximab), proceed with 
cyclophosphamide/vincristine, 
but 
omit 
doxorubicin/dexrazoxane/ch14.18 
(dinutuximab).  
 
5.4.3 
Hypertension 
Hypertension due to neuroblastoma will NOT be considered a reason for removal 
from protocol therapy or alteration in chemotherapy doses.  
 
5.4.4 
Hypotension during Induction Ch14.18 (Dinutuximab) therapy 
If severe hypotension is accompanied by poor perfusion, acidemia, or end 
organ dysfunction follow PALS guidelines and hold ch14.18 (dinutuximab).  
 
• 
Moderate hypotension is defined as: 
i. 
Symptomatic; and/or 
ii. Systolic blood pressure <5th percentile for age/height/sex; and/or 
iii. Systolic or diastolic blood pressure decreased by >20% below baseline 
 
• 
For patients with moderate hypotension in the absence of the above symptoms, 
the following steps should be taken: 
i. 
Immediately hold ch14.18 (dinutuximab)  
ii. Give normal saline bolus (20 mL/kg) 
iii. Decrease narcotic dose if possible 
 
• 
If hypotension persists: 
i. 
Reassess perfusion, end organ function  
ii. Follow PALS algorithm if indicated 
iii. Repeat NS bolus OR: 
a. Consider use of albumin if serum albumin < 3.0 g/dL 
b. Consider use of RBCs if hemoglobin < 9 g/dL 
c. Consider use of platelets if count < 50,000 
iv. Consider PICU transfer 
v. If hypotension persists after 2 boluses, give additional bolus and prepare 
to give pressors (epinephrine or norepinephrine preferred over dopamine 
if possible) 

 
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If significant hypotension resolves: 
• 
May resume ch14.18 (dinutuximab) infusion at 50% of the rate at which the 
reaction occurred  
• 
Carefully assess volume status and consider adjusting fluids to ensure 
euvolemia if increased insensible losses or third spacing is suspected 
• 
If blood pressure remains stable for 2 hours after resumption of the ch14.18 
(dinutuximab), increase to the full ch14.18 (dinutuximab) rate at which the 
reaction occurred.  
• 
If the hypotension has resolved and the patient is due for chemotherapy, may 
give chemotherapy as prescribed.  
 
5.5 
Liver Toxicities during Induction therapy  
5.5.1 
Hyperbilirubinemia during Induction  
Bilirubin is evaluated as per CTCAE v5.0 using total bilirubin. For ≥ Grade 3 
bilirubin (> 3 x ULN if baseline was normal or >3 x baseline if baseline was 
abnormal) prior to planned administration of an etoposide containing cycle, delay 
therapy for up to one week and repeat the bilirubin assessment. If the ≥ Grade 3 
elevation persists, reduce the etoposide dose by 75% (eg, if the initial dose is 200 mg, 
reduce dose to 50 mg). May give full ch14.18 (dinutuximab) dose. 
 
For ≥ Grade 3 bilirubin (> 3 x ULN if baseline was normal or >3 x baseline if baseline 
was abnormal) prior to planned administration of vincristine/doxorubicin/ 
cyclophosphamide/ch14.18 (dinutuximab), delay therapy for up to one week and 
repeat the bilirubin assessment. If the ≥ Grade 3 elevation persists, substitute 
cisplatin/etoposide/ch14.18 
(dinutuximab) 
for 
a 
vincristine/doxorubicin/ 
cyclophosphamide/ch14.18 (dinutuximab) cycle and reduce the etoposide dose by 
75% (eg, if the initial dose is 200 mg, reduce dose to 50 mg). May give full ch14.18 
(dinutuximab) dose.  
 
The 
intent 
of 
Induction 
is 
to 
give 
a 
total 
of 
1 
cycle 
of 
vincristine/doxorubicin/cyclophosphamide/ch14.18 (dinutuximab) and 2 cycles of 
cisplatin/etoposide/ch14.18 (dinutuximab), therefore if cisplatin/etoposide/ch14.18 
(dinutuximab) 
cycle 
is 
substituted 
for 
vincristine/doxorubicin/ 
cyclophosphamide/ch14.18 
(dinutuximab, 
give 
vincristine/doxorubicin/ 
cyclophosphamide/ch14.18 (dinutuximab) later in therapy. If ≥ Grade 3 elevation in 
bilirubin 
is 
detected 
prior 
to 
re-scheduled 
vincristine/doxorubicin/ 
cyclophosphamide/ch14.18 
(dinutuximab) 
chemotherapy, 
omit 
doxorubicin/dexrazoxane and vincristine and give cyclophosphamide/ch14.18 
(dinutuximab).  
 
If Grade 2 bilirubin (> 1.5 but ≤ 3 x ULN if baseline was normal; > 1.5 – 3.0 x 
baseline 
if 
baseline 
was 
abnormal) 
is 
observed 
prior 
to 
Cycle 
4 
vincristine/doxorubicin/cyclophosphamide/ch14.18 (dinutuximab) chemotherapy, 
delay the cycle for one week and repeat the bilirubin. If the elevation persists, reduce 
doxorubicin and vincristine doses by 50%. If the doxorubicin dose is reduced, the 
dexrazoxane dose must also be reduced by the same percent such that the ratio of 
dexrazoxane to doxorubicin remains 10:1. Give the full dose of ch14.18 
(dinutuximab). 

 
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5.5.2 
Elevations in ALT during Induction therapy 
If elevations in ALT 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 
ch14.18 (dinutuximab) should be reduced by 25% for subsequent cycles (i.e. dose: 
13.13 mg/m2). For the purposes of this trial the ULN for ALT is defined as 45 U/L. 
If elevations of this magnitude recur despite the first dose reduction, the dose of 
ch14.18 (dinutuximab) should again be reduced by 25% for subsequent cycles (i.e. 
dose: 8.75 mg/m2). If the dose limiting elevations of the same liver enzyme(s) recur 
despite the second dose reduction, then ch14.18 (dinutuximab) should be omitted 
from the remainder of Induction therapy. An elevation in ALT that causes a delay 
of ≥ 14 days between treatment cycles will also require a 25% reduction in the dose 
of ch14.18 (dinutuximab) for subsequent cycles (i.e. dose: 13.13 mg/m2). If a delay 
of ≥ 14 days between treatment cycles recurs due to elevation in ALT despite the 
dose reduction, then ch14.18 (dinutuximab) should be omitted from the remainder 
of Induction therapy. 
 
5.6 
Other Gastrointestinal Toxicity during Cycles 1-5 of Induction Therapy 
5.6.1 
Mucositis 
If the patient develops Grade 3 or 4 mucositis that resolves to < Grade 2 by Days 
22-29 of a given cycle, no dose adjustments will be made in chemotherapy. If the 
patient develops Grade 3 or 4 mucositis that is NOT attributable to an infectious 
etiology AND recovery to < Grade 2 occurs between Days 30-43 for any cycle of 
Induction, 
reduce 
the 
dose 
of 
the 
suspected 
causative 
agent 
(doxorubicin/dexrazoxane or etoposide) in the next cycle of chemotherapy by 25% 
(eg, if the dose is 25 mg, reduce dose to 18.75 mg). If subsequent chemotherapy is 
tolerated without recurrence of Grade 3 or 4 mucositis, then resume full doses of 
chemotherapy agents in subsequent cycles of Induction that contain the suspected 
causative agent (if any). Ch14.18 (dinutuximab) dose will not be altered for 
mucositis. 
 
If the patient develops Grade 3 or 4 mucositis that is NOT attributable to infectious 
etiology AND recovery to < Grade 2 occurs after Day 43 of any cycle, reduce the 
dose of the suspected causative agent (doxorubicin or etoposide) in the next cycle 
of chemotherapy that contains the suspected causative agent by 50% (eg, if the 
dose is 25 mg, reduce dose to 12.5 mg). If subsequent chemotherapy is tolerated 
without recurrence of Grade 3 or 4 mucositis, then escalate the dose of the 
previously reduced agent by 25% in subsequent cycles of Induction (eg, if the dose 
was reduced to 12.5 mg, increase dose to 18.75 mg). When the dose of doxorubicin 
is adjusted, the dexrazoxane dose should also be adjusted to maintain a 
dexrazoxane:doxorubicin ratio of 10:1.  
 
If the patient develops mucositis that requires intubation for airway management, hold 
subsequent chemotherapy until toxicity resolves to < Grade 2. If the toxicity resolves 
to < Grade 2 by Day 43, proceed with next cycle of chemotherapy but reduce the dose 
of the suspected causative agent (doxorubicin or etoposide) in the next scheduled 
cycle of chemotherapy that contains that agent by 25% (eg, if the dose is 25 mg, 
reduce dose to 18.75 mg). If the doxorubicin dose is adjusted, the dexrazoxane dose 

 
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should be adjusted accordingly. If recovery to < Grade 2 occurs after Day 43 of any 
cycle, reduce the dose of the suspected causative agent (doxorubicin or etoposide) in 
the next cycle of chemotherapy by 50% (eg, if the dose is 25 mg, reduce dose to 
12.5 mg). If subsequent chemotherapy is tolerated without recurrence of Grade 3 or 
4 mucositis, then escalate the dose of the previously reduced agent by 25% in 
subsequent cycles of Induction that contain the suspected causative agent (eg, if the 
dose was reduced to 12.5 mg, increase dose to 18.75 mg). If the doxorubicin dose 
is adjusted, dexrazoxane dose must also be adjusted by the same percent such that the 
ratio of dexrazoxane to doxorubicin remains 10:1. 
 
5.6.2 
Diarrhea 
If the patient develops severe diarrhea (Grade 3 or 4) attributable to chemotherapy, 
and not underlying infection (eg, C. difficile), that resolves by Days 22-29 of a given 
cycle, no dose adjustments will be made in chemotherapy. If recovery to < Grade 2 
occurs between Days 30-43 for any cycle of Induction, reduce the dose of doxorubicin 
or etoposide in next cycle of chemotherapy by 25% (eg, if the dose is 25 mg, reduce 
dose to 18.75 mg). If subsequent chemotherapy is tolerated without recurrence of 
Grade 3 or 4 diarrhea, then resume full doses of chemotherapy agents in all 
subsequent cycles of Induction. If recovery to < Grade 2 occurs after Day 43 of any 
cycle, reduce the dose of doxorubicin or etoposide in the next cycle of chemotherapy 
by 50% (eg, if the dose is 25 mg, reduce dose to 12.5 mg). If subsequent 
chemotherapy is tolerated without recurrence of Grade 3 or 4 diarrhea, then escalate 
the dose of the previously modified agent by 25% in subsequent cycles of Induction 
(eg, if the dose was reduced to 12.5 mg, increase dose to 18.75 mg). If the 
doxorubicin dose is adjusted, the dexrazoxane dose must also be adjusted by the same 
percent such that the ratio of dexrazoxane to doxorubicin remains 10:1. Ch14.18 
(dinutuximab) doses will not be modified for diarrhea. 
 
5.6.3 
Typhlitis 
If a patient develops typhlitis (Grade 3 or 4), reduce the dose of doxorubicin or 
etoposide in the next cycle of Induction chemotherapy by 25%. If there is no 
recurrence of significant intestinal toxicity such as typhlitis, full dose doxorubicin or 
etoposide may be given in subsequent cycles. If the doxorubicin dose is adjusted, the 
dexrazoxane dose must also be adjusted by the same percent such that the ratio of 
dexrazoxane to doxorubicin remains 10:1. 
 
5.7 
Neurologic Toxicity during Induction Therapy 
It is expected that the majority of patients will receive only a single dose of vincristine 
during induction. If other toxicities necessitate therapy substitution with another 
vincristine-containing cycle of therapy, then the following vincristine dose modifications 
apply. If ≥ Grade 3 peripheral neuropathy (vocal cord paralysis, inability to walk or 
perform usual motor functions) or ileus develops from vincristine, vincristine therapy 
should be held until the ileus resolves or the peripheral neuropathy improves. If vincristine 
is to be given with subsequent cycles of chemotherapy (substituted for cisplatin/etoposide 
cycles) restart vincristine at 50% of the calculated dose (eg, if the dose is 0.5 mg, restart at 
0.25 mg,). If ≥ Grade 3 peripheral neuropathy recurs, do not give vincristine if another 
substituted cycle of vincristine/doxorubicin/cyclophosphamide is planned. If the ≥ Grade 

 
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3 peripheral neuropathy does not recur at the lower dose of vincristine, the same dose may 
be given during a subsequent substituted cycle.  
 
If ≥ Grade 3 neuropathy develops following ch14.18 (dinutuximab) therapy, ch14.18 
(dinutuximab) should be held until the neuropathy resolves to baseline prior to the next 
cycle of ch14.18 (dinutuximab)-containing therapy. If the abnormalities resolve when 
criteria to start the next cycle of ch14.18 (dinutuximab)-containing therapy are met, the 
dose of ch14.18 (dinutuximab) in the next ch14.18 (dinutuximab)-containing cycle should 
be reduced by 50%. If the reduced dose is tolerated, consider increasing dose to 100% with 
subsequent cycles. If symptoms recur following the reduced dose of ch14.18 
(dinutuximab), further ch14.18 (dinutuximab) should be omitted from the induction 
regimen. If symptoms do not completely resolve when criteria to start the next cycle of 
ch14.18 (dinutuximab)-containing therapy are met, ch14.18 (dinutuximab) should be 
omitted from the next cycle of therapy.  
Occasionally, ch14.18 (dinutuximab) may cause impaired accommodation and dilated 
pupils with a sluggish light reflex (with or without photophobia). These findings may last 
for weeks to months. If pupillary responsiveness improves by the time of the next 
scheduled cycle, ch14.18 (dinutuximab) can be resumed at full dose. If pupillary 
responsiveness does not improve in this time frame the dose of ch14.18 (dinutuximab) in 
the next cycle should be decreased by 50%. Full dose ch14.18 (dinutuximab) may be 
resumed in subsequent cycles if pupillary responsiveness improves. Dose reductions for 
changes in accommodation are not required.  
 
5.8 
Hypothyroidism during Induction Therapy 
Dose modification is not required due to hypothyroidism, however replacement therapy 
should be initiated per institutional standards.  
 
5.9 
Allergic reactions during Induction Therapy 
5.9.1 
Etoposide 
Etoposide allergic reactions may be managed with pre-medications such as 
diphenhydramine 1 mg/kg IV (maximum single dose: 50 mg), ranitidine 1 mg/kg 
IV (maximum single dose: 50 mg) or equivalent H2 antagonist e.g., famotidine IV, 
and hydrocortisone 1-4 mg/kg IV and by slowing the rate of the infusion. For those 
reactions that cannot be controlled with pre-medication and slowing of the rate of 
etoposide infusion, etoposide phosphate may be substituted in the same dose and 
at the same rate. Pre-medication for etoposide phosphate is recommended. 
 
5.9.2 
Cisplatin 
Platinum compound allergic reactions may be managed with pre-medications such 
as diphenhydramine 1 mg/kg IV (maximum dose: 50 mg), ranitidine 1 mg/kg IV 
(maximum single dose: 50 mg) or equivalent H2 antagonist e.g., famotidine IV, 
and hydrocortisone 1-4 mg/kg IV. If a patient experiences a life threatening 
allergic reaction to cisplatin during Cycle 3 chemotherapy, a cycle of 
vincristine/doxorubicin/cyclophosphamide 
should 
be 
substituted 
for 
cisplatin/etoposide during Cycle 5. 
 

 
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5.9.3 
Ch14.18 (Dinutuximab) 
Note: Coughing may herald the onset of bronchospasm. If this occurs, the 
patient should be closely monitored.  
• 
Mild allergic reactions: limited to rash, flushing, urticaria, mild dyspnea 
i. 
Decrease the rate of the ch14.18 (dinutuximab) infusion to 50% of the rate 
at which the symptoms began; monitor closely. 
ii. Give diphenhydramine 1-2 mg/kg/dose up to 50 mg/dose (if not already 
being given); consider scheduling every 4-6 hours  
iii. Give oral cetirizine (Less than 2 years: 2.5 mg daily, 2-5 years: 5 mg daily, 
> 6 years: 10 mg daily) 
iv. Consider ranitidine or equivalent if not already being given (IV or oral) 
v. Consider oral hydroxyzine (2 mg/kg/day divided every 8 hours)  
vi. When symptoms resolve resume the original infusion rate  
vii. If symptoms recur when original rate is resumed, decrease the infusion to 
half rate 
viii. Infusion must be stopped after 20 hours whether or not the full dose has 
been given 
ix. Document the amount of drug delivered 
 
• 
More severe allergic reactions and anaphylaxis: Any of the following – 
symptomatic bronchospasm with or without urticaria, IV medications required 
for treatment, allergy-related edema/angioedema, OR anaphylaxis  
i. 
Immediately hold ch14.18 (dinutuximab) infusion  
ii. Assess airway, breathing and circulation 
a. For airway concerns: 
i. 
Administer oxygen and albuterol immediately for bronchospasm 
ii. 
Administer IV diphenhydramine (if not already being given) 
iii. 
Administer IM epinephrine immediately if upper airway involved 
or if airway issues are accompanied by cardiovascular collapse 
iii. Administer antihistamines 
a. Give diphenhydramine (if not already being given); schedule q4-6 
hours  
b. Give oral cetirizine (Less than 2 years: 2.5 mg daily, 2-5 years: 5 mg 
daily, > 6 years: 10 mg daily) 
c. Give ranitidine or equivalent if not already being given  
d. Give oral hydroxyzine (2 mg/kg/day divided every 8 hours)  
iv. Administer IV hydrocortisone (2 mg/kg) for any of the following:  
a. Patient has frank anaphylaxis with cardiorespiratory collapse 
b. Two or more doses of epinephrine are required 
c. Moderate to severe symptoms recur upon challenge with ch14.18 
(dinutuximab) [see below regarding resumption of ch14.18 
(dinutuximab) following allergic reactions] 
v. Permanently discontinue ch14.18 (dinutuximab) in patients who 
experienced clinically significant angioedema or life-threatening 
bronchospasm 
 
• 
For patients with angioedema that does not affect the airway or patients with 
≤ Grade 2 bronchospasm  
i. 
If symptoms fully resolve in < 2 hours with the interventions above 
without 
the 
need 
for 
hydrocortisone 
administration, 
ch14.18 

 
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(dinutuximab) can be resumed on the same day but at half of the rate at 
which the symptoms occurred and complete the following: 
a. Continue scheduled H1 and H2 blockers  
b. Monitor closely for additional symptoms 
ii. If symptoms do not resolve rapidly, hold ch14.18 (dinutuximab) until 
complete resolution of symptoms or until the next day, whichever comes 
later 
a. When ch14.18 (dinutuximab) is resumed, administer at half of the rate 
at which symptoms occurred and monitor closely 
b. Continue scheduled H1 and H2 blockers  
iii. If clinically significant symptoms recur when ch14.18 (dinutuximab) is 
resumed despite scheduled antihistamine administration, stop ch14.18 
(dinutuximab) for the current cycle. May administer ch14.18 
(dinutuximab) with the next cycle; but, must infuse at half of the rate at 
which the symptoms occurred. 
 
• 
For hypotension in the setting of an allergic reaction 
i. Hold ch14.18 (dinutuximab) and give 20 mL/kg normal saline bolus 
ii. Stop or adjust doses of narcotics 
iii. For patients with hypotension that resolves with initial volume bolus and 
other allergic symptoms have resolved, resume ch14.18 (dinutuximab) at 
the same rate.  
iv. Consider additional volume resuscitation, ICU transfer and use of 
vasopressors if response is not adequate or hypotension recurs 
 
5.9.4 
Sargramostim 
Mild allergic reactions (erythema around injection site) are not uncommon 
following sargramostim administration. It may be possible to decrease local site 
reactions by alternating sites of administration. Significant reactions are those that 
result in erythema (often with tenderness) that involves an extended area (eg entire 
thigh rather than area immediately around injection site). Hold the next scheduled 
sargramostim dose if this occurs and administer appropriate antihistamines. If the 
reaction resolves by the time the next scheduled dose is due, the dose should be 
given at an alternative site. If a significant reaction is seen again, sargramostim 
should be discontinued for the remainder of the course. Sargramostim should be 
discontinued if an anaphylactic reaction is observed.  
 
Sargramostim will be held if the total white cell count is > 50,000/L. This is not a 
toxicity of sargramostim but rather an expected 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 half dose for the remainder of that cycle of 
therapy. Full dose sargramostim will be used for subsequent sargramostim cycles. If 
patients develop Grade 3 or greater serum sickness during Induction therapy. 
Discontinue sargramostim. 
 
 

 
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5.10 
Other toxicities associated with Induction therapy  
 
5.10.1 Other toxicities associated with Induction chemotherapy 
For any Grade 3 or 4 toxicity not mentioned above with the exception of cisplatin-
associated hearing loss, the treatment should be withheld until patients recover to 
≤ Grade 2 toxicity. No dose modification will be made for hearing loss; full dose 
cisplatin should be given.  
• 
For any non-hematologic Grade 3 or 4 organ toxicity attributed to 
chemotherapy AND not related to underlying infection or metabolic 
derangement that is not discussed in Sections 5.1-5.10, and is not attributed to 
ch14.18 (dinutuximab), and resolves to < Grade 2 by Day 43, reduce the 
subsequent dose of that chemotherapy agent by 25% if that agent is to be given 
as part of a subsequent planned cycle of induction therapy.  
• 
For any non-hematologic Grade 3 or 4 toxicity attributed to therapy AND not 
related to underlying infection or metabolic derangement that is not discussed 
in Sections 5.1-5.10, and is not attributed to ch14.18 (dinutuximab), and 
resolves to < Grade 2 after Day 43, reduce the subsequent dose of that 
chemotherapy by 50% (eg, if the dose is 25 mg, reduce dose to 12.5 mg) if that 
agent is to be given as part of a subsequent planned cycle of induction therapy. 
 
5.10.2 Other toxicities associated with Induction ch14.18 (dinutuximab) therapy 
Please note the maximum infusion time from initiation of ch14.18 (dinutuximab) 
is 20 hours, even if the total dose has not been administered in that timeframe. 
 
Ch14.18 (dinutuximab) doses that are missed or held due to toxicity will not be 
made up. 
 
Ch14.18 (dinutuximab) may cause fever, tachycardia, nausea, emesis, 
hyponatremia, hypokalemia, elevated transaminases and hypoalbuminemia. These 
toxicities are generally transient, and can be readily managed with supportive care. 
See Section 5.3.4 for guidance regarding management of renal dysfunction during 
ch14.18 (dinutuximab) containing cycles of Induction therapy. 
 
 
5.11 
Ch14.18 (dinutuximab)-associated toxicities during post-Consolidation 
 
Please note the maximum infusion time from initiation of ch14.18 (dinutuximab) is 20 
hours, even if the total dose has not been administered in that timeframe. 
 
5.11.1 Treatment of Allergic Reactions and Anaphylaxis during post-Consolidation 
Note: Coughing may herald the onset of bronchospasm. If this occurs, the 
patient should be closely monitored.  
• 
Mild allergic reactions: limited to rash, flushing, urticaria, mild dyspnea 
During post-Consolidation, decrease the rate of the ch14.18 (dinutuximab) 
infusion to 50% of the rate at which the symptoms began; monitor closely  
i. 
Continue sargramostim 
ii. Give diphenhydramine (if not already being given); consider scheduling 
every 4-6 hours  

 
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iii. Give oral cetirizine (Less than 2 years: 2.5 mg daily, 2-5 years: 5 mg daily, 
> 6 years: 10 mg daily) 
iv. Consider ranitidine or equivalent if not already being given (IV or oral) 
v. Consider oral hydroxyzine (2 mg/kg/day divided every 8 hours)  
vi. When symptoms resolve resume original infusion rate  
vii. If symptoms recur when original rate is resumed, decrease the infusion to 
half rate 
viii. Infusion must be stopped after 20 hours whether or not the full dose has 
been given 
ix. Document the amount of drug delivered 
 
• 
More severe allergic reactions and anaphylaxis: Any of the following – 
symptomatic bronchospasm with or without urticaria, IV medications required 
for treatment, allergy-related edema/angioedema, OR anaphylaxis  
i. 
Immediately hold ch14.18 (dinutuximab) infusion and sargramostim 
administration 
ii. Assess airway, breathing and circulation 
a. For airway concerns: 
i. Administer oxygen and albuterol immediately for bronchospasm 
ii. Administer IV diphenhydramine (if not already being given) 
iii. Administer IM epinephrine immediately if upper airway involved 
or if airway issues are accompanied by cardiovascular collapse 
iii. Administer antihistamines 
a. Give diphenhydramine (if not already being given); schedule q4-6 
hours  
b. Give oral cetirizine (Less than 2 years: 2.5 mg daily, 2-5 years: 5 mg 
daily, > 6 years: 10 mg daily) 
c. Give ranitidine or equivalent if not already being given  
d. Give oral hydroxyzine (2 mg/kg/day divided every 8 hours)  
iv. Administer IV hydrocortisone (2 mg/kg) for any of the following:  
a. Patient has frank anaphylaxis with cardiorespiratory collapse 
b. Two or more doses of epinephrine are required 
c. Moderate to severe symptoms recur upon challenge with ch14.18 
(dinutuximab) or cytokine (see below regarding resumption of 
ch14.18 (dinutuximab) and cytokines following allergic reactions) 
v. Permanently discontinue ch14.18 (dinutuximab) or cytokines in patients 
who experienced clinically significant angioedema or life-threatening 
bronchospasm 
 
• 
For patients with angioedema that does not affect the airway or patients with 
≤ Grade 2 bronchospasm  
i. During post-Consolidation, if symptoms fully resolve in < 2 hours with the 
interventions above without the need for hydrocortisone administration, 
ch14.18 (dinutuximab) can be resumed on the same day but at half of the 
rate at which the symptoms occurred and complete the following: 
a. Continue scheduled H1 and H2 blockers 
b. Monitor closely for additional symptoms 
c. Do not resume sargramostim until the following day 

 
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ii. During post-Consolidation, if symptoms do not resolve rapidly, hold 
ch14.18 (dinutuximab) until complete resolution of symptoms or until the 
next day, whichever comes later 
a. When ch14.18 (dinutuximab) is resumed, administer at half of the rate 
at which symptoms occurred and monitor closely 
b. Continue scheduled H1 and H2 blockers  
c. If symptoms do not recur, resume sargramostim on the day following 
resumption of ch14.18 (dinutuximab) 
iii. If clinically significant symptoms recur when ch14.18 (dinutuximab) or 
sargramostim is resumed despite scheduled antihistamine administration, 
stop ch14.18 (dinutuximab) and sargramostim for the current cycle 
 
• 
For hypotension in the setting of an allergic reaction 
i. Hold ch14.18 (dinutuximab) and give 20 mL/kg normal saline bolus 
ii. Stop or adjust doses of narcotics 
iii. For patients with hypotension that resolves with initial volume bolus and 
other allergic symptoms have resolved, during post-Consolidation, resume 
ch14.18 (dinutuximab) at half of the rate at which the reaction occurred 
iv. Consider additional volume resuscitation, ICU transfer and use of 
vasopressors if response is not adequate or hypotension recurs 
 
5.11.2 Treatment of Hypotension during ch14.18 (dinutuximab during post-
Consolidation) 
If severe hypotension is accompanied by poor perfusion, acidemia, or end 
organ dysfunction follow PALS guidelines and hold ch14.18 (dinutuximab) 
and sargramostim 
 
• 
Moderate hypotension is defined as: 
i. 
Symptomatic; and/or 
ii. Systolic blood pressure <5th percentile for age/height/sex; and/or 
iii. Systolic or diastolic blood pressure decreased by >20% below baseline 
 
• 
For patients with moderate hypotension in the absence of the above symptoms, 
the following steps should be taken: 
i. 
Immediately hold ch14.18 (dinutuximab) and sargramostim 
ii. Give normal saline bolus (20 mL/kg) 
iii. Decrease narcotic dose if possible 
• 
If hypotension persists: 
i. 
Reassess perfusion, end organ function  
ii. Follow PALS algorithm if indicated 
iii. Repeat NS bolus OR: 
a. Consider use of albumin if serum albumin < 3.0 g/dL 
b. Consider use of RBCs if hemoglobin < 8 g/dL 
c. Consider use of platelets if count < 50,000 
iv. Consider PICU transfer 
v. If hypotension persists after 2 boluses, give additional bolus and prepare 
to give pressors (epinephrine or norepinephrine preferred over dopamine 
if possible) 
 

 
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• 
If significant hypotension resolves: 
i. 
May resume ch14.18 (dinutuximab) infusion at 50% of the rate at which 
the reaction occurred  
ii. Carefully assess volume status and consider adjusting fluids to ensure 
euvolemia if increased insensible losses or third spacing is suspected 
iii. During Cycles 1 – 5: 
a. If blood pressure remains stable for 2 hours after resumption of the 
ch14.18 (dinutuximab), increase to the full ch14.18 (dinutuximab) rate 
at which the reaction occurred 
b. If blood pressure remains stable for 2 hours thereafter, continue to 
increase the rate stepwise to full rate 
c. If IV sargramostim was being used prior to the hypotensive episode, 
do NOT resume IV administration; change to SC administration of 
sargramostim 
 
5.11.3 Renal Side Effects associated with ch14.18 (dinutuximab) during post-
Consolidation 
Patients may have decreased urine output, develop peripheral edema, and elevated 
creatinine (1.5-2 x baseline). This may be due to decreased renal perfusion and 
intrinsic renal effects of ch14.18 (dinutuximab). The common manifestations of 
renal dysfunction in this setting are weight gain (1-10% of baseline body weight; 
due to fluid retention) and metabolic acidosis.  
• 
Recheck creatinine the following day 
o If creatinine remains > 2 x baseline value at the start of the cycle, 
ch14.18 (dinutuximab) may be continued if parameters for renal 
function in Section 4.9 are met. 
o If creatinine is ≤ 2 x baseline value and criteria in Section 4.9 are 
met, continue ch14.18 (dinutuximab). Check creatinine daily and 
follow the same guidelines for discontinuation if the creatinine 
rises.  
 
5.11.4 Other toxicities associated with ch14.18 (dinutuximab) during post-Consolidation 
Ch14.18 (dinutuximab) may cause fever, tachycardia, nausea, emesis, 
hyponatremia, hypokalemia, elevated transaminases and hypoalbuminemia. These 
toxicities are generally transient, and can be readily managed with supportive care. 
See Section 5.11.3 for guidance regarding management of renal dysfunction 
during ch14.18 (dinutuximab) containing cycles of post-Consolidation therapy. 
 
Occasionally, ch14.18 (dinutuximab) may cause impaired accommodation and 
dilated pupils with a sluggish light reflex (with or without photophobia). These 
findings may last for weeks to months. If pupillary responsiveness improves by the 
time of the next scheduled cycle, ch14.18 (dinutuximab) can be resumed at full 
dose. If pupillary responsiveness does not improve in this time frame the dose of 
ch14.18 (dinutuximab) in the next cycle should be decreased by 50%. Full dose 
ch14.18 (dinutuximab) may be resumed in subsequent cycles if pupillary 
responsiveness improves. Dose reductions for changes in accommodation are not 
required.  
 

 
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5.12 
Sargramostim (GM-CSF)-associated toxicities during post-Consolidation therapy 
 
If sargramostim related toxicities are observed during the sargramostim alone or during the 
ch14.18 (dinutuximab) infusion, the dose of sargramostim should be reduced by 50% or, if 
necessary, discontinued while maintaining the dose of ch14.18 (dinutuximab). 
 
Sargramostim will be held if the total white cell count is > 50,000/L. This is not a toxicity 
of sargramostim but rather an expected 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 half dose for the remainder of that cycle of therapy. Full dose sargramostim will 
be used for subsequent sargramostim cycles.  
 
Mild allergic reactions (erythema around injection site) are not uncommon following 
sargramostim administration. It may be possible to decrease local site reactions by 
alternating sites of administration. Significant reactions are those that result in erythema 
(often with tenderness) that involves an extended area (eg entire thigh rather than area 
immediately around injection site). Hold the next scheduled sargramostim dose if this 
occurs and administer appropriate antihistamines. If the reaction resolves by the time the 
next scheduled dose is due, the dose should be given at an alternative site. If a significant 
reaction is seen again, sargramostim should be discontinued for the remainder of the 
course. Sargramostim should be discontinued if an anaphylactic reaction is observed.  
 
5.13 
Ch14.18 (dinutuximab + sargramostim-associated toxicities during post-
Consolidation therapy 
5.13.1 Expected toxicities that do not require ch14.18 (dinutuximab) dose modification.  
The following expected toxicities will NOT require dose modification provided 
that these toxicities are judged to be tolerable by the responsible clinician, as well 
as the patient and family.  
 
a. Grade 3 pain or pain requiring intravenous narcotics. 
b. Grade 3 nausea, vomiting and diarrhea.  
c. Grade 3 fever.  
d. Grade 3 skin toxicity that remains stable and tolerable, or improves with 
treatment (e.g., antihistamines) within 24 hours. 
e. Grade 3 electrolytes (especially hyponatremia in the absence of CNS 
symptoms and sequelae) that improve with treatment within 24 hours.  
f. 
Grade 3 hepatic toxicity that returns to Grade 1 prior to the time for next 
ch14.18 (dinutuximab) treatment course. 
g. Grade 3 neurotoxicity with subjective findings only (e.g., tingling, hot or cold 
hands, etc.).  
h. Grade 4 hematologic toxicity, which improves to at least Grade 2 or baseline 
pre-therapy values within one week.  
i. 
Decreased performance status (Karnofsky 30 – 50 or Lansky 30 – 50). 
j. 
Impaired visual accommodation, correctable with eye glasses. 
k. Altered taste. 
 

 
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5.13.2 Dose modification of ch14.18 (dinutuximab) + sargramostim 
The following are recommended dose modification guidelines for dinutuximab 
and sargramostim. Since these agents are routinely used in the management of this 
patient population in the post-consolidation setting, institutional standards for dose 
modification may also be used. 
 
a. Significant hypotension – see Section 5.11.2. 
b. Grade 3 capillary leak syndrome (respiratory compromise or fluid support 
required) – see Section 4.9.5.  
c. Allergic reaction and anaphylaxis – see Section 5.11.1.  
d. Grade 3 infection during the period of administraton of ch14.18 (dinutuximab) 
+ sargramostim: do not give additional planned doses of dinutuximab during 
the cycle. Missed doses will not be replaced. May proceed to the subsequent 
planned immunotherapy cycle when infection resolves or is under control 
(asymptomatic and negative blood culture). Administration of sargramostim is 
to continue if the patient completed at least one dose of dinutuximab.  
e. Elevated creatinine – During sargramostim + ch14.18 (dinutuximab) cycles, if 
creatinine is > 2 x the baseline value at the start of the cycle and exceeds the 
maximum for age and sex as per Section 4.9, hold ch14.18 (dinutuximab) and 
repeat the creatinine the following day. If the creatinine is ≤ 2 x baseline value 
for that cycle and criteria in Section 4.9 are met, resume ch14.18 
(dinutuximab). If the creatinine remains > 2 x the baseline value and exceeds 
the maximum for age and sex, hold the ch14.18 (dinutuximab) and repeat the 
creatinine the next day. If the elevation persists discontinue ch14.18 
(dinutuximab) and sargramostim for the remainder of the cycle. If the 
creatinine is < 2 x baseline value for that cycle and criteria in Section 4.9 are 
met, resume ch14.18 (dinutuximab) but do not “make up” missed dose(s). 
 
5.13.3 Criteria for stopping post-Consolidation ch14.18 (dinutuximab) + sargramostim: 
Patients should be taken off immunotherapy if the following toxicities occur 
(please note that patients should remain on study, treated with isotretinoin).  
 
a. True anaphylaxis, clinically significant angioedema, or significant 
bronchospasm as specified in Section 5.11.1.  
b. Grade 3 or higher serum sickness* 
c. Severe, unrelenting neuropathic pain unresponsive to appropriate doses of 
gabapentin (or equivalent), continuous infusion of narcotics and other adjuvant 
measures including lidocaine or ketamine infusions. 
d. Neurotoxicity: 1) Grade 3 sensory changes interfering with daily activities > 2 
weeks after completing a cycle of ch14.18 (dinutuximab) therapy; 2) 
 Grade 3 peripheral motor neuropathy, 3)  Grade 3 ataxia attributable to 
immunotherapy; 4)  Grade 3 encephalopathy attributable to immunotherapy 
persisting > 4 days after completion of ch14.18 (dinutuximab); 5)  Grade 3 
decrease in vision per CTC v.5.0. 
e. Grade 4 hyponatremia (< 120 mEq/L) despite appropriate fluid management. 
f. Grade 4 skin toxicity. 
 
* The following criteria based on timing and signs/symptoms will favor a diagnosis 
of serum sickness: 
 

 
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Timing:  
Serum sickness develops 1-3 weeks after administration of the causative agent. 
Signs and symptoms developing later (1-3 weeks) favor the diagnosis of serum 
sickness. However, it can occur within 12-36 hours in individuals who have been 
previously sensitized through an antecedent exposure. Signs and symptoms 
include arthralgias/arthritis, splenomegaly, lymphadenopathy, glomerulonephritis 
in the presence of persistent fevers and cutaneous eruptions favor the diagnosis of 
serum sickness. 
 
5.14 
Isotretinoin (ISOT)-associated toxicities during post-Consolidation therapy 
If criteria to begin a 14-day course of isotretinoin are not met by the date the therapy is due 
to begin, delay therapy for one week. If criteria are still not met, hold therapy until criteria 
are met, and reduce the isotretinoin dose to 125 mg/m2/day or 4 mg/kg/day if the child 
weighs ≤ 12 kg. An additional dose reduction to 100 mg/m²/day (3.33 mg/kg/day if child 
weighs ≤ 12 kg) should occur if criteria are still not met one week after the due date for 
subsequent cycles. 
 
Decrease isotretinoin dose to 125 mg/m2/day (or 4 mg/kg/day if child weighs ≤ 12 kg) for 
subsequent cycles for the occurrence of any Grade 3 or 4 toxicities EXCLUDING:  
• 
Grade 3 or 4 hematologic toxicities 
• 
Grade 3 hepatic toxicity 
• 
Grade 3 nausea and vomiting 
• 
Grade 3 fever 
 
If the same Grade 3 or 4 toxicity recurs at 125 mg/m2 day, decrease dose to 100 mg/m²/day 
(or 3.3 mg/kg/day if child weighs ≤ 12 kg). If the same toxicity recurs at 100 mg/m²/day, 
discontinue the drug. 
 
If serum creatinine increases is > 2x baseline value documented at the start of post-
Consolidation therapy in any course of post-Consolidation treatment, a creatinine clearance 
(or nuclear medicine GFR) should be done prior to starting the next course. If the creatinine 
clearance and/or GFR are < 50 mL/min/1.73 m², decrease the isotretinoin dose by 50%, 
and monitor serum creatinine twice per week. If the patient develops worsening hematuria, 
and/or proteinuria, hypertension, and/or a further increase in creatinine, hold isotretinoin 
until these parameters return to baseline levels. 
 
If the patient develops > Grade 1 hematuria, > Grade 1 proteinuria, and/or > Grade 1 
hypertension during any cycle of therapy, hold isotretinoin until these symptoms resolve 
 
For localized cheilitis, apply topical agents (eg Vitamin E) to lips for subsequent cycles. If 
this does not control symptoms sufficiently to allow oral intake, decrease dose to 
125 mg/m²/day (or 4 mg/kg/day if child weighs ≤ 12 kg). 
 
If fasting serum triglycerides are > 500 mg/dL when isotretinoin is due to begin, hold 
isotretinoin and repeat fasting triglyceride level. If triglycerides remain > 500 mg/dL, start 
medical therapy for serum triglyceride reduction and begin isotretinoin (full dose) when 
triglycerides are ≤ 500 mg/dL. If triglycerides are still > 500 mg/dL by the time the next 
cycle of isotretinoin is due, then reduce dose to 125 mg/m2/day (or 4 mg/kg/day if child 
weighs ≤ 12 kg) for subsequent cycles. 
 

 
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Isotretinoin has been associated with pseudotumor cerebri. This drug should be 
discontinued in patients who are found to have papilledema. 
 
 

 
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6.0 
DRUG INFORMATION 
 
6.1 
CHIMERIC MONOCLONAL ANTIBODY 14.18 
(dinutuximab, human/murine anti-GD2 monoclonal antibody; chimeric anti-GD2; chimeric 
mAb 14.18; ch14.18, Unituxin) NSC# 764038,  
(02/14/19) 
 
Source and Pharmacology: 
Chimeric MOAB 14.18 (ch14.18, dinutuximab) is an anti-GD2 monoclonal antibody 
composed of the variable region heavy and light chain genes of the murine mAb 14.G2a and 
the human constant region genes for heavy chain IgG1 and light chain kappa. Ch14.18 
(dinutuximab) exerts its antitumor effect by binding specifically to the disialoganglioside GD2, 
an antigen found in human tumors of neuroectodermal origin such as melanoma and 
neuroblastoma. This chimeric antibody has been shown to lyse melanoma and neuroblastoma 
cells through the process of antibody-dependent cell-mediated cytotoxicity and complement-
dependent cytotoxicity. By targeting the GD2 antigen on the cell surface, ch14.18 
(dinutuximab) may also prevent attachment of circulating malignant cells to the extracellular 
matrix. Additionally, ch14.18 (dinutuximab) mediates lysis of several melanoma and 
neuroblastoma cell lines in a dose dependent manner in the presence of potent mediators of 
ch14.18 (dinutuximab)-dependent cytotoxicity, such as human peripheral blood mononuclear 
cells and granulocytes. This is most profound with neutrophils, especially in the presence of 
recombinant human granulocyte-macrophage colony-stimulating factor. 
 
The PK profile of ch14.18 (dinutuximab) has been determined in adults with melanoma 
and children with neuroblastoma. Although the plasma clearance for both groups of 
patients follow a two-compartment model, circulating antibody is cleared from the plasma 
at a much faster rate in children than adults (mean t½β = 66.6 ± 27.4 hours in children 
versus 123 ± 29 hours and 181 ± 73 hours in two adult trials, respectively). Maturation of 
the hepatic and renal systems with age is thought to impact on drug metabolism and 
elimination and could account for these differences. In general, the mAb half-life following 
the first course of treatment was longer than the half-lives following subsequent courses in 
a given patient. 
 
Toxicity:  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MoAb 14.18, chimeric (CH14.18, NSCs 623408 and 764038) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. In addition to the comprehensive list, a 
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs (SPEER) 
is a list of events that are protocol specific exceptions to expedited reporting to NCI (except 
as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd

 
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f for further clarification. Frequency is provided based on 359 patients. Below is the 
CAEPR for MoAb 14.18, chimeric (CH14.18).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower of 
the grades to determine if expedited reporting is required. 
 
 
Version 2.9, January 10, 201971 
 
 Adverse Events with Possible  
 Relationship to MoAb 14.18, chimeric (CH14.18) 
 (CTCAE 5.0 Term) 
 [n= 359] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
Disseminated intravascular 
coagulation 
 
 Disseminated intravascular coagulation 
(Gr 2) 
 
 
Hemolytic uremic syndrome36 
  
CARDIAC DISORDERS 
  
 
 
Cardiac arrest 
  
 
 
Sinus bradycardia 
  
 
Sinus tachycardia 
 
 Sinus tachycardia (Gr 3) 
EYE DISORDERS 
  
 
 
Eye disorders - Other (eye 
disorders)34  
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fever 
 
 
 Fever (Gr 3) 
 
Generalized edema 
 
  
Pain 
 
 
 Pain (Gr 3) 
 
 
Sudden death NOS 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction (Gr 3) 
 
 
Anaphylaxis 
  
 
Serum sickness 
 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection34 
 
 Infection34 (Gr 3) 
 
 
Myelitis34 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 3) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 

 
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 Adverse Events with Possible  
 Relationship to MoAb 14.18, chimeric (CH14.18) 
 (CTCAE 5.0 Term) 
 [n= 359] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Investigations - Other 
(elevated c-reactive 
proteins) 
 
 
 Investigations - Other (elevated c-reactive 
proteins) (Gr 2) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 4) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 3) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
 Hyperkalemia 
 
 Hyperkalemia (Gr 2) 
 
 Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 3) 
 
 Hypocalcemia 
 
  
 
 Hypokalemia 
 
 Hypokalemia (Gr 4) 
 
 Hyponatremia 
 
 Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Back pain 
 
 Back pain (Gr 3) 
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Neuralgia 
 
 Neuralgia (Gr 2) 
 
 
Peripheral motor neuropathy 
  
 
Peripheral sensory neuropathy37 
 
 Peripheral sensory neuropathy37 (Gr 3) 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Renal and urinary disorders - 
Other (atonic urinary bladder)6 
  
 
Urinary retention37 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Bronchial obstruction 
 
  
Cough 
 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Hypoxia 
 
 Hypoxia (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 3) 
VASCULAR DISORDERS 
  
 
Capillary leak syndrome 
 
 Capillary leak syndrome (Gr 3) 
 
Hypertension 
 
  
 
Hypotension 
 
 Hypotension (Gr 3) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. 
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
 
2There have been rare instances of atypical hemolytic uremic syndrome in the absence of documented infection and 
resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension. 

 
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3Neurological disorders of the eye including blurred vision, diplopia, cycloplegia, mydriasis, photophobia, optic nerve 
disorder, eyelid ptosis, and fixed pupils have been observed.  
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5Myelitis expressed as transverse myelitis has occurred in patients treated with chimeric MoAb 14.18. Symptoms may 
include weakness, paresthesia, sensory loss, or incontinence. 
 
6Acute urinary retention occurs during therapy and is thought to be due to fluid shifts and narcotic administration that 
accompany ch14.18 administration. Atonic urinary bladder results in chronic urinary retention (CUR) that requires 
intermittent urethral catheterization days to weeks following chimeric MoAb 14.18 administration.  
 
 
Adverse events reported on MoAb 14.18, chimeric (CH14.18) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MoAb 14.18, chimeric (CH14.18) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(thrombotic microangiopathy [e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic 
syndrome [HUS]); Bone marrow hypocellular; Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Cardiac disorders - Other (gallop on exam); Cardiac disorders - Other (N-
terminal BNP); Chest pain - cardiac; Heart failure; Left ventricular systolic dysfunction; Mobitz (type) II 
atrioventricular block; Myocardial infarction; Palpitations; Pericardial effusion; Supraventricular 
tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain; Hearing impaired 
ENDOCRINE DISORDERS - Endocrine disorders - Other (transient hypoaldosteronism); 
Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Papilledema; 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 

 
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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: MoAb 14.18, chimeric in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
Formulation and Stability:  
Ch14.18 (dinutuximab) is provided as a sterile solution in single-dose vials containing 17.5 mg/5 mL (3.5 
mg/mL) in 20 mM Histidine, 150 mM NaCl, 0.05% Tween 20 at pH 6.8. Intact vials should be stored in 
the refrigerator (2ºC to 8ºC). Stability studies of the intact vials are ongoing. 
 
Withdraw the required dose of ch14.18 (dinutuximab) from the vial(s) and inject the exact volume for the 
17.5 mg/m2/day dose into a bag containing 100 mL of 0.9% sodium chloride. The use of a filter during 
preparation is not required. The final prepared product of ch14.18 (dinutuximab) in NS is stable at room 
temperature for 24 hours when diluted to a concentration between 0.044 mg/mL and 0.56 mg/mL; however, 
the final dosage form should be prepared immediately prior to administration as there is a maximum 
infusion time of 20 hours. The minimum infusion time for the antibody infusion is 10 hours. There is no 
need to keep empty or partially used vials of ch14.18 (dinutuximab). 
 
If a storage temperature excursion is identified, promptly return ch14.18 (dinutuximab) to the refrigerator 
temperature and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov 
for determination of suitability. 
 
Lot number information will be collected on the NCI Investigational Agent (Drug) Accountability Record 
Form (DARF) (see the Agent Accountability section below). 
  
Guidelines for Administration:  
See Treatment, Dose Modifications and/or Supportive Care sections of the protocol. 
 
Patient Care Implications:  
Pain is one of the most common adverse effects of ch14.18 (dinutuximab). It is predominately neuropathic and 
manifests as abdominal cramps or back and extremity pain. Prophylactic administration of morphine by 

 
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continuous infusion is required before and during the infusions of ch14.18 (dinutuximab). Other narcotics such 
as hydromorphone or fentanyl can be used. Gabapentin may be used in conjunction with other pain medications 
per institutional practice. Use of additional pain medications (lidocaine, ketamine) in extenuating circumstances 
should be undertaken in consultation with pediatric pain management specialists. 
 
Acute allergic or infusion reactions are common and may include hypotension, urticaria, hypoxia, and dyspnea. 
Premedication with antihistamines and acetaminophen are required for ch14.18 (dinutuximab) administration. 
 
Human anti-mouse antibodies (HAMA) may block the effectiveness of therapy by prematurely clearing the 
treatment antibody and limiting further immunotherapy. HAMA responses may also be associated with 
immune-complex related adverse events such as serum sickness and anaphylaxis. HAMA responses were 
detected in over 50% of the patients tested. Although no increase in allergic reactions has been observed in 
patients treated with ch14.18 (dinutuximab) in the presence of HAMA, immune complex formation may have 
induced serum sickness in some patients. 
Supplier: Manufactured by United Therapeutics and distributed by the CTEP, DCTD, NCI. Do not use 
commercial supply. 
 
Agent Ordering: 
NCI supplied agent may be requested by the eligible participating investigator (or their authorized designee) 
at each participating institution. The CTEP assigned protocol number must be used for ordering all CTEP 
supplied investigational agents. The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA form 1572 (Statement of Investigator), 
NIH Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several participating 
investigators at one institution, CTEP supplied investigational agents for the study should be ordered under 
the name of one lead participating investigator at that institution. 
 
No starter supplies will be provided. Sites may order supplies once an enrollment has been confirmed by PMB. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. Access to 
OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person registration status. For 
questions about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the 
PMB’s website for specific policies and guidelines related to agent management. 
 
Agent Accountability 
Agent Inventory Records: 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and 
maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation 
and ordering investigator on this protocol. 
Investigator Brochure Availability 
The current version(s) of the IB(s) for the agent will be accessible to site investigators and research staff 
through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, a “current” 
password, and active person registration status. Questions about IB access may be directed to the PMB IB 
coordinator via email. 

 
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Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: https://ctepcore.nci.nih.gov/OAOP/ 
• 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• 
PMB email: PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 
 
6.2 
CARBOPLATIN 
 
(Paraplatin®) NSC #241240 
 
 
 
 
 
(05/06/11) 
 
Source and Pharmacology: 
The mechanism of action of carboplatin would appear to be similar to that of cisplatin. It 
binds to replicating DNA causing single strand breaks and interstrand cross-links with DNA. 
Data suggests that other factors also contribute to cytotoxicity. The α t½ is 1.1 to 2 hours and 
the β t½ is 2.6 to 5.9 hours. Carboplatin is not protein bound. The major route of elimination 
of carboplatin is renal excretion. Patients with creatinine clearances of approximately 
60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 71% of the 
dose within 24 hours. In patients with creatinine clearances below 60 mL/min the total 
body and renal clearances of carboplatin decrease as the creatinine clearance decreases. 
Carboplatin dosages will require adjustment dependent on the glomerular filtration rate. 
 
Toxicity: 
 
Common 
Happens to 21-100 out 
of every 100 children 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting  
 
Hypersensitivity 
reactions2 (anaphylaxis, 
bronchospasm, 
hypotension), 
constipation, diarrhea 
Metallic taste, rash, 
mucositis 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression1 
(anemia, neutropenia, 
leukopenia, 
thrombocytopenia), 
electrolyte 
abnormalities 
(↓ Na, K, Ca, Mg) 
 
↑ LFTs (alkaline 
phosphatase, SGOT 
(AST)), abdominal pain, 
nephrotoxicity (↓ GFR, 
↑ Cr and BUN), asthenia 
 
↑ bilirubin  
Delayed: 
Any time later 
during therapy 
 
Ototoxicity (tinnitus, 
hearing loss) 
Alopecia, temporary loss of 
vision to light and colors, 
peripheral neuropathy with 
mild paresthesias, 

 
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diminished sense of 
vibration, light touch, 
pinprick, and joint position 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary leukemia 
Unknown 
Frequency and 
Timing 
Fetal toxicities and teratogenic effects of carboplatin have been noted in 
animals and may cause fetal harm when administered to pregnant women. It is 
unknown whether the drug is excreted in breast milk. 
1 Thrombocytopenia is more severe or dose limiting.  
2 Hypersensitivity reactions are seen more frequently with repeated courses of therapy (after six 
courses in adults). 
 
Formulation and Stability: 
Carboplatin is available in 50 mg, 150 mg, 450 mg, and 600 mg vials. It is provided as a 
premixed aqueous solution or lyophilized powder for injection. 
 
Aqueous Solution:  
Carboplatin aqueous solution is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous 
solution of carboplatin in multidose vials. Unopened vials of carboplatin aqueous solution 
are stable to the date indicated on the package when stored at 25°C (77°F), excursions 
permitted from 15°-30°C (59°-86°F). Protect from light. Carboplatin aqueous solution 
multidose vials maintain microbial, chemical, and physical stability for up to 14 days at 
25ºC following multiple needle entries. 
 
Powder for Injection: 
Carboplatin powder for injection is a sterile lyophilized white powder in single dose vials 
containing equal parts by weight of carboplatin and mannitol. Unopened vials of 
carboplatin are stable to the date indicated on the package when stored at 25°C (77°F), 
excursions permitted from 15°-30°C (59°-86°F). Protect from light. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
IV: Reconstitute lyophilized powder to concentration of 10 mg/mL with SWFI, D5W, or 
NS, or use the premixed 10 mg/mL aqueous solution. May further dilute in dextrose or 
sodium chloride containing solutions to a final concentration as low as 0.5 mg/mL. 
Carboplatin solutions, when prepared as directed are stable for 8 hours at room 
temperature. 
 
Aluminum can react with carboplatin, causing precipitate formation and potency loss. Do 
not use needles or IV administration sets containing aluminum parts that may come in 
contact with carboplatin for the preparation or administration of the drug. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
more detailed information. 
 
6.3 
CISPLATIN 
(Cis-diamminedichloroplatinum II, CDDP, cis-DDP, Platinol-AQ) NSC #119875   

 
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(11/17/17) 
Source and Pharmacology: 
Cisplatin is an inorganic, water-soluble complex containing a central platinum atom, 2 
chlorine atoms, and 2 ammonia molecules. In aqueous solution, the chloride ions are slowly 
displaced by water generating a positively charged aquated complex. This activated 
complex is then available to react with nucleophilic sites on DNA, RNA, or protein 
resulting in the formation of bi-functional covalent links, very similar to alkylating 
reactions. The intra-strand cross-links, in particular with guanine and cytosine, change 
DNA conformation and inhibit DNA synthesis leading to the cytotoxic and anti-tumor 
effects of cisplatin. Cisplatin has synergistic cytotoxicity with radiation and other 
chemotherapeutic agents. Cisplatin has a rapid distribution phase of 25-80 minutes with a 
slower secondary elimination half-life of 60-70 hours. The platinum from cisplatin, but not 
cisplatin itself, becomes bound to several plasma proteins including albumin, transferrin, 
and gamma globulin. Three hours after a bolus injection and two hours after the end of a 
three hour infusion, 90% of the plasma platinum is protein bound. The complexes between 
albumin and the platinum from cisplatin do not dissociate to a significant extent and are 
slowly eliminated with a minimum half-life of five days or more. Platinum is present in 
tissues for as long as 180 days after the last administration. Both cisplatin and platinum are 
excreted through the kidneys ranging from 10-50%. Fecal elimination is minimal. Cisplatin’s 
penetration into the CNS is poor. 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea (L), vomiting (L) 
 
Metallic taste (L) 
Anaphylactic 
reaction 
(facial 
edema, wheezing, tachycardia, 
and 
hypotension), 
phlebitis, 
extravasation (rare) but if occurs 
= local ulceration (only in 
concentration > 0.5 mg/mL) 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Anorexia 
(L), 
myelosuppression, 
hypomagnesemia (L), high 
frequency hearing loss (L), 
nephrotoxicity (↑ Cr, BUN, 
Uric Acid) (L) 
Electrolyte disturbances (L) 
(hypocalcemia, 
natremia, 
kalemia, 
& 
phosphatemia) 
peripheral 
neuropathy, 
(paresthesias in a stocking-
glove distribution) (L) 
Vestibular 
dysfunction, 
tinnitus (L), rash, seizure (L), 
elevated liver function tests (L)  
Delayed: 
Any 
time 
later 
during therapy 
 
Hearing loss in the normal 
hearing range 
Areflexia, loss of proprioception 
and vibratory sensation, (very 
rarely loss of motor function) (L), 
optic 
neuritis, 
papilledema, 
cerebral blindness, blurred vision 
and altered color perception 
(improvement or total recovery 
usually 
occurs 
after 
discontinuing), 
chronic 
renal 
failure, deafness 
Late: 
Any 
time 
after 
completion 
of 
treatment 
 
 
Secondary malignancy 

 
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Unknown 
Frequency 
and 
Timing: 
Fetal toxicities and teratogenic effects of cisplatin have been noted in animals and cisplatin can 
cause fetal harm in humans. Cisplatin is excreted into breast milk. 
(L) Toxicity may also occur later 
 
Formulation and Stability: 
Available as an aqueous solution containing 1 mg/mL of cisplatin and 9 mg 
(1.54 mEq)/mL of sodium chloride in 50 mL, 100 mL, and 200 mL multi-dose non-
preserved vials. Store at 15°-25°C (68º-77ºF). Do not refrigerate. Protect unopened 
container from light. The cisplatin remaining in the amber vial following initial entry is 
stable for 28 days protected from light or for 7 days under fluorescent room light. Cisplatin 
removed from its amber container should be protected from light if not used within 6 hours. 
 
Guidelines for Administration: 
See the Treatment and Dose Modifications sections of this protocol. 
 
Prior to infusion, dilute cisplatin in NS, D51/2NS or D5NS. Do NOT dilute in D5W. The 
final infusion solution should contain ≥ 0.2% sodium chloride. Dextrose/saline/mannitol 
containing solutions, protected from light, are stable refrigerated or at room temperature 
for 24 to 72 hours, however, cisplatin solutions should not be stored in the refrigerator to 
avoid precipitation. Cisplatin is incompatible with sodium bicarbonate and alkaline 
solutions. 
 
Needles or intravenous sets containing aluminum parts that may come in contact with 
cisplatin should not be used for preparation or administration. Aluminum reacts with 
cisplatin causing precipitate formation and a loss of potency. 
 
Accidental extravasation with solutions that are > 0.5 mg/mL may result in significant 
tissue toxicity. 
 
Supplier: 
Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
6.4 
CYCLOPHOSPHAMIDE INJECTION 
(Cytoxan) NSC #26271 
 
 
 
 
 
(03/13/13) 
 
Source and Pharmacology:  
Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is 
inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in 
the liver to active compounds. The initial product is 4-hydroxycyclophosphamide (4-HC) 
which is in equilibrium with aldophosphamide which spontaneously releases acrolein to 
produce phosphoramide mustard. Phosphoramide mustard, which is an active bifunctional 
alkylating species, is 10 times more potent in vitro than is 4-HC and has been shown to 
produce interstrand DNA cross-link analogous to those produced by mechlorethamine. 
Approximately 70% of a dose of cyclophosphamide is excreted in the urine as the inactive 
carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life ranges from 4.1 to 
16 hours after IV administration.  
 

 
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Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Anorexia, nausea & 
vomiting 
(acute and delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, 
nasal stuffiness with 
rapid administration, 
arrhythmias (rapid 
infusion), skin rash, 
anaphylaxis, SIADH 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L) 
Cardiac toxicity with 
high dose (acute – CHF 
hemorrhagic myocarditis, 
myocardial necrosis) (L), 
hyperpigmentation, nail 
changes, impaired wound 
healing, infection 
secondary to immune 
suppression 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or 
oligospermia (prolonged 
or permanent)1 (L) 
Amenorrhea1 
Gonadal dysfunction: 
ovarian failure1 (L), 
interstitial pneumonitis, 
pulmonary fibrosis2 (L)  
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy 
(ALL, ANLL, AML), 
bladder carcinoma (long 
term use > 2 years), 
bladder fibrosis  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in 
combination with other antineoplastic agents) have been noted in humans. 
Toxicities include: chromosomal abnormalities, multiple anomalies, 
pancytopenia, and low birth weight. Cyclophosphamide is excreted into breast 
milk. Cyclophosphamide is contraindicated during breast feeding because of 
reported cases of neutropenia in breast fed infants and the potential for serious 
adverse effects. 
1 Dependent on dose, age, sex, and degree of pubertal development at time of treatment. 
2 Risk increased with pulmonary chest irradiation and higher doses. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Cyclophosphamide for injection is available as powder for injection or lyophilized powder 
for injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium 
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 
75 mg mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is 
recommended. The product will withstand brief exposures to temperatures up to 30ºC 
(86ºF). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
Cyclophosphamide for Injection:  
If the drug will be administered as undiluted drug at the 20 mg/mL concentration, then 
reconstitute to 20 mg/mL with NS ONLY to avoid a hypotonic solution. If the drug will be 

 
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further diluted prior to administration, then first reconstitute with NS, SWFI, or 
Bacteriostatic Water for Injection (paraben preserved only) to a concentration of 20 
mg/mL. Following reconstitution further dilute in dextrose or saline containing solutions 
for IV use. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.5 
DEXRAZOXANE 
 
 
 
 
 
 
(11/17/17) 
(ICRF-187, ADR-529, Zinecard, Totect) NSC #169780 
 
Source and Pharmacology: 
Dexrazoxane is a synthetic chemical, a cyclic derivative of EDTA that readily penetrates 
cell membranes. Results of laboratory studies suggest that dexrazoxane is converted 
intracellularly to a ring opened chelating agent that interferes with iron mediated free 
radical generation thought to be responsible, in part, for anthracycline-induced 
cardiomyopathy. The disposition kinetics of dexrazoxane are dose-dependent with 
administered doses from 60 to 900 mg/m2. The plasma half-life is 2 to 2.5 hours. 
Qualitative metabolism studies have confirmed the presence of unchanged drug, a 
diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine 
of animals and man. Metabolite levels were not measured in the pharmacokinetics studies. 
Urinary excretion plays an important role in the elimination of dexrazoxane: 42% of the 
drug (500 mg/m2) was excreted in the urine. In vitro studies have shown that dexrazoxane 
is not bound to plasma proteins. The pharmacokinetics of dexrazoxane have not been 
evaluated in patients with hepatic or renal insufficiency. There was no significant effect of 
dexrazoxane on the pharmacokinetics of doxorubicin (50 mg/m2) or its predominant 
metabolite, doxorubicinol, in a crossover study in cancer patients. 
 
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 
 
Pain on injection, phlebitis, transient 
increases 
in 
triglycerides 
and 
amylase, increase in SGPT (ALT)/ 
SGOT (AST) and bilirubin, mild 
nausea, vomiting, diarrhea, increase 
in serum iron, decrease in serum zinc 
and calcium  
Anorexia, 
malaise, 
extravasation (rare) but if 
occurs may = ulceration 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression  
 
Prolongation of PT/PTT  
Late: 
Any 
time 
after 
completion 
of 
treatment 
 
 
Secondary 
malignancies 
(have been reported with oral 
razoxane; 
the 
racemic 
mixture, 
of 
which 
dexrazoxane is the S(+)-
enantiomer) 

 
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Unknown 
Frequency 
and 
Timing: 
Fetal toxicities and teratogenic effects have been noted in animals. Dexrazoxane was 
maternotoxic, embryotoxic, and teratogenic when given to pregnant rats and rabbits during the 
period of organogenesis. It is not known whether dexrazoxane is excreted in human milk. 
 
Formulation and Stability: 
 
Three products are available: 
1. Dexrazoxane for Injection (generic)  
a. Available as a sterile, pyrogen-free lyophilized powder in the following strengths: 
250 mg single dose vial packaged with a 25 mL vial of 0.167 Molar (M/6) Sodium 
Lactate Injection, USP, and 500 mg single dose vial packaged with a 50 mL vial of 
0.167 Molar (M/6) Sodium Lactate Injection, USP.  
b. Store protected from light at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). 
 
2. Dexrazoxane (Zinecard®, Pfizer brand) 
a. Available in as a sterile, pyrogen-free lyophilized powder in 250 mg and 500 mg single 
use vials. Hydrochloric Acid, NF is added to the vials for pH adjustment. 
b. Intact vials should be stored at 25°C (77°F); excursions are permitted to 15° to 30°C 
(59° to 86°F). 
 
3. Totect® (dexrazoxane for anthracycline extravasation only) 
a. Totect is packaged as an emergency treatment carton for single patient use. Each carton 
contains 10 vials of Totect (dexrazoxane for injection) 500 mg and 10 vials of 50 mL 
diluent, which provides a complete three day treatment. 
Reconstitution and dilution requirements and expiration dating vary based on the 
product used. Refer to package insert for additional details. 
1. Dexrazoxane (generic) 
a. Dexrazoxane (250 mg or 500 mg vials) must be reconstituted with a sufficient quantity 
of 0.167 Molar (M/6) Sodium Lactate Injection, USP, to a concentration of 10 mg 
dexrazoxane for each mL of sodium lactate.  
b. Further dilute solution in either D5W or NS to a final concentration of 1.3 to 5 mg/mL.  
c. The final solution is stable for up to 6 hours at room temperature, 15°C to 30°C (59°F 
to 86°F), or under refrigeration, 2°C to 8°C (36°F to 46°F). 
 
2. Dexrazoxane (Zinecard®, Pfizer brand) 
a. Reconstitute with Sterile Water for Injection, USP as follows:  
• 
For 250 mg vials, reconstitute with 25 mL.  
• 
For 500 mg vials, reconstitute with 50 mL.  
• 
The resultant reconstituted solutions will have a concentration of 10 mg/mL.  
b. Following initial reconstitution, Zinecard® is stable for 30 minutes at room temperature 
or up to 3 hours when stored under refrigeration, 2° to 8°C (36° to 46°F).  
c. The pH of the resultant solution is 1.0 to 3.0. Further dilution with Lactated Ringer’s 
Injection, USP is required to achieve a final concentration range of 1.3 to 3 mg/mL in 
intravenous infusion bags. The infusion solution has a pH of 3.5 to 5.5.  
d. The infusion solution is stable for one (1) hour at room temperature or if storage is 
necessary, up to 4 hours when stored under refrigeration, 2° to 8°C (36° to 46°F). 
 

 
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3. Totect® (dexrazoxane for anthracycline extravasation only) 
a. Totect® must be reconstituted with supplied diluent to provide a final concentration of 
10 mg/mL. The patient’s dose of Totect® (based on body surface area) should be 
injected into a 1000 mL bag of NS for infusion.  
b. This solution is stable for 4 hours (begin infusion within 2 hours of preparation) when 
stored at temperatures < 25°C (< 77°F). 
c. Stability studies indicate that Totect® is chemically and physically stable after 
reconstitution with sterile water for injection and dilution in Lactated Ringer’s 
Injection when stored in refrigerated conditions (2-8°C) for no more than 8 hours 
(email communication Cumberland Pharma). 
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
For the prevention of anthracycline-induced cardiomyopathy, administer IV immediately 
prior to anthracycline dose. Administer the anthracycline after completing the infusion of 
dexrazoxane but within 30 minutes of beginning of the dexrazoxane infusion.  
 
The first infusion of Totect® should be administered as soon as possible and within the first 
6 hours following the extravasation. 
 
Supplier: 
Commercially available. See package insert for further information. 
 
6.6 
DOXORUBICIN 
(Adriamycin®) NSC #123127 
 
 
 
 
 
(05/09/11) 
 
Source and Pharmacology:  
An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. The cytotoxic 
effect of doxorubicin on malignant cells and its toxic effects on various organs are thought 
to be related to nucleotide base intercalation and cell membrane lipid binding activities of 
doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA 
polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable 
complexes appears to be an important mechanism of doxorubicin cytocidal activity. 
Doxorubicin cellular membrane binding may affect a variety of cellular functions. 
Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases, and 
dehydrogenases generate highly reactive species including the hydroxyl free radical (OH•). 
Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu 
(II) and Fe (III) reduction at the cellular level. Cells treated with doxorubicin have been 
shown to manifest the characteristic morphologic changes associated with apoptosis or 
programmed cell death. Doxorubicin-induced apoptosis may be an integral component of 
the cellular mechanism of action relating to therapeutic effects, toxicities, or both. 
 
Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is approximately 
5 minutes suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 48 hours 
reflects a slow elimination from tissues. Steady-state distribution volumes exceed 20 to 30 
L/kg and are indicative of extensive drug uptake into tissues. Plasma clearance is in the 
range of 8 to 20 mL/min/kg and is predominately by metabolism and biliary excretion. The 
P450 cytochromes which appear to be involved with doxorubicin metabolism are CYP2D6 

 
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and CYP3A4. Approximately 40% of the dose appears in the bile in 5 days, while only 5 
to 12% of the drug and its metabolites appear in the urine during the same time period. 
Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 
74 to 76% and is independent of plasma concentration of doxorubicin. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, pink or 
red color to urine, sweat, 
tears, and saliva 
Hyperuricemia, facial 
flushing, sclerosis of the 
vein 
Diarrhea, anorexia, 
erythematous streaking 
of the vein (flare 
reaction), extravasation 
(rare) but if occurs = 
local ulceration, 
anaphylaxis, fever, 
chills, 130incristin, 
acute arrhythmias 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia), alopecia  
Mucositis (stomatitis and 
esophagitis), 
hepatotoxicity  
Radiation recall 
reactions, conjunctivitis 
and lacrimation 
Delayed: 
Any time later 
during therapy 
 
Cardiomyopathy1 (CHF 
occurs in 5-20% at 
cumulative doses 
≥ 450 mg/m²) (L) 
 
Cardiomyopathy1 (CHF 
occurs in < 5% at 
cumulative doses 
≤ 400 mg/m²) (L), 
ulceration and necrosis 
of colon, 
hyper-pigmentation of 
nail bed and dermal 
crease, onycholysis 
Late: 
Any time after 
completion of 
treatment 
Subclinical cardiac 
dysfunction 
CHF (on long term 
follow up in pediatric 
patients) 
Secondary malignancy 
(in combination 
regimens) 
Unknown 
Frequency and 
Timing: 
Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of 
doxorubicin have been noted in animal models. Doxorubicin is excreted into 
breast milk in humans 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 
50 mg¹vials and a preservative-free 2 mg/mL solution in 10 mg¹, 20 mg¹, 50 mg¹, 200 mg² 
vials. 
¹ Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF 
(rapid dissolution formula) also contains methylparaben, 1 mg per each 10 mg of 
doxorubicin, to enhance dissolution. 
² Multiple dose vial contains lactose, 0.9% NS, HCl to adjust pH to 3. 
 
Aqueous Solution: Store refrigerated 2°-8°C, (36°-46°F). Protect from light. Retain in 
carton until contents are used. 
 

 
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Powder for Injection: Store unreconstituted vial at room temperature, 15°-30°C (59°-86°F). 
Retain in carton until contents are used. Reconstitute with preservative-free NS to a final 
concentration of 2 mg/mL. After adding the diluent, the vial should be shaken and the 
contents allowed to dissolve. The reconstituted solution is stable for 7 days at room 
temperature and 15 days under refrigeration, 2°-8°C (36°-46°F) when protected from light. 
Doxorubicin further diluted in 50 – 1000 mL of NS or D5W is stable for up to 48 hours at 
room temperature (25°C) when protected from light. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol.  
 
Administer IV through the tubing of rapidly infusing solution of D5W or 0.9% NaCl 
preferably into a large vein. Protect the diluted solution from sunlight. To avoid 
extravasation, the use of a central line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.7 
ETOPOSIDE – INJECTION 
(Toposar®, Etopophos®,VP-16) NSC #141540  
 
 
(11/15/16) 
 
Source and Pharmacology:  
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase 
II and DNA which results in single and double strand DNA breaks. Its main effect appears 
to be in the S and G2 phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal 
half-life is 4 to 11 hours. It is primarily excreted in the urine. In children, approximately 
55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance 
of etoposide is 7 to 10 mL/min/m² or about 35% of the total body clearance over a dose 
range of 80 to 600 mg/m². Etoposide, therefore, is cleared by both renal and non renal 
processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma 
etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide 
elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. 
Metabolism accounts for most of the non renal clearance of etoposide. 
 
The maximum plasma concentration and area under the concentration time curve (AUC) 
exhibit a high degree of patient variability. Etoposide is highly bound to plasma proteins 
(~94%), primarily serum albumin. Pharmacodynamic studies have shown that etoposide 
systemic exposure is related to toxicity. Preliminary data suggests that systemic exposure 
for unbound etoposide correlates better than total (bound and unbound) etoposide. There 
is poor diffusion into the CSF < 5%. 
 
Etoposide phosphate is a water soluble ester of etoposide which is rapidly and completely 
converted to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate 
that etoposide phosphate is bioequivalent to etoposide when it is administered in molar 
equivalent doses. 
 
Toxicity: 
 
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 

 
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Immediate: 
Within 1-2 days 
of receiving drug 
Nausea, vomiting 
Anorexia 
Transient hypotension 
during infusion; 
anaphylaxis (chills, 
fever, tachycardia, 
dyspnea, bronchospasm, 
hypotension) 
Prompt: 
Within 2-3 
weeks, prior to 
next course 
Myelosuppression 
(anemia, 
leukopenia), alopecia 
Thrombocytopenia, 
diarrhea, abdominal pain, 
asthenia, malaise, rashes 
and urticaria 
Peripheral neuropathy, 
mucositis, 
hepatotoxicity, chest 
pain, thrombophlebitis, 
congestive heart failure, 
Stevens-Johnson 
Syndrome, exfoliative 
dermatitis 
Delayed: 
Any time later 
during therapy 
 
 
Dystonia, ovarian 
failure, amenorrhea, 
anovulatory cycles, 
hypomenorrhea, 
onycholysis of nails 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy 
(preleukemic or 
leukemic syndromes) 
Unknown 
Frequency and 
Timing:  
Fetal toxicities and teratogenic effects of etoposide have been noted in animals 
at 1/20th of the human dose. It is unknown whether the drug is excreted in 
breast milk. 
 
Formulation and Stability: 
Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials (5 
mL, 25 mL, or 50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 to 
4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg 
modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) 
alcohol. Vial headspace contains nitrogen. Unopened vials of etoposide are stable until 
expiration date on package at controlled room temperature (20˚-25˚C or 68˚-77˚F). 
 
Etoposide phosphate for injection is available for intravenous infusion as a sterile 
lyophilized powder in single-dose vials containing etoposide phosphate equivalent to 
100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide 
phosphate must be stored under refrigeration (2°- 8°C or 36°- 46°F). Unopened vials of 
etoposide phosphate are stable until the expiration date on the package. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
Etoposide: 
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions 
are stable at room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL; 
stability is 24 hours at room temperature with concentrations of 0.4 mg/mL. The time to 
precipitation is highly unpredictable at concentrations > 0.4 mg/mL. Use in-line filter 
during infusion secondary to the risk of precipitate formation. However, the use of an in-
line filter is not mandatory since etoposide precipitation is unlikely at concentrations of 
0.1-0.4 mg/mL. Do not administer etoposide by rapid intravenous injection. Slow rate 
of administration if hypotension occurs.  

 
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Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags occurred 
with etoposide 0.4 mg/mL in NS. To avoid leaching, prepare the etoposide solution as close 
as possible, preferably within 4 hours, to the time of administration or alternatively as per 
institutional policy; glass or polyethylene-lined (non-PVC) containers and polyethylene-
lined tubing may be used to minimize exposure to DEHP. 
 
Etoposide Phosphate: 
Reconstitute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, D5W, NS, 
Bacteriostatic Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride 
for Injection with Benzyl Alcohol for a concentration equivalent to 20 mg/mL or 
10 mg/mL etoposide equivalent (22.7 mg/mL or 11.4 mg/mL etoposide phosphate), 
respectively. Use diluents without benzyl alcohol for neonates and infants < 2 years of 
age or patients with hypersensitivity to benzyl alcohol.  
 
When reconstituted as directed, etoposide phosphate solutions can be stored in glass or 
plastic containers under refrigeration for 7 days. When reconstituted with a diluent 
containing a bacteriostat, store at controlled room temperature for up to 48 hours. 
Following reconstitution with SWFI, D5W, or NS store at controlled room temperature for 
up to 24 hours. 
 
Following reconstitution, etoposide phosphate may be further diluted to a concentration as 
low as 0.1 mg/mL of etoposide with D5W or NS. The diluted solution can be stored under 
refrigeration or at controlled room temperature for 24 hours. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
6.8 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ 
(Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®, Granix®, 
Zarxio®) NSC #614629  
 
 
 
 
 
(11/15/16) 
 
Source and Pharmacology:  
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by 
recombinant DNA technology. Filgrastim is a 175 amino acid protein with a molecular 
weight of 18,800 daltons manufactured by recombinant DNA technology utilizing E coli 
bacteria into which has been inserted the human granulocyte colony stimulating factor 
gene. It differs from the natural protein in that the N- amino acid is methionine and the protein 
is not glycosylated. G-CSF is a lineage specific colony-stimulating factor, which regulates 
the production of neutrophils within the bone marrow and affects neutrophil progenitor 
proliferation, differentiation, and selected end-cell functional activation (including 
enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory 
burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens). Filgrastim exhibits nonlinear pharmacokinetics with 
clearance dependent on filgrastim concentration and neutrophil count. Filgrastim is cleared 
by the kidney. The elimination half-life is similar for subcutaneous and intravenous 
administration, approximately 3.5 hours. The time to peak concentration when administered 
subcutaneously is 2-8 hours. 
 

 
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Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Local irritation at the 
injection site, headache 
Allergic reactions (more 
common with IV 
administration than 
subq): skin (rash, 
urticaria, facial edema), 
respiratory (wheezing, 
dyspnea) and 
cardiovascular 
(hypotension, 
tachycardia), low grade 
fever  
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Mild to moderate 
medullary bone pain 
Increased: alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid, thrombocytopenia 
Splenomegaly, splenic 
rupture, rash or 
exacerbation of pre-
existing skin rashes, 
sickle cell crises in 
patients with SCD, 
excessive leukocytosis, 
Sweet’s syndrome (acute 
febrile neutrophilic 
dermatosis) 
Delayed: 
Anytime later 
during therapy 
 
 
Cutaneous vasculitis, 
ARDS 
Late: 
Anytime after 
completion of 
treatment 
 
 
MDS or AML (confined 
to patients with severe 
chronic neutropenia and 
long term administration) 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. 
Conflicting data exist in animal studies and filgrastim is known to pass the 
placental barrier. It is unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability:  
Neupogen® supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials. 
Neupogen® vials are preservative free single use vials. Discard unused portions of open 
vials. 
 
Neupogen®, Granix®, and Zarxio® are also available as single use prefilled syringes 
containing 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim for subcutaneous 
administration.  
 
Store refrigerated at 2º - 8ºC (36º - 46ºF). Protect from light. Do not shake. Prior to 
injection, filgrastim and filgrastim-sndz may be allowed to reach room temperature for a 
maximum of 24 hours. Infusion must be completed within 24 hours of preparation. TBO-
filgrastim may be removed from 2ºC – 8ºC (36ºF – 46ºF) storage for a single period of up 
to 5 days between 23ºC to 27ºC (73ºF to 81ºF). Avoid freezing and temperatures > 30ºC.  
 
For IV use, dilute filgrastim (Neupogen®) and tbo-filgrastim (Granix®) in D5W only to 
concentrations >15 mcg/mL. Filgrastim-sndz (Zarxio®) may be diluted in D5W to 
concentrations between 5 mcg/mL and 15 mcg/mL. At concentrations below 15 mcg/mL, 

 
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human serum albumin should be added to make a final albumin concentration of 0.2% 
(2 mg/mL) in order to minimize the adsorption of filgrastim to plastic infusion containers 
and equipment for all 3 products (communication on file from Teva Pharmaceuticals USA). 
Filgrastim or filgrastim-sndz dilutions of 5 mcg/mL or less are not recommended. Tbo-
filgrastim dilutions below 2 mcg/mL are not recommended. Diluted filgrastim biosimilar 
products should be stored at 2º - 8ºC (36º - 46ºF) and used within 24 hours. Do not shake. 
 
Do not dilute with saline-containing solutions at any time; precipitation will occur. 
 
 
Guidelines for Administration:  
See Treatment, Dose Modifications and Supportive Care sections of the protocol. 
 
Filgrastim biosimilar products should not be administered within 24 hours of (before AND 
after) chemotherapy. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information  
 
6.9 
ISOTRETINOIN 
(13-cis-retinoic acid, RO-43,780, Accutane®, Amnesteem® Claravis®, Sotret®) 
NSC#329481 
 
 
 
 
 
 
 
(10/13/17) 
 
Source and Pharmacology: 
Isotretinoin is a naturally occurring analogue of Vitamin A. Retinoids are required for the 
maintenance of normal cell growth, differentiation, and loss within epithelial tissues. 
Various retinoids have been shown to suppress or reverse epithelial carcinogenesis and to 
prevent the development of invasive cancers in many animal systems. Retinoids act 
primarily in the post-carcinogen phases of promotion and progression, which makes them 
more useful for chemoprevention. However in certain malignancies (notably acute 
promyelocytic leukemia and neuroblastoma), high-doses of retinoids can have significant 
anti-tumor activity. The exact mechanism of RA-induced maturation of tumor cells is not 
known. The mechanism by which retinoids regulate the growth and differentiation of 
normal and malignant cells has not been completely elucidated, but it is thought that these 
effects result from the ability of retinoids to modulate the transcriptional regulatory activity 
of a set of nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) 
belonging to the super family of thyroid/steroid hormone receptors. 
 
Isotretinoin is highly lipophilic and 99.9% bound to plasma protein (almost entirely 
albumin) and has a half-life of 10-20 hours. Oral absorption of isotretinoin is enhanced 
when given with a high fat meal increasing both the peak plasma concentration and AUC 
by more than double. Following oral administration of isotretinoin, at least three 
metabolites have been identified in human plasma: 4-oxoisotretinoin, retinoic acid 
(tretinoin-), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic 
acid are geometric isomers and show reversible inter-conversion. The administration of 
one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 
4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. All of these 
metabolites possess retinoid activity that is in some in vitro models more than that of the 
parent isotretinoin. The metabolites of isotretinoin and any conjugates are ultimately 
excreted in the feces and urine in relatively equal amounts (total of 65-83%). In a study 

 
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comparing the pharmacokinetics of isotretinoin in pediatric and adult patients there were 
no statistically significant differences.  
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
 
Nausea and vomiting 
Anaphylaxis, bronchospasm 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Dry skin (L), dry mucosa 
(L), epistaxis, cheilitis, 
(L), photosensitivity, 
elevated ESR, back pain 
(L), arthralgias (L), 
triglyceride elevation (L), 
hypercalcemia (L) 
Rash (L), conjunctivitis 
(L),  
headache (L), decrease in 
high density lipoproteins 
(L), cholesterol elevation 
(L), transaminase 
elevation (L), anemia (L) 
Alopecia, appetite disturbances, 
hyperglycemia, hyper- or hypo- 
skin pigmentation, nail changes, 
eruptive xanthomas, seizures, 
dizziness, pseudotumor-cerebri 
(papilledema, headache, nausea, 
vomiting, visual disturbances), 
psychiatric disorders (depression, 
aggressive and/or violent 
behaviors, suicidal ideation, 
suicide, dream disturbances), 
insomnia, lethargy, malaise, 
nervousness, paresthesias, weight 
loss, myelosuppression, elevated 
platelet counts, agranulocytosis, 
allergic vasculitis (L), chest pain, 
pancreatitis (including very rarely 
fatal hemorrhagic pancreatitis), 
hearing impairment, 
inflammatory bowel disease, 
visual disturbances (decrease in 
night vision, corneal opacities 
which resolve on d/c, 
photophobia, color vision 
disturbances, cataracts), edema, 
inflammation of the gums, drying 
of respiratory tract with voice 
alteration, respiratory infections, 
erythema multiforme, Stevens-
Johnson syndrome (SJS), toxic 
epidermal necrolysis (TEN) 
Delayed: 
Any time later 
during therapy, 
excluding the 
above 
conditions 
 
Skeletal hyperostosis 
Osteoporosis, bone fractures or 
delayed healing, premature 
epiphyseal closure, 
rhabdomyolysis, abnormal 
menses, renal disturbances (WBC 
in urine, proteinuria, hematuria, 
renal calculi), calcification of 
tendon and ligaments 
Unknown 
frequency and 
timing: 
Major human fetal abnormalities related to isotretinoin administration in females have 
been documented. There is an increased risk of spontaneous abortion. In addition, 
premature births have been reported. Documented external abnormalities include: skull 
abnormality; ear abnormalities (including anotia, micropinna, small or absent external 
auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia and 
cleft palate. Documented internal abnormalities include: CNS abnormalities (including 
cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial 

 
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nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid 
hormone deficiency. In some cases death has occurred with certain of the abnormalities 
previously noted. Cases of IQ scores less than 85 with or without obvious CNS 
abnormalities have also been reported. It is not known whether this drug is excreted in 
human milk. Because of the potential for adverse effects, nursing mothers should not 
receive isotretinoin. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Isotretinoin, a retinoid, is available in 10 mg, 20 mg, 30 mg and 40 mg soft gelatin capsules 
for oral administration. Inactive ingredients vary depending on the manufacturer but 
capsule formulations may include the following inactive ingredients: beeswax, butylated 
hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated 
vegetable oil, soybean oil and vitamin E. Gelatin capsules may contain glycerin and 
parabens (methyl and propyl), with the following dye systems: iron oxide (red and black) 
and titanium dioxide; FD&C Red No. 3 or 7, FD&C Blue No. 1 or 2, FD&C Yellow No. 6 
or 10, propylene glycol, and shellac glaze. 
 
Store at controlled room temperature (59°86°F, 15°30°C). Protect from light. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
Give orally with food (ideally, high fat) or milk to enhance absorption. For children unable 
to swallow the capsules whole, the following options may be used: 
 
Soften capsule (in warm water), bite, swallow, or suck out contents or place softened 
capsule in fatty food such as peanut butter and swallow. The method of softening the 
capsule and withdrawing contents with an oral syringe is not preferred as it is difficult to 
remove all of the drug from the capsule. 
 
Squeeze out the entire contents of the capsule into a small medicine cup and give with fatty 
food, such as peanut butter. (If at all possible have the child suck on the empty capsule in 
hopes of getting more of the intended dose.) 
 
The preferred method is to poke a hole in the capsule to allow the capsule to be chewed 
and embed the capsule in a food or candy enjoyed by the child. 
 
Under no circumstances should isotretinoin be removed from the capsules for more than 1 
hour prior to administering to the patient. It is NOT recommended to administer 
isotretinoin through a feeding tube (e.g., NG, ND, or NJ tube) as exposure to isotretinoin 
is suboptimal and may affect response.72 
 
Note: Women of childbearing potential should wear gloves when handling isotretinoin 
capsules.  
 
If the contents are withdrawn from the capsule and mixed with food or milk, administer as 
closely as possible to mixing to avoid oxidation or conversion by exposure to light to a 
more toxic and less potent product. 
 

 
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Isotretinoin is contraindicated in patients with paraben allergies as the capsule is preserved 
with the agent. Patients should be warned about enhanced photosensitivity; the use of 
sunscreen and avoidance of direct sunlight should be recommended. Patients should limit the 
intake of vitamin A. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for further 
information. 
  
SITES WITHIN THE UNITED STATES: 
Isotretinoin MUST be prescribed under the Committed to Pregnancy Prevention Program 
(iPLEDGE). (Physicians must complete a one-time registration with the program in order 
to be able to prescribe the drug. Each physician (or their office representative), dispensing 
pharmacy, and patient must be registered on line @ https://www.ipledgeprogram.com (or 
call 1-866-495-0654 to begin the registration process). 
 
UPON REGISTRATION YOU WILL RECEIVE ALL OF THE INFORMATION AND 
EDUCATIONAL MATERIALS NECESSARY TO PRESCRIBE ISOTRETINOIN. 
Because of isotretinoin’s teratogenicity and to minimize fetal exposure, isotretinoin is 
approved for marketing only under a special restricted distribution program approved by 
the Food and Drug Administration. This program is called iPLEDGE. Isotretinoin must 
only be prescribed by prescribers who are registered and activated with the iPLEDGE 
program. Isotretinoin must only be dispensed by a pharmacy registered and activated with 
iPLEDGE, and must only be dispensed to patients who are registered and meet all the 
requirements of iPLEDGE. The iPLEDGE program is a computer-based risk management 
system that uses verifiable, trackable links between prescriber, patient, pharmacy, and 
wholesaler to control prescribing, using, dispensing and distribution of isotretinoin. 
 
OVERVIEW: PROGRAM REQUIREMENTS 
The iPLEDGE program has specific requirements for prescribers, patients, and 
pharmacists. One of the prescriber’s main responsibilities is knowing and educating 
patients about these requirements. Note: The FDA has provided the following statement 
concerning the physician training aspects of the iPLEDGE site: 
 
“FDA and the sponsors would like the oncology community who uses isotretinoin to enroll 
in iPLEDGE and to know that the “I know how to diagnose and treat the various 
presentations of acne,” statement can be truthfully addressed by oncologists who “know 
how to diagnose and treat” suspected cases by referring these cases to dermatologists for 
management. All the sponsors and FDA agree on this interpretation.” 
 
Prescribers are responsible for registering every patient, who meets the program 
requirements, in the iPLEDGE program via the automated system. They are responsible 
for educating patients about the side effects of isotretinoin and the high risk of birth defects 
for female patients of childbearing potential while taking the drug. As part of this process, 
they are also responsible for counseling patients about the monthly steps they must follow 
to receive isotretinoin. 
 
Prescribers can only write a patient’s prescription for isotretinoin once a month, and then 
only up to a maximum of a 30-day supply. Patients must plan for monthly appointments to 
receive their prescriptions. At each of these appointments, the prescriber must counsel the 

 
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patient about the iPLEDGE program requirements and then confirm via the iPLEDGE 
automated system that this counseling occurred. They must also enter this information after 
the first appointment. 
 
There are different program requirements for male patients and female patients who 
are not of childbearing potential and for female patients of childbearing potential. 
The prescriber must determine if a patient is a female patient of childbearing potential and 
document that she meets the specific requirements of the program. These include taking 
pregnancy tests (processed in a CLIA-certified laboratory) and using 2 forms of birth 
control consistently. Both of these requirements must be followed before, during, and after 
treatment, but are not necessary for patients the physician determines are not of 
childbearing potential. To receive monthly prescriptions, a female patient of childbearing 
potential must also address questions in the iPLEDGE system about the program 
requirements and pregnancy prevention. She must also enter the two forms of birth control 
she is using. In addition to the monthly counseling information, the prescriber must also 
enter into the system the patient’s 2 forms of contraception and the results of the monthly 
pregnancy test obtained from a CLIA-certified laboratory. This information is the criteria 
the system uses to authorize a pharmacy to fill a prescription. 
 
Requirements for Pharmacists 
• 
Isotretinoin can only be obtained from pharmacies registered with and activated in 
the iPLEDGE program. 
• 
Registered and activated pharmacies can obtain isotretinoin only from wholesalers 
registered with the iPLEDGE program. 
• 
The dispensing pharmacist must obtain authorization and a Risk Management 
Authorization (RMA) number before filling and dispensing prescriptions. 
• 
Upon receiving authorization, the dispensing pharmacist can fill a prescription 
for a maximum 30-day supply of isotretinoin. 
• 
Upon authorization, the iPLEDGE system provides a Risk Management 
Authorization (RMA) number to the dispensing pharmacist. The pharmacist should 
record the RMA number directly on the prescription. 
• 
Upon authorization, the iPLEDGE system provides a “Do Not Dispense to 
Patient After” date (7 days from office visit date) to the dispensing pharmacist. The 
pharmacist should record this date on the prescription bag sticker. 
 
6.10 
MELPHALAN 
(L-phenylalanine mustard, phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran®, 
Evomela®) NSC #008806 
 
 
 
 
 
(07/10/18) 
 
 
Source and Pharmacology: 
Melphalan, a phenylalanine derivative of nitrogen mustard, is a bifunctional alkylating agent. 
Melphalan forms covalent cross-links with DNA or DNA protein complexes thereby 
resulting in cytotoxic, mutagenic, and carcinogenic effects. The end result of the alkylation 
process results in the misreading of the DNA code and the inhibition of DNA, RNA, and 
protein synthesis in rapidly proliferating tumor cells. It is cell cycle non-specific. After IV 
administration, melphalan plasma concentrations decline rapidly in a bi-exponential 
manner with distribution phase and terminal elimination phase half-lives of approximately 
10 and 75 minutes, respectively. Plasma melphalan levels are highly variable after oral 

 
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dosing, both with respect to the time of the first appearance of melphalan in plasma (range 
approximately 0 to 6 hours) and to the peak plasma concentration achieved. These results 
may be due to incomplete intestinal absorption, a variable “first pass” hepatic metabolism, 
or to rapid hydrolysis. The oral dose averages 61% ± 26% of that following IV 
administration. The terminal elimination plasma half-life of oral melphalan is 
1.5 ± 0.83 hours. The steady-state volume of distribution of melphalan is 0.5 L/kg. The 
extent of melphalan binding to plasma proteins ranges from 60-90%. Melphalan is 
eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and 
dihydroxymelphalan. The 24-hour urinary excretion of parent drug is approximately 10% 
suggesting that renal clearance is not a major route of elimination of parent drug. 
Penetration into CSF is low. Despite the fact that the contribution of renal elimination to 
melphalan clearance appears to be low, one pharmacokinetic study suggests dosage may need 
to be reduced in patients with renal impairment. 
 
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 
Anorexia, nausea, vomiting, 
hyponatremia (high dose) 
 
Anaphylaxis, hypotension, 
diaphoresis, pruritus 
atrial fibrillation (high dose), 
extravasation (rare) but if 
occurs = local ulceration, 
SIADH, Seizures 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
Myelosuppression (L), 
mucositis, diarrhea, alopecia 
 
Abnormal liver function tests, 
jaundice, hepatitis 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
 
Amenorrhea, testicular 
suppression 
Bone marrow failure, 
hemolytic anemia, pulmonary 
fibrosis, interstitial 
pneumonitis 
Late: 
Any time after 
completion of treatment 
 
Sterility, primary ovarian 
failure 
Secondary malignancy 
Unknown 
Frequency 
and Timing: 
Melphalan was embryolethal and teratogenic in rats following oral (6 to 18 mg/m2/day for 
10 days) and intraperitoneal (18 mg/m²) administration. Malformations resulting from 
melphalan included alterations of the brain (underdevelopment, deformation, meningocele, 
and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible 
and tail, as well as hepatocele (exomphaly). It is unknown whether the drug is excreted in 
breast milk. 
(L) Toxicity may also occur later 
 
Formulation and Stability: 
Melphalan for Injection is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each 
single-use vial contains melphalan hydrochloride equivalent to 50 mg melphalan and 
20 mg povidone. Melphalan for Injection is reconstituted using the sterile diluent provided. 
Each vial of sterile diluent contains sodium citrate 0.2 g, propylene glycol 6.0 mL, ethanol 
(96%) 0.52 mL, and SWFI to a total of 10 mL. Store at controlled room temperature 15°-
30°C (59°-86°F) and protect from light. 
• 
Reconstitute to a concentration of 5 mg/mL by rapidly injecting 10 mL of the supplied 
diluent directly into the vial of lyophilized powder using a sterile needle (20-gauge or 
larger needle diameter) and syringe. Immediately shake vial vigorously until a clear 

 
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solution is obtained. Rapid addition of the diluent followed by immediate vigorous 
shaking is important for proper dissolution.  
• 
Immediately dilute the dose to be administered in NS to a final concentration not to 
exceed 2 mg/mL for IV central line administration or ≤ 0.45 mg/mL for peripheral IV 
administration. 
• 
A precipitate forms if the reconstituted solution is stored at 5°C. Do not refrigerate the 
reconstituted product. 
(The time between reconstitution/dilution and administration of melphalan should be kept 
to a minimum because reconstituted and diluted solutions of melphalan are unstable. Over 
as short a time as 30 minutes, a citrate derivative of melphalan has been detected in 
reconstituted material from the reaction of melphalan with the sterile diluent for 
melphalan. Upon further dilution with saline, nearly 1% label strength of melphalan 
hydrolyzes every 10 minutes.)  
 
Evomela brand of melphalan for injection is supplied as 50 mg, white to off-white 
lyophilized powder in single-dose vial for reconstitution (after reconstitution the solution 
is clear and colorless to light yellow). Each vial contains 50 mg melphalan free base 
equivalent to 56 mg melphalan hydrochloride and 2700 mg Betadex Sulfobutyl Ether 
Sodium, NF. Evomela is light sensitive. Retain in original carton until use. Do not mix 
Evomela® with other melphalan hydrochloride for injection drug products.  
 
• 
Use normal saline solution (0.9% Sodium Chloride Injection, USP) (8.6 mL as 
directed) to reconstitute Evomela and make a 50 mg/10 mL (5 mg/ mL) nominal 
concentration of melphalan. The normal saline used to reconstitute each vial should 
appear to be assisted or pulled into the vial by the negative pressure (partial vacuum) 
present in the vial. Discard any vial (and replace with another vial) if there is no 
vacuum present when reconstituting the vial with normal saline. The reconstituted 
Evomela drug product is stable for 24 hours at refrigerated temperature (5°C) without 
any precipitation due to the high solubility. The reconstituted Evomela drug product is 
stable for 1 hour at room temperature. 
• 
Calculate the required volume of Evomela needed for a patient’s dose and withdraw 
that volume from the vial(s).  
• 
Add the required volume of Evomela to the appropriate volume of 0.9% Sodium 
Chloride Injection, USP to a final concentration of 0.45 mg/mL. The Evomela 
admixture solution is stable for 4 hours at room temperature in addition to the 1 hour 
following reconstitution.  
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
Injection: 
Administer by IV infusion through a peripheral or a central line. The infusion must be 
completed within 60 minutes of product reconstitution. 
 
Evomela: Infuse over 30 minutes via an injection port or central venous catheter 
 
Supplier: 
Commercially available. See package insert for further information. 
 

 
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6.11 
MESNA – INJECTION 
(sodium 2-mercaptoethane sulfonate, UCB 3983, Mesnex) NSC #113891 
 
 
 
 
 
 
 
 
 
 
(10/13/17) 
 
Source and Pharmacology: 
Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis 
induced by ifosfamide. Mesna is rapidly oxidized to its major metabolite, mesna disulfide 
(dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly 
eliminated by the kidneys. In the kidney, the mesna disulfide is reduced to the free thiol 
compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites 
(acrolein and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step in the 
detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a 
nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein 
and to other urotoxic metabolites. In multiple human xenograft or rodent tumor model 
studies, mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or 
multiple courses) failed to demonstrate interference with antitumor efficacy. 
 
After an 800 mg dose the half lives for mesna and dimesna are 0.36 hours and 1.17 hours, 
respectively. Approximately 32% and 33% of the administered dose was eliminated in the 
urine in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered 
was eliminated within 4 hours.  
 
Toxicity1: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Nausea, vomiting, 
stomach pain, fatigue, 
headache 
Facial flushing, fever, 
pain in arms, legs, and 
joints, rash, transient 
hypotension, 
tachycardia, dizziness, 
anxiety, confusion, 
periorbital swelling, 
anaphylaxis, coughing 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
Diarrhea 
 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of mesna have not been noted in 
animals fed 10 times the recommended human doses. There are however no 
adequate and well-controlled studies in pregnant women. It is not known if 
mesna or dimesna is excreted into human milk 
3 
All currently available products in the U.S. are preserved with benzyl alcohol. Benzyl 
Alcohol has been associated with death in pre-term infants weighing less than 2500 g 
and receiving 99-405 mg/kg/day. Benzyl alcohol is normally oxidized rapidly to 
benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid. In 
pre-term infants, however, this metabolic pathway may not be well developed. Onset 
of toxic illness in these infants occurred between several days and a few weeks of age 
with a characteristic clinical picture that included metabolic acidosis progressing to 
respiratory distress and gasping respirations. Many infants also had central-nervous-
system dysfunction, including convulsions and intracranial hemorrhage; hypotension 

 
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leading to cardiovascular collapse was a late finding usually preceding death. [For 
comparison in the ICE regimen of 3000 mg/m²/day of ifosfamide and a daily mesna 
dose of 60% of the ifosfamide dose = to 1800 mg/m²/day; a child would be expected to 
receive 18 mL/m²/day of mesna (concentration of 100 mg/mL and 10.4 mg/mL of 
benzyl alcohol) 187.2 mg/m²/day of benzyl alcohol or 6.24 mg/kg/day.] 
 
Formulation and Stability: 
Mesna for injection is available as 100 mg/mL in 10 mL multidose vials which contain 
0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesna Injection 
multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. Store product 
at controlled room temperature 15º-25C (68º77ºF). Mesna is not light-sensitive, but is 
oxidized to dimesna when exposed to oxygen. Mesna- as benzyl alcohol-preserved vials 
may be stored and used for 8 days. 
 
Guidelines for Administration:  
See Treatment, Dose Modifications, and Supportive Care sections of the protocol. 
 
For IV administration, dilute mesna to 20 mg/mL with dextrose or saline containing 
solutions. Mesna may be mixed with ifosfamide or cyclophosphamide. After dilution for 
administration, mesna is physically and chemically stable for 24 hours at 25ºC (77ºF). 
Mesna may cause false positive test for urinary ketones.  
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.12 
PEGFILGRASTIM, PEGFILGRASTIM-JMDB, PEGFILGRASTIM-CBQV 
(pegylated filgrastim, PEG filgrastim, SD/01, Neulasta®, Fulphila®, Udenyca®) 
NSC #725961 
(01/28/19) 
 
Source and Pharmacology: 
Pegfilgrastim is the PEGylated form of recombinant methionyl human G-CSF (filgrastim). 
Pegfilgrastim 
is 
produced 
by 
covalently 
binding 
a 
20-kilodalton 
(kD) 
monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue of 
filgrastim. The molecular weight of pegfilgrastim is 39 kD. G-CSF is a lineage specific 
colony-stimulating factor which regulates the production of neutrophils within the bone 
marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-
cell functional activation (including enhanced phagocytic ability, priming of the cellular 
metabolism associated with respiratory burst, antibody dependent killing, and the increased 
expression of some functions associated with cell surface antigens). 
 
After subcutaneous injection the elimination half-life of pegfilgrastim ranges from 15 to 
80 hours and the time to peak concentration ranges from 24 to 72 hours. Serum levels are 
sustained in most patients during the neutropenic period postchemotherapy, and begin to 
decline after the start of neutrophil recovery, consistent with neutrophil-dependent 
elimination. After subcutaneous administration at 100 mcg/kg in 37 pediatric patients with 
sarcoma, the terminal elimination half-life was 30.1 (+/- 38.2) hours in patients 0 to 5 years-
old, 20.2 (+/- 11.3) hours in patients 6 to 11 years-old, and 21.2 (+/- 16) hours in children 
12 to 21 years-old. 
 

 
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Toxicity: 
 
Incidence 
Toxicities 
Common 
(>20% of patients) 
• 
Bone pain 
Occasional 
(4-20% of patients) 
• 
Pain in extremity 
Rare 
(<3% of patients) 
• 
Acute respiratory distress syndrome (ARDS) 
• 
Allergic reactions/hypersensitivity, including anaphylaxis, 
skin rash, urticaria, generalized erythema, and flushing  
• 
Antibody development 
• 
Capillary leak syndrome 
• 
Glomerulonephritis 
• 
Injection site reaction 
• 
Leukocytosis 
• 
Sickle cell crisis 
• 
Splenic rupture, splenomegaly 
• 
Sweet’s syndrome (acute febrile neutrophilic dermatosis), 
cutaneous vasculitis  
• 
Aortitis 
Pregnancy & 
Lactation 
Fetal toxicities and teratogenic effects of pegfilgrastim in humans 
are unknown. Adverse events were observed in some animal 
reproduction studies. It is unknown whether the drug is excreted in 
breast milk. 
 
 
Formulation and Stability: 
Pegfilgrastim (Neulasta®): Supplied as a preservative-free solution containing 6 mg 
(0.6 mL) of pegfilgrastim (10 mg/mL) in a single-dose syringe with 27 g, ½ inch needle 
with an UltraSafe™ Needle Guard. The needle cover of the prefilled syringe contains drug 
natural rubber (a derivative of latex).  
 
Pegfilgrastim-jmdb (Fulphila®): Supplied as 6 mg/0.6 mL sterile, clear, colorless 
preservative-free solution (pH 4.0) containing acetate (0.7 mg), D-sorbitol (30 mg), 
polysorbate 20 (0.024 mg) and sodium (0.01 mg) in Water for Injection, USP. It is intended 
for subcutaneous use only and is supplied in a single-dose prefilled syringe with a 29 gauge, 
½ inch needle, with UltraSafe Passive Plus™ Needle Guard. The prefilled syringe does not 
bear graduation marks and is designed to deliver the entire contents of the syringe 
(6 mg/0.6 mL).  
 
Pegfilgrastim-cbqv (Udenyca®): Supplied as 6 mg/0.6 mL syringe in a sterile, clear, 
colorless, preservative- free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 
(0.02 mg), sodium (0.02 mg), and sorbitol (30 mg) in Water for Injection, USP. It is 
supplied in 0.6 mL prefilled single-dose syringes with an UltraSafe Passive™ Needle 
Guard for manual subcutaneous injection. The prefilled syringe does not bear graduation 
marks and is designed to deliver the entire contents of the syringe (6 mg/0.6 mL). The 
needle cap of the prefilled syringe is not made with natural rubber latex. 
 

 
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Storage: 
Store refrigerated between 2° to 8°C (36° to 46°F) in the carton to protect from light. Do 
not shake. Discard Neulasta® and Udenyca® syringes if stored at room temperature for 
more than 48 hours. Fulphila™ syringes should be discarded if stored at room temperature 
for more than 72 hours. Avoid freezing; if frozen, thaw in the refrigerator before 
administration. Discard syringe if frozen more than once.  
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol. 
 
Pegfilgrastim should not be administered in the period between 14 days before and 
24 hours after chemotherapy. Do not shake. The manufacturer does not recommend use of 
the 6-milligram (mg) fixed-dose formulation of pegfilgrastim in infants, children, or 
adolescents under 45 kilograms. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for further 
information. 
 
6.13 
SARGRAMOSTIM 
(Granulocyte Macrophage Colony Stimulating Factor, rhu GM-CSF, rGM-CSF, GM-CSF, 
Leukine®) NSC #613795 
 
 
 
 
 
(11/27/17) 
 
Source and Pharmacology: 
Sargramostim (recombinant human GM-CSF) is a glycoprotein produced in yeast (S. 
cerevisiae) by recombinant DNA technology. rGM-CSF is a hematopoietic growth factor 
which supports survival, clonal expansion, and differentiation of hematopoietic progenitor 
cells. rGM-CSF induces partially committed progenitor cells to divide and differentiate in 
the granulocyte-macrophage pathways. rGM-CSF stimulates the production of monocytes, 
granulocytes, erythrocytes, and sometimes, megakaryocytes in the bone marrow. It also 
induces mature neutrophil and monocytes to increase phagocytosis, superoxide generation, 
ADCC, tumoricidal killing and cytokine production (IL-1 and tumor necrosis factor). 
Recombinant human GM-CSF is a glycoprotein of 127 amino acids characterized by three 
primary molecular masses of 15500, 16800, and 19500 daltons. The amino acid sequence 
differs from the natural sequence by a substitution of leucine at position 23 and the CHO 
moiety may be different from the native protein. After subcutaneous administration of 
sargramostim, peak levels were obtained in 1-4 hours and were detectable at therapeutic 
levels for 12-16 hours post injection. The elimination t½ ranges from 1.5-2.7 hours after SubQ 
or IV administration. 
 

 
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Toxicity: 
 
Common 
Happens to 21-100 children out of 
every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-
2 days of 
receiving drug 
Headache, malaise, fatigue, rash, 
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: 
Any time later 
during therapy 
 
Thrombocytopenia  
 
Unknown 
Frequency 
and Timing:  
Fetal and teratogenic toxicities: It is not known whether sargramostim can cause fetal harm or affect 
reproduction capacity when administered to a pregnant woman. It is unknown whether the drug is 
excreted in breast milk. 
 
Formulation and Stability: 
Sargramostim is available as a lyophilized sterile, white, preservative free powder with 
250 mcg (1.4 million International Units) per vial. 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 

 
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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. 
 
6.14 
THIOTEPA 
(Tepadina®, Tespa, Thiophosphamide, Triethylenethiophosphoramide Tspa, WR-45312) 
NSC #6396 
 
 
 
 
 
 
 
(01/23/18) 
 
Source and Pharmacology:  
Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and 
pharmacologically to nitrogen mustard. The radiomimetic action of thiotepa is believed to 
occur through the release of ethylenimine radicals which, like irradiation, disrupt the bonds 
of DNA. One of the principal bond disruptions is initiated by alkylation of guanine at the 
N-7 position, which severs the linkage between the purine base and the sugar and liberates 
alkylated guanines. Thiotepa is desulfurated by cytochrome P-450 enzymes such as 2B1 
and 2C11 which catalyze the conversion of thiotepa to tepa. Tepa is less toxic than thiotepa 
and has been demonstrated to produce alkali-labile sites in DNA, rather than cross-links. 
These findings indicate that tepa reacts differently from thiotepa and produces 
monofunctional alkylation of DNA. A second metabolite of thiotepa, a mercapturic acid 
conjugate, is formed via glutathione conjugation. Monochloro tepa is the third metabolite 
found in the urine. 
 
Following short intravenous infusion (less than 5 minutes), peak concentrations of thiotepa 
were measured within 5 minutes. At steady state, the volume of distribution was 
independent of dose and ranged from 0.3 to 1.6 liters per kilogram (L/kg). 
 
Approximately 4.2% of the original dose is eliminated in the urine within 24 hours as tepa. 
The elimination half-life of thiotepa ranges from 2.3 to 2.4 hours. The half-life of tepa 
ranged from 3 to 21.1 hours in one study. 
 
Toxicity: 
 
Common 
Happens to 21-100 children out of 
every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to 
< 5 children out of 
every 100 
Immediate: 
Within 
1-2 days 
of 
receiving drug 
Nausea, vomiting, anorexia, fatigue, 
weakness 
Pain at the injection site, 
dizziness, headache, blurred 
vision, 
abdominal 
pain, 
contact dermatitis, rash 
Anaphylaxis, laryngeal 
edema, 
wheezing, 
hives  
Prompt: 
Within 
2-3 weeks, 
prior to next course 
Myelosuppression; at higher doses in 
conditioning regimens for BMT: 
mucositis, esophagitis 
At 
higher 
doses 
in 
conditioning regimens for 
BMT: 
encephalopathy 
(inappropriate 
behavior, 
confusion, 
somnolence), 
increased 
liver 
transaminases, 
increased 
bilirubin, hyperpigmentation 
of the skin (bronzing effect) 
Febrile 
reaction, 
conjunctivitis, dysuria, 
urinary retention 

 
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Delayed: 
Anytime later during 
therapy, excluding the 
above conditions 
Gonadal 
dysfunction/infertility, 
azoospermia, amenorrhea  
 
Alopecia, 
secondary 
malignancy 
Unknown Frequency 
and Timing:  
Fetal and teratogenic toxicities: Carcinogenic and teratogenic effects of thiotepa have been 
noted in animal models at doses ≤ to those used in humans. It is not known if thiotepa is 
excreted into human breast milk. 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Thiotepa for Injection USP, for single use only, is available in vials containing 15 mg of 
nonpyrogenic, sterile lyophilized powder. Store in a refrigerator at 2°-8°C (36°-46°F). 
PROTECT FROM LIGHT AT ALL TIMES. 
 
Note:  FDA is allowing temporary importation of a European thiotepa product 
(Tepadina). Verify product, storage, and preparation instructions prior to dispensation 
and administration. Refer to specific product labeling for details. 
 
Tepadina: Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). Protect 
from light; do not freeze. Reconstituted solution (10 mg/mL) is stable for 8 hours when 
stored at 2°C to 8°C (36°F to 46°F). Solution further diluted for infusion is stable for 24 
hours when stored at 2°C to 8°C (36°F to 46°F), or for 4 hours when stored at 25°C (77°F). 
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
Reconstitute Thiotepa for Injection with 1.5 mL of Sterile Water for Injection resulting in 
a drug concentration of approximately 10 mg/mL. (As per manufacturer’s information: 
Actual content per vial 15.6 mg; withdrawable amount 14.7 mg/1.4 mL; approximate 
reconstituted concentration: 10.4 mg/mL). When reconstituted with Sterile Water for 
Injection, solutions of thiotepa should be stored at refrigerated temperatures 2°-8°C (36°-
46°F) protected from light and used within 8 hours. The reconstituted solution is hypotonic 
and should be further diluted with Sodium Chloride Injection (0.9% NaCl) prior to use. 
Thiotepa at a concentration of 1-5 mg/mL in 0.9% NaCl is stable for 24 hours at room 
temperature. At concentration of 0.5mg/mL it is stable for only one hour and stability 
decreases significantly at concentrations of less than 0.5mg/mL. Therefore, solutions 
diluted to 0.5mg/mL should be used immediately. 
 
In order to eliminate haze, filter solutions through a 0.22 micron filter [Polysulfone 
membrane (Gelman’s Sterile Aerodisc®, Single Use) or triton-free mixed ester of 
cellulose/PVC (Millipore’s MILLEX®-GSFilter Unit)] prior to administration. Filtering 
does not alter solution potency. Reconstituted solutions should be clear. Solutions that 
remain opaque or precipitate after filtration should not be used. 
 
Tepadina: Reconstitute each 15 mg vial with 1.5 mL SWFI, or each 100 mg vial with 10 
mL SWFI, to a concentration of 10 mg/mL. Gently mix by repeated inversions. Solution 
may be clear or opalescent; do not use if particulate matter is present. Further dilute 
reconstituted solution for IV infusion in 500 mL NS (1,000 mL NS if dose > 500 mg). If 
dose is < 250 mg, dilute in an appropriate volume of NS to achieve a final concentration 
of 0.5 to 1 mg/mL. 
 

 
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When thiotepa is given in bone marrow transplant doses, bathe the patient and change linen 
frequently (≥ 2 baths/day) to avoid the contact dermatitis and discoloration of the skin that 
is seen with high dose. 
 
Supplier: Commercially available. See package insert for further information.  
 
6.15 
TOPOTECAN 
(SKF-104864, Hycamtin®) NSC #609699 
 
 
 
(06/03/13) 
 
Source and Pharmacology: 
Topotecan hydrochloride is a semi-synthetic derivative of camptothecin (an alkaloid 
derived from the camptothecin tree which grows widely throughout Asia) and is an anti-
tumor drug with topoisomerase I-inhibitory activity. Topoisomerase I relieves torsional 
strain in DNA by inducing reversible single strand breaks. Topotecan binds to the 
topoisomerase I-DNA complex and prevents re-ligation of these single strand breaks. The 
cytotoxicity of topotecan is thought to be due to double strand DNA damage produced 
during DNA synthesis, when replication enzymes interact with the ternary complex formed 
by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these 
double strand breaks. Topotecan undergoes a reversible pH dependent hydrolysis of its 
lactone moiety; it is the lactone form that is pharmacologically active. At pH ≤ 4, the 
lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates 
at physiologic pH. In vitro studies in human liver microsomes indicate that metabolism of 
topotecan to an N-demethylated metabolite represents a minor metabolic pathway. 
Topotecan exhibits multi-exponential pharmacokinetics with a terminal half-life of 2 to 
3 hours. Total exposure (AUC) is approximately dose-proportional. Binding of topotecan 
to plasma proteins is about 35%. 
 
In humans, about 30% of the dose is excreted in the urine and renal clearance is an 
important determinant of topotecan elimination. In patients with mild renal impairment 
(Clcr of 40 to 60 mL/min.), topotecan plasma clearance was decreased to about 67% of the 
value in patients with normal renal function. In patients with moderate renal impairment 
(Clcr of 20 to 39 mL/min.), topotecan plasma clearance was reduced to about 34% of the 
value in control patients, with an increase in half-life. Dosage adjustment is recommended 
for these patients. Plasma clearance in patients with hepatic impairment (serum bilirubin 
levels between 1.7 and 15.0 mg/dL) was decreased to about 67% of the value in patients 
without hepatic impairment. Topotecan half-life increased slightly, from 2 hours to 
2.5 hours, but these hepatically impaired patients tolerated the usual recommended 
topotecan dosage regimen. 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Nausea, vomiting, diarrhea 
(L), constipation, fever, 
pain (abdominal, skeletal, 
back pain) 
Anorexia, headache, 
asthenia, rash (urticaria, 
pruritus, bullous eruption) 
(L), asymptomatic 
hypotension, dyspnea 
Anaphylaxis, 
angioedema, chest pain, 
rigors 
Prompt: 
Myelosuppression, fatigue, 
febrile neutropenia 
Stomatitis/mucositis, 
increased SGOT 
Elevated bilirubin, 
paresthesias, myalgia, 

 
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Within 2-
3 weeks, prior to 
next course 
(AST)/SGPT 
(ALT)/alkaline 
phosphatase, sepsis 
arthralgia, intratumoral 
bleeding 
Delayed: 
Anytime later 
during therapy 
Alopecia 
 
Microscopic hematuria, 
increased creatinine, 
proteinuria 
Unknown 
Frequency and 
Timing: 
Teratogenic effects of topotecan have been noted in animal models at doses ≤ to 
those used in humans. It is not known if topotecan is excreted into human breast 
milk.  
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Topotecan is available as a lyophilized powder for reconstitution and as a solution 
concentrate. Each vial of lyophilized powder contains topotecan hydrochloride equivalent 
to 4 mg of topotecan as free base. Inactive ingredients are mannitol 48 mg, and tartaric acid 
20 mg. Hydrochloric acid and sodium hydroxide may be used to adjust the pH. Topotecan 
concentrate solution for injection is supplied as a sterile, non-pyrogenic, clear, yellow to 
yellow-green solution at a topotecan free base concentration of 4 mg/4 mL (1 mg/mL) 
available in single use vials. Each mL of topotecan injection contains topotecan 
hydrochloride equivalent to 1 mg of topotecan as free base, 5 mg tartaric acid, NF and 
water for injection, USP. Hydrochloric acid and/or sodium hydroxide may be used for pH 
adjustment. The pH of the solution is approximately 2.6 to 3.2; both products must be 
further diluted prior to administration in a minimum of 50 mL of compatible fluid for 
infusion. Both types of vials should be protected from light in the original cartons and 
stored at controlled room temperature between 20° and 25°C (68° and 77°F). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
Reconstitute each topotecan 4 mg vial with 4 mL SWFI to concentration of 1 mg/mL. 
Further dilute in 50-250 mL D5W or NS. Reconstituted vials of topotecan diluted for 
infusion are stable at approximately 20°-25°C (68°-77°F) and ambient lighting conditions 
for 24 hours. 
 
Supplier: Commercially available. See package insert for further information. 
 
6.16 
VINCRISTINE SULFATE 
(Oncovin®, VCR, LCR) NSC #67574 
 
 
 
 
(08/16/12) 
 
Source and Pharmacology:  
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin, 
disrupting microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. 
The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours, and 85 hours 
respectively; however, the range of the terminal half-life in humans is from 19 to 155 hours. 
The liver is the major excretory organ in humans and animals; about 80% of an injected 
dose of vincristine sulfate appears in the feces and 10% to 20% can be found in the urine. 
The p450 cytochrome involved with vincristine metabolism is CYP3A4. Within 15 to 
30 minutes after injection, over 90% of the drug is distributed from the blood into tissue, 
where it remains tightly, but not irreversibly bound. It is excreted in the bile and feces. There 
is poor CSF penetration.  

 
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Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
 
Jaw pain, headache 
Extravasation (rare) but if 
occurs = local ulceration, 
shortness of breath, and 
bronchospasm 
Prompt: 
Within 2-
3 weeks, prior to 
the next course 
Alopecia, constipation 
Weakness, abdominal 
pain, mild brief 
myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia) 
Paralytic ileus, ptosis, 
diplopia, night blindness, 
hoarseness, vocal cord 
paralysis, SIADH, 
seizure, defective 
sweating 
Delayed: 
Any time later 
during therapy 
Loss of deep tendon 
reflexes 
Peripheral paresthesias 
including numbness, 
tingling and pain; 
clumsiness; wrist drop, 
foot drop, abnormal gait  
Difficulty walking or 
inability to walk; 
sinusoidal obstruction 
syndrome (SOS, formerly 
VOD) (in combination); 
blindness, optic atrophy; 
urinary tract disorders 
(including bladder atony, 
dysuria, polyuria, 
nocturia, and urinary 
retention); autonomic 
neuropathy with postural 
hypotension; 8th cranial 
nerve damage with 
dizziness, nystagmus, 
vertigo and hearing loss 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in 
combination with other antineoplastic agents) have been noted in humans. The 
toxicities include: chromosome abnormalities, malformation, pancytopenia, 
and low birth weight. It is unknown whether the drug is excreted in breast 
milk. 
 
Formulation and Stability: 
Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine 
sulfate 1 mg (1.08 µmol), mannitol 100 mg, SWFI; acetic acid and sodium acetate are 
added for pH control. The pH of vincristine sulfate injection, USP ranges from 3.5 to 5.5. 
This product is a sterile, preservative free solution. Store refrigerated at 2˚-8˚C or 36˚-46˚F. 
Protect from light and retain in carton until time of use. 
 
Do not mix with any IV solutions other than those containing dextrose or saline. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of 
protocol. 
 
The World Health Organization, the Institute of Safe Medicine Practices (United States) 
and the Safety and Quality Council (Australia) all support the use of minibag rather than 
syringe for the infusion of vincristine. The delivery of vincristine via either IV slow push 
or minibag is acceptable for COG protocols. Vincristine should NOT be delivered to the 

 
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Page 152 
patient at the same time with any medications intended for central nervous system 
administration. Vincristine is fatal if given intrathecally. 
 
Injection of vincristine sulfate should be accomplished as per institutional policy. 
Vincristine sulfate must be administered via an intact, free-flowing intravenous needle or 
catheter. Care should be taken to ensure that the needle or catheter is securely within the 
vein to avoid extravasation during administration. The solution may be injected either 
directly into a vein or into the tubing of a running intravenous infusion. 
 
Special precautions: FOR INTRAVENOUS USE ONLY. 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap 
bearing the statement: “Do not remove covering until moment of injection. For intravenous 
use only – Fatal if given by other routes.” 
 
Supplier: Commercially available from various manufacturers. See package insert for 
more detailed information. 
 
 
 
 

 
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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 and 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. 
1 Submit for central review 
2 Submit for central review per Section 14.2 
 
7.2 
Research Studies for which Patient Participation is Optional 
 
 
For full details, see Section 15.0. For a summary of samples, see Appendix V. 
STUDIES TO BE 
OBTAINED 
End of 
Therapy 
Time from End of Therapy (Months) 
At 
Relapse 
 
3  
6 
9 
12 
15 
18 
24 
30 
36 
42 
48 
54 
60 
History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam with VS 
(including BP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ht, Wt, BSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC, differential, 
platelets 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Electrolytes including 
Ca++, PO4, Mg++ 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Creatinine, ALT, 
bilirubin 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Free T4, TSH 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
ECHO 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Audiogram 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Cross sectional imaging 
of primary tumor site 
(MRI or CT)  
X1 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
X1 
123I-MIBG scan if 
positive at baseline 
X1 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
X1 
FDG-PET/CT or 
PET/MR scan if positive 
at baseline 
X1 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
X1 
Bilateral bone marrow 
aspirates and biopsies 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Optional studies  
(see Appendix V ) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 
Criteria for Removal from Protocol Therapy 
a) Repeat eligibility studies (if required) prior to the initiation of protocol therapy are outside 
the parameters required for eligibility (see Section 3.2) 
b) Refusal of further protocol therapy by patient/parent/guardian 
c) Lack of sufficient stem cells to support tandem transplant or inability to harvest stem cells 
prior to Consolidation (see Section 18.2) 
d) Did not receive dinutuximab during Induction therapy 
e) Progressive disease at any time from the end of Induction Cycle 4 until the end of protocol 
therapy. Patients with stable disease or better may remain on protocol therapy. 
f) Completion of planned therapy 
g) Physician determines it is in the patient’s best interest 
h) Delays in therapy that meet the criteria in Sections 4.6.6 and 4.9.1 
i) Development of a second malignancy 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Follow-up data will be required unless patient is taken off study.  
 
8.2 
Off Study Criteria 
a) Death 
b) Lost to follow-up 
c) Patient enrollment onto another COG anti-cancer therapeutic study (e.g., at recurrence) 
d) Withdrawal of consent for any further data submission 
e) Fifth anniversary of the date the patient was enrolled on this study 
 
 

 
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9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size and Study Duration 
Forty-two evaluable patients will be necessary to analyze the primary objective, assessing 
the tolerability and feasibility of ch14.18 (dinutuximab) administration during Induction. 
Enrollment of up to 45 patients may be required in order to generate the 42 evaluable 
patients. The additional 3 patients accounts for an estimated 3% of patients that may 
discontinue protocol therapy during the first 2 cycles of Induction [prior to the first dose of 
ch14.18 (dinutuximab], as reported on the previous COG high-risk neuroblastoma study 
ANBL0532, and losing an additional 5% for other reasons. The 42 eligible, evaluable 
patients will provide suitable operating characteristics to determine whether administration 
of ch14.18 (dinutuximab) and GM-CSF during Induction is tolerable and feasible for 
further study. 
 
Conservative accrual estimates are based on the enrollment on ANBL0532, the previous 
COG high-risk neuroblastoma study. An estimated accrual rate of 18 patients per year was 
observed on ANBL0532 at 8 of the included institutions. The remaining two institutions, 
St. Jude Children’s Research Hospital and Royal Children's Hospital, did not enroll patients 
on ANBL0532, but conservatively expect to accrue 4 and 7 patients per year respectively. 
Therefore, the total expected accrual for ANBL17P1 will be 29 patients per year. Thus, 
accrual of up to 45 patients should be completed in approximately 1.6 years. The study will 
require an additional 12 months for completion of therapy and toxicity evaluation for a 
total study duration of approximately 2.6 years. 
 
The following institutions will participate in this limited-institution study: 
Institutions 
Average Annual 
Enrollment on 
ANBL0532 
St. Jude Children’s Research Hospital, Memphis TN 
4.00* 
Dana-Farber Cancer Institution, Boston, MA 
4.68 
Children’s Hospital of Los Angeles, Los Angeles, CA 
2.86 
Primary Children’s Hospital, Salt Lake City, UT 
2.08 
Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 
2.60 
Children’s National Medical Center, Washington, DC 
1.82 
Columbia University/Herbert Irving Cancer Center, New York, NY 
1.04 
Starship Children’s Hospital, Auckland, New Zealand 
2.08 
The Children’s Hospital at Westmead, Westmead, NSW, Australia 
1.04 
Royal Children's Hospital, Parkville, VIC, Australia 
7.00* 
*Estimated rate; institution did not enroll any patients on ANBL0532 
 
9.2 
Study Design 
This trial is a prospective, single arm, limited institution pilot study to assess the tolerability 
and feasibility of administering ch14.18 (dinutuximab) in combination with a multi-agent 
chemotherapy regimen during the Induction phase for patients with newly-diagnosed high-
risk neuroblastoma. All patients will receive the same treatment. A stopping rule for 
tolerability will be used to closely monitor patients for the occurrence of toxicities deemed 

 
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Page 156 
unacceptable. In addition, we will monitor for the feasibility of administering the intended 
doses of ch14.18 (dinutuximab).  
 
9.3 
Methods of Analysis 
9.3.1 
Evaluability 
Any eligible patient who receives at least one dose of ch14.18 (dinutuximab) 
during Induction will be evaluable for purposes of evaluating the tolerability and 
feasibility monitoring rules. Any eligible patient who receives at least one dose of 
ch14.18 (dinutuximab) during post-Consolidation will be evaluable for 
exploratory study objective 1.3.3 related to HACA development during post-
Consolidation. 
 
9.3.2 
Primary Endpoint 
9.3.2.1 Tolerability 
The primary endpoints used to assess the tolerability aspect of the primary 
objective include: 
a. the number of toxic deaths during Cycles 3-5 of Induction. 
b. the number of patients with unacceptable toxicities (using CTCAE 
v.5.0 for toxicity assessment and grading) related to ch14.18 
(dinutuximab) during Cycles 3–5 of Induction as defined below: 
i. Hypotension requiring the use of pressors for ≥ 24 hours, including 
Grade 4 capillary leak syndrome or Grade 3 and 4 hypotension 
requiring pressors. 
ii. Respiratory toxicity requiring ventilator support ≥ 24 hours, 
including Grade 4 respiratory toxicity. 
iii. Grade 4 neuropathy that does not resolve to baseline prior to the next 
cycle of therapy. 
iv. Grade ≥ 3 neuropathy that recurs following a 50% dose reduction. 
v. Failure to recover ANC to ≥ 750/mm3 by Day 35 of a cycle. 
 
A patient will be counted as having experienced an unacceptable toxicity if 
a toxic death or one of the unacceptable toxicities listed above occurs. Only 
toxicities designated as possibly, probably, or definitely attributed to 
ch14.18 (dinutuximab) during Cycles 3–5 of Induction will be considered. 
 
9.3.2.2 Feasibility 
The feasibility of delivering ch14.18 (dinutuximab) during Cycles 3-5 of 
Induction chemotherapy will be monitored in this trial. The primary 
endpoint used to assess the feasibility aspect of the primary objective will 
be the proportion of patients who are classified as a “failure”. Feasibility 
“failures” are defined as patients that do not receive ≥ 75% of the planned 
ch14.18 (dinutuximab) doses during Induction. Any doses of ch14.18 
(dinutuximab) held during Cycles 3-5 of Induction per protocol due to 
inability to harvest adequate stem cells will not count as planned/intended 
doses. 
 

 
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9.3.3 
Secondary Endpoints 
Response will be determined using the revised International Neuroblastoma 
Response Criteria (INRC).73 Response rate will be calculated as the percentage of 
eligible patients with at least a partial response (PR) or better at the end of 
Induction and will also be considered in determining whether the regimen is worth 
further study. For event-free survival (EFS), time to event will be calculated from 
the time of study enrollment to the occurrence of disease relapse or progression, 
secondary malignancy, or death. For overall survival (OS), death will be the only 
event considered and time to death will be calculated from the time of study 
enrollment. Patients without an event or death will be censored at the time of last 
follow-up. 
 
9.3.3.1 Power Calculations for HACA Development  
With enrollment of up to 45 patients, an estimated 30 evaluable patients 
will be available for evaluation of exploratory study objective 1.3.3 related 
to HACA development during post-Consolidation. This accounts for an 
estimated 35% of patients going off protocol therapy prior to starting post-
Consolidation ch14.18 (dinutuximab). The projected discontinuation from 
protocol therapy is less than was seen on the most recent COG high-risk 
neuroblastoma studies. Approximately 42% of patients treated on 
contemporaneous COG high-risk neuroblastoma protocols did not receive 
post-Consolidation ch14.18 (dinutuximab) on COG ANBL0032 due to 
inadequate disease response, organ toxicity, or family preference. 
However, in a current St. Jude Children’s Research Hospital clinical trial 
(NB2012), the addition of a humanized anti-GD2 mAb to Induction 
therapy demonstrated improved response to Induction therapy, with 95% 
of patients moving on to receive Consolidation and post-Consolidation 
therapy. Five percent discontinued protocol therapy due to family 
preference. This suggests that, although only 58% percent of patients 
enrolled on COG high-risk neuroblastoma trials have completed all 
therapy, the percentage of patients who complete all therapy on this study 
may be higher based on the recent success of NB2012. 
 
The 30 evaluable patients will provide suitable operating characteristics 
and power to evaluate HACA development during post-Consolidation. 
Analyses of data from patients treated with ch14.18 (dinutuximab)-based 
immunotherapy on COG ANBL0032 reported the incidence of 
neutralizing HACA was 4.4%. An increase in neutralizing HACA from 
4.4% to >20% (i.e.: >9 of 45 patients during the Induction phase, or >6 of 
30 during the post-Consolidation phase) would be a sufficiently large 
increase in a biologically meaningful HACA and may have a deleterious 
action on the desired effects of ch14.18 (dinutuximab) during post-
Consolidation. With 45 enrolled patients [30 evaluable patients receiving 
post-Consolidation ch14.18 (dinutuximab)], there will be >96% power at 
the 5% significance level to detect an increase in the proportion of patients 
with a neutralizing HACA (from 4.4% to >20%) during Induction therapy 
and over 87% power during post-Consolidation using a one-sided exact 
test of proportion with binomial enumeration. 
 

 
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9.3.4 
Monitoring 
9.3.4.1 Tolerability  
There may be cause to stop the trial early if the unacceptable toxicity rate 
appears too high. An unacceptable toxicity rate of 10% was observed at 
the interim analysis of the NB2012 study. However, these unacceptable 
toxicities were related to Consolidation therapy and were attributed to the 
Consolidation conditioning regimen (busulfan and melphalan). Since the 
evaluation period for the occurrence of toxicity during treatment is 
approximately 6 months, in order to avoid significant delays in accrual, 
the study will not be halted while the data are gathered for the assessment 
of the monitoring rule. 
 
A one-sided Pocock group-sequential boundary with a sample size of 42 
will be used to monitor the number of patients who experience at least one 
unacceptable toxicity during Cycle 3-5 of Induction (Section 9.3.2.1). 
Interim monitoring will be done after every sixth patient has been fully 
evaluated for the occurrence of unacceptable toxicity (Table 1). The upper 
bound on the number of unacceptable toxicity events needed to declare the 
therapy too toxic uses a cumulative alpha level of 0.13. The probability of 
declaring the regimen too toxic under the alternative hypothesis toxicity 
rates of 25% and 28% appears in Table 2. The average sample size when 
the unacceptable toxicity rate is 10%, 25%, and 28% is 39.22, 22.95, and 
19.64, respectively. 
 
Table 1. Interim monitoring plan and number of observed unacceptable toxicities 
needed to declare therapy too toxic. 
Monitoring 
percent of total 
information 
Number of patients 
fully evaluated for 
toxicity 
Monitoring 
boundary  
Number of observed 
unacceptable toxicities 
to declare too toxic 
14.3% 
6 
1.9028 
(p=0.02854) 
≥ 3 (50%) 
28.6% 
12 
1.8178 
(p=0.03455) 
≥ 4 (33%) 
42.9% 
18 
1.7495 
(p=0.04010) 
≥ 5 (28%) 
57.1% 
24 
1.6961 
(p=0.04493) 
≥ 6 (25%) 
71.4% 
30 
1.6531 
(p=0.04915) 
≥ 7 (23%) 
85.7% 
36 
1.6175 
(p=0.05289) 
≥ 8 (22%) 
100.0% 
42 
1.5872 
(p=0.05624) 
≥ 8 (19%) 
 
 
 

 
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Table 2. Probability of detecting a difference under various alternative hypothesis 
unacceptable toxicity rates. 
Monitoring 
percent of total 
information 
Number 
of 
patients fully 
evaluated for 
toxicity 
Power under a true 
unacceptable 
toxicity rate of 25% 
Power under a true 
unacceptable 
toxicity rate of 28% 
14.3% 
6 
0.1694 
0.2196 
28.6% 
12 
0.3512 
0.4452 
42.9% 
18 
0.4813 
0.5968 
57.1% 
24 
0.5778 
0.7016 
71.4% 
30 
0.6519 
0.7762 
85.7% 
36 
0.7103 
0.8304 
100.0% 
42 
0.8589 
0.9334 
 
If this monitoring rule for tolerability is triggered, CTEP and the study committee 
will review the data and discuss amending the study to reduce the dose of ch14.18 
(dinutuximab) administered during Induction by 25%. If this were to occur, 
discussions related to further steps in accrual to the trial will include re-starting 
rather than resuming accrual, with up to 45 patients enrolling with the reduced 
dosing of ch14.18 (dinutuximab). Only the patients in the cohort enrolled after 
such an amendment would be included in the analysis of tolerability.  
 
9.3.4.2 Feasibility  
We will monitor for inability to administer the intended dose of ch14.18 
(dinutuximab). On COG ANBL1221, 14/51 (27.5%) patients that received 
ch14.18 (dinutuximab) required a dose modification, however therapy was 
discontinued in only 8/51 (15.7%) cases. A feasibility “failure” rate of 
25%, in between the two rates observed on ANBL1221, is expected on this 
trial. The study will not be halted while the data are gathered for the 
assessment of the monitoring rule. 
 
A one-sided Pocock group-sequential boundary with a sample size of 42 
will be used to monitor the number of patients deemed feasibility 
"failures" during Cycle 3-5 of Induction (section 9.3.2.2). Interim 
monitoring will be done after 1/3 and 2/3 of the planned number of patients 
have been fully evaluated as to receiving 75% or more of the intended 
ch14.18 (dinutuximab) doses (Table 3). The upper bound on the number 
of feasibility "failures" needed to declare the therapy not feasible uses a 
cumulative alpha level of 0.10. The probability of declaring the regimen 
not feasible under the alternative hypothesis feasibility "failure" rates of 
45% and 48% appears in Table 4. The average sample size when the 
feasibility "failure" rate is 25%, 45%, and 48% is 40.30, 26.53, and 23.83, 
respectively. 
 

 
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Table 3. Interim monitoring plan and number of observed feasibility "failures" 
needed to declare therapy not feasible. 
Monitoring 
percent of total 
information 
Number 
of 
patients fully 
evaluated 
Monitoring 
boundary  
Number 
of 
observed 
feasibility "failures" to 
declare not feasible 
33.3% 
14 
1.6924 
(p=0.04528) 
≥ 7 (50%) 
66.7% 
28 
1.6477 
(p=0.04971) 
≥ 12 (43%) 
100.0% 
42 
1.6107 
(p=0.05362) 
≥ 16 (38%) 
 
Table 4. Probability of detecting a difference under various alternative hypothesis 
feasibility "failure" rates. 
Monitoring 
percent of total 
information 
Number 
of 
patients fully 
evaluated 
Power under a true 
feasibility "failure" 
rate of 45% 
Power under a true 
feasibility "failure" 
rate of 48% 
33.3% 
14 
0.4539  
0.5451 
66.7% 
28 
0.6596  
0.7678 
100.0% 
42 
0.8544  
0.9257 
 
If this monitoring rule for feasibility is triggered, CTEP and the study 
committee will review the data and discuss amending the study to reduce 
the dose of ch14.18 (dinutuximab) administered during Induction by 25%. 
If this were to occur, discussions related to further steps in accrual to the 
trial will include re-starting rather than resuming accrual, with up to 45 
patients enrolling with the reduced dosing of ch14.18 (dinutuximab). Only 
the patients in the cohort enrolled after such an amendment would be 
included in the analysis of feasibility.  
 
The rate of completion of Consolidation and post-Consolidation therapy 
will also be descriptively monitored to determine the effect of 
administration of ch14.18 (dinutuximab) during Induction on subsequent 
treatment. Of the 378 patients that enrolled on ANBL0532 in 2010 and 
after (when randomization was halted on ANBL0032 and all patients were 
subsequently assigned to the ch14.18 (dinutuximab) arm), 100 were 
randomized to the tandem transplant arm. Of these patients, 75 (75%) went 
on to enroll on ANBL0032 (none enrolled on ANBL0931), indicating 
completion of Consolidation therapy. Sixty-five of the 75 patients 
completed all planned cycles of ch14.18 (dinutuximab) post-
Consolidation therapy; therefore, 65% of the 100 patients randomized to 
the tandem transplant arm on ANBL0532 completed Consolidation and 
post-Consolidation therapy. Similar completion rates of Consolidation and 
post-Consolidation therapy are also expected on this study. Observed rates 
of completion and reasons for inability to complete therapy will be 
tabulated and reported to the data safety monitoring committee. 
 

 
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9.3.5 
Assessment of Study Objectives 
The primary study objective (1.1.1) related to tolerability will be assessed by the 
unacceptable toxicity monitoring rule (Section 9.3.4.1), and in addition, by 
estimation of the combined toxic death and unacceptable toxicity rate together with 
a 95% CI. The therapy will be deemed tolerable at the specified dose level if the 
tolerability monitoring rule is not triggered. 
 
The primary study objective (1.1.1) related to feasibility will be assessed by the 
monitoring rule (Section 9.3.4.2), and in addition, by estimation of the feasibility 
“failure” rate together with a 95% CI. The therapy will be deemed feasible at the 
specified dose level if the feasibility monitoring rule is not triggered.  
 
To address secondary objective 1.2.1, the response rate to treatment will be 
calculated, including placement of a 95% CI on the response rate. Kaplan-Meier 
curves of EFS and OS will also be generated. 
 
To assess exploratory objective 1.3.1, the incidence of naturally occurring anti-
glycan antibodies at different time points during Induction and post-Consolidation 
therapy will be calculated, including placement of a 95% CI on the incidence. In 
addition, anti-glycan levels prior to the start of Induction therapy and prior to the 
start of post-Consolidation therapy will be compared with Wilcoxon's signed-rank 
test for paired data. 
 
Exploratory objective 1.3.2 will be assessed by calculating the incidence of NK 
receptor NKp30 isoforms, including placement of a 95% CI on the incidence. 
 
To address exploratory objective 1.3.3, the relationship between response to 
treatment with > PR at the end of induction and end of therapy (response vs. non-
response) and naturally occurring anti-glycan antibodies, KIR/KIR-L genotyping, 
Fc receptor genotyping, and HACA will be explored with Fisher's exact test for 
categorical and Wilcoxon rank-sum test for continuous host factors. Both the 
presence/absence and level of naturally occurring anti-glycan antibodies will be 
considered. For the KIR/KIR-L analysis, patients will be categorized as either 
matched or mismatched. Patients will be grouped into one of the three genotype 
subgroups of Fc receptor genotyping for that analysis. The presence/absence of 
HACA, anti-idiotype, and PATA/anti-allotype antibody will be considered for the 
HACA analysis. 
 
To assess exploratory objective 1.3.4, the incidence of NK receptor NKp30 
isoforms will be calculated, including placement of a 95% CI on each incidence 
rate. Summary statistics will also be generated for serum cytokine (IL6, CXCL9) 
levels and gene expression of circulating immune function cells. 
 
Exploratory objective 1.3.5 will be assessed by exploring the relationship between 
response to treatment with > PR (response vs. non- response) with circulating GD2 
levels, and GD2 tumor cell expression following therapy with a Wilcoxon rank-
sum test. Changes from baseline will also be analyzed. 
 

 
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9.4 
Evaluability for Response  
All eligible patients will be considered evaluable for response. 
 
9.5 
Evaluability for Toxicity  
All eligible patients treated with at least one dose of study drug will be considered 
evaluable for toxicity. Any eligible patient who receives at least one dose of ch14.18 
(dinutuximab) during Induction will be evaluable for purposes of evaluating the tolerability 
and feasibility monitoring rules (Section 9.3.4). 
 
9.6 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
 
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 
1 
1 
0 
0 
2 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
2 
4 
0 
0 
6 
White 
14 
18 
3 
2 
37 
More Than One Race 
0 
0 
0 
0 
0 
Total 
17 
23 
3 
2 
45 
 
This distribution was derived from ANBL0532. 
 
 
 
 

 
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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). 
 
10.2 
Response Criteria  
This study will use the revised International Neuroblastoma Response Criteria for disease 
assessment.73 The updated response criteria incorporate current approaches to imaging of 
neuroblastoma, including functional imaging. Furthermore, a standardized approach to 
assessment of bone marrow involvement is included. The current INRC do not include 
methods of disease assessment that are less sensitive and/or specific for neuroblastoma 
(99Tc bone scan and catecholamine levels).  
10.2.1 Definitions 
 
Evaluable for toxicity: All eligible patients treated with at least one dose of study 
drug will be considered evaluable for toxicity. Any eligible patient who receives 
at least one dose of ch14.18 (dinutuximab) during Induction will be evaluable for 
purposes of evaluating the tolerability and feasibility monitoring rules (Section 
9.3.4). 
 
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 Key sites and terms 
10.2.2.1 Primary site: The primary site will be identified as a measurable lesion 
≥ 10 mm in diameter as assessed by cross sectional imaging (CT or MRI 
scan). Primary site measurements must be recorded in millimeters (or 
decimal fractions of centimeters). The longest diameter of the primary 
tumor will be recorded at baseline. Serial measurements of the primary 
tumor will include assessment of tumor size in the same orthogonal plane 
at the time of each evaluation.74 In patients with bilateral adrenal lesions, 
response will be based on the sum of the longest dimensions of both 
adrenal lesions unless biopsy proves one to be ganglioneuroma rather than 
neuroblastoma/ganglioneuroblastoma. In patients with multi-focal non-
adrenal disease, the largest tumor will be considered the primary tumor. 
Response in additional lesions will be assessed as described below for 
metastatic lesions. 
  

 
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Tracer avidity (123I-MIBG or FDG-PET/CT or PET/MR) in the primary 
site will be recorded at baseline. The scan appropriate for serial disease 
assessments should be used at each disease re-evaluation time point (e.g. 
123I-MIBG avid primary lesions should be followed using 123I-MIBG scans 
during therapy). 
 
10.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a metastatic lymph node must be ≥ 15 mm in short axis when 
assessed by CT or MRI scan (CT scan slice thickness recommended to be 
no greater than 5 mm). At baseline and in follow-up, only the short axis of 
a discreet lymph node will be measured and followed as per RECIST 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. 
 
For the purposes of response assessment, target lesions are disease sites 
that are measurable (non-nodal soft tissue mass ≥ 10 mm in longest 
dimension or lymph node ≥ 15 mm in short axis) and tracer avid OR are 
biopsy positive for neuroblastoma or ganglioneuroblastoma. The sum of 
diameters of target lesions is defined as the sum of the short axis of discrete 
lymph nodes (i.e., cervical, axillary nodes) added to the sum of the longest 
diameters of non-lymph node soft tissue metastases. 
 
10.2.2.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes with 
≥ 10 to < 15 mm short axis), are considered non-measurable disease. Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions are 
considered non-measurable. 
 
10.2.2.4 Bone lesions: Osteomedullary disease will be assessed using 123I-MIBG 
scans or FDG-PET/CT or PET/MR 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. SPECT may be used to 
confirm the presence or absence of lesions in a given segment of the body. 
The absolute Curie score should be reported at baseline. A relative score 
(Curie score at the time of disease assessment divided by baseline Curie 
score) should be recorded at the time of each disease evaluation. 
10.2.2.5 Bone marrow disease: Bilateral bone marrow aspirates and trephine 
biopsies are required at disease assessment time points. The extent of 
marrow involvement in all four samples should be recorded. Use of 
immunohistochemical staining for evaluation of trephine biopsies is 
strongly encouraged. The percentage of tumor infiltration of bone marrow 
space assessed by histologic evaluation of trephine/biopsies or counting 
the number of tumor cells in aspirates by cytology or immunocytology 

 
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(recommended 
if 
available) 
divided 
by 
the 
number 
of 
hematopoietic/mononuclear cells evaluated to obtain a percentage 
involvement (methodology described by Burchill et al.).75 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-
PET/CT OR PET/MR2) IMAGING 
Complete Response 
(CR) 
• 
< 10 mm residual soft tissue at primary site, 
AND 
• 
complete resolution of MIBG or FDG-
PET/CT or PET/MR 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/CT or PET/MR 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 SITES 
RESPONSE 
ANATOMICAL IMAGING + MIBG (FDG-PET/CT or PET/MR1) 
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/CT or PET/MR 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) or ≥ 50% reduction in 
number of FDG-PET/CT or PET/MR 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/CT or PET/MR 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; 
• 
A new bone site that is FDG-PET/CT or PET/MR 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 ≥ 1.24 
Stable Disease 
(SD) 
Neither sufficient shrinkage for PR nor sufficient increase for PD of non-
primary lesions 
1 Used for MIBG non-avid tumors 
2Sum of diameters is defined as the sum of the short axis of discrete lymph nodes 
(i.e., cervical, axillary nodes) added to the sum of the longest diameters of non-
lymph node soft tissue metastases. Masses of conglomerate non-discrete lymph 
nodes will be measured using longest diameter. 
3 For patients with soft tissue metastatic disease, resolution of MIBG and/or FDG-
PET/CT or PET/MR uptake at the soft tissue sites is not required; all size reduction 
criteria must be fulfilled. 

 
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4Relative Curie score is the absolute score for bone lesions at time of response 
assessment divided by the absolute score for bone lesions at entry onto a clinical 
trial. MIBG-SPECT or MIBG-SPECT/CT may be used for scoring purposes but 
the same imaging methodology should be used for all evaluations. 
 
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 >20% tumor infiltration that has > 0-≤ 5% tumor 
infiltration upon reassessment. 
Stable disease (SD) 
Bone marrow with tumor infiltration that remains positive with > 5% tumor 
infiltration upon reassessment but does not meet CR, MD or PD criteria 
1Immunohistochemistry strongly encouraged 
 
DETERMINATION OF OVERALL RESPONSE 
RESPONSE 
CRITERIA 
Complete Response (CR) 
All components meet criteria for CR 
Partial Response (PR) 
PR in at least one component and all other 
components are either CR, MD (Bone 
marrow), PR (Soft tissue or Bone) or Not 
involved (NI); no component with PD.  
Minor Response (MR) 
PR or CR in at least one component but at least 
one other component with SD; no component 
with PD. 
Stable Disease (SD) 
SD in one component with no better than SD or 
NI in any other component; no component with 
PD. 
Progressive Disease (PD) 
Any component with PD 
NI = Not involved, site not involved at study entry and remains not involved; MD = Minimal Disease, for 
bone marrow assessment only. 
See Appendix VII for additional information regarding overall response assessment 
 

 
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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. 
 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting tables 
assigned to the protocol, using the 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 

 
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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 a NCI IND/IDE since 
these are considered to be serious AEs. 
 
11.4.3 Death 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: Newborn death occurring during the first 28 days after 
birth.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions.” . Evidence that the death was a 

 
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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.  
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.4.5 
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 (301) 897-7404. 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 
to be reported in an expedited manner via CTEP-AERS as Grade 3 
“Pregnancy, 
puerperium 
and 
perinatal 
conditions 
- 
Other 

 
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(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 (eg, elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.5.2 
Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
 
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 

 
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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 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered expected 
for CTEP-AERS reporting purposes. (Formerly referred to as the Agent Specific 
Adverse Event List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the 
NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
multiple investigational agents and has an SAE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific 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 

 
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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. 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will 
be utilized for AE reporting. All appropriate treatment areas should have access to a copy 
of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted electronically to NCI via CTEP-AERS at: 
https://eapps-ctep.nci.nih.gov/ctepaers.  
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to (301) 897-
7497.  
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site. 
 
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
• 
Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 
an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration.  
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE requires 
expedited reporting within 24 hours.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
Any medical documentation supporting an expedited report (eg, H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines.  

 
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Fax supporting documentation for AEs related to investigational agents supplied under 
a CTEP IND to: (301) 897-7404.  
 
Also: Fax or email supporting documentation to COG for all IND studies (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. 
 
 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours. This  does not include hospitalizations 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.  
 

 
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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  
 
 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
The following events do not need to be reported in CTEP-AERS, regardless of 
hospitalization. 
• 
Grades 1-4 myelosuppression (anemia, neutropenia, thrombocytopenia) does not 
require expedited reporting unless associated with >3 week delays in the start of the 
next scheduled therapy.  
• 
Grades 1-2 AST/ALT elevations do not require expedited reporting unless associated 
with >3 week delays in the start of the next scheduled therapy. 
• 
Hospital admission/prolongation of hospitalization for Grade 3 febrile neutropenia 
does not require expedited reporting. 
• 
Hospital admission/prolongation of hospitalization for Grade 3 infection does not 
require expedited reporting. 
• 
Hospital admission/prolongation of hospitalization for Grade 3 sepsis does not require 
expedited reporting. 
• 
Grades 1-3 irritability does not require expedited reporting  
• 
Grades 1-3 urine output decrease does not require expedited reporting 
• 
Grades 1-3 pain does not require expedited reporting 
• 
Grades 1-3 capillary leak does not require expedited reporting 
• 
Grades 1-2 vision decreased or Grade 3 vision decreased that resolve within 7 days of 
onset does not require expedited reporting 
 
For all patients, the following events require CTEP-AERS reports and submission of the 
AE Case Report Form: 
• 
All Grade 4 and 5 pulmonary complications  
• 
All Grade 4 and 5 hepatic complications  
• 
All Grade 4 and 5 cardiac complications 
• 
All Grade 4 and 5 renal complications 
• 
Grade 4 sinusoidal obstruction syndrome (SOS) or Grade 3 SOS PLUS a specific 
organ failure listed below: 
o 
CTC Grade 4 hepatic failure, OR 
o 
Pulmonary dysfunction: Continuous oxygen support for > 48 hours, 
ventilatory support not clearly attributable to another cause, OR 
o 
Renal dysfunction: serum creatinine > 3 times the ULN for age and sex (CTC 
Grade 3 creatinine), or the need for dialysis (CTC Grade 4 acute kidney 
injury), not clearly attributable to another cause. 
 

 
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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. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all CTEP-AERS 
reportable events and all Grade 3 and higher non-hematologic events in the Induction, 
Consolidation, and Post-Consolidation portions of therapy. The following Adverse Events 
will also be collected:  
• 
During Cycles 3-5 of Induction therapy, any adverse event that results in drug 
doses being held or drug dose modification according to Section 5.0. 
 
Delays of ≥ 2 weeks in the start of cycles of Induction therapy, initiation of Consolidation 
therapy ≥ 10 weeks from the start of Cycle 5 of Induction chemotherapy, and initiation of 
post-Consolidation therapy ≥ 14 weeks from Day 0 of the last stem cell transplant will be 
reported in COG case report forms. The reason for the delays must be documented. 
 
12.0 
RECORDS AND REPORTING 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 

 
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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 (eg, 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. 
 
12.3 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
 

 
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a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party 
Data 
solely 
for 
development, 
regulatory 
approval, 
and 
commercialization of its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication. Collaborator(s) will have 30 
days from the date of receipt for review. Collaborator shall have the right to request 
that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 

 
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The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
13.0 
SURGICAL GUIDELINES 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
administrative Policy 5.14 (except where explicitly prohibited within the protocol). 
 
13.1 
Surgical Rationale 
The overall surgical goal in high-risk patients with neuroblastoma is the most 
complete tumor resection with as much preservation of full organ and neurologic 
function as possible. In addition, the surgeon is responsible for the preservation and 
delivery of an adequate surgical specimen to the local hospital laboratory for crucial 
biologic analyses.  
 
Surgical resection of soft tissue disease will occur during Induction therapy. All patients 
will undergo attempt a complete surgical resection of primary tumor following Cycle 4 
chemotherapy (or Cycle 5, if clinically necessary) during induction. Titanium clips should 
be placed around sites of gross residual disease. 
 
13.2 
Pre-Operative Management 
Adequate pre-operative imaging of the primary tumor and sites of regional spread requires 
MRI, CT, or a combination of these modalities. For paraspinal and/or epidural lesions, pre-
operative neurosurgical consultation is recommended, and a baseline neurologic 
assessment should be performed. The planned operation should be discussed with the 
attending pediatric oncologist, and discussion in the context of a multidisciplinary tumor 
board is strongly recommended. The goals of the surgery should be clearly understood by 
all involved services pre-operatively.  
 
13.3 
Specimen/Sampling Requirements at Diagnosis 
In all patients, the primary purpose of the initial surgical procedure is to obtain enough 
tissue to establish the diagnosis, contribute to risk assignment, and secure enough properly 
preserved tumor for required biological studies.  
 
Biopsy of the primary tumor or an accessible metastatic site is acceptable. An adequate 
biopsy to determine the diagnosis and assess biological variables such as histopathologic 
classification and MYCN amplification status is required. Usually at least 1 cubic 
centimeter of viable tissue is needed for these assays. Image-guided percutaneous biopsy, 
minimally invasive surgical biopsy, or open surgical biopsy are all appropriate options for 
obtaining tissue, as best determined by the surgeon, oncologist, and interventional 
radiologist. If percutaneous core biopsy is obtained, multiple cores (25-30) are required 
with a minimum recommended needle size of 16 gauge. It is important to note that a 

 
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significant portion of the tumor may be necrotic. Frozen section pathologic examination 
will verify that viable neuroblastoma is being biopsied.  
 
Placement of the specimen in formalin should be avoided. Rather, the pathologist should 
be alerted and the specimen rapidly transferred from the operating room fresh and sterile. 
The surgeon and/or interventional radiologist should verify with the pathologist that viable 
tissue was sent and is being processed appropriately.  
 
13.4 
Specimen/Sampling Requirements at Definitive Surgery 
13.4.1 The primary purpose of surgery after Induction cycle 4 chemotherapy is definitive 
resection of the primary tumor. However, the surgical specimen obtained will be 
used for important correlative studies, even if portions of the tumor are largely 
necrotic. Placement of the specimen in formalin should be avoided. The specimen 
should be rapidly transferred from the operating room to pathology, fresh and 
sterile.  
 
13.5 
Operative Management 
13.5.1 Central Line Placement 
Patients will require central venous access. It is usually feasible and efficient to 
place a vascular access device and obtain a bone marrow aspirate and biopsy 
during the same anesthetic. The appropriate catheter should be placed at the time 
of initiation of therapy.  
 
Apheresis catheters for stem cell harvest: Medcomp or similar catheters are 
specifically designed as tunneled, permanent apheresis catheters. It may not be 
possible to draw at a sufficient rate from a non-apheresis catheter that is smaller 
than 10 Fr. If a smaller lumen must be placed, or if it is institutional practice to use 
a temporary catheter for pheresis, placement of the pheresis catheter may be 
deferred until Cycle 2.  
 
13.5.2 Diagnostic Surgery 
The great majority of high-risk patients will undergo initial diagnostic biopsy 
without resection. The surgeon should try to obtain at least 1 cm3 of viable tumor 
tissue, if feasible, according to the surgeon’s judgment. Complete excision of the 
primary tumor can occasionally be performed if the tumor is easily resectable 
without a lengthy procedure or extensive dissection. However, a resection should 
not be undertaken initially if a significant delay in the initiation of chemotherapy 
or significant morbidity would be associated with upfront resection. 
 
13.5.3 Epidural Tumors with Intraspinal Extension 
When the tumor approaches the spinal canal on imaging (see Section 16.1), a 
detailed physical examination must assess neurological function.  
 
Laminectomy should not be performed in patients who are neurologically 
asymptomatic. Patients with symptomatic spinal cord compression secondary to 
epidural extension of neuroblastoma through a neural foramina may require 
laminectomy, or osteoplastic laminotomy at diagnosis to prevent permanent 

 
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paralysis. However, treatment with chemotherapy alone or chemotherapy and 
radiation therapy will frequently be sufficient to rapidly reverse symptoms of cord 
compression. Therapeutic decisions in neuroblastoma patients with spinal cord 
compression should be made with the multidisciplinary involvement of the attending 
pediatric oncologist, pediatric surgeon, and pediatric neurosurgeon. 
 
If neurologic deterioration occurs during chemotherapy, neurosurgical evaluation 
should be sought and operative decompression strongly considered. Appropriate 
to the degree of neurological impairment, the treating physicians may decide that 
operative neurosurgical decompression is indicated under these circumstances. If 
feasible, the neurosurgeon should perform an osteoplastic laminotomy, with secure 
replacement of the laminae after decompression has been accomplished. Operative 
details will be recorded in the RAVE system. 
 
13.5.4 Operative Management of Primary Tumors after Chemotherapy 
The majority of patients will undergo resection of the primary tumor after 4 cycles of 
Induction chemotherapy. Surgical resection should be performed when the ANC 
> 500/µL and the patient is medically stable after chemotherapy Cycle 4 of Induction. 
Surgical resection may be performed later in Induction, if necessary, but MUST occur 
prior to Consolidation. Surgical scheduling SHOULD AVOID DELAYS OF 
MORE THAN 6 WEEKS BETWEEN CHEMOTHERAPY CYCLES. THE 
SAME TIME FRAME SHOULD BE OBSERVED WHEN SURGERY 
OCCURS AFTER CYCLE 5. 
 
The goal of the definitive surgical procedure is gross total resection of residual tumor 
in the primary site as well as tumor in areas of regional dissemination (usually lymph 
nodes). Resection with microscopically negative margins may not be feasible because 
of proximity to major vascular structures and the spine. Instead, the surgeon should 
concentrate on removing, as completely as possible, all gross disease. It is acceptable, 
and often necessary, to incise the tumor and remove it in a segmental fashion. 
Titanium clips should be used to mark all areas of residual disease. All attempts 
should be made to preserve organs, especially the kidney. Rarely, nephrectomy may 
be necessary for complete tumor removal but this should only be planned if the 
involved kidney has greatly diminished function. If a nephrectomy is being 
considered pre-operatively, then a differential GFR should be obtained to 
determine what the renal function will be in the remaining kidney, and consult 
with a nephrologist is recommended. The COG Surgical Committee strongly 
recommends kidney preservation when feasible.  
 
It is vital that the operating surgeon dictate a detailed operative note, which should 
include the following information:  
• the completeness of resection, 
• areas of residual disease,  
• estimated blood loss, and  
• any operative complication such as identification of injury to adjacent structures, 
removal of normal organs, renal injury, and vascular injury. 
 

 
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13.6 
Management of Surgical Complications 
Guidance regarding management of surgical complications is provided below. Surgical 
complications will be graded using the Clavien-Dindo scale.76 
 
13.6.1 Intraoperative Complications 
Intraoperative complications are site-dependent. Major hemorrhage from either 
venous or arterial structures is always possible with these infiltrative tumors. The 
principles of vascular surgery, including proximal and distal control, pertain. 
Appropriate intraoperative vascular consultation should be sought if necessary. 
Crucial vessels like the carotid, subclavian, hepatic, superior mesenteric or renal 
arteries should be repaired and flow restored even if bypass grafting is required. 
Nerve injuries may also be incurred and should be primarily repaired using 
magnification. 
 
13.6.2 Post-Operative Complications 
Acute and long-term complications and duration of complications will be 
prospectively monitored, including infectious complications, chylous leak 
(thoracic and abdominal); non-infectious diarrhea; bowel obstruction due to 
intussusception or post-surgical adhesions; and renal dysfunction and/or atrophy 
due to vascular injury. 
 
Pulmonary Complications  
Resection of large abdominal neuroblastoma tumors may result in significant third 
space losses and require vigorous fluid replacement intraoperatively and 
postoperatively. Because of this fluid requirement, patients may require significant 
periods of post-operative ventilation. The need for post-operative monitoring in an 
intensive care environment should be anticipated. Pneumonias or other pulmonary 
complications related to postoperative course (including intubation > 7 days) 
should be reported. 
 
Bowel Obstruction  
Small bowel obstruction may occur for many reasons, including injury, exposure, 
or blunt trauma during the resection, postoperative intussusception, formation of 
adhesions, or related to radiation injury. Obstruction may occur in the early 
postoperative period, or may occur months to years later.  
 
Chylous Leak 
Extensive dissection of the retroperitoneum or mediastinum may result in either 
frank disruption of chylous channels, or interruption causing intraluminal 
lymphatic hypertension and leak. 
 
Renal Injury/Atrophy 
Renal injury may manifest in many forms, related to the nature of the injury or 
insult. While nephrectomy is strongly discouraged, extensive perirenal dissection 
and kidney sparing surgery may still result in vascular occlusion, infarction, 
traumatic compression, or other injury mechanisms sufficient to cause long term 
dysfunction or atrophy. Additionally, radiation therapy may lead to kidney 
damage, again with the long term finding of atrophy.  
 

 
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Diarrhea 
Extensive sympathetic denervation associated with aggressive retroperitoneal 
dissection may result in increased frequency of stooling or diarrhea.  
 
13.7 
Special Techniques 
13.7.1 Nerve Stimulation 
Nerve stimulation can be useful in detecting motor nerves in the brachial or lumbo-
sacral plexus. This requires cooperation from the anesthesiologist as muscle 
relaxation must be allowed to wear off. Nerve stimulation should always be used 
with dissection along the pelvic sidewall or in the neck or thoracic inlet. 
 
13.7.2 Thoracoscopy 
Video-assisted thoracoscopy can be used to remove small posterior mediastinal or 
thoracic inlet tumors provided there is no vascular encasement. One-lung 
ventilation or low pressure insufflation is recommended.  
 
13.7.3 Laparoscopy 
Laparoscopic resection of small adrenal or pelvic primaries can be done. Extensive 
tumors or those with significant vascular encasement, or locoregional nodal spread 
can be more completely resected using standard open approaches. 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
 
14.1 
Rapid Central Pathology Review 
A rapid review of histology (under COG APEC14B1/ANBL00B1) is required to confirm 
the diagnosis of neuroblastoma to determine eligibility of patients for this study. See 
APEC14B1/ANBL00B1 for complete details on specimen requirements. The 
Neuroblastoma Pathology Checklist must be completed by the institutional pathologist 
when tumor tissue is obtained at diagnosis. 
 
As per APEC14B1/ANBL00B1, representative slides MUST be sent to the COG 
Biopathology Center via Federal Express for overnight delivery. The slides will then be 
forwarded to Dr. Hiroyuki Shimada, and Dr. Shimada and Dr. Jason Jarzembowski will 
determine the histologic diagnosis and notify the Neuroblastoma Biology Reference 
Laboratory. The Tracking Center will then determine risk status and will notify the treating 
institution of the results. 
 
14.1.1 Neuroblastoma Tracking Center Activity 
Institutions will first enroll patients on APEC14B1/ANBL00B1 once the patient’s 
age, diagnosis and disease stage have been determined. The COG Statistical Office 
will notify the Tracking Center with the enrollment information. Results of MYCN 
testing will be sent to the Tracking Center and to the treating institution by the 
Neuroblastoma Biology Reference Laboratory as soon as the results are available.  
 

 
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14.1.2 Review Material Required at Diagnosis 
Review materials are submitted through APEC14B1/ANBL00B1. Do not submit 
separate pathology review materials for this protocol. Please refer to 
APEC14B1/ANBL00B1 for submission details.  
 
14.1.3 Review Material at Second Look or Definitive Surgery and/or Relapse 
Pathology materials must be submitted through APEC14B1/ANBL00B1 at the 
time of second look surgery, whether this procedure is a biopsy, partial resection, 
or complete resection, and/also at the time of relapse. Please refer to 
APEC14B1/ANBL00B1 for specimen requirements. 
 
14.1.4 Study Pathologist 
Study Pathologist of record:  
Hiroyuki Shimada, MD 
Department of Pathology 
Children’s Hospital Los Angeles 
 
14.2  
Retrospective Central Review of Bone Marrow Samples 
A retrospective central review of bilateral bone marrow aspirates and biopsies will be 
performed on this study to confirm response status to therapy. The results of the review 
will not be returned to the submitting institution.  
14.2.1 Time points 
Samples will be collected at the following time points.  
• 
End of Induction, Cycle 5 
• 
Prior to post-Consolidation, Cycle 1 
• 
End of therapy 
 
14.2.2 Review Materials Required and Shipping 
At each time point listed above submit:  
• 
Two H&E and 5 unstained slides from each biopsy block 
• 
Representative stained slide(s) from each aspiration procedure.  
• 
Pathology report for each procedure (biopsy and aspiration) 
• 
Specimen Transmittal Form: Bone Marrow Central Review  
 
Label slides and accompanying paperwork with: 
• 
Patient’s COG number 
• 
Specimen type (bone marrow biopsy, clot or aspirate) 
• 
Surgical Pathology ID (SPID) number from corresponding pathology 
report 
• 
Note the course and day of therapy bone marrow was drawn and the 
collection dates on the transmittal form. 
 
Complete the Specimen Transmittal Form: Bone Marrow Central Review in 
RAVE and include a printed copy with the bone marrow central review samples 

 
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and pathology report(s). Slides from all timepoints may be held and sent in one 
shipment. Send via regular mail or using the institution’s courier account to: 
15 
 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol ANBL17P1 
700 Children’s Drive, Room 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. 
 
14.2.3 Central Review Pathologist 
The BPC will forward the bone marrow samples for central review to: 
Dr. Hiroyuki Shimada 
Department of Pathology 
Children’s Hospital Los Angeles 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
15.1 
Optional Studies 
Tumor obtained at diagnosis as part of APEC14B1 or ANBL00B1 may be used. All other 
specimens described in the following section are to be obtained in addition to samples 
submitted as part of ANBL00B1 or APEC14B1. Each of these correlative studies is 
optional, but strongly encouraged. All patients will be eligible for all optional studies on 
ANBL17P1. 
 
A summary table of Optional Studies samples and time points is provided in 
Appendix V. 
 
Every effort should be made to obtain samples from all time points, including the pre-
therapy time point. However, if the baseline sample cannot be obtained, subsequent 
samples should still be collected as specified (see Appendix V). 
 
The study committee recognizes that the blood volume requested for correlative studies at 
both the pre-treatment and prior to post-Consolidation time points is significant. If the 
requested samples exceed the maximum allowable blood draw for a given day, samples 
may be drawn on subsequent days as long as all blood draws are within 1 week prior to 
starting Induction or prior to post-Consolidation. 
 
Study prioritization: 
If blood volume obtainable is limited at a time point, please follow the priority list below. 
This list is written from highest to lowest priority. See the section numbers provided and 
Appendix V for sample details. 
1. HACA/PATA Analysis (Section 15.1.3) / NK Marker Analysis and Genotyping 
(Section 15.1.4)  

 
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2. Anti-glycan Antibodies (Section 15.1.1) 
3. NK Cell Receptor NKp30 Isoform (Section 15.1.2) 
4. Gene Expression Studies: RNA Sequencing (Section 15.1.6) 
5. Cytokine Analysis (Section 15.1.5) 
6. GD2 Biomarkers (Section 15.1.7) 
 
Biospecimen banking 
If material is leftover after the correlative studies below are performed, it will be banked at 
the Biopathology Center if the patient consented to biobanking. Samples sent directly to 
outside labs will not be stored for biobanking. 
 
15.1.1 Naturally occurring anti-glycan antibodies 
 
15.1.1.1 
Specimen Schedule and Requirements 
At each time point, 7 to 10 mL of whole blood should be collected in 
an EDTA tube.  
 
Samples are requested at the following time points: 
• Pretreatment 
• Induction Cycle 3, Day 1  
• Induction Cycle 3, Day 6 
• Induction Cycle 4, Day 1 
• Induction Cycle 4, Day 6  
• Prior to post-Consolidation, Cycle 1 
• At first episode of disease progression or relapse. 
 
15.1.1.2  Specimen Processing 
No onsite processing is required for samples collected Monday to 
Thursday. Samples should be kept at room temperature before 
shipping. Do not store in the refrigerator. Samples must be sent to Dr. 
Alice Yu by next day courier, insulated to guard against extreme heat 
or cold.  
 
For Weekend Collection: If the sample is collected on Friday, 
Saturday or Sunday, then spin the sample at 200-300 RCF for 15 
minutes. Next, remove and freeze the top layer (plasma). The plasma is 
the sample that will be analyzed. Send the plasma and cell layer, at your 
earliest convenience, to Dr. Alice Yu’s laboratory.  
 
15.1.1.3  Specimen Labeling and Shipping 
 Tubes must be labeled with: 
• 
The patient’s COG ID number 
• 
Specimen type (blood or plasma) 
• 
Collection time point (i.e. Induction Cycle 3, Day 6) 
• 
Date collected.  
 
Samples must be sent by next day courier, insulated to guard against 
extreme heat or cold. For samples collected on the weekend, the plasma 

 
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and the cell layer can be sent at the earliest convenience, but must be 
shipped frozen on dry ice. Please contact Dr. Mitchell Diccianni prior 
to shipping to obtain a FedEx account number and provide the FedEx 
tracking number so that the samples can be tracked. Include specimen 
transmittal form with each shipment. 
 
Send samples to: 
Alice Yu, MD, PhD / Mitchell Diccianni, PhD 
UCSD Medical Center 
Clinical Teaching Facility, C-101 
214 Dickinson Street 
San Diego, CA 92103-8447 
Lab Phone: (619)-543-2436 
Lab FAX: 
(619)-543-5413 
E-mail: yulab@ucsd.edu  
 
Lab contact: Dr. Mitchell Diccianni 
(619) 534-2436 
mdiccianni@ucsd.edu  
 
15.1.1.4 
 Methodology 
Antiglycan antibodies will be assessed using an ELISA assay 
previously described and processed by Yu laboratory personnel. This 
work will be performed under the supervision of Dr. Mitchell 
Diccianni at Rady Children’s Hospital- San Diego.  
 
 
15.1.2 NK cell receptor NKp30 isoform 
 
15.1.2.1 Specimen Schedule and Requirements 
At each time point, 2.5 mL of whole blood should be collected in a 
PAXgene RNA tube. PAXgene RNA tubes will be provided by the 
Biopathology Center to sites in North America. To request PAXgene 
tubes, 
please 
access 
the 
BPC 
Kit 
Management 
system 
(https://ricapps.nationwidechildrens.org/KitManagement/) 
and 
select 
“ANBL17P1” for the protocol.  
 
Samples are requested at the following time points: 
• 
Pretreatment; and 
• 
Prior to post-Consolidation Cycle 1 
 
See Section 15.2 for shipping instructions and address. 
 
15.1.2.2 Specimen Processing 
i. For samples collected in PAXgene RNA tubes, blood is placed 
immediately into the tube, which is then inverted 8 - 10 times to 
mix. Blood should be stored upright in a wire rack and placed in -
20°C freezer until shipment. Do not freeze tubes upright in a 

 
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styrofoam tray as this may cause the tubes to crack. Please note that 
if tubes are to be kept at temperatures below -20°C, they must first 
be stored at -20°C for 24 hours before being transferred into a -
70°C or -80°C freezer. Blood in PAXgene RNA tubes is stored 
frozen and it must be shipped on dry ice. 
ii. PAXgene RNA tubes should be batched for each cycle and shipped 
prior to the next cycle. Please ship on dry ice overnight on a day 
that would permit delivery on a working day.  
 
Note: If the PAXgene RNA tube is the only tube to be drawn, blood 
should be drawn into a “Discard Tube” prior to drawing blood into 
the PAXgene RNA tube. Otherwise the PAXgene RNA tube 
should be the last tube drawn. 
 
15.1.2.3 Specimen Labeling  
Tubes must be labeled with: 
• 
The patient’s COG ID number 
• 
BPC number 
• 
Specimen type (blood) 
• 
Date collected.  
 
Specimens are shipped to the BPC. See Section 15.2 for shipping 
instructions and address. 
 
15.1.2.4 BPC Handling 
The BPC will batch transfer frozen PAXgene RNA tubes to the 
laboratory of Dr. Alice Yu at Rady Children’s Hospital – San Diego.  
 
15.1.2.5 Methodology 
NKp30 expression will be performed under the supervision of Dr. Alice 
Yu at Rady Children’s Hospital- San Diego. 
 
15.1.3 Changes in Tumor Markers During Therapy – HACA / PATA analysis 
15.1.3.1 Specimen Schedule and Requirements 
At each time point, 2 mL of whole blood will be collected in an EDTA 
tube.  
 
Samples are requested at the following time points: 
• 
Induction Cycle 5, Day 1 
• 
Induction Cycle 5, Day 6 
• 
Post-Consolidation Cycle 2, Day 1 
• 
Post-Consolidation Cycle 2, Day 7 
• 
Post-Consolidation Cycle 3, Day 1 
• 
Post-Consolidation Cycle 3, Day 7 
• 
Post-Consolidation Cycle 4, Day 7 
• 
Post-Consolidation Cycle 5, Day 7 
 

 
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15.1.3.2 Specimen Processing 
Immediately after collection, gently invert the blood collection tube 5-10 
times to mix the blood and EDTA. Centrifuge the blood at 200-300 RCF 
for 15 minutes at 4ºC (preferred) or room temperature to separate the 
plasma (top layer) from the red blood cells (bottom, red layer). Remove 
the top, straw-colored layer (plasma) and immediately freeze the vials 
upright in a -70oC to -80oC freezer. Retain frozen until ready for batch 
shipment.  
 
15.1.3.3 Specimen Labeling 
Tubes must be labeled with: 
• The patient’s COG ID number 
• BPC number 
• Specimen type (plasma) 
• Time point (cycle number and day) 
• Date collected  
 
Tubes should be sent to the Biopathology Center frozen on dry ice in 
batch shipments. See Section 15.2 for shipping address and additional 
shipping instructions. 
 
For questions about sample processing and shipping, please contact the 
BPC directly.  
 
15.1.3.4 Methodology 
Plasma samples will be assayed for HACA using an ELISA test 
previously described. Analysis will be performed under the supervision 
of Dr. Paul Sondel at The University of Wisconsin Hospital and Clinics. 
 
In addition to the specimens listed in Section 15.1.3.1, HACA/PATA 
analysis will also be performed on plasma obtained from the NK marker 
analysis (see Section 15.1.4). The Yu lab will share plasma with the 
Sondel lab for these studies; no additional samples need to be collected. 
For shared time points, see Appendix V.  
 
15.1.4 Immune Function Profiling: NK marker analysis and genotyping for KIR/KIR 
ligands and FcR 
15.1.4.1 Specimen Schedule and Requirements 
At each time point, 7 mL of whole blood should be collected in an EDTA 
tube. 
 
Samples are requested at the following time points: 
• 
Pretreatment 
• 
Induction Cycle 3, Day 1 
• 
Induction Cycle 3, Day 6 
• 
Induction Cycle 4, Day 1 
• 
Induction Cycle 4, Day 6 

 
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• 
Prior to Post-Consolidation Cycle 1 
• 
Post-Consolidation Cycle 1, Day 7 
• 
Post-Consolidation Cycle 4, Day 1 
• 
Post-Consolidation Cycle 5, Day 1 
• 
Post-Consolidation Cycle 6, Day 15 
 
15.1.4.2 Specimen Processing 
No onsite processing is required. Samples should be kept at room 
temperature before shipping. Do not store in the refrigerator. Samples 
must be sent by next day courier, insulated to guard against extreme heat 
or cold.  
 
For Weekend Collection: No onsite processing is required. If the sample 
is collected on Friday, Saturday or Sunday, the sample should be stored 
at room temperature and shipped immediately the next business day.  
 
15.1.4.3 Specimen Labeling and Shipping 
Tubes must be labeled with: 
• 
The patient’s COG ID number 
• 
Specimen type (whole blood) 
• 
Collection time point (i.e. Induction cycle 3, Day 6) 
• 
Date collected.  
 
Note: A copy of the CBC result with differential obtained on the day 
of the NK marker draw should accompany the specimen. For highest 
accuracy, obtain the CBC on the same draw as the NK marker 
sample. 
 
Samples must be sent by next day courier, insulated to guard against 
extreme heat or cold. For samples collected on the weekend, the blood 
should be shipped immediately the next business day. Please contact Dr. 
Mitchell Diccianni prior to shipping to obtain a FedEx account number 
and provide the FedEx tracking number so that the samples can be 
tracked. Include specimen transmittal form with each shipment. 
 
Send samples to: 
Alice Yu, MD, PhD / Mitchell Diccianni, PhD 
UCSD Medical Center 
Clinical Teaching Facility, C-101 
214 Dickinson Street 
San Diego, CA 92103-8447 
Lab Phone: 
(619)-543-2436 
Lab FAX: 
(619)-543-5413 
E-mail: yulab@ucsd.edu 
 
Lab contact: Dr. Mitchell Diccianni 
(619) 534-2436 
mdiccianni@ucsd.edu 

 
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15.1.4.4 Methodology 
Samples will be processed by the Yu laboratory personnel, and assays for 
immune cell subsets will be performed on site. Phenotyping will be 
performed by direct measurement of surface expression and quantified 
by flow cytometry. This work will be performed under the supervision of 
Dr. Alice Yu at Rady Children’s Hospital- San Diego.  
 
Yu laboratory personnel will then distribute components of the samples 
collected, specifically the plasma, to other co-investigators conducting 
correlative studies on ANBL17P1.  
 
DNA from a granulocyte pellet for KIR/KIR ligand and Fc receptor 
genotyping as well as plasma for HACA testing will be sent from the Yu 
Lab to the Sondel laboratory at the University of Wisconsin. Serum to 
assess for GD2 will be sent to the Balis laboratory at the Children’s 
Hospital of Philadelphia. Please see Appendix V for additional 
information. 
 
15.1.5 Immune function studies: Cytokine analysis 
15.1.5.1 Specimen Schedule and Requirements 
At each time point, 3 mL of whole blood should be collected in a red-top 
tube. 
 
Samples are requested at the following time points: 
• 
Pretreatment 
• 
Induction Cycle 3, Day 1  
• 
Induction Cycle 3, Day 6 
• 
Induction Cycle 4, Day 1 
• 
Induction Cycle 4, Day 6  
• 
Prior to Post-Consolidation Cycle 1 
• 
At first episode of disease progression or relapse. 
 
15.1.5.2 Specimen Processing 
After the blood in red top tubes has clotted, tubes should be centrifuged 
at 1,100-1,300 x g for 15 minutes at room temperature. Serum should be 
collected and transferred to a conical tube for mixing. Evenly dispense at 
least 0.5 mL of the serum into pre-labeled 1.8 mL screw-cap cryotubes. 
Cap the cryovial securely and freeze upright. Storage in an ultra-cold 
freezer (≤ -70oC) or in liquid nitrogen is ideal; use of a non-cycling -20oC 
freezer is acceptable but should be avoided if possible. The serum should 
be batch shipped with other frozen specimens. 
 
15.1.5.3 Specimen Labeling and Shipping 
Tubes must be labeled with: 
• 
The patient’s COG ID number 

 
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• 
BPC number 
• 
Specimen type (serum) 
• 
Collection time point (i.e. Induction Cycle 3, Day 6) 
• 
Date collected.  
 
Specimens are shipped to the Biopathology Center. See Section 15.2 for 
the BPC shipping address and additional shipping instructions. For 
questions about sample processing and shipping, please contact the BPC 
directly.  
 
15.1.5.4 BPC Handling 
The BPC will ship the serum to the laboratory of Dr. Alice Yu at Rady 
Children’s Hospital – San Diego.  
 
15.1.5.5 Methodology 
Serum samples will be assayed for cytokines using an ELISA test 
previously described. Cytokine analysis will be performed under the 
supervision of Dr. Alice Yu at Rady Children’s Hospital- San Diego.  
 
15.1.6 Analysis of Gene Expression Studies: RNA Sequencing 
15.1.6.1 Specimen Schedule and Requirements: PAXgene RNA Sequencing 
Studies 
PAXgene RNA tubes will be provided by the Biopathology Center to 
sites in North America participating in this trial at the start of the study. 
To request PAXgene tubes, please access the BPC Kit Management 
system (https://ricapps.nationwidechildrens.org/KitManagement/) and 
select “ANBL17P1” for the protocol.  
 
At each time point, 2.5 mL of peripheral blood in a PAXgene RNA tube 
should be collected. 
 
Samples are requested at the following time points: 
• 
Pretreatment 
• 
Induction Cycle 1, Day 6 
• 
Induction Cycle 3, Day 1 
• 
Induction Cycle 3, Day 6 
• 
Induction Cycle 4, Day 1 
• 
Induction Cycle 4, Day 6 
• 
Induction Cycle 5, Day 1 
• 
Induction Cycle 5, Day 6 
• 
Induction Cycle 5, Day 21 
• 
Prior to start of post-Consolidation 
• 
Post-Consolidation Cycle 1, Day 4 
• 
Post-Consolidation Cycle 1, Day 7 
• 
Post-Consolidation Cycle 2, Day 4 
• 
Post-Consolidation Cycle 2, Day 7 

 
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• 
Post-Consolidation Cycle 6, Day 15 
• 
Relapse 
 
15.1.6.2 Specimen Processing 
Once blood is collected in the PAXgene RNA tube, the tube should be 
gently inverted 8-10 times to mix. Keep the tube at room temperature for 
2-72 hours and then freeze upright in a wire rack (not Styrofoam holder) 
for 24 hours at -20°C, then transfer to a -70 or -80°C freezer until batch 
shipment. Please note that if tubes are to be kept at temperatures 
below -20°C, they must first be stored at -20°C for 24 hours before being 
transferred into a -70°C or -80°C freezer.  
 
Note: If the PAXgene RNA tube is the only tube to be drawn, blood 
should be drawn into a “Discard Tube” prior to drawing blood into the 
PAXgene tube. Otherwise the PAXgene RNA tube should be the last tube 
drawn. 
 
15.1.6.3 Specimen Labeling 
Tubes must be labeled with: 
• 
The patient’s COG ID number 
• 
BPC number 
• 
Specimen type (blood) 
• 
Collection time point (i.e. Pretreatment, End of Induction) 
• 
Collection date 
 
Tubes should be sent to the BPC frozen on dry ice in batch shipments. 
See Section 15.2 for shipping address and additional shipping 
instructions. 
 
For questions about sample processing and shipping, please contact the 
BPC directly.  
 
15.1.6.4 Methodology 
The BPC will batch transfer frozen PAXgene RNA tubes to the 
laboratory of Dr. Shahab Asgharzadeh at Children’s Hospital of Los 
Angeles. Samples will be processed and analyzed for alterations in the 
circulating immune cells using next generation sequencing.  
 
15.1.7 GD2 Biomarkers 
15.1.7.1 Specimen Schedule and Requirements 
Blood: 
At each time point, 1 mL of whole blood should be collected in a red-top 
tube and processed for serum. 
 
Samples are requested at the following time points: 
• 
Pretreatment 

 
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• 
Induction Cycle 4, Day 15 
• 
Induction Cycle 5, Day 1 
• 
Induction Cycle 5, Day 21 
• 
End of therapy 
 
Bone Marrow Slides: 
At each time point, 3 air-dried smear slides (bone marrow aspirate) and 3 
air-dried touchprep slides (bone marrow biopsy) from each site are 
required. Prior to the administration of the anticancer therapy described 
in this study, baseline bone marrow biopsy and bone marrow aspirate 
samples should be obtained. This can be obtained with pre-study labs 
within 7 days of starting therapy or on Day 1 of Cycle 1. 
 
Samples are requested at the following time points: 
• 
Pretreatment 
• 
Induction Cycle 5, Day 21 
• 
End of therapy  
• 
Progression/relapse.  
 
Tumor Tissue Slides: 
Prior to the administration of the anticancer therapy described in this 
study, baseline tumor biopsy samples should be obtained. At each time 
point, 3 air-dried touchprep slides from each site are required.  
 
Samples are requested at the following time points: 
• 
Pretreatment 
• 
Progression/relapse. Tumor from any site biopsied at this time 
point will be accepted. 
 
15.1.7.2 Specimen Processing and Storage 
Blood: 
After the blood in red top tubes has clotted, tubes should be centrifuged 
at 1,100-1,300 x g for 15 minutes at room temperature. Serum should be 
collected and transferred to a conical tube for mixing. Evenly dispense at 
least 0.5 mL of the serum into pre-labeled 1.8 mL screw-cap cryotubes. 
Cap the cryovial securely and freeze upright. Storage in an ultra-cold 
freezer (≤ -70oC) or in liquid nitrogen is ideal; use of a non-cycling -20oC 
freezer is acceptable but should be avoided if possible. The serum should 
be shipped overnight (frozen) on the following Monday or the next day 
that would permit delivery on a working day. Batching of serum samples 
is acceptable. 
 
Bone Marrow: 
• 
Bone marrow biopsy: 3 air-dried touchprep slides.  
• 
Bone marrow aspirate: 3 air-dried sample smears slides. 
 
Tumor Tissue: 
Tumor biopsy: 3 air-dried touchprep slides.  
 

 
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15.1.7.3 Specimen Labeling 
Serum vials must be labeled with: 
• The patient’s COG ID number 
• BPC number 
• Specimen type (serum) 
• 
Collection Time Point (i.e. Induction Cycle 4, Day 15) 
• Collection date 
 
Bone Marrow Slides must be labeled with: 
• The patient’s COG ID number 
• BPC number 
• Specimen type (bone marrow) 
• Surgical pathology ID from Bone Marrow Report 
• Time Point (i.e. End of Induction) 
• Collection Date 
 
Tissue Slides must be labeled with: 
• The patient’s COG ID number 
• Specimen type (P for primary tissue or M for metastatic tissue) 
• Surgical pathology ID 
• Time Point (i.e. Pretreatment) 
• Collection Date 
 
Note: both the COG and BPC numbers must be included in labeling since 
extractions will be performed in a CLIA lab. 
 
Specimens are shipped to the Biopathology Center. See Section 15.2 for 
the BPC shipping address and additional shipping instructions. 
 
For questions about sample processing and shipping, please contact the 
BPC directly.  
 
15.1.7.4 Methodology 
For circulating GD2 studies, the BPC will transfer 0.5 ml of serum per 
subject to the laboratory of Dr. Frank Balis at The Children’s Hospital of 
Philadelphia. A validated HPLC/MS/MS assay will be used for GD2 
detection in samples from each time point.  
 
For bone marrow and tissue studies, immunocytochemical (IC) analysis 
on touch preps of tumors at diagnosis and relapse, and touch preps of 
bone marrow biopsies and smear slides of bone marrow aspirates will 
utilize both concurrent staining of Phox2b and GD2 to qualitatively 
assess GD2 expression. The studies will be overseen by Dr. Shahab 
Asgharzadeh at Children’s Hospital of Los Angeles. 
 
 

 
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15.2 
Shipping Instructions for Specimens Submitted to the Biopathology Center 
15.2.1 Blocks and slides 
Formalin-fixed and paraffin embedded tumor material and associated pathology 
report(s) should be sent to the COG Biopathology Center (BPC) at room 
temperature using the submitting institution’s courier account.  
 
An ANBL17P1 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 and slides should not be shipped for Saturday delivery. See Section 15.2.4 
for shipping address. 
 
15.2.2 Frozen specimens (snap frozen tissue, PAXgene tube, serum, plasma)  
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 ANBL17P1 BPC specimen transmittal form must be completed in RAVE, 
printed and sent with the specimen. When tissue or bone marrow slides are 
submitted, the corresponding pathology report must also be included in the 
shipment.  
 
Specimen Procurement Kit Instructions for Frozen Specimens 
1. Before frozen 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. When batch 
shipping frozen specimens, allow room for 5 lbs. of dry ice.  
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. 

 
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4. Close the outer lid of the specimen procurement kit and secure with filament or 
other durable sealing tape. 
5. Sites in North American will print a shipping label via the BPC Kit Management 
application and attach to the top of the kit. 
6. Complete the dry ice label (UN 1845). Place the dry ice and Exempt Human 
Specimen labels on the side of the kit. 
7. Arrange for Federal Express pickup per your usual institutional procedure or 
by calling 1-800-238-5355. 
 
Ship frozen specimens on Monday through Thursday for a Tuesday through Friday 
delivery. See Section 15.2.4 for shipping address. 
 
15.2.4 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 
Protocol ANBL17P1 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email: NBLPG@nationwidechildrens.org 
 
*Be sure to include the room number. Packages received without the room number 
may be returned to the sender. 
 

 
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16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
 
Timing of protocol therapy administration, response assessment studies, and other 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 for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable (except where explicitly prohibited within the 
protocol). 
 
Note: the guidelines below are recommendations only and are not intended to replace 
institutional guidelines. 
 
16.1 
Cross Sectional Imaging Studies  
MRI or CT will be utilized for optimum visualization of all areas of bulk tumor (primary 
and metastases). This imaging is required: (1) pre-treatment, (2) post Cycle 4 of Induction 
(prior to surgical resection), (3) at the end of Induction (pre-Consolidation), (4) prior to 
start of post-Consolidation therapy (5) after Cycle 3 of post-Consolidation, (6) at the end 
of therapy, and (7) at relapse. Submission of the MRI or CT scans for central review is 
requested at some of the above time points. See Section 16.6 for specific time points for 
submission of scans for retrospective central review. 
 
16.1.1 MRI Scans 
Typically MRI will be performed on 1.5 T or 3 T MRI units. Axial and at least 1 
additional plane (coronal or sagittal) of the primary tumor will be performed using 
at least 2 pulse sequences (T1, T2, STIR, FLAIR, in/out phase, post contrast). The 
radiologist performing the study will determine the appropriateness of the use of 
intravenous gadolinium (0.2 mL/kg). Slice thickness will be determined by patient 
size and region covered, but should be less than 7 mm. The smallest appropriate 
coil should be used. The longest diameter of the primary tumor will be recorded at 
baseline. Serial measurements of the primary tumor will include assessment of 
tumor size in the same orthogonal plane at the time of each evaluation. 
 
16.1.2 CT Scans 
Imaging of the site of the primary tumor will be performed using low-dose 
technique according to the ALARA (As Low As Reasonably Achievable) concept. 
The studies will be performed using current-generation. CT slice thickness should 
be 5 mm or less. Imaging will be performed during the administration of 
intravenous contrast, whenever possible, generally at 2 mL/kg. The use of oral 
contrast will be determined by the individual radiologist performing the study, but 
may be helpful in abdominal imaging. Images will be reconstructed in soft tissue 
and edge-enhanced bone/lung and liver algorithms. Coronal and sagittal 
multiplanar reconstructions may be helpful. As noted in the preceding section, 
serial measurements of the primary tumor will include assessment of tumor size in 
the same orthogonal plane at the time of each evaluation 
 
MRI is superior to CT in characterizing epidural tumor extension or 
leptomeningeal disease, and is the preferred imaging modality in such cases (neck, 
chest, nonadrenal retroperitoneum) with spinal cord or canal encroachment.77 It 

 
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may also be useful in evaluating an MIBG-avid focus detected in the skeleton or 
soft tissues. With the exceptions noted above, the choice of MRI or CT will be left 
to the referring pediatric radiologist. 
 
16.2 
123I-MIBG Scintigraphy 
123I-MIBG scintigraphy is required on this trial and is the preferred study for assessment of 
osteomedullary disease. 99m Technetium bone scans are no longer recommended. All 
patients will undergo a diagnostic quality 123I–MIBG scan 14 days prior to or 14 days after 
the start of Cycle 1. Preferably, this scan will take place before therapy is initiated. This 
scan is for diagnostic and response evaluation purposes. For patients with MIBG avid 
disease, an MIBG scan is also required at the end of Induction, end of Consolidation (pre-
immunotherapy/isotretinoin), after 3 cycles of post-Consolidation, at the end of post-
Consolidation, and at relapse. Patients with > 5 MIBG positive metastatic sites on the end-
Induction scan should also undergo an MIBG scan post-transplant to facilitate radiation 
therapy decision-making. This scan will usually be performed between Day +30 and Day 
+42, but should be performed with sufficient time to allow radiation to begin as described 
in Section 17.2.  
 
See Table 16.6 for a summary of MIBG scan time points. 
 
Patients with MIBG non-avid disease at diagnosis are not required to undergo subsequent 
diagnostic MIBG scans. In such circumstances, FDG-PET CT or PET/MR scans should be 
substituted for MIBG scans, at the same required time points.  
 
16.2.1 Thyroid Blockade 
Potassium iodide will be administered to reduce thyroid accumulation of free 
radioiodine. A recommended regimen is 13% KI (100 mg iodide/mL) to be 
administered daily beginning on the day prior to radionuclide injection, and 
continuing daily for a total of 3 days. Dose is by weight; 1.2 mg iodine/kg 
(4 mg/drop).  
 
16.2.2 
123I-MIBG Scintigraphy Procedures 
Dose: 10 mCi/1.7 m2 body surface area (approximately 150 Ci/kg; maximum 10 
mCi). 
 
Scintigraphy: Performed to obtain both planar and tomographic images. For 
planar imaging, anterior and posterior spot views from the top of the head to the 
proximal lower extremities are obtained for 10 minutes at approximately 24 hours 
after injection and may be done 48 hours after injection. Anterior views of the 
distal lower extremities are sufficient. A large field of view dual-head gamma 
camera with low-energy or medium-energy collimators is preferred. 
 
SPECT imaging with 123I-MIBG is recommended when available, and should be 
performed approximately 24 hours after injection using a single or multiheaded 
camera with low-energy collimator. Institutional guidelines regarding data 
acquisition and reconstruction should be followed. MIBG-SPECT or MIBG-
SPECT/CT may be used, however the same imaging methodology should be used 
for all evaluations other than the post-therapy scan that follow 131I-MIBG 

 
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treatment. For the time points required to be submitted for central review (see table 
16.6) submit the CT file, the attenuation corrected (AC) SPECT file and a non-
attenuation corrected (NAC) SPECT file. Do not submit screen capture images for 
the SPECT or CT.  
 
16.3 
[18F]–Fluorodeoxyglucose (18FDG)-PET Scintigraphy 
18FDG-PET/CT scan is indicated for patients whose tumors are not 123I-MIBG avid. FDG-
PET/CT is performed at the following time-points: (1) pre-treatment, (2) at the end of 
Induction 
(pre-Consolidation), 
(3) 
at 
the 
end 
of 
Consolidation 
(pre-
immunotherapy/isotretinoin), (4) after 3 cycles of post-Consolidation therapy, (5) at the 
end of post-Consolidation therapy, (6) at relapse. It is recommended that the PET/CT scan 
be performed following count recovery if possible in order to minimize the likelihood that 
augmented marrow signal is related to colony stimulating factor effect/marrow recovery. 
Patients with >5 FDG avid sites of metastatic disease detected on the end-Induction scan 
should have another PET/CT scan performed prior to local radiotherapy if patient exhibits 
> 5 sites of disease. This scan will usually be performed between Day +30 and Day +42, 
but should be performed with sufficient time to allow radiation to begin as described in 
Section 17.2.  
 
The initial FDG-PET/CT scan should be performed prior to initiation of chemotherapy 
when possible, or as soon as possible after documentation of MIBG non-avid disease. The 
patient should be fasted for at least 4 hours prior to injection of FDG. Plasma glucose 
should be checked and, if the patient is substantially hyperglycemic, the study should be 
rescheduled when adequate glucose control has been established. FDG is administered 
intravenously per institutional guidelines. Good hydration is required as the primary route 
of FDG excretion is renal. The patient should drink water or receive intravenous fluids 
after injection to promote urinary FDG excretion. After injection, the patient is kept at rest 
for 45-60 minutes and imaging is then performed. The patient should void his/her bladder 
immediately prior to imaging if he/she is continent of urine. Whole body imaging 
(including extremities) should be obtained using institutional techniques. The attenuation 
correction CT should be acquired per local institutional guidelines using dose reduction 
techniques. PET/MR is also permissible at centers that routinely use this imaging modality. 
 
Because of the short physical half-life of 1.8 hours and the high photon energy of 511 
keV, FDG imaging may follow MIBG (either I-123 or I-131) or a MUGA study on the 
same day. If needed, the FDG imaging may be performed on the day preceding the 
MUGA. 
 
The FDG-PET/CT study is processed for display by an iterative reconstruction algorithm. 
The level of tumor uptake is assessed subjectively by visual inspection and semi-
quantitatively by determination of standardized uptake value (SUV). Uptake time, glucose 
levels, and partial volume effects influence both methods. The SUV method is also 
dependent on body weight and correction of SUV by normalizing for body surface area 
(BSA) reduces this dependency on body weight. Small lesions may have underestimated 
SUVs due to partial volume averaging effects. To calculate the SUV, a region of interest 
(ROI) should be carefully drawn around the area of elevated FDG uptake in the lesion to 
minimize partial volume effects. The SUV should be calculated as SUVBSA=ROI activity 
concentration (nCi/cc) X BSA / injected activity (nCi). The BSA is calculated from body 
mass (kg) and height (cm) using an appropriate algorithm. The SUVBSA for each measured 

 
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lesion should be recorded and the technique for assessing SUVBSA should be consistent on 
follow-up studies. SUV measurements are directly available on almost all PET/CT display 
programs using simple ROIs 
 
PET should be performed in combination with CT on dual modality PET/CT scanners or 
in combination with MRI on dual modality PET/MR scanners. Typically attenuation 
correction imaging (low-dose, non-contrast-enhanced CT, contrast-enhanced CT or MRI) 
is performed from the top of the head through the toes with the patient breathing shallow, 
followed by emission imaging at 3-5 minutes per bed position. 2D acquisitions are 
acceptable in older PET/CT scanners that do not have 3D capability. Most acquisitions will 
be 3D. Data are reconstructed as described above.  
 
16.4 
Tumor Measurement 
Tumors will be measured according to the COG Radiology Group guidelines. Diameter of 
a “measurable mass” must be at least twice the reconstructed slice thickness. Target lesions 
at baseline must be greater than 1 cm. When multiple or metastatic masses are present, all 
masses will be described, and up to 5 target masses will be measured using the same 
method in subsequent follow-ups. See response evaluation section for information 
regarding measurement of soft tissue masses in accordance with revised INRC criteria 
(Section 10.2).  
 
16.5 
Curie Scoring  
Curie scoring will be performed centrally using previously published techniques, in which 
the body is divided into 10 anatomic regions, 9 skeletal and 1 primary soft tissue, and each 
region individually scored based upon the extent of MIBG avidity within that region. A 
patient’s final Curie score will be calculated as the sum of his/her scores over all individual 
regions. The date of scan acquisition is defined as the date of completion of the MIBG 
scan. The results of the central review will not be returned to the institution. 
 
Curie scoring will be will be determined retrospectively by a central imaging committee 
using images from the following time points: 
(1) initial diagnosis, (2) at the end of Induction, (3) prior to start of post-Consolidation 
therapy, (4) at the end of therapy, and (5) at relapse. Exception: Curie scoring will not be 
performed for patients who are found to have MIBG non-avid disease at diagnosis. 
 
 
 

 
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16.6 
Submission of Scans for Central Review 
Curie scoring will be performed centrally.  
 
In addition, cross sectional tumor imaging scans (MRI or CT), FDG-PET/CT or PET/MR 
scans will be evaluated via central review for confirmation of response status. The results 
of the central review will not be returned to the institution. 
 
Table 16.6: Time points mandated for cross sectional tumor imaging scans (MRI or 
CT), MIBG scans and FDG-PET scans 
 
Time 
MRI or CT 
MIBG 
scan 
FDG-PET 
scan1 
Diagnosis 
Yes 
Yes 
Yes 
End-Induction  
 
Yes 
Yes 
Yes 
Prior to start of post-
Consolidation therapy 
Yes 
Yes 
Yes 
End of therapy 
Yes 
Yes 
Yes 
Relapse/Progression 
Yes 
Yes 
Yes 
1 
For patients with MIBG non-avid disease. 
 
Notes: 
• 
For MIBG, submit planar, tomographic images, include SPECT/CT imaging when 
available (see Section 16.2.2) 
• 
Patients with > 5 metastatic sites at end-Induction should undergo an MIBG scan 
post-transplant to assist in radiotherapy planning. See Section 16.2. 
 
Submit the scans listed in Table 16.6 above together with their corresponding reports.  
 
Imaging required for the radiation oncology review (see Section 17.10), and imaging 
central review only need to be submitted once. 
 
Submission of Diagnostic Imaging data in DICOM format is required. Submission of 
the digital files and reports via TRIAD is preferred. Instructions for TRIAD set up are 
below. 
 
Alternatively, the images and reports may be submitted via sFTP to IROC Rhode 
Island. Digital data submission instructions including instructions for obtaining a sFTP 
account, can be found at http://irocri.qarc.org. Follow the link labeled digital data. Sites 
using the Dicommunicator software to submit imaging may continue to use that 
application. 
Please 
contact 
IROC 
RI 
for 
questions 
or 
more 
information: 
DataSubmission@QARC.org or 401-753-7600. 
 
Digital RT Data Submission Using TRIAD (if TRIAD is available at your site): 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application. TRIAD provides sites participating in clinical trials a secure 

 
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method to transmit DICOM and DICOM RT files and other digital objects, 
such as reports. TRIAD de-identifies and validates the images as they are 
transferred. 
 
TRIAD Access Requirements: 
• 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 site roster and be assigned 
the 'TRIAD site user' role on the CTSU roster. Users should contact the site’s 
CTSU Administrator or Data Administrator to request assignment of the TRIAD 
site user role. 
 
TRIAD Installations: 
When a user applies for 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 images. 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. 
 
If you have any questions regarding this information, please send an e-mail 
to the TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
IROC Rhode Island (formerly QARC) will facilitate the central reviews. 
 
 
 
 
 

 
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17.0 
RADIATION THERAPY GUIDELINES 
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care. 
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or 
facility, procedure and/or anesthesia scheduling issues are acceptable (except where explicitly 
prohibited within the protocol). 
 
Radiation therapy (RT) for patients on COG protocols can only be delivered at approved 
COG RT facilities.  
 
To view the ANBL17P1 Contouring Atlas, please visit www.qarc.org and under NCI Groups, select 
COG and follow the link titled “COG Contouring Atlases.” 
 
General Guidelines 
The radiation therapy guidelines for this study were developed specifically for patients with high-
risk neuroblastoma. The objective of radiation therapy is to improve event free and overall survival 
while preserving uninvolved organ function. Three-dimensional conformal radiation therapy (3D-
CRT), intensity-modulated radiation therapy (IMRT), or proton therapy are required for patients 
treated on this protocol to minimize the risk of late-term normal tissue complications.  
 
Radiation therapy will be delivered following 5 cycles of Induction chemotherapy and intensified 
consolidation therapy with autologous stem cell transplantation.  
 
 
 

 
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Credentialing Requirements 
3D-CRT, IMRT and proton therapy will be the allowed treatment methods for this study. Patients 
may not receive intraoperative radiation therapy on this protocol. The credentialing requirements 
by treatment modality are summarized in the following table. 
 
RT 
Credentialing 
Requirements 
Web Link for Credentialing Procedures and Instructions 
http://irochouston.mdanderson.org 
Treatment Modality 
Key Information 
3D-CRT 
IMRT 
Proton 
 
Facility 
Questionnaire 
 
X 
X 
The 
IROC 
Houston 
electronic 
facility 
questionnaire (FQ) should be completed or 
updated with the most recent information about 
your institution. To access this FQ, email 
irochouston@mdanderson.org to receive your 
FQ link. 
Credentialing 
Status Inquiry 
Form 
 
X 
X 
To determine if your institution has completed 
the requirements above, please complete a 
“Credentialing Status Inquiry Form” found under 
Credentialing on the IROC Houston QA Center 
website (http://irochouston.mdanderson.org). 
Phantom 
Irradiation 
 
X 
X 
Sites treating with IMRT and not previously 
credentialed for its use must irradiate IROC 
Houston’s head and neck phantom. Protons 
centers must complete all required phantom 
irradiations for IROC Houston credentialing. 
Instructions for requesting and irradiating the 
phantoms are found on the IROC Houston web 
site. (http://irochouston.mdanderson.org). 
Motion 
Management 
(when used) 
 
X 
X 
If treating with IMRT and gating or tracking 
methods are used to compensate for respiratory 
motion, IROC Houston’s Lung Phantom must be 
irradiated with its accompanying reciprocating 
platform to simulate motion. Instructions for 
requesting and irradiating the phantom are found 
on 
the 
IROC 
Houston 
web 
site 
(http://irochouston.mdanderson.org) 
Credentialing Notification Issued to: 
Institution 
 
 
 
Institution will be credentialed for the treatment 
modality that they intend to use on all patients. 
IROC Houston QA Center will notify the 
institution 
that 
all 
desired 
credentialing 
requirements have been met. 
 

 
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Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed for the use of 
IMRT in National Cancer Institute sponsored (NCI) cooperative group trials. These guidelines are 
available at www.irocri.qarc.org. These guidelines require that the protocol explicitly state their 
requirements and methods for localization and immobilization; the use of volumetric imaging; 
target and organ motion management; nomenclature, definitions and rationale for targets and 
organs at risk; target volume coverage and normal tissue dose constraints; effects of heterogeneity 
in tissues; and quality assurance. 
 
If IMRT is used, the monitor units generated by the IMRT planning system must be independently 
checked prior to the first treatment. Measurements in a QA phantom can suffice for a check as long 
as the patient plan can be directly applied to a phantom geometry. 
 
Guidelines and Requirements for the Use of Proton Therapy 
Proton therapy may be used to deliver radiation on this protocol. Allowed proton therapy methods 
include scattering, uniform scanning and pencil beam scanning depending on institutional 
availability, but the specific beamline in use must have been appropriately credentialed by the 
IROC Houston QA Center. Intensity modulated proton therapy (IMPT) is permitted for those 
centers that have IROC approval. Investigators using proton beam radiation must comply with 
current NCI proton therapy guidelines as outlined in the Guidelines for the Use of Proton Radiation 
Therapy 
in 
NCI 
Sponsored 
Cooperative 
Group 
Clinical 
Trials, 
available 
at 
http://rpc.mdanderson.org/RPC/home_page/Proton_guidelines.htm . 
 
17.1 
Indications for Radiation Therapy 
17.1.1 Treatment Sites and Doses 
All patients will be irradiated and volumetric targeting for radiation therapy 
planning should be priority. 
 
Table 17.1.1 
Site/Target 
Dose 
Primary tumor site and initially involved lymph 
nodes according to imaging criteria or 
documented by surgery (CTV/PTV*) 
21.6 Gy delivered in 1.8 Gy fractions 
Metastatic disease present after Induction 
(mCTVx /mPTVx*) 
21.6 Gy delivered in 1.8 Gy fractions 
Life or organ-threatening disease 
Document and report to Study Coordinator 
Hepatomegaly leading to respiratory distress 
4.5 Gy delivered in 1.5 Gy fractions 
*When proton therapy is used, the prescription target will be the CTV. When photon radiotherapy is used, 
the prescription target for coverage will be the PTV. In either case, dose reporting will reference the PTV 
in accordance with ICRU guidelines. 
 
17.2 
Timing of Radiation Therapy 
Radiation will be given after recovery from the last ASCT. Treatment volumes will be 
based on post-Induction imaging (MIBG, CT and/or MRI) and operative reports. Organ 
toxicity within the radiation field should have resolved. It is recommended that radiation 
therapy begin no sooner than Day +42 and before Day +80 following ASCT. 
 

 
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17.2.1 Consideration for Radiation Delay 
Please see Table 17.2.1 below for circumstances in which delay in radiation 
therapy should be considered based on the organ being irradiated. 
 
Table 17.2.1 
Organ in Radiation Field 
Considerations for Delay of Radiation 
Therapy 
Hematologic 
[Volume of potential marrow 
radiation exceeding 10% of 
total marrow (see Table 
17.2.2)] 
Persistent cytopenias, including absolute 
neutrophil count ≤ 500/µL (off G-CSF for ≥ 48 
hours), and/or transfusion-refractory 
thrombocytopenia with platelet count 
< 40,000/ µL. 
Liver  
Active sinusoidal obstruction syndrome 
without sign of resolution* 
Trachea 
Grade 2 or higher airway edema that requires 
respiratory support  
Abdomen 
Refractory diarrhea, greater than CTCAE 
Grade 2 
Kidneys** 
Persistently elevated serum creatinine for 
age/sex (see Section 3.3.4) or 2 x the creatinine 
value obtained at the start of consolidation 
therapy 
Bladder 
Persistent hematuria 
*Radiation involving the liver should be delayed for active sinusoidal obstruction syndrome (SOS) 
of any grade. Hepatomegaly and fluid accumulation may persist after SOS has begun to resolve, and 
radiation may be initiated providing that hyperbilirubinemia and pain are improving.  
 
**Please refer to Section 17.8.1 for discussion of renal scintigraphy in the event that recommended 
kidney dose constraints are exceeded. 
 
Table 17.2.2 Distribution of Marrow within the Bony Skeleton 
Site 
% Total Marrow 
Skull 
13% 
Upper limb girdle 
8% 
Sternum 
2% 
Ribs 
8% 
Vertebrae 
     Cervical  
     Thoracic 
     Lumbar 
     Sacrum 
 
3% 
14% 
11% 
14% 
Lower limb girdle 
26% 
Adapted from Ellis RE, 1961. 
 
17.3 
Emergency Radiation 
Patients are allowed to have received emergent radiation at diagnosis to sites of life-
threatening or function-threatening disease such as respiratory distress or vision loss (see 
Section 17.5.3). Generally, this treatment is used as a last resort when disease is causing 
symptoms not responding to chemotherapy. This must be reported to the study coordinator at 
the time of registration on study and will not be considered as part of the planned treatment 

 
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course to be delivered at a later time provided normal tissue dose constraints are met. Prior 
radiation therapy dose constraints are included as part of protocol eligibility criteria. 
Regarding further radiation of metastatic sites that received radiation emergently at the time 
of diagnosis, please see Section 17.5.2.1. 
 
17.4 
Equipment and Methods of Delivery and Verification 
17.4.1 Modality 
 
Equipment 
Photons 
IMRT  
Protons 
Electrons 
Linear Accelerator 
X 
X 
 
X 
Proton Beam  
 
 
X 
 
 
To avoid treatment delays resulting from unplanned equipment unavailability, 
photon therapy may be administered instead of proton therapy. 
 
17.4.2 Treatment planning 
CT (volumetric) based planning is required to optimize dose to the target volumes 
while protecting normal tissues. Organs at risk within the irradiated volume should 
be contoured including those required. A DVH is necessary to determine target 
coverage and evaluate dose to normal tissues. CT slice thickness should be 
≤ 3 mm. 
 
17.4.3 In-room Verification of Spatial Positioning 
17.4.3.1 Portal Imaging 
Portal imaging is the most common system used to verify patient position, 
in particular when the target volume is believed to possess a fixed spatial 
relationship with visualized bony anatomy. If volumetric imaging is not 
available, orthogonal paired (AP and lateral) portal images (MV or kV) 
are required to verify that the isocenter is in correct alignment relative to 
the patient position. Beam’s eye view imaging of each treatment port 
should be performed when feasible. 
 
17.4.3.2 Volumetric Imaging 
Volumetric imaging is allowed in this study. This includes in-room 
kV,MV cone beam or conventional CT imaging. Please prepare 
representative axial images for submission showing the isocenter and the 
correct alignment in relationship to the patients’ position. For CT 
tomography where isocenters are not used, a printout of the isodoses 
overlaid on the fused CT images can be printed to demonstrate in room 
verification. 
 

 
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17.4.4 Evaluation and Management of Target and Normal Tissue Motion and Setup 
Variations 
17.4.4.1 Motion Management and 4D Simulation 
Considering motion of target and normal tissue volumes is important. 
Evaluation of target and normal tissue motion is required for patients 
treated with proton therapy and suggested for patients treated with IMRT. 
 
17.4.4.2 Simulation Guidelines 
The following guidelines suggest a framework for achieving improved 
immobilization and targeting: 
• 
Anesthesia: If general anesthesia is used for simulation, this 
should be continued through therapy unless the patient is re-
simulated/re-planned. 
• 
General Guidelines: For most cases, CT simulation supine, in 
neutral position, with arms over head and with adequate upper 
torso wing-board and/or vac-lock support out of the plane of 
treatment ports should be used. 
• 
Simulation Marking: Two axial planes should be marked to 
enhance setup uncertainty even if CBCT is used to verify 
positioning. Markers approximating the anterior superior iliac 
spine and xiphoid process are suggested. 
• 
Site Specific Guidelines: 
o Adrenal: Elevating the lower extremities with behind the knee 
blocks can flatten the lower spine against the treatment table 
to enhance immobilization and attempt to make most of the 
superior/inferior respiratory motion conform to a plane close 
to parallel with the treatment table. (This would not be 
considered useful for pelvic extension or mediastinal 
extension.) 
o Head and Neck: This site is variably imaged and often the 
setup for diagnostic imaging does not align with the treatment 
setup. In these cases, it is preferable to do a diagnostic CT in 
the anticipated treatment position prior to surgery. Close 
coordination with the surgical and oncology team is essential. 
o Paraspinal: There is frequent extension along spinal nerve 
roots. MRI imaging is recommended in these cases and these 
should be completed in the treatment position. 3D acquisition 
techniques such as MPRAGE or SPGR should be considered, 
or if not available, multi-plane (axial, sagittal) reconstructions 
are a reasonable substitute. 
 
17.4.4.3 Motion Management Reporting  
A description of the method used and evidence of the remaining tumor 
motion (e.g., observed motion during fluoroscopy, motion of surrogate 
markers using camera systems, or analysis of 4D CT or 4D MRI) should 

 
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be submitted on the Motion Management Reporting Form with the Quality 
Assurance documentation materials. 
 
17.4.5 Calibration 
All therapy units used for this protocol shall have their calibrations verified by the 
IROC Houston QA Center. 
 
17.5 
Target Volume Definitions 
International Commission on Radiation Units and Measurements (ICRU) Reports 50, 62 
and 78 (www.icru.org) define prescription methods and nomenclature that will be utilized 
for this study. Using the ICRU terminology, the gross tumor volume (GTV) is anatomically 
defined, the clinical target volume (CTV) is anatomically confined and the planning target 
volume (PTV) is comprised of two margins meant to account for physiologic changes in 
the CTV (IM=internal margin) and set-up uncertainty (SM=set-up margin). ICRU-62 
conventions should also be considered by the treating radiation oncologist where organs at 
risk and target volume motion may compromise either preservation of normal tissue 
tolerances or target volume coverage, respectively. 
 
While not expressly used as a target volume, the Gross Tumor Volume Post Chemotherapy, 
Pre-Surgery (GTV_PreSurgery) volume may be useful as a reference for delineating target 
volumes. The GTV_PreSurgery volume includes disease defined by CT, MR and MIBG 
imaging PRIOR to surgery. The GTV_PreSurgery includes radiographically or 
pathologically involved tumor and lymph nodes. (See Contouring Atlas, figure 2). The 
GTV_PreSurgery does NOT include the extent of disease PRIOR to chemotherapy. The 
GTV_PreSurgery does NOT include uninvolved draining lymph node regions. See 
Contouring Atlas. 
 
17.5.1 Primary Site Volume Definitions 
Gross Tumor Volume (GTV) 
• 
The GTV is the volume of tissue representing the anatomical space 
confined by normal tissues which contain the highest concentration of 
residual tumor cells. 
• 
The GTV is bounded superiorly and inferiorly by the GTV_PreSurgery 
volume but anatomically confined to the post-surgery space after adjusting 
for reduced mass effect on surrounding organs at risk. (See Contouring 
Atlas, figure 3) 
• 
The GTV includes additional regions of tumor involvement defined 
intraoperatively that were not readily identified by imaging. Every effort 
should be made to correlate pathologic findings to the complete operative 
report. Discussion with the patient’s surgeon is recommended.  
• 
The GTV is corrected volumetrically to reflect the return of normal 
structures to their proper anatomic position after surgical resection. 
• 
The GTV does NOT include the extent of disease PRIOR to 
chemotherapy. 
• 
The GTV does NOT include uninvolved draining lymph node regions. 
Elective nodal treatment is not recommended. 
• 
See Contouring Atlas for further details. 
 

 
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Special Circumstances (GTV) 
• 
If the primary tumor was grossly resected at diagnosis, the GTV will be 
based on the initial diagnostic tumor volume. However, principles as 
outlined above should be applied – i.e. the GTV should be bounded by 
fixed organs at risk and not extend into adjacent organs/bone/etc. unless 
there is strong suspicion or evidence that the tumor infiltrated or invaded 
these regions. 
• 
In cases where there is discrepancy between imaging studies or 
intraoperative findings, the larger volume will define GTV. 
• 
When the primary tumor expands into a body cavity such as the lung or 
displaces a normal structure (such as the liver without infiltration) and 
following surgical resection the normal structure now occupies the space 
previously occupied by tumor, only the rim (< 3mm) of normal tissue that 
was in contact with the tumor volume should be included within the GTV.  
 
Clinical Target Volume (CTV) 
• 
The CTV is defined as the volume of tissue containing subclinical 
microscopic disease. 
• 
The CTV margin should be an expansion of the GTV to encompass 
microscopic disease. 
• 
The CTV for this protocol is the GTV with an anatomically confined 
margin of 1.0 cm. 
o To be anatomically defined means limiting the treated volume to 
encompass only the potential space with which the tumor came into 
contact. The volume may be adjusted to exclude the normal organs 
that fall back into place after the loss of tumor-related mass effect. 
When clear evidence of invasion of an adjacent organ is documented 
by imaging or in the operative report, the CTV should not be 
anatomically confined to the border of that adjacent organ and instead 
should extend into the region of the organ that is anticipated to likely 
reflect residual disease. In general, the intra-abdominal primary site 
CTV can be modified to exclude the kidney, liver and vertebral bodies 
(see Contouring Atlas, Figure 3). Cervico-thoracic, pelvic and head 
and neck sites should have their CTV’s adjusted to exclude uninvolved 
bone. 
• 
The superior and inferior extent of CTV should cover the extent to the 
superior and inferior extent of the GTV_PreSurgery volume.  
• 
See Contouring Atlas for further details 
 
Planning Target Volume (PTV) 
• 
The PTV is a geometric concept that includes a margin surrounding the 
CTV. 
• 
The PTV should account for physiologic motion in the CTV and set-up 
uncertainty. 
• 
The PTV is defined as the CTV with a geometric margin of 0.3-0.8 cm. 
o Movement prone regions such as the region just under the diaphragm 
should be considered for a more generous PTV closer to 0.5-0.8 cm 
while anatomical sites more apt to rigid immobilization such as the 
head and neck should be considered for tighter margins of 0.3 cm. 

 
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• 
The PTV may vary according to immobilization and patient cooperation, 
although 0.3 cm is the minimum extent of the margin surrounding CTV to 
form PTV. See Contouring Atlas, figure 5 for reference. 
• 
The PTV margin does not have to be uniform in all dimensions; especially 
if it compromises normal tissue volumes or if directional target or normal 
tissue motion is assessed and understood with 4D simulation techniques. 
• 
See Contouring Atlas for further details on target delineation and vertebral 
body inclusion guidelines. 
 
Table 17.5.1 Suggested PTV Margins 
Primary Site 
Non-CBCT 
CBCT 
Head and Neck 
5 mm 
3 mm 
Upper Paraspinal 
5 mm 
3-5 mm 
Intra-thoracic 
5 mm 
5 mm 
Abdomen 
5-8 mm 
3-5 mm 
Lower Paraspinal/Pelvic 
5 mm 
3-5 mm 
 
Target Volume Definitions for Proton Therapy: 
• 
GTV is the same for protons and photons. 
• 
CTV is the same for protons and photons. 
• 
PTV will be uniquely defined for proton therapy. 
 
When passive scattering or uniform scanning methods are used, the boost planning 
target volume (PTV) for proton therapy will include a margin which is added to 
the CTV in 3-dimensions. The margin should be consistent with the motion control 
and setup accuracy for the particular type of treatment at the treating proton center. 
The PTV will be used for dose reporting and not specifically for treatment 
planning. 
 
The goal of treatment planning will be CTV coverage at 100% with measures taken 
for each specific uncertainty. Specific adjustments will be made to (1) aperture 
margin definitions, (2) smearing of compensator (if applicable), (3) range of the 
individual beams (depth of penetration), and (4) modulation width of the SOBP. 
The following parameters must be explicitly reported for each beam: range, 
modulation, smearing radius of the compensator, set-up margin (SM) and PTV 
margin. The specifics of dose reporting for the proton PTV and recommendations 
regarding the PTV margin are discussed below in Section 17.6.4.2. 
 
Accounting for Motion of Target and Normal Tissue Volumes 
• 
For a CTV susceptible to physiologic motion, a margin of 0.5 cm should be 
added to the CTV prior to PTV margin expansion or a PTV margin of 1.0 cm 
should be chosen. 
 
17.5.2 Metastatic Sites 
17.5.2.1 Criteria for Treatment of Metastases 
While the primary site is always irradiated, radiation is only given to those 
metastatic sites with persistent active disease demonstrated at the time of 
evaluation prior to Consolidation based on persistent soft tissue mass 

 
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>1 cm3 and/or MIBG (or FDG) uptake. Sites that are negative on imaging 
prior to Consolidation will NOT be irradiated, even if they had enhanced 
uptake on MIBG (or FDG-PET) at diagnosis. This remains the case for 
sites that received emergent radiation at the time of diagnosis – these sites 
will not receive further radiation providing they are negative on imaging 
prior to consolidation. If greater than 50% of the bone marrow would be 
irradiated using these criteria, treatment fields should be discussed or 
reviewed with the study coordinator prior to simulating the patient for 
radiation therapy (please see Table 17.2.2). 
 
17.5.2.2 Patients with > 5 MIBG or PET avid metastatic sites prior to 
Consolidation 
If the patient had > 5 persistently positive metastatic sites identified by 
MIBG (or PET), the appropriate scan should be repeated after stem cell 
transplant. Only sites remaining positive will then be irradiated. If there 
are still > 5 MIBG (or PET) positive sites, notify the study coordinator or 
chair. 
 
In patients with > 5 persistent lesions that are MIBG (or PET) positive 
lesions prior to transplant and there are concerns regarding hematopoietic 
toxicity, consideration should be given to reserving a portion of the 
collected peripheral blood stem cell product to use as boost after radiation 
if leukocyte counts fall and fail to recover within 2-3 weeks after radiation 
is completed. Please notify study chair if “backup” stem cells are given. 
 
Figure 17.5.2 
  
 

 
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17.5.2.3 Metastatic Site Volume Definitions 
Metastasis Gross Tumor Volume (mGTVx) 
• 
The mGTVx volume is the post-Induction chemotherapy MIBG avid 
disease prior to Consolidation visible on either CT, MRI, and/or 
MIBG scans. 
• 
The “x” refers to the anatomical segment designated in the INRG 
123I-MIBG Scoring system (see Figure 17.5.2). 
 
Metastasis Clinical Tumor Volume (mCTVx) 
• 
The “x” refers to the anatomical segment designated in the INRG 
123I-MIBG Scoring system (see Figure 17.5.2). 
• 
The mCTVx is the mGTV1x volume expanded by 1 cm bounded by 
the mGTVx volume. 
• 
See Table 17.5.2 suggestions for metastatic site CTV modification. 
 
Table 17.5.2 Suggestions for Metastatic Site CTV Modifications 
Treatment Site(s) 
Methods to anatomically confine CTV 
Calvarium 
Adjust CTV to avoid extension into the cerebral cortex unless 
the lesion extends through the skull with suspected dural 
involvement. In cases where the entire calvarium needs to be 
treated, a brain sparing approach such as that used by Wolden et 
al (Pediatr Blood Cancer 2008) should be used.  
Base of Skull 
 
Adjust CTV to avoid extension beyond bony structures unless 
there is radiographic evidence of extension into brain tissue. T2-
weighted imaging can be useful in delineating the target.  
Limb 
Adjust CTV to avoid circumferential limb treatment, growth 
plates & joint spaces (unless involved). 
Spine 
Adjust CTV to facilitate uniform dose to the entire vertebrae 
including the transverse and spinous process, vertebral body, and 
pedicles (regardless of if non-uniformly involved by disease) to 
minimize the risk of scoliosis. The entire vertebral body should 
receive >18 Gy if treatment is required. 
Rib 
The CTV should be adjusted such that CTV does not extend into 
the lung parenchyma unless there is strong evidence of parietal 
pleura involvement. 
 
Metastasis Planning Tumor Volume (mPTVx) 
• 
The “x” refers to the anatomical segment designated in the INRG 
123I-MIBG Scoring system (see Figure 17.5.2.1). 
• 
The mPTVx is the mCTVx volume expanded by 0.5-0.8 cm depending 
on the anatomic site and immobilization. 
 
17.5.3 Emergency Radiation Target Delineation 
17.5.3.1 Emergency Radiation Indications 
Respiratory Distress: In cases where respiratory distress is present at 
diagnosis secondary to liver disease, radiotherapy may be administered 
over three treatments at 1.5 Gy per fraction.  

 
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Vision Loss: In clear cases of vision loss or the development of visual 
field deficits, radiotherapy may be administered over 3 fractions at 1.5 Gy 
per fraction. 
 
17.5.3.2 Emergency Radiation Field Design 
Orbital/Optic Pathway Radiotherapy: In emergent situations when 
simulation is not possible, radiotherapy may be prescribed using a limited 
symmetrical field for several fractions (see Figure 17.5.3). 
Liver Radiotherapy: In general, the entire extent of the liver need not 
be targeted and the bulk of the volume can be selected for treatment to 
minimize dose the abdomen and lungs. 
 
Figure 17.5.3 
 
 
17.6 
Target Dose 
17.6.1 Dose Definition and Specification 
Photon dose is to be specified in Gray (Gy)-to-muscle. For proton beams, the 
absorbed dose, ICRU 78’s DRBE, is specified in Gy(RBE), using a standard RBE of 
1.1 with respect to Cobalt-60.  
 
17.6.2 Prescription Dose and Fractionation 
The daily dose should be 1.8 Gy for the primary and metastatic sites. Sites of 
metastatic disease should be irradiated concurrently with the primary site. 
 
Table 17.6.2 
Nominal Dose by Site 
Dose/fraction 
Number of Fractions 
Primary Site (CTV/PTV) 21.6 Gy 
1.8 Gy 
12 
Metastatic Site(s) post-Induction therapy 
(mCTVx/mPTVx) 21.6 Gy 
1.8 Gy 
12 
Hepatomegaly/Partial Liver 
1.5 Gy 
3 
Craniospinal Dose 
1.8 Gy 
12 
 
17.6.3 Tissue Heterogeneity 
All dose calculations shall take into account the effects of tissue heterogeneities. 
When protons are used, tissue heterogeneity calculations should be performed with 

 
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the CT-based treatment planning system to generate dose distributions from the 
proton relative stopping power. 
 
17.6.4 Dose Uniformity 
17.6.4.1 Coverage Goals 
For photons, at least 95% of the protocol-specified dose should encompass 
100% of the PTV, no more than 10% of the PTV should receive greater 
than 110% of the prescription dose as evaluated by DVH. Wedges, 
compensators, and other methods of generating more uniform dose 
distributions are encouraged.  
 
17.6.4.2 Proton Therapy Specific PTV definition 
For protons, the PTV concept differs from photon therapy. All uncertainties are 
taken into account explicitly to create a robust plan that provides full dose coverage 
of the CTV Proton plans should be evaluated for adequate PTV coverage from the 
summation of all beams. For scattered and uniform scanning beams, the aperture 
margin must include the appropriate beam penumbra for the selected beam energy, 
and setup and internal margins (SM and IM). These margins depend on the patient 
setup techniques used at the treating proton center. The aperture margin may be 
expanded further if a cold spot occurs near the edge of CTV due to insufficient 
lateral scatter. The smearing radius for the range compensator must be equal to the 
setup and internal margins (SM and IM). The beam range should be equal to the 
maximum water equivalent depth of the CTV plus a range margin. Most proton 
centers use 3.5% of the maximum water-equivalent depth of the CTV to account 
for CT HU uncertainty and then add another 3 millimeters to account for 
uncertainties in beam range calibration and compensator fabrication. Additional 
range margin should be applied if internal motion could increase the water 
equivalent depth of the CTV. The modulation width should ensure proximal 
coverage of the target volume. 
 
A PTV should be created by a uniform expansion from CTV for reporting 
purposes. The expansion margin should be consistent with SM and IM and is 
typically 3 mm for a static target volume when daily imaging is performed. With 
the planning guidelines provided herein, no more than 10% of PTV should receive 
greater than 110% of the protocol dose as evaluated by DVH. In most cases, at 
least 95% of the protocol-specified dose should encompass 100% of the PTV. A 
potential exception is when the range margin is smaller than the PTV expansion 
(e.g., 3mm). As a result, the beam may not penetrate deep enough to sufficiently 
cover the distal portion of the PTV. This may occur for shallow target volumes 
where the maximum depth of the CTV is small and the range margin is small. This 
scenario is not expected for this protocol; however, such incomplete coverage of 
the PTV will not constitute a planning deviation because the plan should be 
sufficiently robust to cover the CTV with the protocol specified dose accounting 
for all uncertainties. 
 
17.6.5 Interruptions and Delays 
There will be no planned rests or breaks from treatment, once radiation therapy has 
been initiated. Blood product support should be instituted according to 

 
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institutional/protocol guidelines. If cytopenias are refractory to support and/or 
transfusion, a treatment interruption may be considered based on the specific 
clinical scenario. The reason for any interruptions greater than 3 treatment days 
should be recorded in the patient’s treatment chart and submitted with the QA 
documentation. There should be no modifications in dose fractionation due to age 
or field size.  
 
17.7 
Treatment Technique 
17.7.1 Beam Configuration 
Every attempt should be made to minimize the dose to critical normal tissue 
volumes without compromising coverage of the target volume. If significant 
volumes of vertebral bodies are contained within the treated volume, the dose 
should be distributed homogeneously to the vertebral bodies to avoid growth 
asymmetry (see Figure 17.8.1).  
 
17.7.2 Selection of Proton Beam Arrangements 
The use of posterior or posterior oblique fields is strongly recommended as the 
majority of these tumors are posterior in location (adrenal or paraspinal) and it is 
advisable to avoid uncertainties introduced by tissue heterogeneity and organ 
motion. Any treatment plan including anterior, anterior oblique or lateral fields 
should be discussed with the radiation oncology protocol coordinators prior to 
treatment delivery. The use of a 4D CT is recommended for proton planning to 
evaluate for target volume and organ motion. Gating may be used during treatment. 
 
17.7.3 Patient Position 
Reproducible setups are critical and the use of immobilization devices is strongly 
encouraged. Use of anesthesia is encouraged if necessary for proper positioning. 
 
17.7.4 Field Shaping 
Field shaping for photons will be done with multileaf collimation. Field shaping 
for protons will be done with either customized brass apertures, proton-specific 
multileaf collimation, or through scanning. 
 
17.7.5 Special Consideration for Patient Simulation for Protons 
Patient set-up and immobilization will be determined prior to obtaining the 
planning CT scan. CT planning is required for proton therapy because the relative 
stopping power based on Hounsfield units must be defined. The type of 
immobilization will be determined by the anatomic location of the site to be 
treated. Most patients will be immobilized in the supine position for reproducibility 
and ease of anesthesia administration. The majority of neuroblastomas are located 
posterior (adrenal or para-spinal). Posterior-anterior or posterior oblique fields 
typically allow for improved normal tissue sparing and minimize uncertainties due 
to organ motion and tissue heterogeneity introduced by organ motion or filling (i.e. 
lung, bowel). Posterior field arrangements are strongly recommended and this 
should be taken into consideration at the time of simulation. 4-D CT is 
recommended to evaluate target volume and organ motion. 

 
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17.7.6 Special Site Considerations 
Calvarial Metastases: Brain-sparing radiotherapy for skull metastases should be 
considered in cases where there is diffuse involvement of the calvarium and/or the 
skull base. Mixed photon and patched electron fields may be useful in cases with 
predominately calvarial involvement without base of skull extension.78 In cases 
where there is extensive base of skull involvement, IMRT may be more appropriate 
to achieve sufficient coverage. 
 
Brain Metastases: In cases where brain metastases are noted, the entire cranio-
spinal axis should be treated as these cases are at high risk for distant CNS relapse 
with focal radiotherapy.79  
 
17.8 
Organs at Risk  
Planning should be done to minimize dose to normal tissue volumes including those 
described in the table below. No attempt should be made to spare these structures when 
they intersect or are adjacent to the target volumes. To avoid exceeding the suggested dose 
constraints, the dose coverage may be adjusted provided the guidelines of the protocol are 
observed. 
 
17.8.1 Normal Tissue Tolerances and Special Site Volume Considerations 
Care must be taken to avoid a steep dose gradient that transverses the vertebral 
body. When any part of a vertebral body must be included in the PTV, the entire 
vertebrae (corpus, pedicles, transverse and spinous process) should receive at least 
18 Gy. The target volume should not be modified to include the vertebral body, ; 
rather, the vertebral body should be contoured as an additional pseudo-target 
structure with a specified minimum dose of 18 Gy if any part of it is included in 
the PTV (see Figure 17.8.1.1).  
 
Table 17.8.1 
Organ 
Dose Limit  
Contralateral Kidney* 
<25% > 18 Gy 
Ipsilateral Kidney-whole* 
<75% > 18 Gy 
<100% > 14.4 Gy 
Mean dose ≤ 18 Gy 
Liver** 
Mean dose < 15 Gy 
Vertebrae 
(If vertebral body is included in PTV) 
Minimum dose 18 Gy to entire 
vertebrae and pedicles 
(See Figure 17.8.1) 
Bilateral lungs 
<30%  ≥ 20 Gy 
Ipsilateral lung  
<30%  ≥ 20 Gy 
Contralateral lung 
<10% ≥ 20 Gy 
 
*If kidney dose exceeds the constraints outlined, renal scintigraphy is 
recommended to ensure that both kidneys are functioning prior to beginning 
radiotherapy.  
 

 
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**If liver constraints are exceeded due to need to radiate a liver lesion, extra 
concern should be exercised for patients who are recovering from SOS. 
 
 
Figure 17.8.1 Vertebral Body Low Dose Spillage Adjustment 
 
17.9 
Dose Calculations and Reporting 
Centers participating in this protocol must complete the appropriate credentialing outlined 
in Section 17.0. 
 
17.9.1 Prescribed Dose 
The dose prescription and fractionation shall be reported on the RT1/ Proton 
Dosimetry Summary Forms. If IMRT is used, the monitor units generated by the 
IMRT planning system must be independently checked prior to the first treatment. 
Measurements in a QA phantom can suffice for a check as long as the patient plan 
can be directly applied to a phantom geometry. 
 
17.9.2 Delivered Dose 
The total dose delivered shall be reported on the RT-2 Radiotherapy Total Dose 
Record Form. 
 
17.9.3 Normal Tissues Dosimetry 
The dose to the critical organs indicated should be calculated whenever they are 
included in the radiation field. For patients treated with volume-based techniques, 
the appropriate dose volume histograms should be submitted. If IMRT is used, a 
DVH must be submitted for a category of tissue called “unspecified tissue,” which 
is defined as tissue contained within the skin, but which is not otherwise identified 
by containment within any other structure. 
 

 
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Required normal tissue DVH data according to primary site of treatment: 
 
Table 17.9.3 
 
Treatment Area 
Required DVH 
Standard Names 
Neck 
Thyroid 
Thyroid 
 
Spinal Cord 
SpinalCord 
Chest 
Right Lung 
Lung_R 
 
Left Lung 
Lung_L 
 
Left and Right Lung 
Lungs 
 
Heart 
Heart 
 
Spinal Cord 
SpinalCord 
Abdomen 
Liver 
Liver 
 
Right Kidney 
Kidney_R 
 
Left Kidney 
Kidney_L 
 
Spinal Cord 
SpinalCord 
 
17.10 Quality Assurance Documentation 
Key Points 
• 
No on-treatment review will be required for this study. 
• 
Within 1 week of the completion of radiotherapy. 
o Submit data for the primary site only (see checklist). 
o Primary site data submission must be in digital format. 
o Diagnostic imaging data must be in digital format. 
• 
Only the RT-2 form and a copy of the treatment chart need to be submitted for 
metastatic sites. 
 
 
 
17.10.1 Submission of Diagnostic Imaging Data 
Copies of the diagnostic imaging used to determine the primary treatment volume 
(CT, MRI, and/or MIBG (PET-CT if MIBG negative) scans performed prior to 
surgical resection and after the end of Induction with corresponding diagnostic 
imaging reports; as well as the operative and pathology reports) should be 
submitted. Repeat MIBG (PET-CT) for cases with >5 positive sites after induction. 
Submission via TRIAD is preferred (see Section 16.6). Alternatively, imaging can 
be submitted via sFTP. Instructions for digital diagnostic submissions may be 
found on the IROC Rhode Island website - www.irocri.qarc.org, under Digital 
Data, Diagnostic. If images have been submitted to IROC Rhode Island for central 
imaging reviews (see Section 16.6), duplicate images do not need to be submitted. 
 
 
17.10.2 Submission of Radiotherapy Data 
Digital Submission: 
Submission of treatment plans in digital format as DICOM RT is required. Digital 
data must include CT scans, structures, plan, and dose files. Submission via 
TRIAD is preferred (see Section 16.6), but alternatively sites may use sFTP. 
Instructions for data submission via sFTP are on the IROC Rhode Island web site 
at http://irocri.qarc.org under "Digital Data." Any items on the list below that are 
not part of the digital submission may be included with the transmission of the 

 
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digital RT data via TRIAD or sFTP or submitted separately. Screen captures are 
preferred to hard copy for items that are not part of the digital plan. 
 
17.10.3 Primary Site Data Submission 
Treatment Planning System Output:  
• 
RT treatment plans including CT, structures, dose, and plan files. These items 
are included in the digital plan.  
• 
Digitally reconstructed radiographs (DRR) for each treatment field. 
Submission of DRR’s is not required for IMRT. 
• 
Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest 
dose statistics. 
 
Supportive Data 
• 
Radiotherapy record (treatment chart) including prescription and daily and 
cumulative doses to all required areas and organs at risk. 
• 
If the recommended doses to the organs at risk are exceeded, an explanation 
should be included for review by IROC Rhode Island and the radiation 
oncologist.  
• 
Proton therapy: Smearing radius of the compensator (if applicable), set-up 
margin (SM) and PTV margin for each treatment beam and a description of the 
rationale for the PTV margins. 
 
Forms 
• 
RT1 or Proton Dosimetry Summary Form  
• 
RT-2 Radiotherapy Total Dose Record form 
• 
Motion management reporting form, if applicable 
 
17.10.4 Metastatic Site(s) Data Submission 
• 
The RT-2 Radiotherapy Total Dose Record form. 
• 
Copy of the patient radiotherapy record including prescription and daily and 
cumulative doses to all targeted volumes and critical organs. 
 
These data can be uploaded to TRIAD, sFTP or emailed to: 
DataSubmission@QARC.org 
 
 
Questions regarding the dose calculations or documentation should be directed to: 
COG Protocol Dosimetrist at physics@QARC.org or 401.753.7600 
 
17.11 Definitions of Deviations in Protocol Performance 
In the following table, the GTV, CTV and PTV descriptions and evaluations will applied 
for the primary site radiation treatment plan.  
 
 

 
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DEVIATION 
 
Variation Acceptable 
Deviation Unacceptable 
Prescription Dose 
 
Difference in prescribed or 
computed dose is 6-10% of 
protocol specified dose 
Difference in prescribed or 
computed dose is > 10% of 
protocol specified dose 
Dose Uniformity 
 
>10% PTV received > 110% 
of the prescription dose 
or 
<93% isodose covers 100% 
of PTV 
<90% isodose covers 100% of 
PTV 
Target Volume 
 
CTV or PTV margins are 
less than the protocol 
specified margins in the 
absence of anatomic barriers 
to tumor invasion (CTV) or 
without written justification 
(PTV) 
GTV does not encompass MR-
visible residual tumor 
Organs at Risk 
 
OAR deviations will be 
assessed at the time of final 
review. 
OAR deviations will be assessed 
at the time of final review. 
Radiotherapy Timing 
 
 Radiation started more than 
80 days after consolidation 
Radiation started more than 120 
days after consolidation 
 
 
 

 
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18.0 
HEMATOPOIETIC TRANSPLANT GUIDELINES 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
All transplants performed on COG trials must occur at FACT-accredited SCT programs. 
 
18.1 
Catheter Use 
PBSC may be collected using a large bore double lumen central venous catheter that will allow 
the 1-2 mL/kg/min flow rates required for apheresis. Institutional preference for apheresis 
catheters may be used. 
 
18.2 
PBSC Mobilization 
Institutional standard operating procedures (SOPs) will be used for mobilization and 
pheresis. 
 
In the absence of institutional SOPs, the following suggested guidelines could be used: 
Patients should begin G-CSF starting one to three days after completing a cycle of 
chemotherapy. They should continue on G-CSF 5 mcg/kg/day while recovering from the 
cycle of chemotherapy until the post-nadir ANC > 500-1000/L, at which point it is 
recommended to increase the dose of G-CSF to at least 10 mcg/kg/day per institutional 
policies. 
 
Institutions that time collections using circulating CD34 cell counts will generally begin 
pheresis when the CD34 count is ≥ 10-20 cells/L. Otherwise, the timing of collection is 
within 1-4 days of increasing the G-CSF dose to 10 mcg/kg, when WBC is > 2000 - 5000 
(usually Day 14 from start of chemotherapy). It is critical that G-CSF be given daily until 
PBSC collection is complete. If peripheral WBC is > 60,000, decrease G-CSF dose to 5 
mcg/kg/day. If more than one day of PBSC collection is required, adjust the G-CSF dose 
per institutional guidelines.  
 
If patients are off G-CSF prior to planned PBSC harvest, they should receive G-CSF 10-
16 mcg/kg/day for 3 days prior to the first day of scheduled PBSC harvest (per institutional 
policies), harvest on Day 4 of G-CSF treatment, and continue daily G-CSF until PBSC 
collections are completed.  
 
TIMING: PBSC mobilization is strongly recommended following Cycle 2 
REGARDLESS of disease status in the marrow. Documentation of clearance of tumor 
cells from the bone marrow is NOT REQUIRED because the rate of 
immunocytochemical (ICC) positivity is <1% even in the setting of marrow disease. 
However, if the patient’s medical condition prohibits safe apheresis, it is appropriate 
to delay PBSC mobilization and harvest until after Cycle 3 of Induction therapy. If 
PBSC mobilization is inadequate, an additional harvest may be performed after Cycle 
3. If PBSC mobilization is still inadequate after Cycle 3, an additional harvest may be 
performed after Cycle 4. Significant efforts should be made to collect an adequate 
PBSC product (minimum of 4 x 106 CD34+ cells/kg) following Cycle 2. 

 
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Ch14.18 (dinutuximab) should not be started prior to the PBSC collection. For 
patients who undergo PBSC collection after Cycle 3, the ch14.18 (dinutuximab) 
should be held during Cycle 3. For the rare patient whose stem cell collection is not 
complete until after Cycle 4, ch14.18 (dinutuximab) should be held during Cycles 3 
and 4. 
 
18.3 
PBSC Collection Guidelines 
18.3.1 Laboratory Studies 
For patients < 25 kg, a type and cross for packed red blood cells (PRBC) should be 
performed one day prior to procedure to avoid apheresis delays.  
 
18.3.2 Collection Goals 
It is recommended that large volume apheresis be performed on all patients for 
each collection, per institutional guidelines.  
 
Optimal collection goal (total for all collections) is 10-20 x 106 CD 34+ cells/kg 
for PBSC. The minimum collection is 4 x 106 CD 34+ cells/kg divided in 3 aliquots 
of at least 2 x 106 CD 34+ cells/kg per aliquot. Collections in excess of 20 million 
CD34/kg are allowed. If possible, collection of a 4th aliquot should be considered, 
the aliquot stored as a back-up. : 
• 
Aliquot #1: 2-4x106 CD34+ cells/kg for PBSC support with HSCT #1 
(Thiotepa/Cyclophosphamide) 
• 
Aliquot #2: 2-4x106 CD34+ cells/kg for PBSC support with HSCT #2 
(Carboplatin/Etoposide/Melphalan) 
• 
Aliquot #3: (if possible): 2-4x106 CD34+ cells/kg as a backup for delayed 
engraftment, or for potential subsequent use.  
 
CD34+ cell counts should be done at local institution for each daily collection as 
per institutional SOP. In the event that a patient’s collection is just short of or just 
equal to 4 x 106 CD 34+ cells/kg, it is recommended that the patient undergo an 
additional day of pheresis. If the “additional” pheresis is unable to be performed 
on the subsequent day to the first pheresis, then apheresis may be performed 
following the next cycle of Induction chemotherapy. 
 
18.4 
PBSC Analyses 
The following studies are recommended for each PBSC collection: 
1) 
Culture for bacterial and fungal contamination, 
2) 
Nucleated cell count and differential, 
3) 
CD34+ cell enumeration 
 
 
18.5 
Cryopreservation of PBSC Products 
Each aliquot (as detailed above) should be processed and cryopreserved on the day of 
collection as per Institutional SOPs. These SOPs include the use of 7.5-10% dimethyl 
sulfoxide (DMSO) final concentration in the cryopreservation medium, use of a monitored, 
controlled-rate freezer, and storage in liquid nitrogen with appropriate monitoring. The 

 
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goal is to have multiple aliquots cryopreserved separately to facilitate multiple infusions 
and to provide a potential backup. 
18.6 
Autologous Stem Cell Rescue 
Institutional SOPs may be followed. However, the PBSC product should NEVER be 
irradiated prior to infusion. 
 
18.6.1 Premedication 
DMSO may cause a histamine-like reaction when infused into the patient. 
Therefore, premedication with an antihistamine and acetaminophen is 
recommended. 
 
 
18.6.2 Thawing of PBSC 
PBSC are thawed in a 37C water bath. Only 1 bag of PBSC should be thawed at 
a time – when the infusion of 1 bag is completed, the next bag should be thawed.  
 
Thawed PBSC should be infused as rapidly as tolerated through a central venous 
catheter. The unit may be infused by gravity, or the cells may be drawn up into a 
syringe and pushed by trained personnel. Microaggregate filters and 
leukodepletion filters MUST NOT be used for infusion of PBSC. If a thawed unit 
appears clumpy or stringy and these particles cannot be dispersed with gentle 
kneading, the PBSC product could be infused through a standard 170 micron blood 
filter. 
 
18.6.3 Possible Symptoms during Infusion 
 
Precipitating Factor 
 
Possible Symptoms 
hemolyzed red cells 
 
fever, chills, hemoglobinuria 
cellular clumps and debris 
chest pain, hypoxia, hypertension 
cold 10% DMSO 
 
nausea, headache 
microbial contamination 
fever, chills, hypotension 
plasma proteins  
 
urticaria 
 
 
18.6.4 Recommendations for Stem Cell Infusion 
a. Institutional SOPs may be followed 
b. Discontinue all other IV fluids if possible during stem cell infusion to avoid 
volume overload. 
c. Consider anti-emetics prior to stem cell infusion to limit DMSO-induced 
nausea and vomiting. 
d. Where the DMSO volume in the stem cell product would exceed accepted 
level for infusion within a 24-hour period, stem cell products may be infused 
over 2 days to meet this standard 
e. Hydrate for 6-12 hours post stem cell infusion at 125 mL/m²/hr. 
 
 

 
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APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
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 (https://ctepcore.nci.nih.gov/iam). In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or 
acting as a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/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 CTSU (Cancer Trials Support Unit) websites and applications. In addition, IVRs and NPIVRs 
must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in 
RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
Additional 
information 
can 
be 
found 
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. 
 
 

 
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements For [insert study number] Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
IROC Credentialing Status Inquiry (CSI) Form  
NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling site must 
be aligned to a RTI provider. To manage provider associations access the Provider Association 
tab on the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or 
remove associated providers. Sites must be linked to at least one IROC credentialed provider 
to participate on trials with an RT component. 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
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. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 

 
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Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave 
via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum 
of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the 
DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner of the 
iMedidata page. Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
 
 

 
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APPENDIX II: INTERNATIONAL NEUROBLASTOMA RISK GROUP (INRG) STAGING 
SYSTEM80,81 
 
 
INRG Stage  
Description  
L1 
Localized tumor not involving vital structures as defined by the list of 
image-defined risk factors* and confined to one body compartment. 
L2 
Locoregional tumor with presence of one or more image-defined risk 
factors.* 
M 
Distant metastatic disease (except MS). 
MS 
Metastatic disease in children younger than 18 months with metastases 
confined to skin, liver, and/or bone marrow (bone marrow involvement 
should be limited to < 10% of total nucleated cells on smears or biopsy). 
Primary tumor may be L1 or L2 as defined above. 
* See Appendix VIII 
 
Bone marrow disease is determined by morphology on smears and aspirates. 
 
 
 

 
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Page 230 
APPENDIX III: 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 
alfentanil4,5  
acalabrutinib5 
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
ergotamine4 
erlotinib 
eplerenone5 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 
 
 

 
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Page 231 
ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
telaprevir 
tamoxifen 
temsirolimus 
teniposide 
tetracycline 
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 4.1.2.1 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 232 
APPENDIX IV: 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. 
 
Carboplatin 
Drugs that may interact with carboplatin 
• 
Antibiotics like gentamicin or tobramycin 
• 
Anti-seizure medications like fosphenytoin or phenytoin 
• 
Arthritis medications like leflunomide, tofacitinib 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Other medications like clozapine or natalizumab 
 
Food and supplements that may interact with carboplatin 
• 
Echinacea 
 
 
Cisplatin 
Drugs that may interact with cisplatin 
• 
Antibiotics like gentamicin or tobramycin 
• 
Anti-seizure medications like fosphenytoin or phenytoin 
• 
Arthritis medications like leflunomide or tofacitinib 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Other medications like bumetanide, clozapine, furosemide, natalizumab 
 
Food and supplements that may interact with cisplatin 
• 
Echinacea 
 
 

 
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Page 233 
Cyclophosphamide 
Drugs that may interact with cyclophosphamide 
• 
Allopurinol 
• 
Amiodarone 
• 
Carbamazepine 
• 
Cyclosporine 
• 
Digoxin  
• 
Efavirenz 
• 
Etanercept  
• 
Hydrochlorothiazide 
• 
Lumacaftor 
• 
Mifepristone 
• 
Pentostatin 
• 
Rifampin 
• 
Ritonavir 
• 
Warfarin 
 
Food and supplements that may interact with cyclophosphamide 
• 
St. John’s Wort 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
 
Doxorubicin 
Drugs that may interact with doxorubicin* 
• Antibiotics 
• 
Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics 
• 
Clozapine, fluoxetine, fluvoxamine, nefazodone, paroxetine 
• 
Antibiotics and Antifungals 
• 
Fluconazole, isavuconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• 
Arthritis medications 
• 
Leflunomide, tofacitinib 
• 
Antiretrovirals and antivirals 
• 
Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, lopinavir, 
nelfinavir, ritonavir, saquinavir, Stribild®, telaprevir, tipranavir, zidovudine 
• 
Anti-seizure medications 
• 
Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• 
Heart medications 
• 
Amiodarone, diltiazem, dronedenarone, ranolazine, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Ado-trastuzumab emtansine, bevacizumab, idelalisib, trastuzumab, taxane derivatives 
• 
Many other drugs, including the following: 
• Aprepitant, cyclosporine, fosaprepitant, fosnetupitant, deferasirox, ivacaftor, mifepristone, 
natalizumab, netupitant 
 

 
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Page 234 
Food and supplements that may interact with doxorubicin 
• Echinacea 
• Glucosamine  
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
 
Etoposide 
Drugs that may interact with etoposide 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
• 
Clozapine, nefazodone 
• 
Antifungals  
• 
Fluconazole, itraconazole, 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 
• 
Anti-seizure medications  
• 
Carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone 
• 
Heart medications  
• 
Amiodarone, dronedenarone, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
• 
Aprepitant, atovaquone, bosentan, deferasirox, ivacaftor, lomitapide, mifepristone, modafinil 
natalizumab, pimozide 
 
Food and supplements that may interact with etoposide 
• Echinacea 
• Glucosamine 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
Isotretinoin 
Drugs that may interact with isotretinoin 
• Aminiolevulinic Acid 
• Carbamazepine  
• Some oral contraceptives 
• Some antibiotics, like doxycycline, tetracycline, and tigecycline 
 

 
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Page 235 
Food and supplements that may interact with isotretinoin 
• St. John’s Wort 
• Vitamin A supplements or multivitamins that contain vitamin A 
 
 
Melphalan 
Drugs that may interact with melphalan 
• Clozapine, leflunomide, natalizumab, tofacitinib 
 
Food and supplements that may interact with melphalan 
• Echinacea 
 
 
Thiotepa 
Drugs that may interact with thiotepa 
• Arthritis medications like leflunomide or tofacitinib 
• Other medications like bupropion, clozapine, efavirenz, methadone, promethazine, or natalizumab 
 
Food and supplements that may interact with thiotepa 
• 
Echinacea 
 
 
Topotecan 
Drugs that may interact with topotecan 
• 
Antibiotics and antifungals 
o Clarithromycin, erythromycin, itraconazole, ketoconazole 
• 
Arthritis medications  
o Leflunomide, tofacitinib 
• 
Antiretrovirals and antivirals  
o Lapatinib, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, velpatasvir, voxilaprevir 
• 
Anti-seizure medications 
o Fosphenytoin, phenytoin 
• 
Heart medications  
o Amiodarone, carvedilol, dronedenarone, propafenone, quinidine, ranolazine, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
o Clozapine, eltrombopag, ivacaftor, natalizumab, tolvaptan 
 
Food and supplements that may interact with topotecan 
• Echinacea 
 
 

 
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Page 236 
Vincristine 
Drugs that may interact with vincristine 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• Antifungals  
o Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tocilizumab, tofacitinib 
• Anti-rejection medications 
o Cyclosporine 
• Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, lapatinib 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, telaprevir, tenofovir, 
tipranavir 
• Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, carvedilol, diltiazem, dronedenarone, propafenone, quinidine, ranolazine, 
verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Aprepitant, bosentan, cobicistat, conivapatan, deferasirox, fosnetupitant, ivacaftor, 
mifepristone, modafinil, natalizumab, nefazodone, netupitant 
 
Food and supplements that may interact with vincristine 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
 

 
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Page 237 
APPENDIX V: SUMMARY OF OPTIONAL CORRELATIVE STUDIES 
 
Correlative Studies: Induction 
 
Time point 
Sample 
Type 
Volume per 
tube 
Quantity 
Tube Type / Sample Prep 
Notes  
Ship to 
Section 
Number 
CORRELATIVE STUDIES: INDUCTION 
Pre-Tx 
Blood 
7 – 10 mL 
2 tubes 
EDTA 
Ship immediately 
Yu 
15.1.1 
15.1.41 
2.5 mL 
2 tubes 
PAXgene RNA 
 
BPC 
15.1.2 
15.1.6 
Blood 
3 mL 
1 tube 
Red Top 
Process for serum  
BPC 
15.1.5 
1 mL 
1 tube 
Red Top 
Process for serum 
BPC 
15.1.7 
Tumor 
Tissue2,3 
 
3 
Air dried touchprep slides 
 
BPC 
15.1.7 
Bone 
Marrow 
 
 
3 of each 
slide type 
• Air-dried smear slides (aspirate) 
• Air-dried touchprep slides (biopsy) 
 
BPC 
15.1.7 
Cycle 1, Day 6 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
 
Cycle 3, Day 1 
Blood 
7 – 10 mL 
2 tubes 
EDTA 
Ship immediately 
Yu 
15.1.1 
15.1.41 
Blood 
3 mL 
1 tube 
Red Top 
Process for serum  
BPC 
15.1.5 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 3, Day 6 
Blood 
7 – 10 mL 
2 tubes 
EDTA 
 
Yu 
15.1.1 
15.1.41 
Blood 
3 mL 
1 tube 
Red Top 
Process for serum  
BPC 
15.1.5 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 4, Day 1 
Blood 
7 – 10 mL 
2 tubes 
EDTA 
Ship immediately 
Yu 
15.1.1 
15.1.41 
Blood 
3 mL 
1 tube 
Red Top 
Process for serum  
BPC 
15.1.5 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 4, Day 6 
Blood 
7 – 10 mL 
2 tubes 
EDTA 
Ship immediately 
Yu 
15.1.1 
15.1.41 
Blood 
3 mL 
1 tube 
Red Top 
Process for serum  
BPC 
15.1.5 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 4, Day 15 
Blood 
1 mL 
1 tube 
Red Top 
Process for serum  
BPC 
15.1.7 
Cycle 5, Day 1 
Blood 
2 mL 
1 tube 
EDTA 
Process for plasma  
BPC 
15.1.3 
Blood 
1 mL 
1 tube 
Red Top 
Process for serum  
BPC 
15.1.7 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 5, Day 6 
Blood 
2 mL 
1 tube 
EDTA 
Process for plasma  
BPC 
15.1.3 

 
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Page 238 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 5, Day 21  
Blood 
1 mL 
1 tube 
Red top 
Process for serum  
BPC 
15.1.7 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Bone 
Marrow 
 
 
3 of each 
slide type 
• Air-dried smear slides (aspirate) 
• Air-dried touchprep slides (biopsy) 
 
BPC 
15.1.7 
1 Samples collected on 15.1.4 (NK Marker Analysis) will be shared for use on 15.1.3 (HACA/PATA) and KIR/KIRL and Fc 
Receptor genotyping. Additional samples do not need to be collected at these shared time points. CBC results obtained on the day 
of the NK Marker Analysis specimen should accompany the specimen transmittal form. 
2. Only collect if not submitted on APEC14B1 or ANBL00B1.  
3. Paraffin embedded tissue block may be sent instead of slides. 
 
 
Correlative Studies: Post-Consolidation 
Time point 
Sample 
Type 
Volume per 
tube 
Quantity 
Tube Type / Sample Prep 
Notes  
Destina
tion 
Lab 
Section 
Number 
CORRELATIVE STUDIES: POST-CONSOLIDATION 
Prior to post-
Consolidation, 
Cycle 1 
Blood 
7 – 10 mL 
2 tubes 
EDTA 
Ship immediately 
Yu 
15.1.1 
15.1.41 
2.5 mL 
2 tubes 
PAXgene RNA 
 
BPC 
15.1.2 
15.1.6 
Blood 
3 mL 
1 tube 
Red Top 
Process for serum 
BPC 
15.1.5 
Cycle 1, Day 4 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 1, Day 7 
Blood 
7 mL 
1 tube 
EDTA 
 
Yu 
15.1.41 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 2, Day 1 
Blood 
2 mL 
1 tube 
EDTA 
Process for plasma 
BPC 
15.1.3 
Cycle 2, Day 4 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 2, Day 7 
Blood 
 2 mL 
1 tube 
EDTA 
Process for plasma 
BPC 
15.1.3 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Cycle 3, Day 1 
Blood 
2 mL 
1 tube 
EDTA 
Process for plasma 
BPC 
15.1.3 
Cycle 3, Day 7 
Blood 
2 mL 
1 tube 
EDTA 
Process for plasma 
BPC 
15.1.3 
Cycle 4, Day 1 
Blood 
7 mL 
1 tube 
EDTA 
Ship immediately 
Yu 
15.1.41 
Cycle 4, Day 7 
Blood 
2 mL 
1 tube 
EDTA 
Process for plasma 
BPC 
15.1.3 
Cycle 5, Day 1 
Blood 
7 mL 
1 tube 
EDTA 
Ship immediately 
Yu 
15.1.41 
Cycle 5, Day 7 
Blood 
2 mL 
1 tube 
EDTA 
Process for plasma 
BPC 
15.1.3 
Cycle 6, Day 15 
Blood 
7 mL 
1 tube 
EDTA 
Ship immediately 
Yu 
15.1.41 

 
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Page 239 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
End of therapy  
Blood 
1 mL 
1 tube 
Red top 
Process for serum 
BPC 
15.1.7 
Bone 
Marrow2 
 
3 of each 
slide type 
• Air-dried smear slides (aspirate) 
• Air-dried touchprep slides (biopsy) 
 
BPC 
15.1.7 
Relapse / 
Progression 
Blood 
7 – 10 mL 
1 tube 
EDTA 
Ship immediately 
Yu 
15.1.1 
3 mL 
1 tube 
Red Top 
Process for serum 
BPC 
15.1.5 
Blood 
2.5 mL 
1 tube 
PAXgene RNA 
 
BPC 
15.1.6 
Bone 
Marrow 
 
3 of each 
slide type 
• Air-dried smear slides (aspirate) 
• Air-dried touchprep slides (biopsy) 
 
BPC 
15.1.7 
Tumor 
Tissue3 
 
 
3 
 
 
Air dried touchprep slides 
 
 
 
BPC 
 
15.1.7 
1 Samples collected on 15.1.4 (NK Marker Analysis) will be shared for use on 15.1.3 (HACA/PATA) and KIR/KIRL and Fc 
Receptor genotyping. Additional samples do not need to be collected at these shared time points. CBC results obtained on the day 
of the NK Marker Analysis specimen should accompany the specimen transmittal form. 
2. Only collect if bone marrow was positive for tumor immediately prior to Post-Consolidation. 
3. Only collect if not submitted on APEC14B1 or ANBL00B1. 
 
 

 
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Page 240 
APPENDIX VI: EMERGENCY MANAGEMENT OF CH14.18 (DINUTUXIMAB) TOXICITIES 
 
 
This document is for rapid reference. See Section 5.11 for further information regarding 
management of acute toxicities during ch14.18 (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 ch14.18 (dinutuximab) infusion and sargramostim 
• 
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 ch14.18 (dinutuximab) and/or 
cytokine 
 
For hypotension in setting of allergic reaction: 
• 
Hold ch14.18 (dinutuximab) and sargramostim 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 ch14.18 
(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, ch14.18 (dinutuximab) can be resumed at half rate with very close 
observation 
• 
Do not resume sargramostim until the next day 
 
Minimal criteria for resumption of ch14.18 (dinutuximab) infusion: 
• 
Complete resolution of airway symptoms 
• 
Complete resolution of hypotension 
 
 
 

 
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Page 241 
APPENDIX VII: OVERALL RESPONSE CRITERIA 
 
 
Primary Tumor 
Soft Tissue and Bone Metastatic Disease 
(MIBG or FDG-PET/CT or PET/MR) 
Bone Marrow Metastatic Disease  
Overall 
CR 
CR 
CR 
CR 
CR for one response component with either CR or NI for other components 
CR 
CR 
CR 
MD 
PR 
CR 
PR 
CR 
PR 
CR 
PR 
MD 
PR 
CR 
PR 
NI 
PR 
CR 
NI 
MD 
PR 
PR 
CR 
CR 
PR 
PR 
CR 
NI 
PR 
PR 
CR 
MD 
PR 
PR 
PR 
CR 
PR 
PR 
PR 
NI 
PR 
PR 
PR 
MD 
PR 
PR 
NI 
CR 
PR 
PR 
NI 
NI 
PR 
PR 
NI 
MD 
PR 
NI 
CR 
MD 
PR 
NI 
PR 
CR 
PR 
NI 
PR 
MD 
PR 
NI 
PR 
PR 
PR 
CR 
CR 
SD 
MR 
CR 
PR 
SD 
MR 
CR 
SD 
CR 
MR 
CR 
SD 
MD 
MR 
CR 
SD 
SD 
MR 
CR 
SD 
NI 
MR 
CR 
NI 
SD 
MR 
PR 
CR 
SD 
MR 
PR 
PR 
SD 
MR 
PR 
SD 
CR 
MR 
PR 
SD 
MD 
MR 
PR 
SD 
SD 
MR 
PR 
SD 
NI 
MR 
PR 
NI 
SD 
MR 
SD 
CR 
CR 
MR 
SD 
CR 
MD 
MR 
SD 
CR 
SD 
MR 
SD 
CR 
NI 
MR 
SD 
PR 
CR 
MR 
SD 
PR 
MD 
MR 
SD 
PR 
SD 
MR 
SD 
PR 
NI 
MR 
SD 
SD 
CR 
MR 
SD 
NI 
CR 
MR 
NI 
CR 
SD 
MR 
NI 
PR 
SD 
MR 
NI 
SD 
CR 
MR 
SD 
SD 
MD 
SD 
NI 
SD 
MD 
SD 
SD 
NI 
MD 
SD 
NI 
NI 
MD 
SD 
SD 
SD 
SD 
SD 
SD 
NI 
SD 
SD 
SD 
SD 
NI 
SD 
SD 
NI 
NI 
SD 
NI 
SD 
SD 
SD 
NI 
SD 
NI 
SD 
NI 
NI 
SD 
SD 
PD in any one component 
PD 
Response of Not Evaluable for any one of the 3 components that had measurable/evaluable tumor at study enrollment and no 
PD for any component 
Not Evaluable 
No response evaluation performed for any of the 3 components 
Not Done 
CR: Complete Response; MD: Minimal Disease; PR: Partial Response; MR: Minor Response; SD: Stable Disease; PD: Progressive disease; NI: 
not involved; site not involved at study entry and remains not involved. 

  
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APPENDIX VIII: INTERNATIONAL NEUROBLASTOMA RISK GROUP (INRG) IMAGE 
DEFINED RISK FACTORS 
 
Risk factors related to localization: 
 
1) Neck: 
• 
Tumor encasing carotid and/or vertebral artery and/or internal jugular vein 
• 
Tumor extending to base of skull 
• 
Tumor compressing the trachea 
 
2) Cervico-thoracic junction: 
• 
Tumor encasing brachial plexus roots 
• 
Tumor encasing subclavian vessels and/or vertebral and/or carotid artery 
• 
Tumor compressing the trachea 
 
3) Thorax: 
• 
Tumor encasing the aorta and/or major branches 
• 
Tumor compressing the trachea and/or principal bronchi 
• 
Lower mediastinal tumor, infiltrating the costo-vertebral junction between T9 and T12 
 
4) Thoraco-abdominal: 
• 
Tumor encasing the aorta and/or vena cava 
 
5) Abdomen/Pelvis: 
• 
Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament 
• 
Tumor encasing branches of the superior mesenteric artery at the mesenteric root 
• 
Tumor encasing the origin of the celiac axis, and/or of the superior mesenteric artery 
• 
Tumor invading one or both renal pedicles 
• 
Tumor encasing the aorta and/or vena cava 
• 
Tumor encasing the iliac vessels 
• 
Pelvic tumor crossing the sciatic notch 
 
6) Dumbbell tumors with or without symptoms of spinal cord compression: 
• 
Whatever the localization 
 
7) Infiltration of adjacent organs/structures: 
• 
Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery 
 
 

  
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APPENDIX IX: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ANBL17P1 
(for children from 7 through 12 years of age) 
 
A Study of a New Way to Treat Children with Neuroblastoma (NBL) 
 
1. We have been talking with you about your illness, neuroblastoma (NBL). NBL is a kind of cancer 
that grows in the soft tissue in your body. It can grow in different parts of the body. After doing 
tests, we have found that you have high-risk NBL. It is called high-risk because your tumor is 
difficult to treat. 
 
2. We are asking you to take part in a research study because you have high risk NBL. 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, surgery and x-ray 
treatment followed by additional chemotherapy. Chemotherapy is a type of medicine that destroys 
cancer cells. Study doctors would like to learn if your cancer responds to treatment. 
 
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. 
Other things may happen to you that we do not know about yet. 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. There may be other treatments for your illness that your doctor can tell 
you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect some extra blood and bone marrow. We will take the 
extra blood and bone marrow when other regular tests are done to avoid extra needle sticks. We are 
also asking your “okay” to collect any tumor tissue that is left over from any operations you have 
while you are part of this study. We want to see if there are ways to tell how the cancer will react 
to treatment. You can still take part in this study even if you do not allow us to collect the extra 
blood and bone marrow or save the leftover tumor tissue for research. 
 
 
 

  
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INFORMATION SHEET REGARDING RESEARCH STUDY ANBL17P1 
(for teens from 13 through 17 years of age) 
 
A Study of Ch14.18 (dinutuximab) Added to Standard Induction Therapy for Children with Newly 
Diagnosed High-Risk Neuroblastoma (NBL) 
 
1. We have been talking with you about your illness, neuroblastoma (NBL). NBL is a type of cancer 
that grows in the soft tissue in your body. It can grow in different parts of the body. After doing 
tests, we have found that you have high-risk NBL. It is called high-risk because your tumor is 
difficult to treat..  
 
2. We are asking you to take part in a research study because you have high risk NBL. A research 
study is when doctors work together to try out new ways to help people who are sick.  
 
3. Children and teens who are part of this study will be treated with chemotherapy, surgery and x-ray 
treatment followed by additional chemotherapy. Chemotherapy is a type of medicine that destroys 
cancer cells. Study doctors would like to learn if your cancer responds to treatment. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is a better chance of 
getting rid of your cancer for as long as possible. But we don’t know for sure if there is any benefit 
of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that the study treatment may be less effective 
than other therapy options. It is also possible that the study treatment may cause more side effects 
than other therapies. Your doctors will monitor you closely for signs of any side effects. Other 
things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We are asking your permission to collect extra blood and bone marrow. We will take blood and 
bone marrow samples when other regular tests are done to avoid extra needle sticks. We are also 
asking your permission to collect any tumor tissue that is left over from any surgeries you have 
while you are part of this study. We would like to use the blood, bone marrow, and tumor tissue to 
do tests to see if there are ways to tell how the cancer will respond to treatment. If there is any 
tumor tissue left over from these tests, we would like to save it for other research tests in the future. 
You can still be treated on this study even if you do not allow us to collect the extra blood and bone 
marrow or save the leftover tumor tissue for research.  
 
  
 

  
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