A Phase 2 Study of Human-Mouse Chimeric Anti-disialoganglioside Monoclonal Antibody ch14.18 (Dinutuximab, NSC# 764038) in Combination With Sargramostim (GM-CSF) in Patients With Recurrent Osteosarcoma
Phase: PHASE2
Conditions: Metastatic Malignant Neoplasm in the Lung, Metastatic Osteosarcoma, Recurrent Osteosarcoma
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 
 
 
 
 
May 22, 2017 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #2 to protocol AOST1421, A Phase 2 Study of Human-
Mouse Chimeric Anti-Disialoganglioside Monoclonal Antibody ch14.18 (Dinutuximab, 
NSC# 764038, IND# 4308) in Combination with Sargramostim (GM-CSF) in Patients with 
Recurrent Osteosarcoma.  
 
This amendment updates the protocol by modifying treatment with dinutuximab from 2, 
20-hour infusions on Days 4 and 5 of a cycle to 4, 10-hour infusions on Days 4-7 of a cycle. 
With the change in infusion schedule, the PK will now be mandatory for all patients. 
Unexpected death that is not related to disease and probably/likely related to treatment has 
been added to the list of unacceptable toxicities. The inclusion criteria have been updated 
to require a normal QTc interval per EKG and to only allow patients without a history of 
seizure disorder.  
 
The CAEPR and risks associated with ch14.18 have been updated in response to an RRA 
from Dr. Jeffrey Moscow (jeffrey.moscow@nih.gov).     
 
Several other administrative changes have been made; specific changes are detailed below. 
Minor administrative updates (such as the correction of typographical errors or updates to 
the numbers of referenced sections) are tracked in the protocol but not specified below. 
 
Please let me know if we can offer further information. 
 
Sincerely,  
 
Jeannette Cassar, BA, Protocol Coordinator (for)  
Pooja Hingorani, MD, AOST1421 Study Chair 
Peter Adamson, MD, Children’s Oncology Group Chair 

                                                           
     
 
AOST1421 
ii 
 
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. 
General 
All 
Updated the protocol version date in the footer.  
2. 
Title page 
1 
Updated Version Date and Amendment number. 
3. 
Contact Information 
2 
Updated the instructions for submission of site registration documents.  
4. 
Study Committee 
8 
Updated the protocol coordinator to Jeannette Cassar. 
5. 
Experimental 
Design Schema 
10 
Updated schema to reflect the change in Ch14.18 (dinutuximab) treatment 
from a 2-day to a 4-day infusion schedule and mandatory PK sampling 
for all patients enrolled after this amendment. 
6. 
1.2.1 
11 
Revised the aim “To characterize the pharmacokinetics of ch14.18 
(dinutuximab) in patients with recurrent osteosarcoma in the proposed 
administration schedule.” 
7. 
2.1 
12-13 
• 
Updated text to reflect the change in Ch14.18 (dinutuximab) 
treatment to a 4-day infusion schedule. 
• 
Deleted text referring to dosing ch14.18 in an alternative (2-day) 
infusion schedule. 
The two recent SAEs on AOST1421 of sudden death and grade 4 toxicity 
may have been related to potentially higher peak plasma concentrations 
of dinutuximab from the experimental 2-day infusion schedule being used 
on AOST1421. Therefore, a decision was made by the study committee 
and COG leadership to change the dinutuximab infusion to the standard 
4-day schedule as used in neuroblastoma patients as much more 
experience exists with treating patients on this schedule.    
8. 
2.5.1 
15 
Updated section to include the serious adverse events observed with the 
alternative (2-day) infusion schedule and modifications to the infusion 
schedule effective with the approval of this amendment. 
9. 
2.5.2 
16 
Updated section to provide justification for now requiring PK sampling 
for all patients enrolled after the approval of this amendment. 
10. 
3.1.2 
19 
Updated the instructions for submission of IRB/REB documents. 
11. 
3.2.4 
23 
Updated the link to the performance status scales scoring.  
12. 
3.2.7.4 
24 
Added inclusion criteria: “Baseline EKG shows normal QTc interval 
of ≤ 470 ms.” -This has been added in light of the recent SAE of sudden 
death the cause for which remains unexplained but could have been a 
cardiac event secondary to dinutuximab therapy. Addition of this 
inclusion criteria would potentially ensure that at baseline, a patient is not 
at increased risk for arrhythmias. 
13. 
3.2.7.6 
24 
Modified inclusion criteria to only allow patients with no known history 
of seizure disorder.  
-Patients with a known epilepsy disorder are at increased risk of “Sudden 
Death in Epilepsy Patients” (SUDEP), the cause for which remains 
unknown. Given the concern for increased neurotoxicity with 
dinutuximab patients, this risk may be potentiated in patients with 

                                                           
     
 
AOST1421 
iii 
 
# 
Section 
Page(s) 
Change 
underlying epilepsy. Therefore, for patient safety, we would like to 
exclude patients with underlying seizure disorder.   
14. 
4.1 
26 
• 
Updated section to reflect the change in Ch14.18 (dinutuximab) 
treatment to a 4-day infusion schedule and mandatory PK sampling 
for all patients enrolled after this amendment. 
• 
Added 24-hour patient observation: “Patients will be observed in 
the hospital for an additional 24 hours after completion of the last 
day of dinutuximab infusion in each cycle.”  
- This was added as the risk of SAEs seems to be highest during and 
shortly after infusion completion. Additional observation in the hospital 
will potentially mitigate the risk of these events happening outside of the 
hospital. 
15. 
4.1.1.4 
27 
Updated the link to the COG supportive care guidelines. 
16. 
4.2.1 
28 
Updated section to reflect the change in Ch14.18 (dinutuximab) treatment 
to a 4-day infusion schedule. 
17. 
4.2.2.i 
29 
Updated TDM and Required Observations to include mandatory PK 
testing for patients enrolled after the approval of this amendment. 
18. 
4.2.3 
30-32 
• 
Updated the administration instruction of sargramostim from days 4 
and 5 to days 4-7. 
• 
Updated the administration of dinutuximab to the 10-hour x 4 day 
schedule.  
• 
For pain management, changed the dose of morphine from milligrams 
to micrograms to be consistent with other sections of the protocol.  
• 
Added specific dosing details for alternative pain management 
regimen.  
19. 
4.3.1 
33 
Updated section to reflect the change in Ch14.18 (dinutuximab) treatment 
to a 4-day infusion schedule. 
20. 
4.3.2.f 
34 
Updated TDM and Required Observations to include mandatory PK 
testing for patients enrolled after the approval of this amendment. 
21. 
4.3.3 
35 
• 
Updated the administration instruction of sargramostim from days 4 
and 5 to days 4-7. 
• 
Updated the administration of dinutuximab to the 10-hour x 4 day 
schedule.  
22. 
5.2.1.1 
40 
Added the following text clarifying the procedures for restarting 
dinutixumab for patients who required pressors for hypotension: “If the 
50% rate is tolerated without further hypotension, rate can be 
increased to 100% as tolerated. If patient becomes hypotensive again 
at 100% rate, it should be decreased back to 50% after patient is 
clinically stable to receive the infusion again and remainder of the 
infusion should be completed at the decreased rate.” 

                                                           
     
 
AOST1421 
iv 
 
# 
Section 
Page(s) 
Change 
23. 
6.1  
46-52 
• 
Updated the toxicity/ CAEPR information per the RRA received from 
CTEP. 
Added New Risk:  
• 
Also Reported on MoAb 14.18, chimeric Trials But With 
Insufficient Evidence for Attribution: Cardiac disorders - Other 
(gallop on exam); Cardiac disorders - Other (N-terminal BNP); 
General disorders and administration site conditions - Other (cold 
and clammy); Syncope  
 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Also Reported on MoAb 14.18, 
chimeric Trials But With Insufficient Evidence for Attribution: 
Hypocalcemia 
• 
Changed to Rare but Serious from Also Reported on MoAb 14.18, 
chimeric Trials But With Insufficient Evidence for Attribution: 
Myelitis; Reversible posterior leukoencephalopathy syndrome; 
Sudden death NOS 
 
• 
Updated the preparation instructions to align with the new dosing 
amount and schedule and to be consistent with other COG protocols 
that use ch14.18. 
• 
Clarified supplier and indication to not use commercial supply.  
• 
Updated information regarding agent accountability.  
• 
Added information where to obtain the investigator’s brochure. 
• 
Added a section for useful links.  
24. 
6.2 
53-55 
Updated information for Canadian sites. 
25. 
7.2 
57 
Updated footnote to reflect mandatory PK sampling for all patients 
enrolled after the approval of this amendment. 
26. 
8.1.b 
58 
Updated reference to Section 9.3. 
27. 
9.3 
59-60 
• 
Updated section to reflect mandatory PK sampling for all patients 
enrolled after the approval of this amendment. 
• 
Added “Unexpected death” as an Unacceptable Toxicity. 
28. 
15.1.4 
77 
Updated section to indicate that the BPC will forward tumor tissue for the 
GD2 assay to Cambridge Biomedical.  
29. 
15.2 
78 
Updated section to reflect mandatory PK sampling for all patients enrolled 
after the approval of this amendment. 
30. 
15.2.1 
78 
Updated timing of PK sampling to reflect the change in Ch14.18 
(dinutuximab) infusion schedule. 
31. 
Appendix I 
88-89 
Updated the instructions for submitting regulatory documents.  
32. 
Appendix II: YIS 
age 13-17 
91 
Deleted text about the PKs being done in the first 10 patients because with 
this amendment, the PK tests will be mandatory for all patients.  
33. 
Appendix III 
N/A 
Removed Appendix III which contained examples of calculations for 
extended ch14.18 administration based on the 2-day infusion schedule. 
 

                                                           
     
 
AOST1421 
v 
 
 
 
SUMMARY OF CHANGES: CONSENT DOCUMENTS 
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. 
General 
All 
Updated version date to match the version of the protocol.  
2. 
Summary of Study 
Treatment 
3 
Updated the days of ch14.18 treatment from Days 4-5 to Days 4-7. 
3. 
Diagram of 
Treatment 
4 
Updated the diagram of treatment to indicate the correct number of days 
of administration for ch14.18.  
4. 
Treatment for 
Subjects  
5 
• 
Updated the table to indicate the correct number of days of 
administration for ch14.18. 
• 
Added that patients will be required to stay in the hospital for an 
additional 24 hours after the end of the last infusion of ch.14.18 for 
observation.  
5. 
Ch14.18 PK Studies 
6 
• 
Added that the PK for ch14.18 is required. 
• 
Removed language regarding the PK being optional. 
6. 
Optional Research 
Study Tests 
6 
Deleted paragraph about optional PK testing.  
7. 
Risks of Study 
8 
Added paragraph describing serious side effects experienced by 2 
patients.  
8. 
Possible Side 
Effects of ch14.18 
9 
Increase in Risk Attribution: 
• Changed to Rare from Also Reported on MoAb 14.18, chimeric Trials 
But With Insufficient Evidence for Attribution (i.e., added to the Risk 
Profile): Death; Swelling of the spinal cord; Brain damage which may 
cause headache, seizure, blindness (also known as Reversible Posterior 
Leukoencephalopathy Syndrome).  
 
Provided Further Clarification: 
• Anemia which may cause tiredness, or may require blood transfusion 
(under Occasional) and Anemia, kidney problems which may cause 
swelling, or may require dialysis (under Rare) are now reported as 
Anemia, kidney problems which may cause tiredness, or may require 
blood transfusion or dialysis (under Occasional). 
• High blood pressure which may cause headaches, dizziness, blurred 
vision (under Occasional) is now reported as High blood pressure which 
may cause dizziness, blurred vision (under Occasional). 
9. 
Where Can I get 
More Information? 
14 
Updated the URL for the patient and family handbook.  
10. 
Specimens for 
Optional Research 
Tests 
16 
Removed signature/choice option for the PK tests as they are now 
mandatory.  
 

                                                           
     
 
AOST1421 
Page 1 
Version date: 05/17/2017 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
AOST1421 
 
 
A Phase 2 Study of Human-Mouse Chimeric Anti-Disialoganglioside Monoclonal Antibody ch14.18 
(Dinutuximab, NSC# 764038, IND# 4308) in Combination with Sargramostim (GM-CSF) in 
Patients with Recurrent Osteosarcoma  
 
 
NCI Supplied Agent: ch14.18 (Dinutuximab, NSC# 764038, IND# 4308) 
IND sponsor for ch14.18: DCTD, NCI 
 
 
A COG Groupwide Phase 2 Study 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH MEANS A 
SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO 
DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED 
BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE 
INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE PROCEDURES IN 
THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, 
AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL 
CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST 
LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
STUDY CHAIR 
 
Pooja Hingorani, MD 
Phoenix Children’s Hospital 
1919 East Thomas Road 
Phoenix, AZ 85016 
Phone:  (602) 933-0920 
Fax:  
(602) 933-2492  
Email:  phingorani@phoenixchildrens.com 
 
 
 
 
Activated: 11/30/15 
Version Date: 05/17/2017 
Closed: 
      
Amendment: 
#2 

                                                           
     
 
AOST1421 
Page 2 
Version date: 05/17/2017 
 
 
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. 
 
 

 
 
 
AOST1421 
Page 3 
Version date: 05/17/2017 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
7 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Aims 
11 
1.2 
Secondary Aims 
11 
1.3 
Exploratory Aims 
11 
2.0 
BACKGROUND 
11 
2.1 
Introduction/Rationale for Development 
11 
2.2 
Preclinical Studies 
13 
2.2.1 
Rationale for anti-GD2 Therapy in Osteosarcoma 
13 
2.2.2 
Rationale for Using Cytokines in Combination with Ch14.18 
13 
2.3 
Adult Studies 
13 
2.4 
Pediatric Studies 
14 
2.5 
Dosing Rationale 
15 
2.5.1 
Alternative Dosing Schedule of Ch14.18 (Dinutuximab) 
15 
2.5.2 
Pharmacokinetics 
16 
2.6 
Correlative studies 
16 
2.6.1 
To Assess the Relationship Between Probability of Disease Control and 
Tumor GD2 Expression 
16 
2.6.2 
Rationale for Genotyping FcR, KIR and KIR Ligand 
16 
2.6.3 
Rationale for NKp30 Isoform and B7-H6 Ligand Levels Determination 17 
2.6.4 
Banking Metastatic Osteosarcoma Tumor Samples for Future Research 
Studies 
18 
2.6.5 
To Determine a Descriptive Profile of Human Anti-Chimeric Antibody 
(HACA) During Immunotherapy. 
18 
2.6.6 
Circulating Tumor DNA (ctDNA) 
18 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
19 
3.1 
Study Enrollment 
19 
3.1.1 
Patient Registration 
19 
3.1.2 
IRB Approval 
19 
3.1.3 
Reservation Requirements 
20 
3.1.4 
Study Enrollment 
21 
3.1.5 
Timing 
21 
3.1.6 
Participation in Biology Studies 
22 
3.2 
Patient Eligibility Criteria 
22 
3.2.1 
Age 
22 
3.2.2 
Diagnosis 
22 
3.2.3 
Specimen Submission 
23 
3.2.4 
Performance Level 
23 
3.2.5 
Prior Therapy 
23 
3.2.6 
Concomitant Medications Restrictions 
23 
3.2.7 
Organ Function Requirements 
24 
3.2.8 
Exclusion Criteria 
24 

 
 
 
AOST1421 
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Version date: 05/17/2017 
3.2.9 
Informed Consent/Assent 
25 
4.0 
TREATMENT PROGRAM 
26 
4.1 
Overview of Treatment Plan 
26 
4.1.1 
Concomitant Medications and Supportive Care 
26 
4.1.2 
Criteria to Start All Cycles 
27 
4.2 
Cycle 1 
28 
4.2.1 
Therapy Delivery Map – Cycle 1 
28 
4.2.2 
Required Observations in Cycle 1 
29 
4.2.3 
Treatment Details for Cycle 1 
30 
4.3 
Cycles 2-5 
33 
4.3.1 
Therapy Delivery Map – Cycles 2-5 
33 
4.3.2 
Required Observations During Cycles 2-5 
34 
4.3.3 
Treatment Details for Cycles 2-5 
35 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
38 
5.1 
Dose Modifications for Hematologic Toxicity 
38 
5.2 
Dose Modifications for Non-Hematologic Toxicity 
38 
5.2.1 
Dinutuximab/Sargramostim Specific Dose Modifications and Toxicity 
Management Recommendations 
38 
5.2.2 
Management of Sargramostim (GM-CSF) Related Toxicities 
45 
6.0 
DRUG INFORMATION 
46 
6.1 
Chimeric Monoclonal Antibody 14.18 (Dinutuximab)   
46 
6.2 
Sargramostim                
53 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
56 
7.1 
End of Therapy & Follow-up 
56 
7.2 
Correlative Research Studies 
57 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
58 
8.1 
Criteria for Removal from Protocol Therapy 
58 
8.2 
Off Study Criteria 
58 
9.0 
STATISTICAL CONSIDERATIONS 
58 
9.1 
Sample Size and Study Duration 
58 
9.2 
Study Design 
58 
9.3 
Methods of Analysis 
59 
9.4 
Evaluability for Disease Control 
61 
9.5 
Evaluability for Toxicity 
61 
9.6 
Statistical Considerations for Exploratory Aims 
61 
9.6.1 
To Assess the Relationship between Probability of Disease Control and 
Tumor GD2 Expression 
61 
9.6.2 
To Assess KIR and FcγR Genotypes, NKp30 Isoforms and its Circulating 
Ligand, B7-H6, and their Relationships to the Probability of Disease Control
 
61 
9.6.3 
Banking of Tumor Samples. 
62 
9.6.4 
To Determine a Descriptive Profile of Human Anti-Chimeric Antibody 
(HACA) During Immunotherapy 
62 
9.6.5 
Circulating Tumor DNA (ctDNA) 
62 
9.7 
Gender and Minority Accrual Estimates 
63 

 
 
 
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10.0 
EVALUATION CRITERIA 
63 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
63 
10.2 
Disease Evaluation 
63 
10.2.1 Definition of Progressive Disease (PD) 
64 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
64 
11.1 
Purpose 
64 
11.2 
Determination of Reporting Requirements 
64 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
65 
11.4 
Special Situations for Expedited Reporting 
65 
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
65 
11.4.2 Persistent or Significant Disabilities/Incapacities 
65 
11.4.3 Death 
65 
11.4.4 Secondary Malignancy 
66 
11.4.5 Second Malignancy 
66 
11.4.6 Pregnancy, Fetal Death, and Death Neonatal 
66 
11.5 
Reporting Requirements for Specialized AEs 
67 
11.5.1 Baseline AEs 
67 
11.5.2 Persistent AEs 
67 
11.5.3 Recurrent AEs 
68 
11.6 
Exceptions to Expedited Reporting 
68 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
68 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
68 
11.7 
Reporting Requirements - Investigator Responsibility 
68 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
69 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
70 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
71 
11.11 Reporting of Adverse Events for Commercial Agents – CTEP-AERS Abbreviated 
Pathway 
71 
11.12 Routine Adverse Event Reporting 
71 
12.0 
STUDY REPORTING AND MONITORING 
72 
12.1 
CDUS 
72 
12.2 
Data and Safety Monitoring Committee 
72 
12.3 
CRADA/CTA 
72 
13.0 
SURGICAL GUIDELINES 
75 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
75 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
75 
15.1 
Tumor GD2 Expression (Mandatory Participation) 
75 
15.1.1 Required Specimen 
75 
15.1.2 Sample Collection and Processing 
76 
15.1.3 Sample Labeling and Shipping 
76 
15.1.4 BPC Sample Processing 
77 
15.1.5 Methodology 
77 
15.1.6 Banking of Leftover Specimens 
77 
15.2  
Ch14.18 (Dinutuximab) Pharmacokinetics and HACA sampling 
78 
15.2.1 Timing of Pharmacokinetic Sampling 
78 
15.2.2 Timing of HACA Sampling 
78 
15.2.3 Sample Collection and Processing 
78 

 
 
 
AOST1421 
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Version date: 05/17/2017 
15.2.4 Sample Labeling and Shipping 
79 
15.3  
Determination of FcR and Kir Genotype, NKp30 Isoforms and its Circulating 
Ligand, B7-H6 
80 
15.3.1 Study Prioritization 
80 
15.3.2 Sample Collection and Processing 
80 
15.3.3 Sample Labeling and Shipping 
80 
15.4 
Circulating Tumor DNA (ctDNA) 
81 
15.4.1 Streck Cell-Free DNA BCT Tube Ordering 
81 
15.4.2 Specimen Collection 
81 
15.4.3 Time points for ctDNA sample collection 
81 
15.4.4 Specimen Labeling and Shipment 
82 
15.4.5 Methodology 
83 
15.5  
Banking of Tumor Tissue 
83 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
84 
16.1 
Required Osteosarcoma Imaging 
84 
16.1.1 Overview of Required Imaging Studies 
84 
16.1.2 Technical Guidelines for Imaging Studies 
85 
16.1.3 X-ray 
85 
16.1.4 Bone Scan 
85 
16.1.5 [18F]–Fluorodeoxyglucose Positron Emission Tomography (FDG PET) 
Imaging (Recommended) 
86 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
88 
APPENDIX II: YOUTH INFORMATION SHEETS 
90 
APPENDIX III EXAMPLES OF CALCULATIONS FOR CH14.18 (DINUTUXIMAB) 
ADMINISTRATION (EXTENDED INFUSION ON DAYS 6 AND 7, IF NEEDED).
 
ERROR! BOOKMARK NOT DEFINED. 
REFERENCES 
92 
 
 
 

  
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STUDY COMMITTEE 
 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Pooja Hingorani, MD  
Justin Merrill Marken Cates, MD PhD  
Hematology/Oncology 
Pathology 
Phoenix Children’s Hospital 
Vanderbilt University/Ingram Cancer Center 
Hematology/Oncology 
Pathology, Microbiology 
1919 E. Thomas Road 
MCN C-3322 
Phoenix, AZ 85016 
1161 21st Avenue South 
Phone: (602) 933-0920 
Nashville, TN 37232 
Email: phingorani@phoenixchildrens.com 
Phone: (615) 936-6694 
 
Fax: 
(615) 322-0511 
STUDY VICE CHAIR 
Email: justin.m.cates@vanderbilt.edu 
Michael Isakoff, MD  
 
Hematology/Oncology 
Steven G. DuBois, MD  
Connecticut Children’s Medical Center 
Hematology/Oncology 
Pediatric Oncology 
Dana-Farber/Harvard Cancer Center 
282 Washington Street 
Pediatric Oncology 
Hartford, CT 06106 
450 Brookline Avenue, Dana 3141F 
Phone: (860) 545-9630 
Boston, MA 02215 
Fax: 
(860) 545-9622 
Phone: (617) 632-5460 
Email: misakoff@connecticutchildrens.org 
Fax: 
(617) 632-5710 
 
Email: steven_dubois@dfci.harvard.edu 
STUDY STATISTICIAN 
 
Mark Krailo, PhD  
Richard G. Gorlick, MD  
Statistics 
Hematology/Oncology 
Children's Oncology Group 
Montefiore Medical Center - Moses Campus 
222 E. Huntington Drive 
Section of Pediatric Hematology/Oncology 
Suite 100 
3415 Bainbridge Avenue 
Monrovia, CA 91016 
Rosenthal 3rd floor 
Phone: (626) 241-1529 
Bronx, NY 10467 
Fax: 
(626) 445-4334 
Phone: (718) 741-2342 
Email: mkrailo@childrensoncologygroup.org 
Fax: 
(718) 920-6506 
 
Email: rgorlick@montefiore.org 
STUDY COMMITTEE MEMBERS 
 
Jim Bradley, MA CCRP  
Jill Lunsford Lee, MSN CPNP-AC  
Clinical Research Associates 
Nursing 
University of North Carolina at Chapel Hill 
University of Minnesota/Masonic Cancer Center 
Pediatrics - Hematology/Oncology 
Nursing/Pediatric Hematology/Oncology 
1185C Physicians Office Bldg;170 Manning Dr 
420 Delaware St. 
CB#7236 UNC-Chapel Hill 
MMC 484 
Chapel Hill, NC 27599-7220 
Minneapolis, MN 55455 
Phone: (919) 966-0987 
Phone: (612) 624-9139 
Fax: 
(919) 966-7629 
Fax: 
(612) 626-2815 
Email: james_bradley@med.unc.edu 
Email: jllee@umphysicians.umn.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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STUDY COMMITTEE MEMBERS 
STUDY COMMITTEE MEMBERS 
Carol Diane Morris, MD MS  
Richard Berry Womer, MD  
Surgery 
Division of Oncology, CTRB10 
Johns Hopkins University/Sidney Kimmel Cancer Center 
Children's Hospital of Philadelphia 
601 N Caoline Street 
Philadelphia, PA 19104 
Baltimore, MD 21287 
Phone: (215) 590-2229 
Phone: (410) 955-2888 
Fax: 
(215) 590-2183 
Email: cmorri61@jhmi.edu 
Email: rwomer@mail.med.upenn.edu 
 
 
Betsy Poon, PharmD FCCP  
Alice Lin-Tsing Yu, MD PhD  
Pharmacy 
Hematology/Oncology 
Florida Hospital Orlando 
Rady Children's Hospital - San Diego 
Department of Pharmacy 
Department of Pediatrics 
601 East Rollins Street 
Div of Hematology-Oncology 
Orlando, FL 32803 
200 West Arbor Dr. (8447) 
Phone: (407) 303-1530 
San Diego, CA 92103-8447 
Fax: 
(407) 303-9448 
Phone: (619) 543-2438 
Email: betsy.poon@flhosp.org 
Fax: 
(619) 543-5413 
 
Email: aliceyu@ucsd.edu 
Robert Lor Randall, MD FACS  
 
Surgery 
Brian Crompton, MD 
Primary Children's Hospital 
Hematology/Oncology 
Dept. of Orthopaedic Surgery 
Dana-Farber/Harvard Cancer Center 
c/o Huntsman Cancer Institute 
Pediatric Oncology 
200 Circle of Hope Drive Room 4262 
450 Brookline Avenue 
Salt Lake City, UT 84112 
Boston, MA 02215 
Phone: (801) 585-0300 
Phone: (617) 582-8553 
Fax: 
(801) 585-7084 
Email: brian.crompton@childrens.harvard.edu 
Email: r.lor.randall@hci.utah.edu 
 
 
RESEARCH COORDINATOR 
Paul M. Sondel, MD PhD  
Justin Davis 
Hematology/Oncology 
Children's Oncology Group 
University of Wisconsin Hospital and Clinics 
222 E. Huntington Drive 
Dept of Pediatric Hem-Onc 
Suite 100 
4159 WIMR Bldg. 
Monrovia, CA 91016 
111 Highland Ave 
Phone: (626) 241-1509 
Madison, WI 53792 
Fax: 
(626) 445-4334 
Phone: (608) 263-9069 
Email: JDavis@childrensoncologygroup.org 
Fax: 
(608) 263-4226 
 
Email: pmsondel@wisc.edu 
PROTOCOL COORDINATOR 
 
Jeannette Cassar 
Lisa A. Teot, MD  
Children's Oncology Group 
Pathology 
222 E. Huntington Drive 
Dana-Farber Cancer Institute 
Suite 100 
Staff Pathologist 
Monrovia, CA 91016 
Children’s Hospital Boston 
Phone: (626) 241-1532 
300 Longwood Avenue Bader 110 
Fax: 
(626) 445-4334 
Boston, MA 02115 
Email: jcassar@childrensoncologygroup.org 
Phone: (857) 218-4962 
 
Fax: 
(617) 730-0207 
AGENT 
 
NSC#  
Email: lisa.teot@childrens.harvard.edu 
Dinutuximab 
 
764038  
 
Sargramostim 
 
613795  
 
SEE SECTION 15 FOR SPECIMEN SHIPPING ADDRESSES 
 

  
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies. 
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others 
 
 
ABSTRACT 
Patients with recurrent osteosarcoma have a dismal prognosis with an overall survival of less than 30% at 
5 years. Limited treatment options exist for these patients, with surgery remaining the mainstay of therapy 
at recurrence. A subset of patients with recurrent osteosarcoma is able to achieve a second or subsequent 
complete surgical remission and this subset holds a better prognosis than those who do not achieve a 
complete surgical remission. Nonetheless, the majority of patients who achieve a second or subsequent 
complete surgical remission will recur. GD2 is a cell surface disialoganglioside that is ubiquitously 
expressed on osteosarcoma tumor cells and therefore is a rational therapeutic target. Historical experience 
from neuroblastoma (NB) trials shows that anti-GD2 based therapy works best in the setting of minimal 
residual disease. Therefore, we propose to evaluate the effects of ch14.18 (dinutuximab), an anti-GD2 
antibody, in combination with sargramostim (GM-CSF) in patients with pulmonary recurrence of 
osteosarcoma that are able to achieve a complete surgical resection. The main objective of the study is to 
determine the disease control rate in patients with recurrent osteosarcoma treated with ch14.18 
(dinutuximab) in combination with sargramostim. Secondary objectives include analysis of 
pharmacokinetics and toxicity of ch14.18 (dinutuximab) in this patient population.   
 
 
 

  
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recurrent osteosarcoma 
< 30 years of age with complete 
surgical resection 
Study entry 
Cycle 1 
Ch14.18 (dinutuximab) Days 4-7* 
+ GM-CSF# Days 1-14 
Cycle 2 
Ch14.18 (dinutuximab) Days 4-7* 
+ GM-CSF# Days 1-14 
Cycles 3-5 
Ch14.18 (dinutiximab) Days 4-7* 
+ GM-CSF# Days 1-14 
Evaluation 
Progressive Disease or 
Unacceptable Toxicity 
Off Protocol Therapy 
End of Protocol 
Therapy 
*Ch14.18 (dinutuximab) infusion will be given over 4 days. 
 #GM-CSF = sargramostim 
Pharmacokinetic sampling will be mandatory for all patients enrolled after protocol 
amendment #2. 
Evaluation 

  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Aims 
 
To determine the disease control rate in patients with completely resected recurrent 
osteosarcoma treated with ch14.18 (dinutuximab) in combination with 
sargramostim (GM-CSF) as compared to historical COG experience. 
 
1.2 
Secondary Aims 
 
To characterize the pharmacokinetics of ch14.18 (dinutuximab) in patients with 
recurrent osteosarcoma.  
 
To determine the occurrence of unacceptable toxicity (UT) in patients with 
recurrent osteosarcoma treated with ch14.18 (dinutuximab) in combination with 
sargramostim. 
 
1.2.3 
To assess the relationship between probability of disease control and tumor GD2 
expression. 
 
1.3 
Exploratory Aims 
 
To assess the relationship between probability of disease control and tumor GD2 
expression. 
 
 
1.3.3 
To attempt banking of tumor samples for future research studies from patients 
enrolled on study who undergo biopsy or resection of suspected metastatic disease 
recurrence while on protocol therapy or during the evaluation period.  
 
1.3.4 
To determine a descriptive profile of human anti-chimeric antibody (HACA) 
during immunotherapy. 
 
1.3.5  To bank serial plasma samples for future studies of circulating tumor DNA 
(ctDNA) detection as a marker of disease progression and response.   
 
 
2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
Treatment of patients with recurrent osteosarcoma remains challenging with very few 
effective therapeutic options. A subset of patients with relapsed disease is able to achieve 
subsequent surgical remission, but the majority of patients will subsequently relapse. 
Hence these patients continue to have a dismal prognosis.  
 
The main predictors of survival after osteosarcoma recurrence include the time to first 
recurrence, disease burden, and ability to achieve complete surgical remission after 
recurrence. Solitary pulmonary nodule and greater than 24 months to first recurrence are 

  
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favorable prognostic factors.1 Data from the Cooperative Osteosarcoma Study Group 
(COSS) as well as for other studies show that for patients with first osteosarcoma relapse 
that the median time to first relapse is 15-18 months from the time of original diagnosis.2,1 
The median time to second relapse from first relapse is around 8 months and all subsequent 
relapses occur within approximately 6 months.3 Although the median time to first relapse 
seems longer than subsequent relapses, a large duration of this interval includes 
administration of upfront therapy for osteosarcoma (an average of 9 months). Therefore, 
the median time to first relapse from the end of upfront therapy is not significantly different 
compared to median time to second relapse.  
 
Five-year overall survival rates of 39% are reported for patients with first relapse who are 
able to achieve a second surgical remission, and 32% for patients who are able to achieve 
a third surgical remission (COSS data).2,3 Data from the Rizzoli Institute show reported 5-
year event-free actuarial survival of 38% after first metastasectomy and 32% after second 
metastasectomy, suggesting that patients who had the second metastasectomy had the same 
probability of survival as patients after the first metastasectomy.4 The disease-free interval 
was an important prognostic factor in this study with longer interval portending a favorable 
outcome within the first 5 years but this difference was annulled after 5 years. Together, 
these data indicate that the most important factor for survival after pulmonary relapse is 
complete surgical resection and that long term survival is not significantly different in 
patients with one or more subsequent relapses.  
 
The Bone Tumor Committee has performed a detailed review of the past COG studies, 
which included recurrent osteosarcoma patients. A review of seven single-agent Phase 2 
studies conducted by COG over the past 15 years identified 96 eligible patients with 
relapsed osteosarcoma who had measurable disease at the time of enrollment. The 
estimated 4-month progression-free survival probability was 12% with a 95% confidence 
interval of 6%-19%. AOST0221, a Phase 2 study of inhaled sargramostim (GM-CSF) in 
patients with first pulmonary recurrence of osteosarcoma who achieved a complete 
resection, is the only study available to estimate EFS in a cohort with complete surgical 
remission. Of the 43 eligible patients who received inhaled sargramostim, 41 were 
evaluated for disease outcome. The 12-month EFS was 20% with a 95% confidence 
interval of 10-34% (Mark Krailo, personal communication). Based on the above data for 
the fully resected cohort, disease control (DC) rate, defined as the probability of patients 
who do not have progressive disease or death due to progressive disease 12 months after 
start of protocol therapy, will be the primary outcome measure for this study. 
 
Limited progress has been made in identifying novel targets that may be therapeutic in 
osteosarcoma and there remains an urgent need for development of new agents that are 
effective in improving survival. GD2, a cell surface disialoganglioside that is ubiquitously 
expressed in malignancies such as melanoma and neuroblastoma, has been successfully 
used in NB to improve overall and event-free survival. GD2 has also been shown to be 
expressed in more than 95% of osteosarcoma samples, as discussed below,  thus making it 
a potential therapeutic target for osteosarcoma.   
 
This study is a Phase 2 trial to evaluate disease control rate as compared to historical 
experience in patients with recurrent pulmonary osteosarcoma who achieve a complete 
surgical resection following treatment with ch14.18 (dinutuximab) plus cytokine therapy. 
Based on data from NB clinical trials, it is well established that anti-GD2 therapy is most 
beneficial in the setting of minimal residual disease and hence in this trial, only patients 

  
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with recurrent osteosarcoma who achieve a complete surgical remission are eligible. 
Enrolled patients will receive ch14.18 (dinutuximab) as a 10-hour infusion per day for 4 
days in each cycle. This updated schedule has been modified from the prior experimental 
schedule of 20-hour infusion over 2 days. Therapy will be delivered every 28 days for a 
total of 5 cycles or until disease progression or recurrence. If ch14.18 (dinutuximab) plus 
cytokine therapy is found to be tolerable and effective the COG Bone Tumor Committee 
will consider incorporating this agent into the therapeutic regimen for patients with 
osteosarcoma in first remission.  
 
2.2 
Preclinical Studies  
Strong immunoreactivity for the GD2 antigen was detected in 15 of 17 
osteosarcomas, including both primary and metastatic tumors.5 Moreover, each of 
24 patient-derived osteosarcoma cell lines showed strong expression of GD2 and 
only 4.3% of osteosarcoma patient samples (n=44) were negative for GD2 by 
immunohistochemical analysis using 14.2G-2a antibody.6 These data suggest that 
GD2, which is expressed in most osteosarcomas, may be a rational 
immunotherapeutic target for this disease.  
 
Preclinical data with murine monoclonal antibodies (MoAb) 3F8 and 14G2a 
demonstrated that the in vitro and in vivo activity against tumor cells was mediated 
by activation of complement and antibody dependent cell mediated toxicity (CDC 
and ADCC respectively) by effector cells such as lymphocytes, NK cells, 
neutrophils and monocytes.7,8 Cytokines such as sargramostim and IL-2 
augmented the ADCC effect of anti-GD2 antibodies.9,10 This was also confirmed 
with ch14.18 which is 50-100 times more efficient than the murine antibody in 
mediating tumor ADCC in vitro.11 Therefore, clinical trials have used anti-GD2 
antibody in conjunction with cytokines for potentially enhanced efficacy of the 
antibody. However, for the purpose of AOST1421, IL-2 will not be used for the 
following reasons: a) more recent trials conducted by SIOP have shown that IL-2 
may not have any additive benefit to GD2 antibody therapy and b) IL-2 causes 
significant treatment related toxicity and this may be intolerable in the adolescent 
and young adult osteosarcoma patient population. GM-CSF and ch14.18 cycles on 
the other hand are much better tolerated in the NB protocols. The dose and 
schedule for GM-CSF is identical to what is used in the current COG NB protocols. 
 
2.3 
Adult Studies 
Both the murine and the chimeric anti-GD2 antibodies have undergone Phase 1-3 clinical 
trials over the past two decades, primarily in patients with NB and melanoma. At least four 
clinical trials have been completed using ch14.18 (dinutuximab) either alone or in 
combination with cytokines in adults with melanoma or sarcoma. In a Phase 1 trial of 
ch14.18 (dinutuximab) in patients with malignant melanoma, patients received ch14.18 
(dinutuximab) as a single dose of 5-100 mg. The major toxicity was infusion-related 
abdominal-pelvic pain syndrome requiring intravenous morphine. In a subsequent Phase 
Ia/Ib trial of ch14.18 (dinutuximab) and sargramostim in patients with malignant 
melanoma, patients received ch14.18 (dinutuximab) in doses between 15-60 mg/m2 
intravenously for 4 hours on Day 1. Dose limiting toxicities were observed at 60 mg/m2. 
Significant side effects included abdominal or extremity pain, headache, nausea, diarrhea, 

  
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myalgias, blood pressure changes and weakness. No antitumor activity was seen. In a Phase 
Ib trial of ch14.18 (dinutuximab) with interleukin-2 (IL2) in melanoma patients, the 
ch14.18 (dinutuximab) maximum tolerated dose (MTD) was 7.5 mg/m2/day x 5 days. 
Major adverse events included abdominal, chest or extremity pain, severe allergic reaction, 
weakness and pericardial effusion. Antitumor activity included one complete response, one 
partial response, stable disease in eight patients, and one patient with >50% decrease in 
hepatic metastases. More recently, a Phase 1 trial of ch14.18 (dinutuximab) along with R24 
monoclonal antibodies and IL2 was completed in patients with melanoma (23 patients) and 
sarcoma (4 patients). The MTD of ch14.18 (dinutuximab) was 5 mg/m2/day x 5 days, lower 
than the 7.5 mg/m2/day determined with IL2 alone. Two melanoma patients had partial 
responses, four patients had stable disease (one patient had gastrointestinal stromal 
sarcoma) and one patient remained without evidence of disease. Anecdotal evidence of 
anti-GD2 therapy exists in osteosarcoma from prior Phase 1 trials that included patients 
with osteosarcoma. In a Phase 1/1B trial of the murine antibody (14.2G2a) plus IL2, 2 of 
33 patients had osteosarcoma. One patient had multiple bone metastases and received one 
cycle of therapy. Two months later, repeat scans showed a complete response. This patient 
remained disease free for 8 months but subsequently relapsed.12 In a Phase 1 trial of 
ch14.18 (dinutuximab) in patients with refractory NB and osteosarcoma, 1 of 11 treated 
patients had metastatic osteosarcoma to the bones and lungs. The patient had improvement 
in bone pain but progression of the lung lesions after one cycle.  
    
2.4 
Pediatric Studies 
 
Phase 1 trial of ch14.18 (dinutuximab) in children with refractory NB and 
osteosarcoma established the safety of antibody administration, although no MTD 
was reached. Pain was the most common side effect during treatment. Clinical 
responses (1 partial response and 4 mixed responses) were observed in 5 of 10 NB 
patients.  Subsequently a Phase 1 trial of ch14.18 (dinutuximab) in combination 
with sargramostim and aldesleukin (interleukin-2, IL2) in patients with NB 
immediately following autologous bone marrow transplant was performed. The 
MTD of ch14.18 (dinutuximab) was determined to be 25 mg/m2/d x 4 days every 
28 days (NCI product); IL2 was given during Cycles 2 and 4 at a dose of 
3 MU/m2/d for 4 days one week before the antibody and at a dose of 4.5 MU/m2/d 
for 4 days concurrently with the antibody; sargramostim was administered in 
Cycles 1, 3 and 5 at 250 mcg/m2/d subcutaneously starting 3 days prior to ch14.18 
(dinutuximab) and continued for 3 days after the antibody therapy. Common 
toxicities including neuropathic pain, fever, hypersensitivity reactions and 
capillary leak syndrome were manageable with aggressive supportive care. No 
patient developed human anti-chimeric antibody (HACA). The study 
demonstrated feasibility of incorporating sargramostim and IL2 with dinutuximab. 
In another Phase 2 trial of ch14.18 (dinutuximab) (50 mg/m2/day over 5 hours x 4 
days) plus sargramostim (10 mcg/kg/d x 14 days) pain, fever and tachycardia were 
the main adverse events. Of the 27 patients evaluable for response, there was one 
complete response, three partial responses, one mixed response and two stable 
disease. These early trials were followed by a Phase III randomized trial in patients 
with newly diagnosed NB who achieved complete or a partial response after 
induction chemotherapy.13 Interim analysis revealed a significant increases in 2-
year OS (86% versus 75%; P=0.02) and EFS (66% versus 46%; P=0.01) for 
patients randomized to the ch14.18 (dinutuximab) plus cytokine arm along with 

  
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cis-retinoic acid compared to the cis-retinoic acid alone.14 This trial established the 
efficacy of this regimen in patients with minimal residual disease.  
 
Rationale for Anti-GD2 Strategy in Minimal Residual Disease Setting in 
Osteosarcoma  
Objective radiographic responses are rare in osteosarcoma, even with active 
neoadjuvant chemotherapy regimens in newly diagnosed patients. This is likely 
due to the presence of calcified bone matrix within these tumors. Based on the data 
from the NB trials in the setting of minimal residual disease detailed above, the 
committee believes that if active in osteosarcoma, the greatest potential for benefit 
would similarly be in following complete surgical resection of metastases, i.e. in a 
setting of minimal residual disease.  
 
2.5 
Dosing Rationale 
In the COG NB trials, the MTD of ch14.18 (dinutuximab) was determined to be 
25 mg/m2/day (based upon NCI product which was used in these trials; equivalent 
to 17.5 mg/m2/day of the United Therapeutics product to be used in the AOST1421 
study) infused over 10 hours per day x 4 days every 28 days; IL2 was given in 
Cycles 2 and 4 at a dose of 3 MU/m2/day for 4 days one week before the antibody 
and at a dose of 4.5 MU/m2/day for 4 days concurrently with the antibody; 
sargramostim was administered in Cycles 1, 3 and 5 at 250 mcg/m2/day 
subcutaneously starting 3 days prior to ch14.18 (dinutuximab) and continued for 7 
days after antibody therapy. Common toxicities were neuropathic pain, fever, 
hypersensitivity reactions and capillary leak syndrome, likely related to ch14.18 
(dinutuximab) infusion alone and in combination with cytokines. Data from Dr. 
Frank Balis’ lab based on simulations of different antibody administration 
schedules with the same total dose per cycle (daily for 10 hours x 4 days; 
continuous 48 hour infusion; continuous 96 hour infusion; and continuous 120 
hour infusion) in 14 NB patients reveal no differences in the overall area under the 
curve (AUC) and drug exposure of ch14.18 (dinutuximab) (personal 
communication, Dr. Balis) and hence we hypothesized that the schedule of 
administration should not affect the efficacy of dinutuximab. Therefore, patients 
enrolled on this study were given dinutuximab as a 20-hour infusion each day for 
a total of 2 days (35 mg/m2/day for a total of 70 mg/m2/cycle). The infusion was 
allowed to be extended for an additional 2 days, if needed, for managing adverse 
effects.  
 
However, during the conduct of this trial, there were two serious adverse events 
experienced by 2 separate patients who were treated on protocol therapy. One 
patient experienced sudden unexplained death and the other experienced Grade 4 
neurotoxicity (depressed level of consciousness and respiratory depression). While 
the exact cause of these events remains unclear, it is possible that these events may 
have been related to the experimental infusion schedule of dinutuximab, possibly 
leading to higher peak concentrations of the drug. In light of these events, the 
infusion schedule of dinutuximab has been modified for the remainder of the study 
to a 10-hour infusion each day for a total of 4 days. This revised schedule is 
identical to the schedule used in COG NB trials.  
 

  
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The total dose of ch14.18 (dinutuximab) delivered per cycle will be 70 mg/m2 
(United Therapeutics compound), which is equivalent to 100 mg/m2 of the NCI 
compound used historically in NB studies. We will evaluate the median time to 
infusion completion in our study patients.  
 
Recent data from SIOPEN presented at the 2014 Advances in Neuroblastoma 
Research meeting showed that ch14.18 (dinutuximab) + IL2 is more toxic than 
ch14.18 (dinutuximab) alone, and no more effective.15 IL2 will therefore not be 
used in this study due to lack of conclusive data that it adds to the efficacy of 
ch14.18 (dinutuximab) therapy and significant concerns regarding toxicity of IL2, 
such as capillary leak syndrome in the adolescent patient population. 
  
In Phase 1 trials of dinutuximab, the plasma clearance of ch14.18 (dinutuximab) 
followed a biphasic pattern. In patients with NB, the t½ was 3.4±3.1 hours and 
the t½β was 66.6±27.4 hours.16 In adult patients with melanoma and one patient 
with osteosarcoma, the t½ and t½β were significantly longer than in younger 
patients with NB.17 However, more recent data at the current dosing schedule in 
young NB patients show comparable t½ and AUCs to adults,18 but PK data are 
lacking for the adolescent population. Although the simulation data from Dr. Balis’ 
lab suggest that the AUC should remain similar with varying schedules of ch14.18 
(dinutuximab) infusion, it remains to be confirmed in actual patient samples. 
Therefore, PK analysis at defined time points was mandatory for a minimum of 10 
patients who received the experimental infusion schedule in this study.  
 
Further, in order to obtain the most data possible to identify any changes in PK 
parameters such as Cmax and serum half-life, we will require all patients who 
enroll subsequent to the approval of this amendment to consent to pharmacokinetic 
sampling as outlined in the amended protocol.  
 
2.6 
Correlative studies  
No data currently exist on the correlation between GD2 expression level in tumors 
and clinical response. We hypothesize that patients with increased expression of 
GD2 antigen will have an increased probability of response. Formalin-fixed, 
paraffin-embedded (FFPE) tissue blocks or cut sections of the tumor tissue (from 
the most recent surgery showing metastatic osteosarcoma) will be required from 
institutions for patients enrolled on this study.  
 
In general, the anti-tumor activities of unconjugated mAbs require the contribution 
of either complement- or Fcγ-receptor (FcγR)-expressing effector cells to achieve 
tumor cell killing. However, because most tumor cells express increased amounts 
of complement-inhibiting proteins, which protect against complement-mediated 
lysis, antibody-dependent cell cytotoxicity (ADCC) is considered the key 
antitumor mechanism of therapeutic antibodies in vivo. Natural killer (NK) cells, 
T-lymphocytes, monocytes and granulocytes are capable of mediating ADCC 

  
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against antibody-coated targets via their expression of FcγR for IgG. The FcγR 
genes display polymorphisms that greatly influence the affinity of IgG for the Fcγ 
receptor. NK cells bearing the FcγRIIIa 158V/V allele mediate ADCC more 
effectively than those with F/F allele. Similarly, for FcγRIIA, the high-affinity H 
allele at position 131 results in greater affinity of FcγRIIa for IgG, whereas the 
low-affinity R allele is associated with decreased binding. The FCGR3A and 
FCGR2A gene polymorphism was reported to influence the response of lymphoma 
to rituximab (anti-CD20). As ch14.18 (dinutuximab) is very effective in mediating 
ADCC, its efficacy in osteosarcoma may be associated with FCGR3 and/or 
FCGR2 genotype. 
 
Killer-Immunoglobulin-like Receptors (KIR) recognize specific HLA molecules, 
regulate function of human natural killer (NK) cells and control self-tolerance. The 
interactions between KIR on donor NK cells and KIR ligands (KIR-L) on recipient 
tissues influence anti-tumor efficacy of allogeneic hematopoietic stem cell 
transplantation (HSCT).19 Furthermore, inherited KIR and KIR-L alleles influence 
the antitumor effects of autologous HSCT. Since the genes encoding for 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 
relapsed/refractory NB receiving humanized anti-GD2 antibody linked to IL2, 7 
of 24 mismatched patients experienced either complete response or improvement 
of their disease after immunocytokine therapy, while no responses or comparable 
improvements of disease were observed in 14 patients who were KIR and KIR-L 
matched (p = 0.03).20 This data suggests that patients with KIR receptor-ligand 
mismatch may show better clinical responses to immunotherapy with anti-GD2 
antibody.  
 
The 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. Three NKp30 splice 
variants have been shown to be of prognostic significance in gastrointestinal 
stromal tumor sarcoma (GIST), which expresses NKp30 ligands and that is treated 
with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those 
with GIST show different NKp30 isoform expression patterns. In GIST patients, 
predominant expression of the immunosuppressive NKp30c isoform (compared to 
the immunostimulatory NKp30a and NKp30b isoforms) was associated with 
reduced survival, decreased NKp30-dependent tumor necrosis factor-α (TNF-α), 
IL10 and CD107a release, and defective secretions of interferon-γ (IFN-γ) and 
interleukin 12 (IL12) involved in NK-DC cross-talk. Preferential NKp30c 
expression resulted partly from a single-nucleotide polymorphism at position 3790 
in the 3' untranslated region of the gene encoding NKp30. 21 In a recent French 
study, high levels of the immunosuppressive Nkp30c-isoform were associated with 
worse prognosis (PFS, P= 0.01) in patients with high risk NB.22 No impact of the 
Nkp30a-isoform was noted.  B7H6 is a tumor cell ligand for the NK cell receptor 
NKp30,23 which is shed from tumor cells into circulation.24 Soluble B7-H6 
accumulated in the serum of high risk NB patients, correlating with NKp30 down 
regulation on peripheral blood NK cells, disease dissemination and resistance to 
chemotherapy.25 Since NK cytotoxicity plays a major role in tumor immunity in 
general, and in anti GD2-mediated tumor cytotoxicity in particular, the impact of 

  
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NKp30 isoforms and circulating B7-H6 levels may be more pronounced in patients 
receiving ch14.18 (dinutuximab) therapy. 
 
While a significant number of primary tumor samples have been banked as part of 
the osteosarcoma biology study AOST06B1, a striking paucity exists in the 
number of banked relapsed or metastatic samples. The majority of osteosarcoma 
patients who succumb to disease die of progressive metastatic or recurrent disease. 
In several cancers, metastatic or recurrent tumors have been shown to have a 
distinct molecular phenotype compared to the primary tumor. Therefore, it is 
imperative to analyze the metastatic and relapse samples of osteosarcoma, in 
addition to the primary tumor, to be able to identify novel therapeutic targets in 
recurrent disease. This study will attempt to increase the number of available 
metastatic and relapsed osteosarcoma samples to aid in future research studies in 
this specific cohort.  
 
Any available tumor specimen (either formalin-fixed or frozen) obtained from 
biopsy or resection of a suspected disease recurrence site will be requested for 
banking at the COG tumor bank for potential future research studies that may 
require analysis of metastatic or relapsed samples. Left over specimens from the 
GD2 tumor expression analysis will be banked for future research studies. 
 
While no significant development of HACA has been observed in recent trials in 
neuroblastoma with using ch14.18 (dinutuximab) in comparable doses as this 
study, the immune profile of neuroblastoma patients is likely significantly different 
due to majority of patients having undergone an autologous stem cell transplant. 
The recurrent osteosarcoma patient population will likely be more 
immunocompetent and may have a higher potential of developing HACA or 
neutralizing antibodies to dinutuximab. Therefore, these will be assessed in 
peripheral blood of all patients receiving ch14.18 (dinutuximab) during the course 
of therapy. 
 
There are few biomarkers proven to predict outcome in osteosarcoma. Percent 
tumor necrosis has been a useful measure of treatment response in this disease 
although its value remains questionable across studies. In addition, histologic 
necrosis is not helpful to predict response at diagnosis or any sooner than definitive 
surgery usually around Week 11 of therapy. Further, no biomarker currently exists 
to predict early relapse in these patients. Thus, a new approach to measuring 
disease response would aid in developing risk-stratification approaches for adding 
new therapies to standard three-drug chemotherapy treatment for this disease. One 
appealing alternative approach includes minimal residual disease testing by 
detection, quantification and serial tracking of ctDNA, also known as liquid biopsy 
studies, obtained from peripheral blood draws. Liquid biopsy technologies have 
demonstrated superior detection and quantification rates compared to assays for 
circulating tumor cells.26 Furthermore, ctDNA can be reliably extracted from 
plasma using commercially available kits making it feasible for any clinical or 

  
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research laboratory to draw and ship appropriate samples for ctDNA studies. The 
integrity of ctDNA can be further enhanced by the use of specialized blood tubes, 
such as Streck Cell-Free DNA BCT tubes, widely employed for circulating fetal 
DNA studies and increasingly utilized in ctDNA assays. Many reports have now 
demonstrated the clinical utility of detecting and quantifying circulating tumor 
DNA from patients with solid tumors.26,27 These assays have been used to assess 
disease burden, track disease response to therapy, identify clonal evolution, and 
predict relapse after remission. However, the application of cell free DNA 
technologies has yet to be applied systematically in pediatric osteosarcoma. In this 
study, we propose to bank serial plasma samples from patients on therapy to aid in 
future studies to develop ctDNA strategies in osteosarcoma. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Study Enrollment 
 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number.  
 
This number is obtained via the COG Registry system once authorization for the 
release of protected health information (PHI) has been obtained. The COG patient 
ID number is used to identify the patient in all future interactions with COG. If you 
have problems with the registration, please refer to the online help.   
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB 
approval and supporting documentation to the CTSU Regulatory Office before 
they can be approved to enroll patients. Allow 3 business days for processing. The 
submission must include a fax coversheet (or optional CTSU IRB Transmittal 
Sheet) and the IRB approval document(s). The CTSU IRB Certification Form may 
be submitted in lieu of the signed IRB approval letter. All CTSU forms can be 
located on the CTSU web page (https://www.ctsu.org). Any other regulatory 
documents needed for access to the study enrollment screens will be listed for the 
study on the CTSU Member’s Website under the RSS Tab.  
 

  
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IRB/REB approval documents may be submitted to the CTSU Regulatory Office 
via the Regulatory Submission Portal, where they will be entered and tracked in 
the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ web site by entering credentials at https://www.ctsu.org. For sites under 
the CIRB initiative, IRB data will automatically load to RSS. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. This information will be provided to the CTSU Regulatory 
Office from the CIRB at the time the site’s Signatory Institution accepts the CIRB 
approval. The Signatory site may be contacted by the CTSU Regulatory Office or 
asked to complete information verifying the participating institutions on the study. 
Other site registration requirements (ie, laboratory certifications, protocol-specific 
training certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
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.  
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in OPEN. Prior to discussing 
protocol entry with the patient, site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available for 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.  

  
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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_Q
uickReference_SiteUserGuide_102612.pdf&ftype=PDF 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on 
either the lead protocol organization (LPO) or participating organization roster. 
 
All site staff will use OPEN 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.  
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than fourteen (14) calendar days after the date 
of study enrollment. Patients who are started on protocol therapy on a Phase 2 
study prior to study enrollment will be considered ineligible.  
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 

  
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Protocol therapy will begin no sooner than 14 days after the last major surgical 
procedure. The study enrollment must be within 4 weeks from the last surgical 
procedure to achieve complete remission. 
  
During the informed consent process, patients/guardians must be made aware that 
this study requires submission of research samples for pharmacokinetic and 
biology studies, including the fact that a number of non-standard blood samples 
will be required.  
 
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: CBC with 
differential, bilirubin, ALT (SGPT), AST, electrolytes 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.  
 
Required imaging studies must be completed prior to enrollment as outlined in Table 
16.1.1. A repeat post-operative CT chest must be obtained within 7 days prior to 
enrollment to provide a post-operative baseline for comparison with future scans. 
 
 
Patients must be less than 30 years of age at enrollment. 
 
 
Patients must have histologic diagnosis of osteosarcoma at original 
diagnosis. 
 
3.2.2.2 
Patients must have had at least one episode of disease recurrence in the 
lungs without limitation on number of episodes of recurrence as long as 
they meet the following criteria: 
o Surgical resection of all possible sites of suspected pulmonary 
metastases in order to achieve a complete remission within 4 weeks 
prior to study enrollment.* 
o Pathologic confirmation of metastases from at least one of the 
resected sites.  

  
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* For patients with bilateral pulmonary metastases, resection must 
be performed from both lungs and the study enrollment must be 
within 4 weeks from date of the last lung surgery. 
 
Note: If surgery related changes such as atelectasis are seen on the post-
operative CT scan, patients will remain eligible to enroll as long 
as the operating surgeon believes that all sites of metastases were 
resected. Patients with positive microscopic margins will be 
eligible to enroll. 
 
Patient must have adequate tumor specimen available for submission (see Section 
15.1). 
 
Patients must have a performance status corresponding to ECOG scores of 0, 1 or 
2. Use Karnofsky for patients > 16 years of age and Lansky for patients  16 years 
of 
age. 
See 
https://www.cogmembers.org/_files/protocol/Standard/
PerformanceStatusScalesScoring.pdf.  
 
Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 
 
a. Myelosuppressive anti-cancer therapy: Must not have been received within 
2 weeks of study entry (4 weeks if prior nitrosourea). 
b. Biologic (anti-neoplastic agent): At least 7 days since the completion of 
therapy with a biologic agent.  
c. Radiation therapy (RT):  2 weeks for local palliative RT (small port); 
 6 weeks must have elapsed if prior craniospinal RT or if  50% radiation of 
pelvis;  6 weeks must have elapsed if other substantial BM radiation. 
 
d. Surgery:  2 weeks from last major surgery, including pulmonary 
metastasectomy, with the exclusion of a central line placement and core 
needle or small open biopsies. 
 
a. Patient must not have received pegfilgrastim within 14 days of enrollment. 
b. Patient must not have received filgrastim (G-CSF, Neupogen) within 7 days 
of enrollment. 
c. Patient must not have received immune suppressants: corticosteroids (for other 
than allergic reactions and anaphylaxis), cyclosporine or tacrolimus within 7 
days of enrollment. 
Note: The use of topical and/or inhalational steroids is allowed. 
 
Please see Section 4.1.1 for the concomitant therapy restrictions for patients during 
treatment. 
 

  
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Hematological: 
• 
Total absolute phagocyte count [APC = (%neutrophils + 
%monocytes) x WBC] is at least 1000/μL 
• 
Platelet count ≥ 50,000/μL 
 
Adequate Renal Function Defined As: 
- 
Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR.28  
 
Adequate Liver Function Defined As: 
- 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. 
- 
SGPT (ALT) ≤ 110 U/L (for the purpose of this study, the ULN 
for SGPT is 45 U/L). 
- 
Serum albumin ≥ 2 g/dL. 
  
Adequate Cardiac Function Defined As: 
- 
Baseline EKG shows normal QTc interval of ≤ 470 ms. 
- 
Shortening fraction of ≥ 27% by echocardiogram, or 
- 
Ejection fraction of ≥ 50% by radionuclide angiogram or 
echocardiogram. 
 
Adequate Pulmonary Function Defined As: 
- 
No evidence of dyspnea at rest, no history of exercise intolerance, 
and a pulse oximetry > 94%. 
 
Central Nervous System Function Defined As: 
- 
Patient has no known history of seizure disorder.   
- 
CNS toxicity including peripheral neuropathy  Grade 2. 
 
Patients with distant bone metastases at original diagnosis or relapse 

  
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(patients with only skip lesions will be eligible).  
 
Patients with concurrent local and pulmonary recurrence at the time of 
enrollment. Note: patients who had local recurrence previously that has 
been treated and now present with an isolated pulmonary recurrence and 
meet the surgical resection criteria stated above will be eligible (see 
Section 3.2.2.2). 
 
Patients with primary refractory disease with progression of the primary 
tumor on initial therapy. 
 
Patients with CNS disease or other sites of extra-pulmonary metastases 
at the time of most recent episode of disease recurrence preceding 
enrollment. 
 
Patients with a prior hypersensitivity reaction to sargramostim. 
 
3.2.8.6 Patients who have received prior anti-GD2 therapy, including CAR T 
cells directed against GD2 antigen. 
 
3.2.8.7 Pregnancy and Breast Feeding 
3.2.8.7.1 Female patients who are pregnant are ineligible.  
 
3.2.8.7.2 Lactating females are not eligible unless they have agreed not 
to breastfeed their infants. 
 
3.2.8.7.3 Female patients of childbearing potential are not eligible 
unless a negative pregnancy test result has been obtained. 
 
3.2.8.7.4 Sexually active patients of reproductive potential are not 
eligible unless they have agreed to use an effective 
contraceptive method for the duration of their study 
participation. 
Patients 
should 
maintain 
adequate 
contraception for a minimum of 2 months after the last dose 
of ch14.18 (dinutuximab). 
 
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative 
therapies will be carefully explained to the patient or the patient’s parents or 
guardian if the patient is a child, and a signed informed consent and assent will be 
obtained according to institutional guidelines. All institutional, FDA, and NCI 
requirements for human studies must be met. 
 
 
 
 

  
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4.0 
TREATMENT PROGRAM 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
In this single arm trial, eligible patients will receive 70 mg/m2/cycle of ch14.18 
(dinutuximab). Ch14.18 (dinutuximab) will be delivered as 17.5 mg/m2/day for 4 days. The 
minimum infusion duration will be 10 hours per day with the option to increase up to 20 
hours per day if the infusion needs to be slowed down for managing adverse events. Further 
rate escalation or reduction will be as guided by the dose modifications listed in Section 5. 
The maximum duration of infusion each day is 20 hours from the start time of ch14.18. 
Patients will be observed in the hospital for an additional 24 hours after completion of the 
last day of dinutuximab infusion in each cycle.  
 
Sargramostim (GM-CSF), 250 mcg/m2/day will be administered subcutaneously once 
daily for 14 days/cycle starting 3 days prior to the start of ch14.18 (dinutuximab) infusion 
in each treatment cycle. The maximum dose for sargramostim is 500 micrograms/dose. It 
is strongly encouraged that Day 1 of all 5 cycles be on a Friday and the start of ch14.18 
(dinutuximab) infusion be the subsequent Monday. If Monday is a holiday, the ch14.18 
(dinutuximab) infusion can start on Tuesday for that particular cycle.  
 
A baseline disease evaluation will be performed prior to study enrollment (Please see the 
table in Section 16.1.1 for details). Imaging studies can be repeated for clinical care at any 
time per institutional preference or as clinically indicated. 
  
Subsequent disease evaluations will be performed after Cycles 2 and 5 of treatment, at 
months 8 and 12 from the start of therapy, and at relapse if it occurs during therapy or the 
subsequent evaluation period. Disease evaluations may include a CT scan of the chest, 
nuclear medicine imaging to evaluate for bone metastases (bone scan or PET scan, per 
institutional standard for osteosarcoma) and an MRI of the original primary tumor site 
(substituting plain radiograph if metallic hardware impedes MRI scan). 
 
Pharmacokinetic (PK) sampling during the first and second cycles of treatment will be 
required for the first 10 patients enrolled on this study and for all patients enrolled after 
protocol amendment #2. HACA samples are required of all patients.  
 
Pneumocystis Prophylaxis 
In the neuroblastoma protocols using dinutuximab, pneumocystis 
prophylaxis is routinely recommended. On this study, the use of 
pneumocystis prophylaxis will be left to the discretion of the treating 
physician. 

  
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Other Anti-Cancer Therapy 
No other systemic anti-cancer therapy will be permitted. Radiotherapy 
is also not permitted during protocol therapy.  
 
Corticosteroid Therapy 
Pharmacologic doses of systemic corticosteroids should be used ONLY 
for life-threatening conditions (i.e., life-threatening allergic reactions 
and anaphylaxis such as bronchospasm, stridor) unresponsive to other 
measures. The use of dexamethasone as an anti-emetic is not permitted. 
Corticosteroid therapy can be used as a premedication for transfusion in 
patients known to have a history of transfusion reactions or for treatment 
of an unexpected transfusion reaction (hydrocortisone 2 mg/kg or less 
or an equivalent dose of an alternative corticosteroid). The use of 
steroids during protocol therapy requires clear justification and 
documentation.  
 
Other Supportive Care 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes 
and general supportive care are to be used as necessary. Note: the use of 
gabapentin as an adjunct for pain management should be considered.  
 
For COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-
guidelines under Standard Sections for Protocols. 
 
a. No evidence of serious infection, or infection under control with no active 
disease and negative blood culture. 
b. Serum creatinine less than or equal to the upper limit of normal based on age 
(see Section 3.2.8.2). 
c. Platelet count > 50,000/µL (untransfused).  
d. Absolute phagocyte count of ≥ 1000/µL. 
e. Total bilirubin  1.5 x upper limit of normal (ULN) for age 
 
Note: Cycle-specific requirements for ALT (Cycle 1 vs Cycles 2-5) and skin 
toxicity (Cycles 2-5) are outlined on the first page of each therapy delivery map.

  
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Cycle 1 
4.2 
Cycle 1 
 
This cycle lasts 28 days. 
This TDM is on 2 pages. 
____________________________  
________________________ 
Patient COG ID number 
 
DOB 
 
 
Criteria to start this cycle: ALT ≤ 110 U/L; no evidence of serious infection, or infection under control with negative blood culture; serum creatinine ≤ ULN based on age 
(see Section 3.2.8.2); total bilirubin  1.5x ULN for age; platelet count > 50,000/µL; absolute phagocyte count of ≥ 1000/µL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS IMPORTANT NOTES 
Sargramostim (GM-
CSF) 
SubQ  
250 micrograms/m2/dose  
1-14 
See administration guidelines in Section 4.2.3. Start on Friday whenever possible. 
The maximum dose is 500 micrograms/dose. 
 ch14.18 
(Dinutuximab) 
 
IV for 4 days 
17.5 mg/m2/dose over 
10 hours/day$ 
4-7 
$The daily ch14.18 infusion may be extended up to a total of 20 hours per day for anticipated 
toxicities. The max. ch14.18 dose for one cycle is 70 mg/m2. See Section 4.2.3 for detailed 
administration guidelines, including premedications and monitoring during the infusion. 
Start on Monday whenever possible. 
 
 
 
 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
Sargramostim
____ mcg 
Ch14.18 (dinutuximab) _____mg 
 
Studies 
 
 
 
Enter calculated dose for total cycle above and actual dose administered below 
 
 
 
 
 
 
 
 
Start Date/Time 
______/ _______ 
Stop Date/Time 
______/ _______ 
Infusion 
Interrupted? Yes/No 
Dose Delivered 
_____mg 
Infusion Rate 
Start/ End 
 
 
 
1 
____mcg 
 
 
 
 
 
a-h, j-n 
 
 
2 
____mcg 
 
 
 
 
 
 
 
 
3 
____mcg 
 
 
 
 
 
 
 
 
4 
____mcg 
_____   / _____ 
_____   / _____ 
Yes/No 
_____mg* 
_____   / _____ 
a, b, c, d, i 
 
 
5 
____mcg 
_____   / _____ 
_____   / _____ 
Yes/No 
_____mg* 
_____   / _____ 
a, b 
 
 
6 
____mcg 
_____   / _____ 
_____   / _____ 
Yes/No 
_____mg* 
_____   / _____ 
a, b 
 
 
7 
____mcg 
_____   / _____ 
_____   / _____ 
Yes/No 
_____mg* 
_____   / _____ 
a, b, i 
 
 
8 
____mcg 
 
 
 
 
 
 
 
 
9 
____mcg 
 
 
 
 
 
 
 
 
10 
____mcg 
 
 
 
 
 
 
 
 
11 
____mcg 
 
 
 
 
 
a, c, d 
 
 
12 
____mcg 
 
 
 
 
 
 
 
 
13 
____mcg 
 
 
 
 
 
 
 
 
14 
____mcg 
 
 
 
 
 
 
 
 
 
 
28 
Begin next cycle on Day 29 or when criteria to begin cycle are met, whichever occurs later. See Section 4.2.3. 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
* Please record actual dinutuximab dose delivered each day. 
 
Page 1 of 2 

  
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Cycle 1 
 
 
All baseline studies must be performed prior to starting protocol 
therapy unless otherwise indicated below. Observations a-h, m can be 
performed up to 7 days before the start of therapy. 
 
a. PE, weight: daily during ch14.18 (dinutuximab) infusion; once between Day 11-
14. Note: height is only required at the beginning of this cycle.  
b. Electrolytes, creatinine, BUN, Ca++, PO4, Mg++. Note: perform daily during 
ch14.18 (dinutuximab) infusion;  
c. CBC/diff/platelets. Note: perform once between Day 11-14. 
d. Bilirubin, AST, ALT, albumin. Note: perform once between Day 11-14. 
e. Performance status. 
f. EKG. 
g. MUGA or ECHO.  
h. GFR or creatinine clearance (if serum creatinine abnormal for age). 
i. 
Pharmacokinetics. Mandatory for patients enrolled after amendment #2. See 
Section 15.2 for extensive details, including data reporting requirements. 
j. 
Imaging evaluation (MRI/X-ray of primary site, CT chest, bone scan or whole 
body PET/CT). See Section 3.2 and Section 16. 
k. Pregnancy test. A negative pregnancy test is required in females of childbearing 
potential prior to starting treatment; sexually active patients must use an acceptable 
method of birth control. 
l. 
Tumor GD2 expression. See Section 15.1 for details. 
m. Correlative biology studies: KIR/ FCR/ NKp30/ B7-H6 and ctDNA (consenting 
patients only). Samples can be obtained up to 7 days before the start of therapy. 
See Section 15.3 for details. 
n. HACA sampling: once, anytime between Day 1 and Day 4. See Section 15.2 for 
details. 
 
This listing only includes evaluations necessary to answer 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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Cycle 1 
 
 
Each 28-day cycle consists of ch14.18 (dinutuximab) and sargramostim (GM-
CSF). 
 
NOTE: It is suggested that Day 1 of Cycle 1 be on a Friday.  
 
Drug doses should be adjusted based on the BSA calculated from height and 
actual weight obtained within one week prior to the beginning of each cycle. 
 
Sargramostim (GM-CSF): Subcutaneous  
Dose: 250 micrograms/m²/dose (maximum 500 mcg/dose) subcutaneously daily. 
Days: 1 through 14. 
 
NOTE: On Days 4 to 7 of ch14.18 (dinutuximab) infusion, sargramostim should 
be administered prior to start of dinutuximab, around 8:00 - 9:00 AM. Follow 
sargramostim with 0.9% sodium chloride (NS) bolus (10 mL/kg) over 1 hour on 
each day of antibody infusion. 
 
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. 
Sargramostim will be held until the total white cell count is < 20,000/L and then 
will be resumed at 50% dose for the remainder of the cycle. Full dose sargramostim 
will be used for subsequent cycles.  
 
If criteria for holding sargramostim are met (e.g., see Sections 5.2.1.8 and 5.2.2), 
then ch14.18 (dinutuximab) should be continued without sargramostim. 
 
Dinutuximab: IV infusion over 10 hours per day* for 4 days  
Dose: 70 mg/m2/cycle to be given as 17.5 mg/m2/dose once daily times four days 
on Days 4-7 of the cycle. 
 
Ch14.18 (dinutuximab) infusion may be extended up to 20 hours per day for 
anticipated toxicities that are not responsive to supportive measures. Infusion must 
be stopped after 20 hours from the start time.  
 
NOTE: Begin antibody infusion one hour after sargramostim injection on Day 4 (ie, 
immediately following the IV bolus of normal saline). Each daily dose should start 
at 0.88 mg/m2/hour x 0.5 hour  and then increased gradually to 1.75 mg/m2/hour 
for the remainder of the infusion as tolerated. Further rate escalation or reduction 
should be guided by the dose modifications listed in Section 5. 
 
The rate and the duration of infusion should be recorded carefully each day so the 
total daily dose can be calculated. 
 
• 
Recommended premedications include: 
o Hydroxyzine (0.5-1 mg/kg; max dose 50 mg) PO or diphenhydramine (0.5-
1 mg/kg; maximum dose 50 mg) PO/IV over 10 minutes to start 
approximately 20 minutes prior to ch14.18 (dinutuximab) infusion; may be 

  
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Cycle 1 
repeated every 6 hours as needed during ch14.18 (dinutuximab) infusion. 
Note: intravenous hydroxyzine is NOT recommended. 
o Acetaminophen (10-15 mg/kg; max dose 650 mg) PO given approximately 
20 minutes prior to ch14.18 (dinutuximab) infusion; in patients not able to 
tolerate oral medications, acetaminophen 15 mg/kg (max dose 650 mg) IV 
over 15 minutes can be used; may be repeated every 4-6 hours as needed for 
fever.  
 
• 
Recommended pain management*: 
o Morphine sulfate loading dose immediately prior to ch14.18 (dinutuximab) 
administration. A dose of 50 micrograms/kg is recommended, though this may 
be adjusted based on a given patient’s pain history. 
o Continue with morphine sulfate infusion titrated to effect. The recommended 
dose range for the continuous morphine infusion is 20-50 micrograms/kg/hour 
to continue for 2 hours after completion of the ch14.18 (dinutuximab) infusion. 
o 
Other opiates such as hydromorphone or fentanyl can be used instead of 
morphine as clinically indicated. 
o 
Gabapentin may be used in conjunction with other pain medications per 
institutional practice. 
o The use of additional pain medications (lidocaine, ketamine) in extenuating 
circumstances should be undertaken in consultation with pediatric pain 
management specialists. 
• 
For example, a lidocaine infusion may be used in conjunction with IV 
bolus of morphine on prn basis. Suggested administration guidelines 
for a lidocaine infusion are shown below: 
• 
Give lidocaine IV bolus at 2 mg/kg in 50 mL NS over 30 minutes 
prior to the start of ch14.18 (dinutuximab) infusion. 
• 
At the beginning of ch14.18 (dinutuximab) infusion, start IV 
lidocaine infusion at 1 mg/kg/hour and continue until two hours 
after the completion of ch14.18 (dinutuximab) infusion. 
• 
May give morphine IV bolus 20-50 micrograms/kg every 2 hours 
prn pain. 
• 
Patient should be monitored closely for sedation scale, EKG (rate 
and rhythm), HR, BP, RR, oxygen saturation (pulse oximeter) and 
pain score. If patient develops dizziness, perioral numbness, 
tinnitus attributable to lidocaine, then stop lidocaine infusion. 
o Another alternative pain regimen that may be used in subsequent cycles if the 
above regimen is not well tolerated or inadequate to control pain is a 
combination of hydromorphone and dexmedetomidine as described by Gorges 
et al.29 and outlined in Section 4.3.3. This should be undertaken in consultation 
with pediatric pain management specialists and institutional guidelines 
followed for monitoring. 
1. Start both hydromorphone and dexmedetomidine infusions 1 hour 
prior to commencement of ch14.18 (dinutuximab) infusion. 
2. Start hydromorphone at 2 micrograms/kg/hour and titrate up to a 
maximum of 8 micrograms/kg/hour 
3. Start dexmedetomidine at 0.1 micrograms/kg/hour and titrate up 
to a maximum of 0.6 micrograms/kg/hour to achieve adequate 
analgesia 
4. Alternate increases in hydromorphone and dexmedetomidine 

  
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Cycle 1 
every 30 minutes as needed. 
5. Patients should be monitored closely for hypotension and respiratory 
depression. 
6. Gabapentin can be used in conjunction with this regimen as 
detailed above.   
 
* Please note that all of the above pain management guidelines are suggestions and can 
be varied based on institutional/ patient preference as long as they meet safety 
standards. 
 
• 
Monitoring during ch14.18 (dinutuximab) infusion: 
o Vital signs should be assessed every 15 minutes for the first hour of the 
infusion, then hourly during the remainder of the infusion if stable after the 
first hour. More frequent assessment may be required based on the patient’s 
clinical condition.  
o Strict observation of intake and output is required on the days of ch14.18 
(dinutuximab) administration. 
o Daily physical examination including a careful eye exam for pupillary reflexes 
and extraocular movements. 
o Patients should be weighed daily on the days of ch14.18 (dinutuximab) 
administration. 
 
• 
Have immediately available during the ch14.18 (dinutuximab) infusion: 
o Epinephrine (1:10,000) 0.01 mg/kg or 0.1 mL/kg: IVP (max 5 mL) every 3-
5 minutes. 
o Hydrocortisone 2 mg/kg (max 100 mg) IVP. Only use it for life-threatening 
reactions (hypotension, bronchospasm, angioedema involving the airway) not 
responsive to other measures.  
 
See Section 5.0 for Dose Modifications based on Toxicities. Information on management of toxicities 
including anaphylaxis and hypertension is also included in Section 5.0. It is recommended that these be 
reviewed, printed and available on the inpatient unit to facilitate treatment decisions. 
 
Following completion of Cycle 1, Cycle 2 starts on Day 29 or when starting criteria are met, (whichever occurs 
later). If the starting criteria are not met within 4 weeks, then the patient will go off protocol therapy. 
 
 
 

  
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Cycles 2-5 
4.3 
Cycles 2-5 
 
Each cycle lasts 28 days. This TDM is on 2 pages. Use a copy of this page once for each cycle. 
Please note cycle number below. 
____________________________  ________________________ 
Patient COG ID number                                 DOB 
Criteria to start a cycle: ALT < 5x ULN (45 U/L) 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; skin toxicity ≤ Grade 1; no evidence of serious infection, or infection under control with no active disease and negative blood 
culture; serum creatinine ≤ ULN based on age as stated in Section 3.2.7.2; platelet count ≥ 50,000/µL; absolute phagocyte count of ≥ 1000/µL; total bilirubin ≤ 1.5 x ULN for age. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Sargramostim 
(GM-CSF) 
SubQ  
250 micrograms/m2/dose  
1-14 
See administration guidelines in Section 4.3.3. Start on Friday whenever possible. 
The maximum dose is 500 micrograms/dose. 
ch14.18  
(Dinutuximab) 
IV for 4 days  
17.5 mg/m2/dose over 
10 hours/day$ 
4-7 
$The daily ch14.18 infusion may be extended up to a total of 20 hours per day for anticipated 
toxicities. The max. ch14.18 dose for each cycle is 70 mg/m2. See Section 4.3.3 for detailed 
administration guidelines, including premedications and monitoring during the infusion. Start on 
Monday whenever possible. 
 
Enter Cycle #: _____ 
 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date Given 
Day 
Sargramostim ____ mcg 
Ch14.18 (dinutuximab)                     _____mg 
Studies 
 
 
 
Enter calculated dose for total cycle above and actual dose administered below 
 
 
 
 
 
 
 
 
Start Date/Time 
____ __/ _______ 
Stop Date/Time 
____ __/ _______ 
Infusion Interrupted? 
Yes/No 
Dose Delivered 
_____mg 
Infusion Rate 
Start/ End 
 
 
 
1 
____mcg 
 
 
 
 
 
a, e, f, h, i, j 
 
 
2 
____mcg 
 
 
 
 
 
 
 
 
3 
____mcg 
 
 
 
 
 
 
 
 
4 
____mcg 
_____   / _____ 
_____   / _____ 
Yes/No 
_____mg* 
_____   / _____ 
a, b, c, d 
 
 
5 
____mcg 
_____   / _____ 
_____   / _____ 
Yes/No 
_____mg* 
_____   / _____ 
a, b 
 
 
6 
____mcg 
_____   / _____ 
_____   / _____ 
Yes/No 
_____mg* 
_____   / _____ 
a, b 
 
 
7 
____mcg 
_____   / _____ 
_____   / _____ 
Yes/No 
_____mg* 
_____   / _____ 
a, b 
 
 
8 
____mcg 
 
 
 
 
 
 
 
 
9 
____mcg 
 
 
 
 
 
 
 
 
10 
____mcg 
 
 
 
 
 
 
 
 
11 
____mcg 
 
 
 
 
 
a, c, d 
 
 
12 
____mcg 
 
 
 
 
 
 
 
 
13 
____mcg 
 
 
 
 
 
 
 
 
14 
____mcg 
 
 
 
 
 
 
 
 
 
 
28 
Begin next cycle on Day 29 or when criteria to begin cycle are met (whichever occurs later). See Section 4.3.3. Treatment should continue 
for a total of 5 cycles, in the absence of disease progression or unacceptable toxicity. If disease progression or unacceptable toxicity occurs, 
the patient will be taken off protocol therapy. See Section 7.1 for End of Therapy evaluations including required imaging. 
g, j 
* Please record actual dose delivered each day. 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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Cycles 2-5 
 
 
 
a. Height: Day 1 only. PE, weight: perform on Day 1, daily during ch14.18 
(dinutuximab) infusion and once between Day 11-14.  
b. Electrolytes, creatinine, BUN, Ca++, PO4, Mg++. Note: perform daily during 
ch14.18 (dinutuximab) infusion.  
c. CBC/diff/platelets. Note: perform once between Day 11-14. 
d. Bilirubin, AST, ALT, albumin. Note: perform once between Day 11-14. 
e. Performance status. 
f. Pharmacokinetics. Perform once before the start of Cycle 2 only. Mandatory 
for patients enrolled after protocol amendment #2. See Section 15.2 for 
extensive details, including data reporting requirements. 
g. Imaging evaluation. CT of the chest must be obtained between Day 24 to 28 
of Cycle 2 and also during a 7-day window around the last day of Cycle 5. 
Primary tumor site imaging and bone scan/ PET-CT scan should be obtained 
during a 7 day window around the last day of Cycle 5. See Section 16 for 
details. 
h. Correlative biology study. B7-H6 ligand (consenting patients only). Obtain 
this sample before the start of Cycle 2 only. See Section 15.3 for details. 
i. 
HACA sampling: once, anytime between Day 1 and Day 4. See Section 15.2 
for details. 
j. 
Correlative biology study. ctDNA (consenting patients only). Obtain sample 
prior to ch14.18 infusion start and at end of Cycle 2 and 5 along with tumor 
evaluations. See Section 15.4 for details.  
 
This listing only includes evaluations necessary to answer 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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Version date: 05/17/2017 
Cycles 2-5 
 
 
Each cycle consists of ch14.18 (dinutuximab) and sargramostim, and lasts 28 days.  
 
NOTE. It is suggested that Day 1 of each cycle be on a Friday.  
 
 
Drug doses should be adjusted based on the BSA calculated from height and 
weight obtained within one week prior to the beginning of each cycle. 
 
Sargramostim (GM-CSF): Subcutaneous  
Dose: 250 micrograms/m²/dose (maximum 500 mcg/dose) subcutaneously daily. 
Days: 1 through 14. 
 
NOTE: On Days 4 to 7 of ch14.18 (dinutuximab) infusion, sargramostim should 
be administered prior to start of dinutuximab, around 8:00 - 9:00 AM. Follow 
sargramostim with 0.9% sodium chloride (NS) bolus (10 mL/kg) over 1 hour on 
each day of ch14.18 (dinutuximab) infusion. 
 
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. 
Sargramostim will be held until the total white cell count is less than 20,000/L 
and then will be resumed at 50% dose for the remainder of that cycle. Full dose 
sargramostim will be used for subsequent cycles.  
 
If criteria for holding sargramostim  are met (e.g., see Sections 5.2.1.8 and 5.2.2), 
then ch14.18 (dinutuximab) should be continued without sargramostim.  
 
Dinutuximab: IV infusion over 10 hours per day* for 4 days 
Dose: 70 mg/m2/cycle to be given as 17.5 mg/m2/dose once daily times four days 
on Days 4- 7 of the cycle.  
 
Ch14.18 (dinutuximab) infusion may be extended up to a total 20 hours per day 
for anticipated toxicities that are not responsive to supportive measures. Infusion 
must be stopped after 20 hours from the start time.  
 
NOTE: Begin antibody infusion one hour after sargramostim injection on Day 4 (ie, 
immediately following the IV bolus of normal saline). Each daily dose should start 
at 0.88 mg/m2/hour x 0.5 hour and then increase infusion gradually to 
1.75 mg/m2/hour for the remainder of the infusion as tolerated. Further rate 
escalation or reduction should be guided by the dose modifications listed in Section 
5.  
 
The rate and duration of the infusion should be recorded carefully each day so the 
total daily dose can be calculated. 
 
• 
Recommended premedications include: 
o Hydroxyzine (0.5-1 mg/kg; max dose 50 mg) PO or diphenhydramine 
(0.5-1 mg/kg; max dose 50 mg) IV over 10 minutes to start approximately 
20 minutes prior to ch14.18 (dinutuximab) infusion; may be repeated 

  
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Version date: 05/17/2017 
Cycles 2-5 
every 6 hours as needed during ch14.18 (dinutuximab) infusion. Note: 
intravenous hydroxyzine is NOT recommended. 
o Acetaminophen (10 mg/kg; max dose 650 mg) PO given approximately 
20 minutes prior to ch14.18 (dinutuximab) infusion; in patients not able to 
tolerate oral medications, acetaminophen 15 mg/kg (max dose 650 mg) IV 
over 15 minutes can be used; may be repeated every 4-6 hours as needed 
for fever.  
 
• 
Recommended pain management*: 
o Morphine sulfate loading dose immediately prior to ch14.18 
(dinutuximab) 
administration. 
A 
dose 
of 
50 micrograms/kg is 
recommended, though this may be adjusted based on a given patient’s pain 
history. 
o Continue with morphine sulfate drip titrated to effect. The recommended 
dose 
range 
for 
the 
continuous 
infusion 
morphine 
is 
20-
50 micrograms/kg/hour to continue for 2 hours after completion of the 
ch14.18 (dinutuximab) infusion. 
o Other narcotics such as hydromorphone or fentanyl can be used.  
o Gabapentin may be used in conjunction with other pain medications per 
institutional practice. 
o The use of additional pain medications (lidocaine, ketamine) in 
extenuating circumstances should be undertaken in consultation with 
pediatric pain management specialists. 
• 
For example, a lidocaine infusion may be used in conjunction with 
IV bolus of morphine on prn basis. Suggested administration 
guidelines for a lidocaine infusion are shown below: 
• 
Give lidocaine IV bolus at 2 mg/kg in 50 mL NS over 
30 minutes prior to the start of ch14.18 (dinutuximab) 
infusion. 
• 
At the beginning of ch14.18 (dinutuximab) infusion, start IV 
lidocaine infusion at 1 mg/kg/hr and continue until two hours 
after the completion of ch14.18 (dinutuximab) infusion. 
• 
May give morphine IV bolus 20-50 microgram/kg every 
2 hours prn pain. 
• 
Patient should be monitored closely for sedation scale, EKG 
(rate and rhythm), HR, BP, RR, oxygen saturation (pulse 
oximeter) and pain score. If patient develops dizziness, 
perioral numbness, tinnitus attributable to lidocaine, then stop 
lidocaine infusion. 
o Another alternative pain regimen that may be used in subsequent cycles if 
the above regimen is not well tolerated or adequate to control pain is a 
combination of hydromorphone and dexmedetomidine as described by 
Gorges et al.29 This should be undertaken in consultation with pediatric 
pain management specialists. 
1. Start both hydromorphone and dexmedetomidine infusions 1 hour 
prior to commencement of ch14.18 (dinutuximab) infusion. 
2. Start hydromorphone at 2 micrograms/kg/hour and titrate up to a 
maximum of 8 micrograms/kg/hour 
3. Start dexmedetomidine at 0.1 micrograms/kg/hour and titrate up 

  
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Cycles 2-5 
to a maximum of 0.6 micrograms/kg/hour to achieve adequate 
analgesia 
4. Alternate increases in hydromorphone and dexmedetomidine 
every 30 minutes as needed. 
5. Patients should be monitored closely for hypotension and respiratory 
depression. 
6. Gabapentin can be used in conjunction with this regimen as 
detailed above.   
 
* Please note that all of the above pain management guidelines are suggestions and 
can be varied based on institutional/ patient preference as long as they meet safety 
standards. 
 
 
• 
Monitoring during ch14.18 (dinutuximab) infusion: 
o Vital signs should be assessed every 15 minutes for the first hour of the 
infusion, then hourly during the remainder of the infusion if stable after 
the first hour. More frequent assessment may be required based on the 
patient’s clinical condition. Between antibody doses, vitals should be 
assessed every 4 hours.  
o Strict observation of intake and output is required on the days of ch14.18 
(dinutuximab) administration. 
o Daily physical examination including a careful eye exam for pupillary 
reflexes and extraocular movements. 
o Patients should be weighed daily on the days of ch14.18 (dinutuximab) 
administration. 
 
• 
Have immediately available at the bedside during the ch14.18 (dinutuximab) 
infusion: 
o Epinephrine (1:10,000) 0.01 mg/kg or 0.1 mL/kg: IVP (max 5 mL) every 
3-5 minutes. 
o Hydrocortisone 2 mg/kg (max 100 mg) IVP. Only use it for life-
threatening reactions (hypotension, bronchospasm, angioedema involving 
the airway) not responsive to other measures.  
 
See Section 5.0 for Dose Modifications based on Toxicities. Information on management of toxicities 
including anaphylaxis and hypertension is also included in Section 5.0. It is recommended that these be 
reviewed, printed and available on the inpatient unit to facilitate treatment decisions. 
 
Following completion of a cycle, the next cycle starts on Day 29 or when starting criteria are met, (whichever 
occurs later). If the starting criteria are not met within 4 weeks, then the patient will go off protocol therapy. 
 
 
 
 
 

  
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
In addition to dose modifications, this section provides information regarding management 
of toxicities known to be associated with protocol therapy. 
 
5.1 
Dose Modifications for Hematologic Toxicity 
If there is a delay of ≥ 28 days in recovery of APC to ≥ 1000/µL and/ or platelets to 
≥ 50,000/µL to start the next treatment cycle, the patient will be removed from protocol 
therapy. 
 
Patients who develop atypical hemolytic uremic syndrome (which is one of the extremely 
rare side effects of ch14.18) should discontinue all further protocol therapy. 
 
5.2 
Dose Modifications for Non-Hematologic Toxicity 
An elevation in ALT that causes a delay of ≥ 14 days between treatment cycles will require 
a 25% reduction in the dose of ch14.18 (dinutuximab) for subsequent cycles (i.e., ch14.18 
(dinutuximab) dose: 52.5 mg/m2/cycle). If a delay of ≥ 14 days between treatment cycles 
recurs due to elevation in ALT despite the dose reduction, the patient will be removed from 
protocol therapy. 
 
Treatment of ch14.18 (dinutuximab) induced hypotension (without 
evidence of allergic reaction) 
• 
If hypotension is severe and accompanied by poor perfusion, end 
organ dysfunction, or acidemia – Pediatric Advanced Life Support 
(PALS) or Advanced Cardiovascular Life Support (ACLS) 
guidelines should be followed and ch14.18 (dinutuximab) infusion 
should be discontinued for this cycle. 
 
• 
In the absence of poor perfusion, end organ dysfunction or 
acidemia, moderate hypotension is defined as: 
o Symptomatic decreases in blood pressure and/or 
o Systolic blood pressure (SBP) < 80 mmHg for age > 12 years 
o SBP < 70 mmHg for age 1-12 years 
o SBP < 65 mmHg for age < 1 year OR 
o SBP or DBP decreased by > 20 % below baseline 
 
• 
If moderate hypotension is observed: 
o Immediately hold dinutuximab 
o Give normal saline bolus (20 mL/kg as rapidly as possible) 
o Stop or adjust doses of narcotics and sedating H1 blockers 
o Consider use of Trendelenberg position 
 
• 
If hypotension persists after the above measures have been taken: 
o Reassess perfusion and end organ function; follow PALS or 
ACLS algorithm if needed 

  
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o Repeat NS bolus 
o Consider use of albumin if albumin < 3 gm/dL 
o Consider use of PRBCs if Hb < 10 gm/dL 
o Consider transfer to intensive care setting  
 
• 
If hypotension persists following 2 volume boluses, give an 
additional bolus and prepare to administer pressors 
o Adrenergic pressors, norepinephrine or epinephrine, are 
preferred over dopamine. 
 
• 
Resumption of ch14.18 (dinutuximab)  
o For patients whose hypotension resolves promptly and 
completely with limited volume resuscitation (≤ 40 mL/kg) and 
without 
requirement 
for 
pressor 
support, 
ch14.18 
(dinutuximab) may be restarted at 50% of the previous infusion 
rate. The ch14.18 (dinutuximab) may be restarted once the 
blood pressure has normalized and remains stable for a 
minimum of 2 hours after volume resuscitation is completed. If 
blood pressures are stable for 2 hours after the restart of 
ch14.18 (dinutuximab) at 50% rate, the infusion may be given 
at full rate for that day and subsequent days. If the patient again 
experiences hypotension requiring multiple volume boluses 
(≥ 40 mL/kg) when ch14.18 (dinutuximab) is given at full rate 
but tolerates the 50% infusion rate, the remaining days’ 
infusion of ch14.18 (dinutuximab) should be given at the 
tolerated 50% rate of infusion once blood pressures are stable 
again. The infusion may be started at the full rate at the start of 
subsequent cycles. 
o For patients who require multiple volume boluses (> 40 mL/kg) 
for hemodynamic stabilization, ch14.18 (dinutuximab) should 
be resumed the following day at 50% of the initial infusion rate.  
▪ If blood pressures are stable for 2 hours after 
resumption of ch14.18 (dinutuximab) at the reduced 
rate, the remainder of the antibody infusion may be 
given at the full rate. If hypotension recurs at full rate, 
but patient tolerates the 50% rate, then continue 
ch14.18 (dinutuximab) infusion at 50% rate for the 
remaining duration of infusion once blood pressures 
are stable again. 
▪ If hypotension recurs at the reduced rate, the measures 
above should again be taken and once blood pressure 
is stable for 2 hours post volume resuscitation, ch14.18 
(dinutuximab) can be resumed at a further 50% 
decrease in rate. If the patient’s blood pressures are 
stable at the second 50% reduction in rate the 
remaining days’ infusion of ch14.18 (dinutuximab) 
should be given at that rate until 4 days from the start 

  
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of ch14.18 are completed. 
▪ If hypotension recurs at the second rate reduction, 
discontinue ch14.18 (dinutuximab) for that day. The 
antibody infusion may be restarted the following day 
after ensuring the patient is volume replete at the rate 
that was reached with second 50% reduction. If blood 
pressure remains stable, continue daily 20-hour 
infusions at this rate until 4 days from the start of the 
ch14.18 (dinutuximab) infusion are completed. The 
infusion may be started at the full rate at the start of 
subsequent cycles. 
 
o For patients who require pressors for treatment of hypotension, 
if blood pressure is stable off pressors for at least 6 hours, 
administration of ch14.18 (dinutuximab) may be resumed at 
50% of the initial infusion rate on the day following the 
hypotensive episode as long as it is within the 4 day window 
from the start of ch14.18 (dinutuximab). If the 50% rate is 
tolerated without further hypotension, rate can be increased to 
100% as tolerated. If patient becomes hypotensive again at 
100% rate, it should be decreased back to 50% after patient is 
clinically stable to receive the infusion again and remainder of 
the infusion should be completed at the decreased rate. Care 
should be taken to ensure that the patient is volume replete. 
Ch14.18 (dinutuximab) should not be given to patients who 
continue to require pressor support. Patients who require 
pressor support for ≥ 24 hours due to treatment-related 
hypotension despite appropriate volume resuscitation should 
discontinue protocol therapy. Patients who again require 
pressor support when ch14.18 (dinutuximab) is resumed should 
discontinue protocol therapy.  
 
 
Treatment of Allergic Reactions/Infusion Reactions  
5.2.1.2.1 
Mild allergic reactions/infusion reactions to ch14.18 
(dinutuximab) infusion 
• 
A mild allergic reaction is limited to rash, flushing, 
urticaria, mild dyspnea – Grade 1 or 2 
• 
The following recommendations do NOT apply to Grade 
3 or 4 allergic reactions, including anaphylaxis 
• 
Management 
o Decrease rate of ch14.18 (dinutuximab) to 50% of 
full rate 
o Perform serial exams at bedside 
o Administer H1 blocker (diphenhydramine, 
cetirizine recommended) 
o Administer H2 blocker 

  
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o When symptoms resolve, resume original infusion 
rate 
o If symptoms recur when original rate is resumed, 
decrease to 50% rate again 
o Infusion must be stopped after 4th day infusion is 
completed (whether the full dose of ch14.18 
(dinutuximab) has been administered or not); 
document total amount of drug given in the 4 day 
period 
 
5.2.1.2.2 
Moderate to severe allergic reactions/infusion reactions to 
ch14.18 (dinutuximab) infusion 
• 
Moderate to severe reactions include any of the 
following: symptomatic bronchospasm, allergy-related 
edema/angioedema, hypotension, or anaphylaxis – 
Grade 3 or 4 
• 
The following recommendations do NOT apply to Grade 
1 or 2 allergic reactions 
• 
Management 
o Immediately hold ch14.18 (dinutuximab)  
o Assess airway, breathing and circulation 
o Follow institutional guidelines for rapid response 
team notification if clinically indicated 
o For airway concerns 
▪ Administer oxygen and albuterol immediately 
for bronchospasm 
▪ Administer IV diphenhydramine 
▪ Administer 
epinephrine 
(1:1000 
IM 
recommended) immediately if upper airway 
involved or if airway issues are accompanied by 
cardiovascular collapse 
▪ Administer IV hydrocortisone (1-2 mg/kg) if 
the patient has frank anaphylaxis with 
cardiorespiratory collapse OR if ≥ 2 doses of 
epinephrine are required OR if moderate to 
severe symptoms recur upon rechallenge with 
dinutuximab 
o For hypotension in the setting of allergic reaction 
▪ Give normal saline bolus (20 mL/kg as rapidly 
as possible) 
▪ Stop or adjust doses of narcotics and sedating 
H1 blockers 
▪ Consider use of Trendelenberg position 
▪ See previous section for management of 
persistent hypotension 
o For patients with mild bronchospasm or angioedema 

  
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that does not impact breathing, completely resolves 
without the use of epinephrine and hydrocortisone 
and for patients whose hypotension resolves 
following volume bolus, ch14.18 (dinutuximab) 
may be resumed at 50% of the previous rate of 
infusion on the same day as the reaction occurred. If 
symptomatic 
angioedema 
or 
asymptomatic 
bronchospasm 
recurs 
when 
the 
ch14.18 
(dinutuximab) 
is 
restarted, 
discontinue 
immunotherapy for that day and if symptoms/signs 
resolve completely that day, resume the next day 
with additional pre-medication of hydrocortisone 1-
2 mg/kg IV. For this re-challenge, the infusion 
should be given in an ICU setting. 
o For patients whose bronchospasm or angioedema 
requires the use of systemic epinephrine, protocol 
therapy should be discontinued. 
o For patients with bronchospasm or angioedema that 
does not require systemic epinephrine but whose 
hypotension requires more extensive volume 
resuscitation, guidance in Section 5.2.1.1 should be 
followed. 
 
Management of Capillary Leak Syndrome (≥ Grade 3) 
• 
Hold ch14.18 (dinutuximab) infusion 
• 
Provide oxygen, fluids as needed 
• 
Diuretics should be used with caution and hypotension avoided 
• 
See Section 5.2.1.1 for management of hypotension  
• 
Do NOT resume ch14.18 (dinutuximab) therapy if symptoms of 
severe capillary leak syndrome persist on the same day or subsequent 
days of a given cycle. Only resume ch14.18 (dinutuximab) therapy 
when the capillary leak syndrome resolves or requires less 
significant intervention (Grade 2 or less). 
• 
If capillary leak resolves, may resume ch14.18 (dinutuximab) 
infusion at 50% rate the same day and for subsequent days during a 
given cycle. The infusion may be given at the full rate at the start of 
subsequent cycles 
• 
If mechanical ventilation (any duration) or pressor support for 
≥ 24 hours is required due to therapy-related capillary leak 
syndrome, the patient should discontinue protocol therapy. 
 
Management of Renal Insufficiency (unrelated to hypotension) 
• 
Consider the possibility of renal hypoperfusion in the context of 
borderline hypotension; administer volume if appropriate 
• 
If the patient’s creatinine is elevated to ≥ 2 x the upper limit of 
normal for age/gender (see table in Section 3.2.7.2) and elevation 
persists despite optimized fluid management, hold dinutuximab 

  
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• 
Modify dosing of concomitant medications that may contribute to or 
be affected by renal insufficiency 
• 
When urine output returns to normal and creatinine returns to < 2 x 
upper limit of normal for age/gender, resume ch14.18 (dinutuximab) 
at 50% rate. If renal function normalizes by the following day, 
ch14.18 (dinutuximab) may be administered at full rate. If renal 
function is not sufficiently improved (urine output normal and 
creatinine < 2 x ULN for age/gender) by Day 7 of the cycle, no 
further ch14.18 (dinutuximab) should be given during that cycle of 
therapy. If renal function has normalized by the planned start date 
for the next cycle, retreatment with ch14.18 (dinutuximab) is 
permitted starting at full rate 
 
Management of Hyponatremia (≥ Grade 3; Na < 130 mEq/L) 
• 
Change hypotonic fluids to isotonic fluids as compatibilities permit 
• 
Avoid administration of oral free water 
• 
Correct fluid losses due to diarrhea  
• 
3% sodium chloride may be used to correct hyponatremia as per 
institutional discretion 
• 
If Grade ≥ 3 hyponatremia persists despite optimal fluid 
management, discontinue ch14.18 (dinutuximab) for the remainder 
of the cycle. Sodium should be monitored closely during the next 
cycle of therapy. Empiric dose reduction is not required at the start 
of the next cycle of therapy, though ch14.18 (dinutuximab) would 
again be discontinued if Grade 4 hyponatremia were to persist 
despite optimal fluid management. In such cases, no additional cycle 
of therapy would be given. 
 
Management of Fever in the Absence of Hypotension 
• 
Administer antipyretics 
• 
Adjust fluids to account for insensible losses if fever is persistent 
• 
Obtain blood culture 
• 
Administer empiric antibiotics if suggested by institutional policy 
 
Management of Treatment-Related Pain*  
• 
No further ch14.18 (dinutuximab) therapy should be given to 
patients who experience treatment related pain that cannot be 
controlled despite intensive pain management during a given cycle. 
Treatment with gabapentin or similar agent should be initiated if not 
already being administered. If pain that is not controlled with opiates 
(along with either lidocaine or dexmedetomidine) recurs during a 
subsequent cycle, the patient should discontinue protocol therapy  
• 
For patients with treatment-related pain requiring intravenous 
narcotics for ≥ 48 hours following completion of ch14.18 
(dinutuximab) therapy, gabapentin or similar agent should be 
initiated if not already being administered. If pain requiring 

  
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prolonged intravenous narcotics (≥ 96 hours following completion 
of ch14.18 (dinutuximab) therapy) recurs during a subsequent cycle 
despite this intervention, the patient should discontinue protocol 
therapy.  
*Note: For patients who have previously undergone amputation of an 
extremity for local tumor control and experience phantom pain, there is 
a possibility of worsening of phantom pain with ch14.18 (dinutuximab) 
therapy. This should be managed similar to guidelines for pain 
management listed in Sections 4.2.3 and 4.3.3. In addition, tricyclic anti-
depressants such as amitriptyline can be considered for these patients as 
it has shown to be of benefit in patients with phantom pain. Protocol 
therapy should be discontinued if phantom pain is uncontrolled despite 
aggressive pain management. 
 
Management of Visual Changes 
• 
Ch14.18 (dinutuximab) should be discontinued for the cycle for 
patients who develop dilated pupils with sluggish light reflexes with 
or without photophobia during administration of the antibody. 
Sargramostim should be completed for that cycle. If pupillary 
abnormalities remain stable or improve before the next 
immunotherapy cycle is due, the patient should receive ch14.18 
(dinutuximab) at a dose that is 50% reduced compared to the prior 
dose. Full dose sargramostim should be given. If the lower dose of 
ch14.18 (dinutuximab) is tolerated without worsening of ocular 
toxicity, full dose ch14.18 (dinutuximab) should be given in 
subsequent cycles. If visual toxicity worsens on the 50% reduced 
dose, the patient should discontinue all immunotherapy. 
• 
Dose reductions for changes in accommodation are not required 
 
Management of Serum Sickness 
• 
Identification of serum sickness – signs and symptoms include 
arthralgias/arthritis, splenomegaly, lymphadenopathy, 
glomerulonephritis in the presence of persistent fevers, cutaneous 
eruptions 
• 
Serum sickness typically develops 1 to 3 weeks after administration 
of the causative agent, but can develop within 12-36 hours in patients 
who have previously been sensitized to the causative agent 
• 
Patients with ≥ Grade 3 serum sickness should discontinue protocol 
therapy. 
• 
For Grade 2 serum sickness, antihistamines should be prescribed 
 
Management of Neurotoxicity 
• 
Patients who develop Grade 4 neurotoxicity should discontinue 
protocol therapy. 
• 
Ch14.18 (dinutuximab) should be discontinued for the remainder of 
the current cycle of therapy for patients who develop Grade 3 
sensory neuropathy or Grade 3 motor neuropathy. If abnormalities 

  
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resolve by start of next cycle of therapy the patient may receive 50% 
total dose of ch14.18 (dinutuximab) per cycle (ie, ch14.18 
(dinutuximab) dose: 35 mg/m2). If symptoms do not completely 
resolve or recur with ch14.18 (dinutuximab) then the patient should 
discontinue protocol therapy. 
 
• 
Hold sargramostim if total white blood cell count is > 50,000/µL; resume at 
50% dose when the count is < 20,000/µL. Administer full dose with 
subsequent cycles and modify again if the count exceeds 50,000/µL. Ch14.18 
should be continued as per protocol in the event sargramostim is held. 
• 
Localized skin reactions to sargramostim are common, and sargramostim can 
be continued when reactions are mild. Rotation of sites of injections is 
recommended rather than use of subcutaneous catheters, such as Insuflon for 
subcutaneous injection when skin reactions occur. Consider use of 
antihistamines. If ≥ Grade 3 injection site reactions occur, stop sargramostim 
for the current cycle and discontinue sargramostim for subsequent cycles of 
therapy. 
• 
A syndrome characterized by respiratory distress, hypoxia, flushing, 
hypotension, syncope, and/or tachycardia has been reported following the 
administration of the first dose of sargramostim in a particular cycle. This 
syndrome generally resolves with symptomatic treatment and usually does not 
recur with subsequent doses of sargramostim in the same cycle of treatment. 
For safety purposes in this study, if such a “first dose reaction” occurs, the 
sargramostim dose will be reduced to 50% for the next dose (ie, sargramostim 
dose 125 mcg/m2). If a similar reaction occurs at the 50% dose, the 
sargramostim will be discontinued for that patient. If the first dose at 50% does 
not cause any recurrent severe symptoms, subsequent doses can be escalated 
back to 100%. If recurrent severe symptoms are observed at 100% dose, then 
the dose will be reduced to 50%. If 50% is tolerated, that dose should be 
administered for all subsequent protocol treatment for that patient. If recurrent 
severe symptoms are seen at the 50% dose, the sargramostim will be 
discontinued for subsequent cycles of therapy. 
 
 

  
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6.0 
DRUG INFORMATION  
6.1 
Chimeric Monoclonal Antibody 14.18 (Dinutuximab)  
 
(05/12/2017) 
(Chimeric Monoclonal Antibody 14.18; human/murine anti-GD2 monoclonal antibody; 
chimeric anti-GD2; chimeric mAb 14.18; ch14.18, dinutuximab, Unituxin®) NSC# 764038, 
IND# 4308 
 
Source and Pharmacology: 
Chimeric MOAB 14.18 (ch14.18, UTC) is an anti-GD2 monoclonal antibody composed of the 
variable region heavy and light chain genes of the murine mAb 14.G2a and the human 
constant region genes for heavy chain IgG1 and light chain kappa. Ch14.18 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 may also prevent attachment of circulating 
malignant cells to the extracellular matrix. Additionally, ch14.18 mediates lysis of several 
melanoma and neuroblastoma cell lines in a dose dependent manner in the presence of potent 
mediators of ch14.18-dependent cytotoxicity, such as human peripheral blood mononuclear 
cells and granulocytes. This is most profound with neutrophils, especially in the presence of 
recombinant human granulocyte-macrophage colony-stimulating factor. 
 
The PK profile of ch14.18 has been determined in adults with melanoma and children with 
neuroblastoma. Although the plasma clearance for both groups of patients follow a two-
compartment model, circulating antibody is cleared from the plasma at a much faster rate 
in children than adults (mean t½β = 66.6 ± 27.4 hours in children versus 123 ± 29 hours and 
181 ± 73 hours in two adult trials, respectively). Maturation of the hepatic and renal 
systems with age is thought to impact on drug metabolism and elimination and could 
account for these differences. In general, the mAb half-life following the first course of 
treatment was longer than the half-lives following subsequent courses in a given patient. 
 
Toxicity:  
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MoAb 14.18, chimeric (CH14.18, NSCs 623408 and 764038) 
 
 The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI 
(except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further 
clarification. Frequency is provided based on 351 patients. Below is the CAEPR for MoAb 14.18, chimeric 
(CH14.18).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
 
 

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

  
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 Adverse Events with Possible  
 Relationship to MoAb 14.18, chimeric (CH14.18) 
 (CTCAE 4.0 Term) 
[n= 351] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
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 
  
 
 
Myelitis5 
  
 
Neuralgia 
 
 Neuralgia (Gr 2) 
 
 
Peripheral motor neuropathy   
 
Peripheral sensory 
neuropathy6 
 
 Peripheral 
sensory 
neuropathy6 (Gr 2) 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Renal and urinary disorders - 
Other (atonic urinary 
bladder)6 
  
 
Urinary retention6 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Bronchial obstruction 
 
  
Cough 
 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Hypoxia 
 
 Hypoxia (Gr 3) 
 
Stridor 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 

  
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 Adverse Events with Possible  
 Relationship to MoAb 14.18, chimeric (CH14.18) 
 (CTCAE 4.0 Term) 
[n= 351] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
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. 
 
3Neurological disorders of the eye including blurred vision, diplopia, cycloplegia, mydriasis, photophobia, optic nerve 
disorder, eyelid ptosis, and fixed pupils have been observed.  
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5Myelitis expressed as transverse myelitis has occurred in patients treated with chimeric MoAb 14.18. Symptoms may 
include weakness, paresthesia, sensory loss, or incontinence. 
 
6Acute urinary retention occurs during therapy and is thought to be due to fluid shifts and narcotic administration that 
accompany ch14.18 administration.  Atonic urinary bladder results in chronic urinary retention (CUR) that requires 
intermittent urethral catheterization days to weeks following chimeric MoAb 14.18 administration.  
 
Adverse events reported on MoAb 14.18, chimeric (CH14.18) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MoAb 14.18, chimeric (CH14.18) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(thrombotic microangiopathy [e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic 
syndrome [HUS]); Bone marrow hypocellular; Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (gallop on exam); 
Cardiac disorders - Other (N-terminal BNP); Chest pain - cardiac; Heart failure; Left ventricular systolic 
dysfunction; Mobitz (type) II atrioventricular block; Myocardial infarction; Palpitations; Pericardial 
effusion; Supraventricular tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain; Hearing impaired 
ENDOCRINE DISORDERS - Endocrine disorders - Other (transient hypoaldosteronism); 
Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Papilledema; Scleral disorder 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Cheilitis; Colitis; Constipation; 
Duodenal obstruction; Dysphagia; Enterocolitis; Esophageal stenosis; Esophageal ulcer; Esophagitis; 
Gastrointestinal disorders - Other (pneumatosis intestinalis); Gastroparesis; Hemorrhoidal hemorrhage; 
Ileus; Intra-abdominal hemorrhage; Lower gastrointestinal hemorrhage; Mucositis oral; Oral pain; Rectal 
hemorrhage; Stomach pain; Typhlitis 

  
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; 
Edema trunk; Fatigue; General disorders and administration site conditions - Other (cold and clammy); 
Hypothermia; Injection site reaction; Irritability; Localized edema; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (cholestasis) 
IMMUNE SYSTEM DISORDERS - Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alkaline phosphatase increased; 
Blood bilirubin increased; Cardiac troponin I increased; Cholesterol high; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; Fibrinogen decreased; GGT increased; INR increased; 
Investigations - Other (isolated glycosuria); Lipase increased; Lymphocyte count increased; Urine output 
decreased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; 
Hyperglycemia; 
Hypermagnesemia; 
Hypernatremia; 
Hypertriglyceridemia; 
Hypoglycemia; 
Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Bone 
pain; Chest wall pain; Muscle weakness lower limb; Myalgia; Neck pain 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Depressed level of consciousness; 
Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Headache; Hydrocephalus; 
Meningismus; Movements involuntary; Nystagmus; Oculomotor nerve disorder; Paresthesia; Seizure; 
Somnolence; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Delirium; Hallucinations; Insomnia; 
Personality change; Restlessness 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Hematuria; Renal 
and urinary disorders - Other (acute renal insufficiency); Renal and urinary disorders - Other (urethritis); 
Renal hemorrhage 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Hematosalpinx; Ovarian hemorrhage; 
Pelvic pain; Penile pain; Prostatic hemorrhage; Spermatic cord hemorrhage; Testicular hemorrhage; 
Uterine hemorrhage; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Apnea; Atelectasis; Bronchospasm; Laryngeal edema; Laryngopharyngeal dysesthesia; 
Laryngospasm; Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumonitis; Pulmonary edema; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (tachypnea); Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Erythema multiforme; Hyperhidrosis; 
Periorbital edema 
VASCULAR DISORDERS – Flushing 
 
Note: MoAb 14.18, chimeric (CH14.18) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
Formulation and Stability:  
Please note that the following information pertains only to the ch14.18 drug product 
manufactured by UTC and supplied by CTEP. The UTC manufactured drug is the only 
supply permitted on this clinical trial.  
 
Ch14.18 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. 
 

  
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Withdraw the required dose of ch14.18 (dinutuximab) from the vial(s) and inject the exact 
volume for the dose (17.5 mg/m2/dose) into a bag containing 100 mL of 0.9% sodium 
chloride. The use of a filter during preparation is not required. The final prepared product 
of ch14.18 (dinutuximab) in NS is stable at room temperature for 24 hours when diluted to 
a concentration between 0.044 mg/mL and 0.56 mg/mL; however, the final dosage form 
should be prepared immediately prior to administration as there is a maximum infusion 
time of 20 hours. The minimum infusion time for the antibody infusion is 10 hours. There 
is no need to keep empty or partially used vials of ch14.18 (dinutuximab). 
 
Lot number information will be collected on the NCI Drug Accountability Record Form 
(DARF) (see the Agent Accountability section below). 
  
Guidelines for Administration:  
See Treatment, Dose Modifications and/or Supportive Care sections of the protocol. 
 
Patient Care Implications:  
Pain is one of the most common adverse effects of ch14.18. It is predominately neuropathic 
and manifests as abdominal cramps or back and extremity pain. Prophylactic administration 
of morphine by continuous infusion is required before and during the infusions of ch14.18. 
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, dexmedetomidine) 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 administration. 
 
Human anti-chimeric antibodies (HACA) may block the effectiveness of therapy by 
prematurely clearing the treatment antibody and limiting further immunotherapy. HACA 
responses may also be associated with immune-complex related adverse events such as serum 
sickness and anaphylaxis. Although no increase in allergic reactions has been observed in 
patients treated with ch14.18 in the presence of HACA, immune complex formation may have 
induced serum sickness in some patients. 
 
Supplier: Manufactured by United Therapeutics and distributed by CTEP, DCTD, NCI. Do 
not use commercial supply.  
 
Agent Ordering: 
NCI supplied agent may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution. Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated. PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained.) The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there 
are several participating investigators at one institution, CTEP supplied investigational 

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

  
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• 
CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov 
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
6.2 
Sargramostim  
 
 
 
 
 
 
 (11/15/2016) 
(Granulocyte Macrophage Colony Stimulating Factor, rhu GM-CSF, rGM-CSF, GM-CSF, 
Leukine®) NSC #613795 
 
 
 
 
 
 
 
 
 
Source and Pharmacology: 
Sargramostim (recombinant human GM-CSF) is a glycoprotein produced in yeast (S. 
cerevisiae) by recombinant DNA technology. rGM-CSF is a hematopoietic growth factor 
which supports survival, clonal expansion, and differentiation of hematopoietic progenitor 
cells. rGM-CSF induces partially committed progenitor cells to divide and differentiate in 
the granulocyte-macrophage pathways. rGM-CSF stimulates the production of monocytes, 
granulocytes, erythrocytes, and sometimes, megakaryocytes in the bone marrow. It also 
induces mature neutrophil and monocytes to increase phagocytosis, superoxide generation, 
ADCC, tumoricidal killing and cytokine production (IL-1 and tumor necrosis factor). 
Recombinant human GM-CSF is a glycoprotein of 127 amino acids characterized by three 
primary molecular masses of 15500, 16800, and 19500 daltons. The amino acid sequence 
differs from the natural sequence by a substitution of leucine at position 23 and the CHO 
moiety may be different from the native protein. After subcutaneous administration of 
sargramostim, peak levels were obtained in 1-4 hours and were detectable at therapeutic 
levels for 12-16 hours post injection. The elimination t½ ranges from 1.5-2.7 hours after SubQ 
or IV administration. 
 
 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-
2 days of 
receiving drug 
Headache, malaise, 
fatigue, rash, pruritis, bone 
pain, myalgia, arthralgia, 
fever, chills 
Abdominal pain, 
weakness, anorexia, 
nausea, local injection 
reactions 
Anaphylaxis, “first dose 
reaction” (hypoxia, dyspnea, 
hypotension, fever, tachycardia, 
diaphoresis, flushing, back pain), 
vomiting, diarrhea, phlebitis, 
SVT, pericardial effusion 
Prompt: 
Within 2-
3 weeks, prior 
to the next 
course 
 
Weight gain 
In high doses: capillary leak 
syndrome: (pleural effusion, 
peripheral edema, ascites, weight 
gain, hypotension), pneumonitis, 
peripheral edema, elevation of 
creatinine, bilirubin and hepatic 
enzymes in patients with pre-
existing renal or hepatic 
dysfunction 
Delayed: 
 
Thrombocytopenia  
 

  
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Any time later 
during therapy 
Unknown 
Frequency 
and Timing:  
Fetal and teratogenic toxicities: It is not known whether sargramostim can cause fetal 
harm or affect reproduction capacity when administered to a pregnant woman. It is 
unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability: 
Sargramostim is available as a lyophilized sterile, white, preservative free powder with 
250 mcg (1.4 million International Units) per vial and as a sterile, preserved injectable 
solution in a 500 mcg/mL (2.8 million International Units/mL) 1 mL vial. The sargramostim 
reconstituted lyophilized vial contains 40 mg/mL mannitol, USP; 10 mg/mL sucrose, NF; 
and 1.2 mg/mL tromethamine, USP, as excipients. The liquid formulation also contains 
1.1% benzyl alcohol (11 mg/mL).Store refrigerated at 2-8°C (36-46°F). Do not freeze or 
shake. 
 
Guidelines for Administration: See Treatment, 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.  
 
Supplier: Commercially available. See package insert for more detailed information. Only 
sargramostim (yeast-derived recombinant human GM-CSF) will be used in this study. The 
Escherichia coli-derived product (molgramostim) will not be used. 
 
CANADIAN SITES 
Sargramostim is not commercially available in Canada. Sites may purchase and import the 
USA commercial supply of Liquid Leukine® (500 µg/1 mL) or Lyophylized Leukine® 
(250 µg/vial) manufactured by Genzyme USA via an International Distributor (Pharma 
Exports LLC; Contact: Pete Bigley, phone: 1-412-885-3700, fax: 1-412-885-8022, email: 
pharexp@aol.com or pbigley@pharma-whitehall.com) under the authority of the 
protocol’s No Objection Letter (NOL).   
 
Consult the product monograph for appropriate reconstitution and infusion preparation 
instructions. The Canadian Senior Medical Officer (SMO)’s office is responsible for 
coordinating the “Fax Back” approval with Health Canada’s Biologics and Genetic 
Therapies Directorate for all lots for use in Canada on behalf of all Canadian sites. and a A 
list of approved lot numbers is  posted on the C17 website (www.c17.ca)  under the protocol 
titled Sargramostim. If an unapproved lot is received from the distributor, quarantine the 
lot and contact the COG Canada Regulatory Affairs Office at 780-492-7064.    
 

  
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Canadian sites must keep a drug accountability log (DAL) recording, at a minimum, 
manufacturer, lot number and expiry date of all formats for all doses dispensed to any 
registered study patient.   
 
Note: Sargramostim may have orders placed and Drug Accountability Logs maintained on 
a multiple protocol basis (Multiple Protocol—Imported Biologic) as long as each protocol 
has an NOL and the DAL clearly indicates which protocol the subject is registered on. 
 
 
 
 
 

  
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
7.1 
End of Therapy & Follow-up 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
 
Observation 
End of 
Therapy 
End of month 8 and 12 
from the start of therapy 
At relapse 
 
Physical exam  
 
 
 
Height, weight 
 
 
 
CBC with diff/platelets  
 
 
 
AST, ALT, bilirubin, albumin 
 
 
 
Electrolytes, creatinine, BUN, 
Ca++, PO4, Mg++  
 
 
 
Performance status 
 
 
 
MUGA or ECHO 
 
 
 
GFR or creatinine Clearance (if 
serum creatinine abnormal for age) 
 
 
 
HACA/Neutralizing antibodies  
Xd 
 
 
Imaging evaluationa (CT or 
MRI/X-ray of primary site; CT 
chest)  
b 
c 
 
Bone scan or whole body PET/CT 
Xb 
Xe 
 
ctDNAf 
X 
X 
X 
 
a CT or MRI with gadolinium or plain X rays for patients who have undergone surgery with 
prosthetic implants that may cause imaging artifact. 
b Can be performed during a 7-day window around the last day of Cycle 5 (See Section 16 for 
details). 
c Can be performed during a 14-day window around the last day of Months 8 and 12 from start of 
protocol therapy (see Section 16 for details). Subsequently imaging is recommended every 
3 months until 2 years off therapy, then per institutional policy. 
d See Section 15.2 for details. 
e. End of month 12 from the start of therapy only. 
f. See Section 15.4 for details. 
 
 

  
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7.2 
Correlative Research Studies 
 
Study 
Pre-
therapy 
 
Cycle 1  Prior to 
Cycle 2 
Prior to 
Cycles 2-5 
End of 
Cycle 
2 
End of 
Cycle 5 
Within 4 
weeks of 
the end of 
Cycle 5 
During first 
12 months 
from 
enrollment 
End of 
therapy and 
end of month 
8 and 12 
from start of 
therapy 
Relapse 
Pharmacokinetics% 
 
X 
X 
 
 
 
 
 
 
 
HACA and 
neutralizing antibody 
testing 
X 
 
 
X 
 
X 
 
 
 
 
Tumor GD2 assay* 
 
 
 
 
 
 
X 
 
 
 
KIR/ FcγR genotypes 
and NKp30 isoforms# 
X 
 
 
 
 
 
 
 
 
 
B7-H6 ligand# 
X 
 
X 
 
 
 
 
 
 
X 
Banking#  
X 
 
 
 
 
 
 
 
 
 
ctDNA# 
X 
 
 
 
X 
X 
 
 
X 
X 
% Pharmacokinetic sampling is mandatory for the first 10 patients enrolled in this trial, and for 
patients enrolled after protocol amendment #2. 
# Patient participation is optional. 
* Tumor tissue for GD2 is recommended to be submitted at enrollment but can be submitted 
anytime until 4 weeks after end of Cycle 5. 
 
For additional details on research studies, see Section 15.0. 
 
 
 

  
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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) Progressive disease 
b) Unacceptable toxicity due to protocol therapy (see Section 9.3) 
c) Refusal of further protocol therapy by patient/parent/guardian 
d) Completion of planned therapy 
e) Physician determines it is in patient’s best interest 
f) Development of a second malignancy 
g) Repeat eligibility studies (if required) are outside the parameters required for eligibility 
(see Section 3.2) 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see 
below). Follow-up data will be required unless patient is taken off study. 
 
8.2 
Off Study Criteria 
a) Death 
b) Lost to follow-up 
c) Patient enrollment onto another COG study with tumor therapeutic intent (eg, at 
recurrence) 
d) Withdrawal of consent for any further data submission 
e) The fifth anniversary of the date the patient was enrolled on this study 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size and Study Duration 
A maximum of 39 evaluable patients are required for this study. Providing for possible 
ineligible and disease control inevaluable patients, the maximum enrollment is expected to 
be 44 patients. Based on enrollment to AOST0221, we expect 1.6 patients per month to be 
enrolled on study. The probability we will enroll 44 patients in 2.5 years after the study is 
opened is approximately 68% and that probability is 96% for an enrollment period of 3 
years. 
 
9.2 
Study Design 
The primary outcome measure is disease control during the first 12 months after 
enrollment. Patients considered evaluable for the primary outcome of disease control will 
be assessed during the first 12 months of enrollment, if the patient’s protocol therapy is 
terminated for reasons other than death or disease progression prior to the completion of 
therapy (‘evaluation period’).  
 
We are not interested in promoting the agent for further investigation if the probability of 
remaining analytic event free at 12 months after enrollment in any particular individual is 
less than or equal to 30%. We will be interested in promoting the agent for further 
investigation if the probability of remaining analytic event free in any particular individual 

  
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is at least 50%. The statistical analysis of AOST0221 demonstrated that the current point 
estimate of the 12 month EFS is 0.2 with an upper 95% confidence bound of approximately 
30%, so the target 12 month EFS probability is associated with an odds ratio of 2.3 
compared with the largest plausible value for 12 month EFS supported by the historical 
data. One group of 39 evaluable patients will be enrolled. The maximum time by which 
the final assessment will be made is when all patients have experienced an analytic event 
or the last patient enrolled is followed for 12 months, whichever occurs first. If 15 or fewer 
of the planned 39 patients in this cohort are confirmed disease free at 12 months after 
enrollment, we will have determined the therapy does not offer sufficient disease control 
to warrant further study. If all 39 patients are enrolled and the true 12 month disease control 
probability is 30%, the therapy will not be considered for further development with 
probability 0.91. If all 39 patients are enrolled and the true 12 month disease control 
probability is 50%, the therapy will be considered for further development with probability 
0.90. Enrollment will be terminated in this cohort with the conclusion that ch14.18 
(dinutuximab) will not be considered for further development if, at any time, more than 
24 patients demonstrate disease progression or die prior to 12 months after study 
enrollment. 
 
9.3 
Methods of Analysis 
Aim 1.1.1: The analysis for the decision rule is described in Section 9.2. Only evaluable 
patients will be considered in the analysis; patients who are not evaluable may be replaced for 
execution of the study decision rule. Only patients who can be confirmed to be free of 
detectable disease 12 months after enrollment, without intervening disease progression, will 
be considered to have experienced 12 month disease control. All other evaluable patients will 
not be considered to have experienced 12 month disease control. 
 
The time to adverse event will be calculated for each evaluable patient as the time from study 
enrollment until disease progression, death, occurrence of a second malignant neoplasm or 
last patient contact, whichever comes first. Patients who experience disease progression, are 
diagnosed with a second malignant neoplasm or die will be considered to have experienced 
an event; all other patients will be considered censored at last patient contact. The probability 
of remaining event-free as a function of time since enrollment will be estimated by the method 
of Kaplan and Meier.31 The complementary log-log transformation of the Kaplan-Meier 
estimate of the 12 month disease control probability will be used to construct confidence 
intervals of that probability.32 
 
Aim 1.2.1: For the secondary objective of characterizing pharmacokinetics of dinutuximab, 
the parameters that will be estimated for each patient who participates in this aspect of the 
trial will be 
. The average and standard deviation of these 
estimates will be reported. In order to obtain the most data possible to identify any changes 
in PK parameters such as Cmax and serum half-life, we will require all patients who enroll 
subsequent to the approval of amendment #2 to consent to pharmacokinetic sampling as 
outlined in the amended protocol.  The equality of the mean of the various PK parameters 
for the original schedule with that of the same parameter on the revised schedule will be 
tested using the Wilcoxon signed rank test.  Since the sample size for these comparison is 
fixed by the number of post-amendment patients to be enrolled, power calculations to 
justify the sample size choice were not executed.  
 
1
1
max
0
2
2
,
,
t
t
C
and AUC


−

  
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Aim 1.2.2: We will monitor each cycle for unacceptable toxicity (UT). We will base the 
definition of UT on Section 9.3.3 of study ANBL0931. Any of the following will be 
considered an “Unacceptable Toxicity”: 
• 
Grade ≥ 4 allergic reaction  
• 
Grade ≥ 4 capillary leak syndrome 
• 
Grade ≥ 3 peripheral motor neuropathy, duration ≥ 2 weeks  
• 
Grade ≥ 4 pain, requiring narcotics/lidocaine AND persisting ≥ 4 days after the end of 
ch14.18 (dinutuximab) infusion 
• 
Anaphylaxis 
• 
Unexpected death where unexpected is defined as death on protocol therapy or within 
30 days of the last dose of protocol therapy that is not possibly, probably, or likely 
related to disease. 
 
The analytic unit for toxicity monitoring will be the patient-cycle. Any cycle in which the 
patient receives at least 85% of planned protocol therapy, or in which a UT is observed will 
be considered a reporting period in which a toxicity event has occurred. All other evaluable 
RPs will be considered free of a toxicity event.   
 
We will use a Bayesian rule to monitor for excessive toxicity. We will assume a beta prior 
distribution with α=0.4 and =1.6. If this posterior probability of the chance of UT is at 
least 30% exceeds 80%, we will identify the regimen to the COG DSMC, Bone Tumor 
leadership and CTEP as associated with a toxicity profile that may require modification of 
the regimen. Descriptive analyses of this safety information will be performed and will 
include the incidence of adverse events, severe adverse events, serious adverse events, and 
fatal adverse events. Type, frequency, and severity of laboratory abnormalities will also be 
analyzed. 
 
Examples of situations in which this rule will indicate unacceptable toxicity have been 
noted and are presented below: 
 
Number of 
Toxicity-
Evaluable Cycles 
Number 
of 
Cycles 
with 
Unacceptable 
Toxicity Observed 
P (pUnacceptable Toxicity > 
0.30|Data) 
5 
3 
0.95 
10 
4 
0.90 
15 
5 
0.86 
20 
6 
0.83 
25 
7 
0.80 
30 
9 
0.88 
35 
10 
0.87 
40 
11 
0.85 
 
Feasibility of delivery of treatment according to protocol will be evaluated in every eligible 
patient who receives at least one dose of protocol therapy. Such patients will be designated 
as feasibility-evaluable patients. Any feasibility-evaluable patient: (1) who has protocol 
therapy terminated because of unacceptable toxicity (see Section 8.1 (b)); (2) who dies on 
protocol therapy or within 30 days of the termination of protocol therapy for a cause 
considered possible, probably or likely related to protocol therapy will be considered have 
experienced a feasibility-event. 

  
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At any time, if more than 6 individuals experience a feasibility-event, we will identify the 
regimen to the COG DSMC, Bone Tumor leadership and CTEP as associated with a 
feasibility profile that may require modification of the regimen. If 39 patients are enrolled 
and the true feasibility-event rate is 0.10, the rule will determine the therapy to have an 
excessive feasibility-event rate with probability 8.9%. If 39 patients are enrolled and the 
true feasibility-event rate is 0.25, the rule will determine the therapy to have an excessive 
feasibility-event rate with probability 89%. 
 
9.4 
Evaluability for Disease Control 
Any eligible patient who receives at least one dose of ch14.18 (dinutuximab) will be 
considered evaluable for disease control. 
 
9.5 
Evaluability for Toxicity  
Only eligible patients will be considered in the assessment of toxicity. The analytic unit for 
unacceptable toxicity monitoring will be the patient-cycle. Any cycle in which the patient 
receives at least 85% of planned protocol therapy, or in which a UT is observed will be 
considered a reporting period in which a toxicity event has occurred. All other evaluable 
RPs will be considered free of a toxicity event.   
 
9.6 
Statistical Considerations for Exploratory Aims 
 
Aim 1.3.2: We expect at least 70% of patients will submit a peripheral blood 
specimen prior to the start of chemotherapy for the assessment of KIR, NKp30 and 
FcγR genotype. Only eligible patients with evaluable KIR and/ or FcγR results will 
be considered in this analysis. The FcγR genotype result characterized as H/R, R/R 
or H/H will be considered as the predictor variable of interest. KIR/KIR ligand 
mismatch will be categorized as present or absent. Presence of the 
immunosuppressive isoform NKp30c will be categorized as present or absent. The 
outcome measure will be DC success (Yes v. No). Logistic regression using the 
categorical FcγR result will be fitted to the data. The fitted coefficients from the 
logistic regression, and the p-value for the test of the hypothesis of no relationship 
between FcγR result and probability of DC success will be used to characterize 
this exploratory analysis. Logistic regression using the categorical KIR/KIR ligand 
mismatch (present v. absent) will be fitted to the data. The fitted coefficients from 
the logistic regression, and the p-value for the test of the hypothesis of no 

  
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relationship between FcγR result and probability of DC success will be used to 
characterize this exploratory analysis. 
 
The analytic plan for circulating ligand B7-H6 entails quantifying the change in 
the ligand between enrollment and the end of the first cycle of therapy. 
Additionally, serum for the evaluation of ligand levels at relapse will be requested. 
The primary analytic endpoint for this aim will be the change in B7-H6 levels 
between enrollment and the end of the first cycle. The change will be estimated by 
the average intra-patient change and the variance will be estimated by the variance 
of the intra-patient differences. Since some enrolled patients will not be assessable 
at the end of the first cycle of treatment because the patient will have been removed 
from protocol treatment prior to that time, and that this loss likely will be at most 
10%, we expect at least 63% of patients will provide samples for this goal. 
 
Aim 1.3.3: No specific statistical plan currently exists for the banking aim of the 
study. Individual statistical plans will be developed for future studies answering a 
specific question using these banked tumor specimens. 
 
HACA will be determined using a sample of blood taken before the start of each 
cycle and within 30 days after the end of Cycle 5. All patients will contribute data 
from each cycle for the qualitative and quantitative evaluation of human anti-
chimeric antibody (HACA). At each time point, the optical density of the ELIZA 
bridging assay will be calculated. Patients will be identified as HACA positive if 
there is any optical density above background levels and the quantitative level of 
HACA activity will be taken as the optical density (OD) at a wavelength of 405 or 
492 nm. The number of patients who are HACA positive divided by the number 
of patients with a successful HACA assay at each time point will be used to 
quantify the fraction of patients displaying HACA activity. We will also graph the 
average OD of the ELIZA assay over all patient at each time point, where time 
point is the number of days from the start of treatment with the study agent. For 
patients found to be positive for HACA, neutralizing antibodies will also be 
assessed in the same blood sample. 
 
Serial plasma samples from consenting patients will be stored at the BPC for future 
studies to evaluate the utility of ctDNA detection in osteosarcoma. Separate 
biology proposals for access of these samples for the conduct of such studies will 
be required and reviewed by the bone tumor committee and statistical 
considerations for specific studies will be provided as part of these proposals. 
 

  
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9.7 
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 
0 
0 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
1 
6 
0 
0 
7 
White 
14 
20 
1 
1 
36 
More Than One Race 
0 
0 
0 
0 
0 
Total 
16 
26 
1 
1 
44 
 
This distribution was derived from AOST0221. 
 
 
10.0 
EVALUATION CRITERIA 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 4.0 can be downloaded 
from the 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 v4.0’ is understood to represent the most current version of CTCAE 
v4.0 as referenced on the CTEP website (ie, v4.02 and all subsequent iterations prior to version 
5.0). 
 
10.2 
Disease Evaluation  
For the purposes of this study, patients will be evaluated for disease progression following 
Cycle 2, Cycle 5 and then at months 8 and 12 from the start of therapy.  
  

  
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Disease progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).33 
 
The appearance of one or more new lesions is considered progression. Please see 
Section 16.1.1 for further details. 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Certain adverse events must be 
reported in an expedited manner to allow for timelier monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated 
with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Application (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply. 
• 
Concurrent administration: When an investigational agent is used in 
combination with a commercial agent, the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration: When a study includes an investigational agent 
and a commercial agent on the same study arm, but the commercial agent is 
given for a period of time prior to starting the investigational agent, 
expedited reporting of adverse events that occur prior to starting the 
investigational agent would follow the guidelines for commercial agents. 
Once therapy with the investigational agent is initiated, all expedited 
reporting of adverse events follow the investigational agent reporting 
guidelines. 
 

  
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11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, 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 
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  
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.  
 
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. 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: A disorder characterized by cessation of life during the first 
28 days of life.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5.  

  
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o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other 
(Progressive Disease)” under the system organ class (SOC) of the same 
name. Evidence that the death was a manifestation of underlying disease 
(e.g., radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
 
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. 
 
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. 
 
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.” 
 
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 301-230-0159. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.4.6.1 Pregnancy 

  
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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 
(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 Fetal Death 
Fetal death, defined in CTCAE as “A disorder characterized by death in 
utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation”, needs to 
be reported expeditiously, as Grade 4 “Pregnancy, puerperium and 
perinatal conditions - Other (pregnancy loss)”. Do NOT report a fetal 
death as a Grade 5 event since CTEP-AERS recognizes any Grade 5 
event as a patient death. 
 
11.4.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” needs to be 
reported expeditiously, as Grade 4 “General disorders and 
administration - Other (neonatal loss)” when the death is the result of 
a patient pregnancy or pregnancy in partners of men on study. Do 
NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men on study as a Grade 5 event since CTEP-
AERS recognizes any Grade 5 event as a patient death.  
 
11.5 
Reporting Requirements for Specialized AEs 
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. 
 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  

  
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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. 
 
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 
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. 
 
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.   
 

  
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11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting and are located on 
the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted 
electronically 
to 
NCI 
via 
CTEP-AERS 
at: 
https://eapps-
ctep.nci.nih.gov/ctepaers.  
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to 301-897-
7497.  
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site.   
 
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 
an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE requires 
expedited reporting within 24 hours.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the 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: 301-230-0159 (back-up: 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 

  
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days of learning of the AE.  
 
1SAEs that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
• 
All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  
 
 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
• 
Grades 1-4 myelosuppression (anemia, neutropenia, thrombocytopenia) do not 
require expedited reporting.  
• 
Grade 1-4 fever does not require expedited reporting 
• 
Grades 1-2 AST/ALT elevations do not require expedited reporting. 
• 
Grade 1-2 visual changes or Grade 3 visual changes that resolve within 14 days 
of onset do not require expedited reporting 
• 
Grade 1-3 hypotension does not require expedited reporting 
 
11.11 Reporting of Adverse Events for Commercial Agents – CTEP-AERS Abbreviated 
Pathway 
 
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this study. 
Commercial reporting requirements are provided in Table B.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy With a Commercial Agent or Within 30 Days1 
 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, Probable, Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial agent, 
regardless of attribution.  Any death that occurs more than 30 days after the last dose of 
treatment with a commercial agent that can be attributed (possibly, probably, or definitely) to 
the agent and is not due to cancer recurrence must be reported via CTEP-AERS. 
 
 
11.12 Routine Adverse Event Reporting 
 

  
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Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all toxicities 
reported via CTEP-AERS and all Grade 3 and higher Adverse Events. In addition, the 
following AEs will require routine reporting: Grade 2 allergic reactions, hypotension, 
capillary leak syndrome, dyspnea, cytokine release syndrome and serum sickness. 
 
 
12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (eg, termination, dropping 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 
NCI/DCTD Standard Language to Be Incorporated into All Protocols Involving 
Agent(s) Covered by a Clinical Trials Agreement (CTA), a Cooperative Research and 
Development Agreement (CRADA) or a Clinical Supply Agreement, hereinafter referred 
to as Collaborative Agreement: 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 

  
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(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”): 
 
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. 

  
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6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication. Collaborator(s) will have 30 
days from the date of receipt for review. Collaborator shall have the right to request 
that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
 

  
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13.0 
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 (except 
where explicitly prohibited within the protocol). 
 
See COG Surgical Guidelines for osteosarcoma at: 
https://members.childrensoncologygroup.org/_files/Disc/surgery/handbooks/OsteoBoneHandboo
k.pdf 
 
Please note: banking of tumor samples is encouraged from patients who undergo biopsy or 
resection of suspected metastatic disease recurrence while on protocol therapy or during the first 
12 months from enrollment. 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
All patients enrolling on this protocol require institutional histological confirmation of 
osteosarcoma at the time of original diagnosis. In addition, pathologic confirmation of metastatic 
recurrence of osteosarcoma in at least one of the resected lung nodules is required.  
 
Please note: At enrollment, all patients must have adequate tumor specimen available for submission 
as detailed in Section 15.1. Submission of tissue for banking of tumor samples is strongly 
encouraged (see Section 15.4 for details). 
 
Autopsy  
In the event of patient death on AOST1421, a complete unrestricted postmortem examination is 
strongly encouraged.  
 
COG sites: For patients enrolled on AOST06B1, tissue submission at autopsy is requested. (See 
AOST06B1 protocol.) 
 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
15.1 
Tumor GD2 Expression (Mandatory Participation) 
Submission of a formalin-fixed, paraffin-embedded (FFPE) sample of tumor 
(tissue block or 4 unstained slides) from the most recent surgery is mandatory. The 
tumor material is strongly recommended to be submitted at enrollment but can be 
submitted up until 4 weeks from the last cycle of protocol therapy. The paraffin 
block/slides will not be returned to the institution. 
 
Note: Although FFPE tissue is preferred, tumor tissue can be provided frozen 
instead.  
 

  
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FFPE samples and slides can be stored indefinitely at room temperature prior to 
shipment. 
Frozen tissue should be frozen (at -70ºC or colder) until shipped on dry ice. 
 
All tumor material must be labeled with the following information: 
• 
GD2 assay 
• 
COG patient ID number 
• 
specimen type (P for primary or M for metastatic) 
• 
surgical pathology ID (SPID) number 
• 
block number  
• 
collection date 
 
Please include a COG Specimen transmittal form and the corresponding pathology 
report with each shipment.  
 
FFPE samples can be batched and shipped at room temperature. Instructions to 
hold and ship tissue that is frozen are described below.  
 
The BPC will provide a specimen procurement kit upon request. This kit is for the 
shipment of frozen specimen submitted to the BPC. If you are shipping 
ambient specimens (blocks or slides),  you must use your own shipping container 
and supplies. Blocks and slides are shipped using the institution’s courier account 
or regular mail. 
 
Kits are ordered via the BPC Kit Management application. To access the 
application click on the ‘Biopathology Center Application’ link on either the 
Protocol or the CRA Home Page of the COG web site. On the Biopathology Center 
Applications page, select the BPC Kit Management link to enter the Kit 
Management application. 
 
The Biopathology Center provides Specimen Procurement Kits to institutions in 
the US and Canada. Institutions outside of the US and Canada are expected to 
provide their own supplies for submission of samples. 
 
Please note that tissue sample submissions to the BPC for AOST1421 must 
include the following documentation: 
1. Institutional pathology report 
2. Institutional operative report (Can be provisional as long as final report is sent 
when available) 
3. COG Generic Specimen Transmittal Form 
 
Snap frozen tissue must be sent on dry ice. Using at least 4 lbs. total, layer ½ 
the dry ice in the bottom of the compartment until it is approximately one third 
full. Place the frozen specimens on top of the dry ice. Cover the specimens with 
dry ice until the compartment is almost completely full. Secure the foam lid. 
Remember to include the COG Specimen Transmittal Form, pathology report and 
operative report with each shipment. 
 

  
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Close the outer lid of the kit and tape with filament or other durable packing tape. 
COG sites will access the Kit Management application to print a FedEx shipping 
label. Non-COG sites should contact the BPC by phone (800-347-2486) or email 
(BPCBank@nationwidechildrens.org) to request a shipping label. A blank label 
is provided in the kit to use when printing the shipping label. Attach the label to 
the top of the kit. Complete the dry ice label (UN 1845) and secure both this 
label and the Exempt Human Specimen label to the side of the box. A shipping 
label will only be provided when frozen tissue is submitted. Blocks and 
slides must be shipped using the institution’s courier account or regular 
mail. 
 
Send samples to: 
 
Biopathology Center  
Nationwide Children’s Hospital  
Protocol AOST1421 
700 Children’s Drive, WA1340*  
Columbus, OH 43205 
Phone: (614) 722-2865 
Fax: 
(614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
*Be sure to include the room number. Packages received without the room number 
may be returned to the sender. 
 
Specimens should be shipped Monday through Thursday for delivery on 
Tuesday through Friday.  Do not ship specimens the day before a holiday. 
 
The BPC will forward tumor tissue specimen for the GD2 assay to  
 
Cambridge Biomedical 
1320 Soldiers Field Road 
Boston, MA 02135 
 
Immunohistochemistry will be performed on whatever osteosarcoma tissue is 
received for GD2 expression.  
 
If the patient consents, any specimens left over after the required GD2 expression 
tests are performed will be banked at the BPC for future research studies. 
Left-over tumor material must be labeled with: 
• 
the patient’s COG patient ID number 
• 
specimen type (primary or metastatic) 
• 
collection date  
 
Include the surgical pathology ID (SPID) number and block number when 
submitting a block or slides.  
 

  
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15.2  
Ch14.18 (Dinutuximab) Pharmacokinetics and HACA sampling  
The first 10 evaluable patients and patients enrolled after protocol amendment #2 are 
required to provide serial blood samples for the assessment of ch14.18 (dinutuximab) 
serum concentrations. Providing blood samples for HACA testing is mandatory for all 
patients. 
 
Blood will be drawn during Cycles 1 and 2 for the PK study. Timing of 
pharmacokinetic sampling will be as follows:  
 
Cycle 
Day 
Time 
1 
 
4* 
• 
Prior to infusion of ch14.18 (dinutuximab) 
• 
4-6 hours after the start of the first 10 hour infusion 
• 
Within one hour of the end or at the end of the day 4 
infusion 
 
7* 
• 
4-6 hours after the start of the 4th 10 hour infusion  
• 
Within one hour of the end or at the end of the day 7 
infusion 
• 
4-8 hours following the termination of infusion# 
• 
4-10 days following the termination of infusion 
 
2 
0 or 1 
• 
Prior to the start of Cycle 2. 
*Note: if there is any change in infusion rate during an ongoing infusion, 
please record the date, time and new infusion rate. If there is an interruption 
during a planned infusion, please record the stop/start date and time.  
 
Sampling for the HACA study will be prior to ch14.18 (dinutuximab) infusion for 
Cycles 1-5 and can occur anytime between Day 1 and Day 4, and during the end-
of-therapy visit after Cycle 5.  
 
15.2.3.1 Pharmacokinetics Study 
1. Collect approximately 2 mL of blood in preservative-free heparin 
(green top tube) and mix thoroughly. Record the calendar date and 
exact time of the blood draw on the AOST1421 PK/HACA Specimen 
Transmittal Form. 
2. Within 12 hours of collection, centrifuge the specimen for 10-
15 minutes at 3000 rpm. 
3. Label 2 cryovials as detailed below in Section 15.2.3. One tube will 
serve as a backup specimen for storage at the clinical site. 
4. Pipette approximately 0.5 mL plasma aliquots into each cryovial. 

  
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5. Freeze samples immediately at < -10°C until shipment to the 
bioanalytical laboratory on dry-ice. 
NOTE: Blood samples can be stored at 2-8ºC for up to 72 hours after drawing, and 
then be processed as described above. 
 
15.2.3.2 HACA study  
1. Collect approximately 2 mL of blood in preservative-free heparin 
(green top tube) and mix thoroughly. Record the calendar date and 
exact time of the blood draw on the AOST1421 PK/HACA Specimen 
Transmittal Form. 
2. Within 12 hours of collection, centrifuge the specimen for 10-
15 minutes at 3000 rpm. 
3. Label two 2 mL cryovials as detailed below in Section 15.2.3. One 
tube will serve as backup specimen for storage at the clinical site. 
4. Pipette approximately 0.5 mL plasma aliquots into each cryovial. 
5. Freeze samples immediately at < -10°C until shipment to the 
bioanalytical laboratory on dry-ice. 
 
Each tube should have a freezer-safe label with the following information: 
• 
AOST1421  
• 
COG patient ID number  
• 
Sampling date and time  
• 
Cycle and day of therapy blood was drawn 
• 
Test type (PK or HACA) 
 
NOTE: Samples should be batched and shipped once all specimens for a patient 
have been collected. The backup specimens will be retained at the site and 
transported later if necessary. 
 
All shipments must be accompanied by a completed AOST1421 PK/HACA 
Specimen Transmittal Form (provided in the CRF packet on the protocol 
webpage). Please note on the form any specimens that are hemolyzed. 
 
Package the shipping tubes to prevent breakage and contamination in Styrofoam 
boxes containing a generous supply of dry ice that will allow for 3 days in transit. 
 
Contact the bioanalytical laboratory prior to the shipment of specimens, by phone, 
fax or email (details below). An advanced electronic copy of the AOST1421 
PK/HACA Specimen Transmittal Form should also be provided to the laboratory. 
In addition, a copy of the completed AOST1421 PK/HACA Specimen Transmittal 
Form must be uploaded into RAVE. 
 
When possible, samples should be shipped overnight, on dry ice, on a Monday, 
Tuesday or Wednesday via Federal Express Priority Overnight to: 
 
BioAgilytix Labs 
2300 Englert Drive  
Durham, NC 27713 

  
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Phone: (919) 287-1538 
Fax: 
(919) 381-6099 
Email: Krystal.alligood@bioagilytix.com 
 
15.3  
Determination of FcR and Kir Genotype, NKp30 Isoforms and its Circulating Ligand, B7-
H6  
The 10 mL blood sample in an EDTA tube will be used for FcR and Kir 
genotyping, NK cell receptors, NKp30 SNP determination and detection of its 
ligand, B7-H6, in plasma. Blood samples in PAXgene™ tubes will be used for 
NKp30 isoform determination. 
 
If there is an inadequate amount of blood for both the KIR/FcR study and the 
NKp30 isoforms/B7-H6 study, the blood in PAXgene™ tubes for NKp30 isoform 
study will be omitted. 
 
Within 1 week prior to the first sargramostim injection, collect the following: 
• 
10 mL blood (7 mL if < 12 kg) in an EDTA-containing (purple top) tube 
• 
5 mL blood divided into two PAXgene™ Blood RNA Tubes. Note: If 
PAXgene™ Blood RNA Tubes are not available, one EDTA-containing 
(purple top) tube can be used instead. 
 
In addition, prior to the start of Cycle 2 therapy and at relapse, collect 5 mL blood 
in an EDTA tube for B7-H6 measurement.  
 
Each tube should be labeled with: 
• 
AOST1421 
• 
COG patient ID number 
• 
specimen type (blood) 
• 
date blood was drawn 
 
NOTE: EACH specimen should be sent with a completed COG Specimen 
Transmittal form. 
 
Freshly-obtained samples should be sent at room temperature. Care should be 
taken to ship the blood samples with ice packs in the summer to prevent 
overheating and with extra insulation in the winter to prevent freezing.  
 
Samples should be shipped Monday through Thursday only. It is recommended 
that the patient is seen between Monday and Thursday of the week before starting 
GM-CSF on Friday of that week to facilitate adequate sample collection.   
 
Samples should be sent via Priority Overnight shipping using the COG Courier 
account referenced in the usage guidelines (refer to 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf) 
to:  
 

  
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Alice Yu, MD, PhD (Attention Jenna Mielke or Dr. Diccianni) 
UCSD Medical Center 
Clinical Teaching Facility, B-114* 
212 W. Dickinson Street 
San Diego, CA 92103-8447 
Phone (619)-543-2438 (Lab) 
Fax: 
(619)-543-5413 (Lab) 
E-mail: yulab@ucsd.edu 
Lab contact: Jenna Mielke 
 
*Be sure to include the room number. Packages received without the room number 
may be returned to sender. 
 
15.4 
Circulating Tumor DNA (ctDNA) 
IMPORTANT: If the patient has consented to ctDNA study, tubes MUST be 
ordered immediately following patient enrollment to allow time for 
processing and shipment from Streck. See the Streck tube order form in the 
CRF packet. The form can be completed and sent by email, please follow the 
instructions provided on the form. 
 
Peripheral blood samples should be obtained as follows:  
• 
Blood should be collected in Streck Cell-Free DNA BCT tubes  
• 
For patients > 5 kg collect 20 mL (10 mL per tube x 2 tubes)  
• 
For patients > 2 kg but < 5 kg collect 10 mL (one tube)  
• 
For patients < 2 kg research samples will not be collected  
In all cases, blood draw volumes should strictly adhere to institutional limitations, 
taking other blood draws into consideration. However, if a reduction in volume is 
required, samples should be collected in 10 mL increments (ie. 0, 10, or 20 mL 
should be collected such that each Streck Cell-Free DNA BCT is completely 
filled). 
 
If patient consents for this biology study, peripheral blood will be required at the 
following time points: 
• 
Study entry (within 7 days prior to treatment start) 
• 
Cycle 2 any time prior to the infusion of Day 4 Ch14.18 
• 
At time of tumor evaluations at the end of Cycle 2 and 5 of therapy  
• 
At Month 8 and 12 from start of protocol therapy 
• 
At time of relapse 
 
Established institutional guideline should be followed for blood collection via 
vascular access devices. Heparin should be avoided in pre-collection flush 
procedures. If therapeutic heparin dosing contamination is a possibility, 
venipuncture is recommended as a first choice collection method. If a Streck Cell-
Free DNA BCT tube immediately follows a heparin tube in the draw order, we 

  
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recommend collecting an EDTA tube as a waste tube prior to collection in the 
Streck Cell-Free DNA BCT. 
 
For patients who do not have indwelling catheters, blood should be collected via 
venipuncture. To guard against backflow, observe the following precautions: 
• 
Keep patient’s arm in the downward position during the collection 
procedure. 
• 
Hold the tube with the stopper in the uppermost position so that the tube 
contents do not touch the stopper or the end of the needle during sample 
collection. 
• 
Release tourniquet once blood starts to flow in the tube, or within 2 
minutes of application. 
• 
Fill tube completely. 
• 
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results.  
 
Tubes must be labeled with the patient’s COG patient ID number, BPC number, 
specimen type (blood), and date.  
 
Specimen should be shipped by FedEx Priority Overnight at room temperature to 
the COG Biopathology Center for immediate separation, extraction, and storage of 
plasma and cellular DNA. Samples should be shipped from Monday through 
Friday for Tuesday through Saturday delivery. If blood is collected in the Streck 
tube over the weekend or on the day before a holiday, the sample can be stored at 
room temperature until shipped on the next business day.  
 
Ship to the COG Biopathology Center (BPC) using a Federal Express shipping 
label obtained through the BPC Kit Management application. See Section 15.1.3 
for instructions on accessing the BPC Kit Management application.  
 
A COG Generic Specimen Transmittal form must be included with each shipment. 
The time point listed on the transmittal form must be written on the transmittal 
form exactly as listed in Section 15.4.3. 
 
Ship specimens to the following address: 
 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol AOST1421 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: 
(614) 722-2865 
 
*Be sure to include the room number. Packages received without the room 
number may be returned to the sender. 
 

  
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For questions about this correlative study, please contact the study chair, Dr. 
Hingorani. For questions about sample processing and shipping, please contact the 
BPC directly. 
 
Serial plasma samples from consenting patients will be stored at the BPC for future 
studies to evaluate the utility of ctDNA detection in osteosarcoma. 
 
15.5  
Banking of Tumor Tissue 
Submission of additional tumor tissue to be banked for future research studies is strongly 
encouraged. Tumor tissue obtained as a result of biopsy or resection of a suspected disease 
recurrence site prior to therapy and during the first 12 months from the time of enrollment 
is requested for banking. Snap frozen, blocks or slides (at least 10 cut sequentially from 
the same block) will be accepted. 
Note: this is a separate submission from the required submission of tumor samples for the 
GD2 assay. 
 
Sample Labeling and Shipping 
Label biology specimens with: 
• 
the patient’s COG ID number  
• 
specimen type (primary or metastatic) 
• 
collection date.  
Include the surgical pathology ID (SPID) number and block number in the labeling when 
submitting a block or slides. 
 
A specimen procurement kit may be requested from the BPC for shipping frozen tissue. 
See Section 15.1.3 for shipping details.  
 
Include a transmittal form, pathology report and operative report with each shipment. 
 
 

  
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16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
16.1 
Required Osteosarcoma Imaging 
 
Site 
Anatomic Imaging 
Functional 
Imaging 
Timing 
Primary tumor 
site 
CT or MRI with 
gadolinium or plain 
X rays for patients 
who have undergone 
surgery with 
prosthetic implants 
that may cause 
imaging artifact. 
 
1. Within 
6 
weeks 
prior 
to 
enrollment*  
2. During a 7-day window around 
the last day of Cycle 5  
3. During a 14-day window around 
the last day of months 8 and 12 
from start of protocol therapy 
Chest 
CT 
 
1. Baseline 
post-operative 
CT 
within 
7 
days 
prior 
to 
enrollment** 
2. Between Day 24-28 of Cycle 2 
3. During a 7-day window around 
the last day of Cycle 5 
4. During a 14-day window around 
the last day of Months 8 and 12 
from start of protocol therapy  
Whole body 
 
MDP bone 
scintigraphy  
 
OR 
 
FDG-
PET/CT  
 
1. Within 
6 
weeks 
prior 
to 
enrollment 
2. During a 7-day window around 
the last day of Cycle 5 
3. During a 14-day window around 
the last day of Month 12 from 
start of protocol therapy 
* Repeat tumor imaging if necessary. 
** For patients with bilateral lung metastases, who undergo consecutive lung 
surgeries for metastasectomies, baseline post-operative CT chest should be 
performed after the last surgical procedure performed to achieve complete 
remission. 
 
NOTE: Patients with new lesions or progression of any pre-existing small 
lesions, on any follow up imaging: if these lesions do not unequivocally 
represent tumor progression as per RECIST 1.1 (e.g., very small size; positive 

  
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bone scan or PET scan without associated CT/MRI changes) then patients 
should undergo confirmatory imaging 4 weeks after the initial evaluation 
demonstrating a confirmed progression (additional imaging time point) or 
histological confirmation of progression by biopsy or surgical resection. 
 
CT and MRI guidelines are available on the COG Member site at: 
http://members.childrensoncologygroup.org/_files/reference/RefMaterial/Diagno
sticImagingGuidelines_MRI&CT.pdf 
If possible, MRI should include diffusion weighted scans (parameters e.g. 
(TR/TE/b-value=6400ms/55ms/0, 600-800). Apparent diffusion coefficient 
(ADC) maps should be generated and submitted for central review. Tumor ADC 
values will be calculated for different time points before and after therapy. 
 
Two-view plain radiographs of the primary tumor site can be performed for 
patients who have a metallic prosthetic implant instead of CT or MRI if a 
significant metal artifact would occur by those imaging modalities. If there is 
suspicion for tumor recurrence on plain radiographs, CT or MRI should be 
performed to confirm tumor recurrence.   
 
MDP bone scintigraphy  
• 
Whole body bone scintigraphy should be performed and include planar 
images of the skeleton, including anterior and posterior views of the axial 
skeleton. Anterior and/or posterior views should be obtained of the 
appendicular skeleton. 
• 
Delayed (skeletal phase) images should be performed in all cases with flow 
and blood pool images as per local custom and clinical need. 
• 
Dose Administration: Dose administered should be according to standard 
weight-based protocols. Injection site should be away from lesion extremity 
or contralateral extremity if flow imaging is to be performed. Three-phase 
imaging is not required unless warranted by symptoms for a focal lesion to 
assess hyperemia. 
• 
Imaging Parameters: Whole body delayed imaging is acquired 2-3 hours 
after injection of the radiopharmaceutical. Spot views should be acquired of 
specific sites of symptoms or of any sites of abnormality as warranted by the 
whole body views. 
• 
Single-photon emission computed tomography (SPECT) is recommended, 
but not required, particularly in cases with suspicion of lung metastases. 
• 
SPECT Imaging: SPECT should be performed of the lesion site. SPECT 
imaging should be performed as recommended by the camera manufacturer. 
Typical acquisition and processing parameters are 360° circular orbit, 60–
120 stops, 64 ´ 64 ´ 16 or greater matrix, and 10–40 s/stop. An equivalent 
total number of counts should be acquired if continuous acquisition is used. 
• 
Special Consideration: Imaging of pelvis can be difficult due to overlying 
bladder activity. To lessen this problem, repeat imaging can be performed 
immediately after patient voiding. Bladder catheterization may be used, but 
should be reserved for patients in whom visualization of the pelvis is 

  
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essential. For SPECT acquisition of the pelvis: Single or multiple rapid (5-
10 min/acquisition) SPECT acquisition(s) are preferred to avoid artifacts 
caused by changing activity in the bladder. Bladder artifacts are exaggerated 
in the plane in which the SPECT acquisition begins and ends. Beginning 
SPECT acquisition with the camera heads in the left and right lateral 
positions (for dual-head camera) or posterior position (for single-head 
camera) will help reduce bladder filling artifact.  
 
18FDG PET or bone scan is required at baseline and following Cycle 5 and end of 
months 8 and 12. It is recommended to obtain MRI or CT scan of any lesion 
positive on bone or 18FDG PET scan.  
 
Patient Guidelines 
The patient should fast for at least 4 hours prior to injection of FDG. FDG PET 
imaging may follow a MUGA study on the same day, or FDG PET imaging may 
be performed on the day preceding this study. Plasma glucose should be checked 
and, if the patient is hyperglycemic (plasma glucose > 250 mg/dL), appropriate 
treatment with small doses of insulin may be given to bring the plasma glucose 
into the normal range prior to FDG PET imaging. However, insulin administration 
may result in excessive muscle uptake of FDG and consequent tumor non-
visualization. If possible, the study should be postponed until the plasma glucose 
is under better control. 
 
Good hydration is required, as the primary route of FDG excretion is renal. The 
patient should drink water or receive intravenous fluids (not containing dextrose) 
after FDG injection to promote urinary excretion of the radioactive substrate. After 
injection, the patient must be kept in a resting state for 45-60 minutes prior to 
imaging. The patient should empty the bladder immediately prior to imaging. 
 
Imaging Technique 
The technique will vary by local institutional guidelines. In general, FDG is 
administered intravenously at a dose of 0.125-0.200 mCi/kg or by algorithms that 
adjust the dose by body surface area, with a minimum total dose of 2.0 mCi and 
maximum total dose of 20.0 mCi.  
 
The body should be imaged from the top of the ears to the bottom of the feet. If 
there is suspicion of involvement of the skull or skull contents, the volume that is 
imaged should be expanded.  
 
Imaging with a dedicated positron emission tomograph/computed tomography 
(PET/CT) camera is standard.   
 
The length of time needed to perform head to toe CT will depend on the patient’s 
height but will be approximately 45 seconds. Contiguous axial images should be 
obtained at 5 mm thickness using 90 mA and 120 Kv and adjusted for local 
institutional protocol. No oral or IV contrast is required but either or both are 
permissible and may be of benefit in cases where intraabdominal or pelvic 
pathology is a specific concern. With regard to patient positioning, the arms can 

  
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be placed in a comfortable position at the patient’s sides as long as they fit into the 
field of view. If the patient is large it may be necessary to lay the arms across the 
abdomen and hold in position with a stabilizing device. 
 
Study Processing 
The FDG PET study is processed for display by an iterative reconstruction 
algorithm. FDG activity should be corrected for attenuation, scatter, and 
radioactive decay. Attenuation correction is necessary, as apparent uptake will 
otherwise vary with depth of the lesion in the body and the nature of surrounding 
tissues. The procedure used for attenuation correction should be recorded. The 
level of tumor uptake is assessed subjectively by visual inspection and semi-
quantitatively by determination of standardized uptake values (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. SUVs 
should be calculated for lesions known to be 1.2 cm or larger in diameter. Smaller 
lesions may have underestimated SUVs due to partial volume averaging effects at 
typical scanner resolutions (0.6-1.2 cm). 
 
To calculate the SUV, a region of interest (ROI) should be carefully drawn around 
as much of the area of elevated FDG uptake as can be done. The SUV should be 
calculated as SUVBSA = ROI activity concentration (nCi/cc) x BSA / injected 
activity (nCi). SUVMAX is obtained by determining the activity of the pixel with 
the highest FDG uptake. 
 
The BSA is calculated from body mass (kg) and height (cm) using an appropriate 
algorithm. The SUVBSA for each measured lesion should be recorded and the 
technique for assessing SUVBSA should be consistent on follow-up studies. 
 
 
  
 

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

  
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Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the AOST1421 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
▪ Click on the Protocols tab in the upper left of your screen 
▪ Click on the COG link to expand, then select trial protocol AOST1421. 
▪ Click on the Site Registration Documents link 
 
Requirements for AOST1421 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB)  
• 
Verification that training has been completed by appropriate institutional personnel.  
 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
 
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 1100 
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: 
 
Check the status of your site’s registration packets by querying the RSS site registration status page 
of the members’ section of the CTSU website. (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ Click on the Regulatory tab at the top of your screen 
▪ Click on the Site Registration tab 
▪ Enter your 5-character CTEP Institution Code and click on Go 
 
 
 

  
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APPENDIX II: YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY AOST1421 
(for subjects from 7 through 12 years of age) 
A study of a new drug to treat children with osteosarcoma that has come back. 
 
1. We have been talking with you about your illness, osteosarcoma. Osteosarcoma is a type of cancer 
that grows in the cells that produce bones. Your cancer came back after treatment. After it came 
back you had surgery to remove tumors. 
 
2. We are asking you to take part in a research study because your cancer came back. A research study 
is when doctors work together to try out new ways to help people who are sick. We are trying to 
learn more about how to treat cancer that came back after treatment. We will do this by giving you 
two drugs. We do not know if this treatment will keep the cancer from coming back. That is why 
we are doing this study. 
 
3. Children and teens on this study will be given two drugs. You will also have tests to see if the 
cancer comes back during your treatment. We also want to learn more about how children’s bodies 
handle one of the drugs you will receive. To do this, we will collect extra blood samples. These 
samples will be drawn through your central line if you have one. Collecting these blood samples 
may involve extra needle sticks. 
 
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 your cancer will 
not come back 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.” One risk to you is that the study treatment may not work or stop your tumor from 
growing or coming back. Another risk is that you may have more side effects than you would on 
another therapy. We do know that the study treatment can cause a lot of pain so you will also be 
given drugs to help lower the pain. The drugs that fight pain will be given before, during and after 
treatment. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We want to see if there are ways to tell how the cancer will respond to treatment. We are asking 
your permission to collect extra blood samples. These samples would be taken when other blood 
samples are being taken, so there would be no extra needle sticks. We would also like to collect 
tumor tissue to keep for other studies later on. This tissue would be taken when you have surgery, 
so there would be no extra surgeries. You can still take part in this study even if you don't allow us 
to collect the extra blood samples or tissue for research.  
 
 
 

  
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INFORMATION SHEET REGARDING RESEARCH STUDY AOST1421 
(for teens from 13 through 17 years of age) 
A study of ch14.18 (dinutuximab) and sargramostim (GM-CSF) to treat patients with recurrent 
osteosarcoma. 
 
1. We have been talking with you about your osteosarcoma. Osteosarcoma is a type of cancer that grows 
in the bones. Recurrent means that the cancer has come back after treatment. After doing tests, we have 
found that you have this type of cancer.  
 
2. We are asking you to take part in a research study because you have recurrent osteosarcoma and the 
tumor(s) that came back have now been removed by surgery. A research study is when doctors work 
together to try out new ways to help people who are sick. In this study, we are trying to learn more 
about how to treat osteosarcoma that has come back. We will do this by giving an experimental drug 
called ch14.18 (dinutuximab) along with a drug called sargramostim. Both drugs are FDA-approved, 
but not for osteosarcoma treatment. We don’t know for sure if these two drugs together will keep the 
tumor from coming back. That is why we are doing this study. 
 
3. Children, teens and young adults who are part of this study will be given ch14.18 (dinutuximab) and 
sargramostim. You will have imaging tests to see if the cancer comes back during your treatment. We 
will collect blood samples for research tests. We are trying to learn how child, teenage and young adult 
bodies handle dinutuximab. This study may help subjects who receive this drug in the future. These 
blood tests will be drawn through your central line if you have one. Otherwise, collecting these blood 
samples will involve extra needle sticks.  
 
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 that your cancer will not 
come back, 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.” Being in this study may involve special risks, which your doctor will discuss with you. 
The risks to you from this study are that the study treatment may not stop your tumor from growing or 
coming back. 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. We do know that the 
study treatment can cause a lot of pain so you will be given pain medication to help reduce the pain. 
Pain medication will be given before, during and after treatment as needed. Other things may happen 
to you that we don’t yet know about. 
 
6. You or 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. Please talk this over with your parents. There may be other 
treatments for your illness that your doctor can tell you about. Make sure to ask your doctors any 
questions that you have. 
 
7. We are asking your permission to collect additional blood. We want to see if there are ways to tell how 
the cancer will respond to treatment. These blood samples would be taken when other standard blood 
tests are being performed, so there would be no extra needle sticks. We would also like to collect tumor 
tissue to keep for other studies later on. This tissue would be taken when you have surgery, so there 
would be no extra surgeries. You can still take part in this study even if you don't allow us to collect 
the extra blood samples or tissue for research.  
 
 

  
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REFERENCES 
1. 
Hawkins DS, Arndt CA: Pattern of disease recurrence and prognostic factors in patients with 
osteosarcoma treated with contemporary chemotherapy. Cancer 98:2447-2456, 2003 
2. 
Kempf-Bielack B, Bielack SS, Jurgens H, et al: Osteosarcoma relapse after combined modality 
therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). 
J Clin Oncol 23:559-68, 2005 
3. 
Bielack SS, Kempf-Bielack B, Branscheid D, et al: Second and subsequent recurrences of 
osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma 
study group patients. J Clin Oncol 27:557-65, 2009 
4. 
Briccoli A, Rocca M, Salone M, et al: Resection of recurrent pulmonary metastases in patients with 
osteosarcoma. Cancer 104:1721-1725, 2005 
5. 
Heiner JP, Miraldi F, Kallick S, et al: Localization of GD2-specific monoclonal antibody 3F8 in 
human osteosarcoma. Cancer Res 47:5377-81, 1987 
6. 
Roth M, Linkowski M, Tarim J, et al: Ganglioside GD2 as a therapeutic target for antibody-
mediated therapy in patients with osteosarcoma. Cancer 120:548-54, 2014 
7. 
Cheung NK, Saarinen UM, Neely JE, et al: Monoclonal antibodies to a glycolipid antigen on human 
neuroblastoma cells. Cancer Res 45:2642-9, 1985 
8. 
Mujoo K, Cheresh DA, Yang HM, et al: Disialoganglioside GD2 on human neuroblastoma cells: 
target antigen for monoclonal antibody-mediated cytolysis and suppression of tumor growth. 
Cancer Res 47:1098-104, 1987 
9. 
Munn DH, Cheung NK: Interleukin-2 enhancement of monoclonal antibody-mediated cellular 
cytotoxicity against human melanoma. Cancer Res 47:6600-5, 1987 
10. 
Kushner BH, Cheung NK: GM-CSF enhances 3F8 monoclonal antibody-dependent cellular 
cytotoxicity against human melanoma and neuroblastoma. Blood 73:1936-41, 1989 
11. 
Mueller BM, Romerdahl CA, Gillies SD, et al: Enhancement of antibody-dependent cytotoxicity 
with a chimeric anti-GD2 antibody. J Immunol 144:1382-6, 1990 
12. 
Frost JD, Hank JA, Reaman GH, et al: A phase I/IB trial of murine monoclonal anti-GD2 antibody 
14.G2a plus interleukin-2 in children with refractory neuroblastoma: a report of the Children's 
Cancer Group. Cancer 80:317-33, 1997 
13. 
Gilman AL, Ozkaynak MF, Matthay KK, et al: Phase I study of ch14.18 with granulocyte-
macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after 
autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology 
Group. J Clin Oncol 27:85-91, 2009 
14. 
Yu AL, Gilman AL, Ozkaynak MF, et al: Anti-GD2 antibody with GM-CSF, interleukin-2, and 
isotretinoin for neuroblastoma. N Engl J Med 363:1324-34 
15. 
Ruth Ladenstein, et al: OR067 Myeloablative Therapy (MAT) and Immunotherapy (IT) with 
ch14.18/CHO for High Risk Neuroblastoma: Update and News of Randomised Results from the 
HR-NBL1/SIOPEN Trial.  
16. 
Uttenreuther-Fischer MM, Huang CS, Yu AL: Pharmacokinetics of human-mouse chimeric anti-
GD2 mAb ch14.18 in a phase I trial in neuroblastoma patients. Cancer Immunol Immunother 
41:331-8, 1995 
17. 
Saleh MN, Khazaeli MB, Wheeler RH, et al: Phase I trial of the chimeric anti-GD2 monoclonal 
antibody ch14.18 in patients with malignant melanoma. Hum Antibodies Hybridomas 3:19-24, 
1992 
18. 
Desai A FE, DiSipio TC, et al.: Pharmacokinetics (PK) of the chimeric anti-GD2 antibody, ch14.18, 
in children with high-risk neuroblastoma. J Clin Oncol 30, 2012 
19. 
Ruggeri L, Capanni M, Urbani E, et al: Effectiveness of donor natural killer cell alloreactivity in 
mismatched hematopoietic transplants. Science 295:2097-2100, 2002 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AOST1421 
Page 93 
Version date: 05/17/2017 
20. 
Delgado DC, Hank JA, Kolesar J, et al: Genotypes of NK cell KIR receptors, their ligands, and Fcγ 
receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy. Cancer Res 
70:9554-9561, 2010 
21. 
Delahaye NF, Rusakiewicz S, Martins I, et al: Alternatively spliced NKp30 isoforms affect the 
prognosis of gastrointestinal stromal tumors. Nat Med 17:700-707, 2011 
22. 
Semeraro M, Rusakiewicz S, Delahaye NF, et al: Impact of NKp30/NCR3 receptor isoforms in 
progression free survival of neuroblastoma patients. SIOPEN AGM, 2011. 
23. 
Brandt CS, Baratin M, Yi EC, et al: The B7 family member B7-H6 is a tumor cell ligand for the 
activating natural killer cell receptor NKp30 in humans. J Exp Med 206:1495-1503, 2009 
24. 
Schlecker E, Fiegler N, Arnold A, et al: Metalloprotease-mediated tumor cell shedding of B7-H6, 
the ligand of the natural killer cell-activating receptor NKp30. Cancer Res 74:3429-3440, 2014 
25. 
Semeraro M, Rusakiewicz S, Minard-Colin V, et al: ANR POT003 2014.  
26. 
Bettegowda C, Sausen M, Leary RJ, et al: Detection of circulating tumor DNA in early- and late-
stage human malignancies. Sci Transl Med 6:224ra24, 2014 
27. 
Olsson E, Winter C, George A, et al: Serial monitoring of circulating tumor DNA in patients with 
primary breast cancer for detection of occult metastatic disease. EMBO Mol Med, 2015 
28. 
Schwartz GJ, Gauthier B: A simple estimate of glomerular filtration rate in adolescent boys. J 
Pediatr 106:522-526, 1985 
29. 
Gorges M, West N, Deyell R, et al: Dexmedetomidine and hydromorphone: a novel pain 
management strategy for the oncology ward setting during anti-GD2 immunotherapy for high-risk 
neuroblastoma in children. Pediatr Blood Cancer 62:29-34, 2015 
30. 
Meignan M, Gallamini A, Itti E, et al: Report on the Third International Workshop on Interim 
Positron Emission Tomography in Lymphoma held in Menton, France, 26-27 September 2011 and 
Menton 2011 consensus. Leuk Lymphoma 53:1876-81, 2012 
31. 
Kaplan EL, Meier P: Nonparametric estimate from incomplete observations. J Amer Statist Assoc 
53:457-481, 1958 
32. 
Kalbfleisch JD, Prentice RL: The statistical analysis of failure time data (ed Second). New York, 
John Wiley and Sons, 2002  
33. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009