A Phase 1/2 Study of Nivolumab in Children, Adolescents, and Young Adults With Recurrent or Refractory Solid Tumors as a Single Agent and in Combination With Ipilimumab
Phase: PHASE1
Conditions: Metastatic Melanoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Hodgkin Lymphoma, Recurrent Malignant Solid Neoplasm, Recurrent Melanoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Rhabdomyosarcoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Hodgkin Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Melanoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Rhabdomyosarcoma, Stage III Cutaneous Melanoma AJCC v7, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7, Unresectable Melanoma
Sponsor: National Cancer Institute (NCI)

Pediatric Early Phase Clinical Trial 
Network (PEP-CTN) and  
Developmental Therapeutics (DVL) 
Chair 
Brenda J. Weigel, M.D. 
weige007@umn.edu 
 
PEP-CTN and  
Developmental Therapeutics (DVL) 
Vice Chair  
Elizabeth Fox, M.D. 
elizabeth.fox@stjude.org 
 
PEP-CTN Operations  
Data & Statistics Center Director 
Thalia Beeles, MPH 
tbeeles@childrensoncologygroup.org 
 
PEP-CTN Statistician  
Charles G. Minard, Ph.D. 
minard@bcm.edu 
 
 
PEP-CTN and  
DVL Chair’s Office 
University of Minnesota/ 
Masonic Cancer Center 
Masonic Children’s Hospital 
420 Delaware Street, SE 
MMC 366 
Minneapolis, MN  55455 
 
P 612 626 5501 
F 612 624 3913 
 
 
Children’s Oncology Group 
Group Chair 
Douglas S. Hawkins, MD 
Seattle Children’s Hospital 
Pediatric Hematology/Oncology 
Mailstop: MB.8.501 
4800 Sand Point Way 
Seattle, WA 98105 
P 206 987 3096 
F 206 987 3946 
doug.hawkins@seattlechildrens       
.org  
 
 
PEP-CTN Operations Data & 
Statistics Center 
800 Royal Oaks Drive 
Suite 210  
Monrovia, CA 91016 
 
P 626 241 1500 
F 626 445 4334 
 
 
A National Cancer Institute-  
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
 
 
Page i 
March 30, 2020 
 
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 #11 to ADVL1412, A Phase 1/2 Study of 
Nivolumab in Children, Adolescents, and Young Adults with Recurrent or 
Refractory Solid Tumors as a Single Agent and in Combination with Ipilimumab. 
 
This amendment is administrative in nature and includes the addition of off-study 
criteria for patients on Arm E.  
 
Specific changes are detailed in the Summary of Changes table below. Minor 
administrative updates (such as the correction of typographical errors, spelling, or 
updates to the numbers of referenced sections) are tracked in the protocol but not 
specified. 
 
 
Please let me know if you have any questions or need additional information. 
 
Sincerely, 
 
 
Patrice Navrude, MS, Protocol Coordinator for 
Crystal Mackall, MD, ADVL1412 Study Chair, and 
Brenda Weigel, MD, PEP-CTN Chair 
 
Changes to Protocol Document:  
# 
Section 
Page 
Change 
1. 
Throughout -- 
The version date and amendment number has been updated 
2. 
10.2 
 
100 days after the last dose of the investigational agent (Patients 
on Part A or C that are not enrolled at the MTD; Patients on Part 
E). 
 
Changes to Informed Consent Documents (Parts A& B; Parts C, D & E): 
# 
Section 
Page 
Change 
1. 
Throughout -- 
The version date and amendment number has been updated 

 
 
 
 
 
                                                                                                                                                                
                                                                                                                                                               
Version Date: 03/30/2020 
 
Page 1 
 
Activated: 
February 2, 2015 
Version Date: 
03/30/2020 
Closed: 
 
Amendment #:  
11 
 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
ADVL1412 
 
A PHASE 1/2 STUDY OF NIVOLUMAB IN CHILDREN, ADOLESCENTS, AND YOUNG 
ADULTS WITH RECURRENT OR REFRACTORY SOLID TUMORS AS A SINGLE AGENT 
AND IN COMBINATION WITH IPILIMUMAB  
 
Lead Organization: COG Pediatric Early Phase Clinical Trials Network (PEP-CTN) 
 
 
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 
Crystal Mackall, M.D. 
Stanford Cancer Institute 
Lucile Packard Children's Hospital Stanford University 
265 Campus Dr. G3141A, MC5456 
Stanford, CA 94305 
Phone: 650-723-5535 
E-mail: cmackall@stanford.edu 
 
 
 
For COG PEP-CTN Operations Contacts see: http://members.childrensoncologygroup.org 
 
 

 
 
ADVL1412 
 
 
 
 
 
Version Date: 03/30/2020 
 
Page 2 
 
 
TABLE OF CONTENTS 
SECTION 
PAGE 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims 
8 
1.2 
Secondary Aims 
8 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Preclinical Studies 
11 
2.3 
Adult Studies 
12 
2.4 
Pediatric Studies 
17 
2.5 
Overview of Proposed Pediatric Study 
18 
2.6 
Rationale for Inclusion of Melanoma Cohort (Amendment #2B) 
20 
2.7 
Rationale for Inclusion of Neuroblastoma- MIBG Evaluable Cohort (Amendment #2C) 21 
2.8 
Incidence and Proposed Management of Pleural Effusions in Patients Treated with 
Nivolumab 
21 
2.9 
Rationale for Inclusion of Part D (Amendment #4) 
22 
2.10 
Rationale for Inclusion of relapsed lymphoma patients post-allogeneic transplant 
(AMD#4) 
22 
2.11 
Rationale for Inclusion of Part E (Amendment #8B) 
23 
2.12 
Rationale for Secondary Aims 1.2.3-1.2.5 (Amendment #8B) 
23 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
24 
3.1 
Current Study Status 
25 
3.2 
IRB Approval 
25 
3.3 
Patient Registration in the COG Registry 
26 
3.4 
Reservation and Contact Requirements 
26 
3.5 
Informed Consent/Assent 
26 
3.6 
Screening Procedures 
26 
3.7 
Eligibility Checklist 
26 
3.8 
Institutional Pathology Report 
26 
3.9 
Study Enrollment 
26 
3.10 
Dose Assignment 
27 
4.0 
PATIENT ELIGIBILITY 
27 
4.1 
Inclusion Criteria 
27 
4.2 
Exclusion Criteria 
31 
5.0 
TREATMENT PROGRAM 
32 
5.1 
Overview of Treatment Plan 
32 
5.2 
Protocol therapy will continue to be administered until patient meets one of the off protocol 
criteria in Section 10.1.Criteria for Starting Subsequent Cycles 
35 
5.3 
Grading of Adverse Events 
35 
5.4 
Definition of Dose-Limiting Toxicity (DLT) 
35 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
37 

 
 
ADVL1412 
 
 
 
 
 
Version Date: 03/30/2020 
 
Page 3 
 
6.1 
Dose Modifications for Hematological Toxicity 
37 
6.2 
Dose Modifications for Non-Hematological Toxicity 
37 
6.3 
Dose Modifications for Infusion-Related Reactions 
37 
6.4 
Dose Modifications for Skin Rash and Oral Lesions 
38 
6.5 
Dose modifications for Hepatic/Pancreatic Adverse Events 
39 
6.6 
Dose modifications for Gastrointestinal Adverse Events 
41 
6.7 
Dose Modifications for Pneumonitis 
43 
6.8 
Dose Modification and Adverse Event Management Algorithm for Pleural Effusion and 
Ascites 
44 
6.9 
Dose Modifications for Fatigue 
46 
6.10 
Dose Modifications for Neurologic Adverse Events 
46 
6.11 
Dose Modifications for Endocrine Adverse Events 
47 
6.12 
Dose Modifications for Fever 
48 
6.13 
Dose Modifications for Renal Adverse Events 
49 
6.14 
Dose Modifications for Nivolumab + Ipilimumab Cardiac Toxicities 
50 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
50 
7.1 
Concurrent Anticancer Therapy 
50 
7.2 
Investigational Agents 
50 
7.3 
Supportive Care 
50 
7.4 
Growth Factors 
52 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
53 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
53 
8.2 
Radiology Studies 
54 
8.3 
Pharmacokinetics (Required) 
55 
8.4 
Vaccinated Antibody Studies (optional) 
56 
8.5 
Anti-drug antibody (ADA) analysis (Required) 
57 
8.6 
Tumor Assessment PD-L1 and CD8 (required, if available) 
58 
8.7 
Tumor Assessment FoundationOneCDx (Optional): Part E 
59 
8.8 
Cytokine studies (optional) 
59 
9.0 
AGENT INFORMATION 
60 
9.1 
Nivolumab 
60 
9.2 
Ipilimumab 
68 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
74 
10.1 
Criteria for Removal from Protocol Therapy 
74 
10.2 
Off Study Criteria 
75 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
75 
11.1 
Sample Size and Study Duration 
75 
11.2 
Definitions 
78 
11.3 
Determination of Recommended Phase 2 Dose for Nivolumab as a Single Agent (Part A):
 
79 
11.4 
Phase 2 Evaluation of Nivolumab (for Part B): 
79 
11.5 
Dose Escalation and Determination of Recommended Phase 2 Dose for Nivolumab plus 
Ipilimumab (Part C): 
81 
11.6 
Phase 2 Evaluation of Nivolumab (3 mg/kg) in Combination with Ipilimumab (1 mg/kg) 
(for Part D): 
82 
11.7 
Phase 2 Evaluation of Nivolumab (1 mg/kg) in Combination with Ipilimumab (3 mg/kg) 
(for Part E): 
83 

 
 
ADVL1412 
 
 
 
 
 
Version Date: 03/30/2020 
 
Page 4 
 
11.8 
Inclusion of Children, Women and Minorities 
84 
11.9 
Pharmacokinetic and Correlative Studies and Response Analysis 
85 
12.0 
EVALUATION CRITERIA 
85 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
85 
12.2 
Response Criteria for Patients with Solid Tumors 
85 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
90 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
91 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
92 
12.6 
Best Response 
93 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
95 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
95 
13.2 
When to Report an Event in an Expedited Manner 
98 
13.3 
Expedited Reporting Methods 
99 
13.4 
Definition of Onset and Resolution of Adverse Events 
99 
13.5 
Other Recipients of Adverse Event Reports 
99 
13.6 
Reporting Secondary AML/MDS 
100 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
100 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
101 
14.1 
Categories of Research Records 
101 
14.2 
Access to Rave for Data Submission/ Data Reporting 
102 
14.3 
CDUS 
102 
14.4 
CRADA/CTA/CSA 
102 
14.5 
Data and Safety Monitoring Plan 
104 
REFERENCES 
105 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
109 
APPENDIX II: CORRELATIVE STUDIES GUIDE 
110 
APPENDIX IIIA:  PHARMACOKINETIC STUDY FORM (PARTS A AND B) 
111 
APPENDIX IIIB:  PHARMACOKINETIC STUDY FORM (PARTS C, D AND E) 
112 
APPENDIX IV: VACCINATED ANTIBODY STUDY FORM 
114 
APPENDIX V: ANTI-DRUG ANTIBODY (ADA) STUDY FORM 
115 
APPENDIX VI: TISSUE STUDIES FORM 
116 
APPENDIX VII: CYTOKINE STUDY FORM 
117 
APPENDIX VIII: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
118 
APPENDIX IX: TOXICITY-SPECIFIC GRADING 
119 
APPENDIX X: CTEP AND CTSU REGISTRATION PROCEDURES 
120 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 5 
 
STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS  
Crystal Mackall, M.D. 
Brenda J. Weigel, MD 
Stanford Cancer Institute 
Chair, Developmental Therapeutics  
Lucile Packard Children's Hospital  
Hematology/Oncology 
Stanford University 
University of Minnesota/Masonic Cancer Center 
265 Campus Dr G3141A, MC5456 
Department of Pediatrics 
Stanford, CA 94305 
420 Delaware Street, SE  MMC 366 
Phone: 650-723-5535 
Minneapolis, MN 55455 
E-mail: cmackall@stanford.edu 
Phone:   (612) 626-5501 
 
Fax:  
 (612) 624-3913 
STUDY VICE CHAIR  
E-mail: weige007@umn.edu 
Kara Davis, DO 
 
Lucile Packard Children's Hospital  
Elizabeth Fox, MD 
Stanford University 
Vice Chair, Developmental Therapeutics 
Pediatric Hematology/Oncology 
Saint Jude Children’s Research Hospital 
1000 Welch Road Suite 300 
262 Danny Thomas Place 
Palo Alto, CA 94304 
Memphis, TN 38105 
Phone: (650) 723-5535 
Phone: (901) 595-3300 
E-mail:kardavis@stanford.edu  
Fax: (901) 595-7031 
 
Email: elizabeth.fox@stjude.org 
 
 
SENIOR STATISTICIAN  
 
Charles Minard, PhD 
 
Baylor College of Medicine  
Sharon A. Mavroukakis, RN MS 
Dan L. Duncan Institute 
Lucile Packard Children’s Hospital 
One Baylor Plaza 
Stanford University 
Suite 100D, BCM 122 
725 Welch Rd. 
Houston, TX 77030 
Palo Alto, CA 94304 
Phone:   (713) 798-2353 
Phone:   (301) 455-5476 
Fax:  
 (713) 798-2816 
E-mail: Sharon_Mavroukakis@nih.gov 
E-mail: minard@bcm.edu 
 
 
STUDY NURSE 
STATISTICIAN 
Stacey Crane, MSN BSN CCRP CPON 
Xiaowei Liu, MS 
Riley Hospital for Children 
Children’s Oncology Group – Operations Center 
Indiana University School of Nursing 
222 E. Huntington Drive, Suite 100 
NU 338, 111 Middle Dr. 
Monrovia, CA  91016 
Indianapolis, IN 46202 
Phone: (626) 241-1535 
Phone: (513) 508-3936 
Fax: 
(626) 445-4334 
Fax: (317) 278-2021 
E-mail: xwliu@childrensoncologygroup.org 
E-mail: cranes@iupui.edu 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 6 
 
STUDY COMMITTEE, cont. 
 
 
PROTOCOL COORDINATOR 
STUDY PHARMACIST  
Patrice Navrude, MS 
Olga Militano, PharmD  
Children’s Oncology Group – Operations Center 
Children’s Oncology Group – Operations Center 
222 E. Huntington Drive, Suite 100 
222 E. Huntington Drive, Suite 100 
Monrovia, CA  91016 
Monrovia, CA  91016 
Phone: (626) 241-1607 
Phone: (626) 241-1517 
Fax: 
(626) 445-4334 
E-mail:omilitano@childrensoncologygroup.org 
E-mail: pnavrude@childrensoncologygroup.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Group Operations (GOC), 
 
Pediatric Early Phase Clinical Trials Network (PEP-CTN), 
 
Statistics & Data Center (SDC) contacts see: 
 
http:members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
NCI-Supplied Agents*: 
Nivolumab (BMS-936558, MDX-1106) 
 
(NSC # 748726) 
 
Ipilimumab (BMS-734016; MDX-010 Transfectoma-
derived) (NSC # 732442) 
 
 
 
 
 
 
 
 
 
 
 
 
 
IND Sponsor:  DCTD, NCI 
 
 
 
 
SEE SECTIONS 8.3.6, 8.4.1, 8.4.5, 8.5.6, 8.6.3, 8.7.3, and 8.8.5 FOR SPECIMEN SHIPPING 
ADDRESSES 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 7 
 
 
This trial is covered by 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 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 
The goal of Part A is to define the recommended phase 2 dose (RP2D), which is a tolerable dose of 
nivolumab that provides systemic exposure similar to that achieved by the RP2D in adults.  
Part A will enroll at least six evaluable children with recurrent or refractory solid tumors, excluding brain 
tumors, and patients enrolled on Part A must have measurable or evaluable disease. Patients on Part A will 
receive 3 mg/kg nivolumab every 2 weeks until disease progression or until toxicity requires treatment 
interruption.   
Part B will evaluate the activity of nivolumab at its RP2D in expanded cohorts for patients with 
neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Hodgkin lymphoma non-Hodgkin 
lymphoma, and melanoma. Measurable disease is required for enrollment on Parts B1-B6, measurable or 
evaluable disease is required for Part B7 (melanoma), and MIBG evaluable disease without measurable 
disease in patients with neuroblastoma (Part B8). The primary objective of Part B is to identify histologic 
subtypes where there is a signal for anti-tumor activity, using a Simon’s optimal two-stage design, with the 
exception of Part B7, which will serve as a non-statistical access cohort for the rare diagnosis of melanoma, 
to remain open to enrollment until Parts B1-B6, B8 are complete.  
Part C will enroll all histologies with the same eligibility criteria required for enrollment on Part A with 
the goal of identifying the RP2D of the combination of nivolumab plus ipilimumab using a rolling 6 design. 
Patients will be monitored for response and toxicity using standard criteria.  
Part D will evaluate nivolumab in combination with ipilimumab in selected disease cohorts 
(neuroblastoma, rhabdomyosarcoma, non-Hodgkin lymphoma, osteosarcoma, or Ewing sarcoma). Part D 
will open to accrual if there is insufficient activity in the initial stage of the Simon’s optimal two-stage 
design in Part B.  Part D will use a Simon’s optimal two-stage design to evaluate the activity of nivolumab 
in combination with ipilimumab at the RP2D and schedule determined in Part C, nivolumab (3 mg/kg) in 
combination with ipilimumab (1 mg/kg) (See Section 11.6). 
Part E will evaluate alternative dosing of nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) 
in rhabdomyosarcoma or Ewing sarcoma/Peripheral PNET.  
 
EXPERIMENTAL DESIGN SCHEMA 
 
Parts A and B:  
 
 
 
 
 
 
 
 
 
Cycle:   
    
 
     Day 1 
 
 
Day 15  
  
             Day 28 (Evaluation*) 
 
 
 
 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 8
Parts C, D and E:
Cycle
1-4 : 
     Day 1 
             Day 21 (Evaluation*)
      
       
Cycle
5+ :
     Day 1
Day 15
             Day 28 (Evaluation*)
                  
Nivolumab
Ipilimumab
*See Table 8.1 for required disease evaluations. Therapy will be discontinued if there is evidence of progressive 
disease or drug related dose-limiting toxicity that requires removal from therapy. Cycle length for Parts A and B is 28
days.  Cycle length for Parts C, D, and E in cycle 1-4 (combination therapy) is 21 days, and 28 days for subsequent 
cycles (nivolumab alone).
1.0
GOALS AND OBJECTIVES (SCIENTIFIC AIMS)
1.1
Primary Aims
Determine the tolerability, and define and describe the toxicities of nivolumab 
administered as a single agent in children with relapsed or refractory solid tumors
at the adult recommended dose of 3 mg/kg.
Determine if systemic nivolumab exposure in children is similar to the systemic 
exposure in adults following a 3 mg/kg dose.
Determine the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose (RP2D) and define and describe the toxicities of nivolumab plus ipilimumab 
administered to children with relapsed or refractory solid tumors.
Assess antitumor effects of nivolumab across selected childhood solid tumors in 
seven expansion cohorts (Parts B1-B6, B8); neuroblastoma (2 cohorts:  
measurable disease; MIBG positive only non-measurable disease), osteosarcoma, 
rhabdomyosarcoma, Ewing sarcoma, Hodgkin lymphoma, and non-Hodgkin 
lymphoma. A non-statistical access cohort for the rare diagnosis of melanoma 
(Part B7) will remain open to enrollment until Parts B1-B6, B8 are complete B7 
to preliminarily define the antitumor effects of nivolumab within the confines of 
a phase 1/2 study.
Assess antitumor effects of nivolumab in combination with ipilimumab across 
selected childhood solid tumors in two dose combinations (Part D and Part E).
Characterize the pharmacokinetics of nivolumab alone and in combination with 
ipilimumab, including AUC, Cmax, Cmin, using intensive sampling.
Assess immunogenicity of nivolumab alone and in combination with ipilimumab 
by measuring anti-drug antibody (ADA) levels
1.2
Secondary Aims
Conduct exploratory studies of the phenotypic and functional effects of 
nivolumab (alone and in combination with ipilimumab), as well as changes in 
antibodies to previously vaccinated viruses, in serum samples.
Explore whether correlations exist between PD-L1 expression on tumor and 
antitumor effects of nivolumab (alone and in combination with ipilimumab) in 
pediatric solid tumors and to conduct exploratory studies of potential tumor 
associated biomarkers of response in tumor tissue (at least five out of the 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 9
following markers: NRAS, BRAF, MEK, KIT, PDGF, TP53, RB1 and 
BRCA1, Akt phosphorylation, IL-17 or PD-L1). 
Explore presence of tumor infiltrating lymphocytes and their association with 
antitumor effects of nivolumab (alone and in combination with ipilimumab). 
Conduct exploratory studies of the effect of nivolumab (alone or in 
combination with ipilimumab) on cytokine levels in serum samples. 
For Part E, determine tumor mutational burden of diagnostic specimens using 
FoundationOneCDx testing to explore immune-related gene expression or 
mutation and its association with antitumor response to nivolumab in 
combination with ipilimumab.
2.0
BACKGROUND
2.1
Introduction/Rationale for Development
Checkpoint Inhibitors as a New Class of Immunotherapeutics
Progressive optimization of cytotoxic regimens substantially improved cure rates for 
pediatric solid tumors between 1970 and 1995, but the rate of progress has diminished since 
then.  Children with childhood cancer who present in many high risk groups, including 
those who are diagnosed with metastatic disease and those with disease recurrence after 
frontline therapy have poor survival rates, which have not changed substantially in many 
years.  Current standard regimens for high-risk pediatric solid tumors already employ dose 
intensive cytotoxic therapy with significant short-term and long-term toxicity, thus further 
dose escalation of such regimens is unlikely to improve outcomes, but will almost certainly 
increase toxicity.  For these reasons, there is an urgent need to develop new classes of 
therapeutics to treat childhood cancer, based upon biologic insights into the tumor itself or 
the host response to cancer.
Immunotherapy for cancer has recently demonstrated increasing success, evidenced by 
FDA approval of a therapeutic vaccine for prostate cancer1, improved survival for patients 
with high risk neuroblastoma treated with an anti-GD2 based immunotherapy regimen 
following autologous stem cell transplant2, dramatic anti-leukemia effects with adoptive 
therapy with genetically engineered T cells3-6 and with bi-specific antibodies that activate 
host T cells.4  Anti-CTLA4 (ipilimumab), the first of a new class of immunomodulatory 
agents, called checkpoint inhibitors, has been FDA approved for the treatment of metastatic 
melanoma.7 Anti-PD1 is a second-generation checkpoint inhibitor, and blocking mAbs 
targeting PD-1 have shown antitumor effects in melanoma, renal cell carcinoma and lung 
cancer.8,9  This trial will evaluate toxicity and potential antitumor activity of nivolumab, a 
PD1 blocking mAb being developed by BMS, in children with refractory solid tumors and 
will test a combination regimen of nivolumab plus ipilimumab, which has shown 
impressive activity in melanoma.10
Immunomodulatory “checkpoint inhibitors” induce antitumor effects by blocking 
inhibitory immune receptors. 11 Development of this class of agents for cancer is based on 
the hypothesis that anti-tumor immune responses exist in patients with cancer, but are 
inhibited by tonic activation of inhibitory pathways.  Blockade of inhibitory receptors 
uncovers antitumor immune responses that can mediate antitumor effects. CTLA4 is 
considered the prototypic checkpoint molecule.  Under normal circumstances, CTLA4 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 10 
 
signaling broadly limits T cell responses to self-antigens and prevents autoimmunity. But 
blockade of CTLA4 results in increased activating signals via CD28, as both CTLA4 and 
CD28 bind to the same ligands (B7-1, B7-2) on antigen presenting cells. Experience 
gleaned during clinical development of anti-CTLA4 based therapeutics is informing 
development of nivolumab, and will be discussed in detail here.   
Two antibodies which block CTLA4 signaling were tested in clinical trials:  ipilimumab 
(Yervoy, BMS) and tremelimumab (Pfizer). Two randomized trials demonstrated 
prolonged survival in patients with metastatic melanoma treated with ipilimumab.  In the 
first, ipilimumab (3 mg/kg) alone or ipilimumab plus anti-gp100 vaccine was compared to 
a gp100 vaccine alone arm, and both ipilimumab arms showed superior overall survival, 
with a median OS of 10.1 months for ipilimumab alone vs 6.4 months with vaccine alone.12  
This trial demonstrating a survival improvement for patients with metastatic melanoma 
served as the basis for FDA approval of ipilimumab, at the 3 mg/kg dose for metastatic 
melanoma.  A subsequent trial demonstrated superior survival with ipilimumab (10 mg/kg) 
plus dacarbazine, compared to dacarbazine alone (11.1 months median OS vs. 9.2 months 
median OS) in metastatic melanoma. 13 Lessons learned from these studies were several:   
1) At doses beyond 3 mg/kg, dose-response and dose-toxicity effects for ipilimumab 
remain unclear with similar response rates and toxicity rates observed at 3 mg/kg and 10 
mg/kg.  The current FDA approved dose is 3 mg/kg although results of ongoing Phase III 
trials evaluating 10 mg/kg are pending.   
2) Objective responses were difficult to assess because patients not infrequently had 
clinical evidence of tumor progression that was subsequently followed by tumor shrinkage.  
Such “pseudoprogression” has been attributed to inflammation associated with immune 
mediated antitumor effects and has led to a consensus that patients with tumor progression 
(within well-defined limits) may remain on trial if they remain clinically stable and meet 
criteria to continue therapy.  While RECIST remains the gold standard for defining an 
antitumor response, RECIST responses may ultimately occur in a delayed fashion after 
initial apparent tumor progression in patients treated with checkpoint blockade. 
3) The adverse effect profile of anti-CTLA4 was significant but limited to immune 
mediated toxicity.  In 15-45% of patients, autoimmune reactions occurred that typically 
involved one or two organs, and could be severe.  Colitis, hypophysitis, hepatitis, rash, 
pancreatitis, thyroiditis and iritis were commonly observed and have been coined “immune 
related adverse events”.  Autoimmune related adverse events were treated by 
discontinuation of the anti-CTLA4 therapy with or without treatment with corticosteroids.  
Inflammation of endocrine glands, such as thyroid and pituitary typically resulted in 
irreversible dysfunction requiring long-term hormone replacement, whereas tissue damage 
in non-endocrine organs were typically reversible.  In general, patients who developed 
autoimmune related adverse events had a higher response rate, suggesting that these 
syndromes are potential biomarkers of immune activity and that treatment with 
corticosteroid does not abrogate antitumor effects.  
4) The optimal schedule for anti-CTLA4 remains unclear with most regimens using an 
induction phase administered every three weeks followed by maintenance dosing 
administered approximately every 3 months.  However, the role for maintenance dosing is 
unclear and some investigators recommend induction therapy every 3 weeks x 4, followed 
by re-induction as necessary based upon disease activity.   Tremelimumab did not show 
activity in randomized trials but was dosed every 3 months in the pivotal trial, raising the 
possibility that suboptimal dosing can limit efficacy of these agents.14 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 11 
 
 
 
 
2.2 
Preclinical Studies 
 
Antitumor Activity 
PD-1 (Programmed Death 1) is the second immune checkpoint receptor developed 
for cancer immunotherapy.  Unlike CTLA4, which is expressed on nearly all 
regulatory T cells and appears to be important in controlling T cell proliferation 
during T cell development, PD-1 is upregulated on peripheral T cells following 
chronic activation.  PD-1 signaling on T cells is induced following binding to either 
PD-L1 (B7-H1, CD274, considered widely expressed, especially on macrophages 
and some tumors) or PD-L2 (B7-DC, CD273, more limited expression, on antigen 
presenting cells). Murine studies showed impressive effects when blocking 
antibodies to PD-1 were administered to mice with chronic viral infection, 
resulting in recovery of antiviral immunity and reversal of “T cell exhaustion”.15  
Furthermore, mice genetically induced to be deficient in PD-1 developed a variety 
of autoimmune-like diseases.  Hence, PD-1 signaling has been associated with 
chronic T cell activation and T cell exhaustion and current concepts hold that 
blocking PD-1 may augment responses in the setting of chronic immune activation.  
The differences in the biology between CTLA4 and PD-1 leads to the prediction 
that PD-1 blockade is less likely to induce de novo autoimmunity and more likely 
to restore responses in the setting of chronic antigen exposure.   
Several preclinical studies demonstrated antitumor effects of anti-PD1 in tumor 
models.  A landmark manuscript by Dong et al. demonstrated robust tumor 
expression of PD-L1 as well as expression of PD-L1 on tumor-associated 
macrophages, but not on other normal tissues.16  This group further demonstrated 
that interferon gamma induced upregulation of PD-L1 on tumor cell lines, thus 
providing a means for tumor immune escape through signaling of PD-1 on 
activated T cells, which induces suppressive signaling pathways.  PD-1 signaling 
has been demonstrated to contribute to immune escape in vivo in murine 
myeloma17, Sa1N fibrosarcoma, MC38 colorectal adenocarcinoma, and B16 
melanoma.18 
As discussed above, PD-1 has not been extensively studied in preclinical models 
of pediatric cancer.  However recent work demonstrated expression of PD-L1 on 
two murine embryonal rhabdomyosarcoma cell lines including M3-9-M, which is 
derived from an HGFTgp53+/- genetically engineered mouse and 76-9, a 
spontaneous rhabdomyosarcoma.19  In immunocompetent mice inoculated with 
either line, treatment with anti-PD1 prevented tumor growth if administered 
coincident with tumor inoculation.  However, when anti-PD1 was administered in 
the presence of established tumors, anti-PD1 therapy had antitumor effects but was 
not curative.  This work demonstrated that anti-PD1 therapy did augment immune 
responses to tumor antigens expressed on M3-9-M mice.  Interestingly, this work 
demonstrated that co-treatment with anti-PD1 plus anti-CXCR2 antibodies, which 
prevent trafficking of myeloid derived suppressor cells into the tumor bed was 
more effective than treatment with anti-PD1 alone.  These results implicate 
myeloid derived suppressor cells in tumor immune escape in rhabdomyosarcoma 
and suggest that a future clinical approach that combines anti-PD1 with other 
immunomodulators holds promise.  PD-1 signaling has also been implicated in 
immune escape in acute myeloid leukemia,20 and unpublished work has 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 12 
 
demonstrated PD-L1 expression on tumor infiltrating myeloid cells in 
medulloblastoma tissue section and in medulloblastoma cell lines. 
 
Preclinical Biomarker Studies (Amendment #10C) 
A non-clinical biomarker study to characterize the expression levels of PD-L1 and 
presence of tumor-infiltrating lymphocytes in multiple pediatric tumor types and 
to identify tumor types likely to show response to nivolumab treatment was 
conducted as a measure for the nivolumab Pediatric Investigation Plan agreed upon 
by the Pediatric Committee of the European Medicines Agency. 
 
In this study, high rates of PD-L1+ staining at a > 1% threshold (≥1+ intensity, 
minimum 100 tumor cells evaluated) were observed in samples from NHL (Burkitt 
Lymphoma) (8/10; 80%) and glioblastoma (7/20; 35%). Positive PD-L1 staining 
was also observed in 16/114 (14%) neuroblastoma samples (including both whole 
slide sections and TMA samples), ganglioneuroblastoma (2/18; 11%), 
ependymoma (2/40; 5%) and rhabdomyosarcoma (2/54; 4%). Other tumor types 
demonstrating positive PD-L1 expression in at least one sample included 
osteosarcoma (1/20; 5%), supratentorial primitive neuroectodermal tumor (1/5; 
20%) and the single synovial sarcoma sample (1/1, 100%). 
 
No PD-L1 expression was observed in any medulloblastoma, ganglioneuroma or 
Ewing sarcoma tumor samples examined. 
 
Immune cell infiltration was examined in a subset of the tumors assessed for PD 
L1 expression. CD45RO+ cells (memory T cells) were the most ubiquitously 
present immune cells, seen in 49/60 (81%) tumors. CD8+ cells (cytotoxic T cells) 
were commonly observed as well (46/60; 77%). PD-1+ and FoxP3+ expression 
were seen in 28 (47%) and 25 (42%) tumors, respectively. CD4+ staining was only 
observed in 13 (22%) of tumors assessed. 
 
Regardless of presence or absence of PD-L1 expression, the presence of immune 
cells (macrophages and lymphocytes), and specifically CD45RO+ (memory) and 
CD8+ (cytotoxic) T cells in tumors was common, suggesting an presence of an 
immune active environment in tumors of pediatric cancer patients.21 The clinical 
utility of PD-L1 expression and characteristics of tumor associated immune cells 
could not be determined in this study. 
 
Animal Toxicology 
None pertaining to this trial.  The anti-PD1 mAb does not bind murine PD-1 or 
non-human primate PD-1 and therefore these are not informative for toxicity in 
humans. 
 
Preclinical Pharmacokinetic Studies 
Such studies do not significantly inform this trial as the pharmacokinetic studies 
from the adult early phase trials are more informative. 
 
2.3 
Adult Studies 
 
Studies in Adults 
Results of early phase clinical testing of two checkpoint inhibitors which block 
Programmed Death 1 (PD-1)/PD-L1 interactions in adult cancer patients have been 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 13 
 
published. In general, these have demonstrated impressive antitumor activity is 
melanoma, lung cancer and renal cell cancer with less toxicity than that observed 
with ipilimumab. 
 
Topalian et al. reported in June 2012 on 296 adult patients treated on a Phase I 
study of nivolumab (then called BMS-936558) a fully human IgG4 blocking 
mAb.8  Patients received drug every 2 weeks for up to 2 years, unless they had a 
complete response, unacceptable side effects, progressive disease or they declined 
to continue therapy.  Response was assessed every 8 weeks and due to concerns 
regarding pseudoprogression seen with other checkpoint inhibitors, patients were 
allowed to remain on study if they were clinically stable despite progression on 
routine restaging unless progression was confirmed on a subsequent restaging 8 
weeks later.  Doses tested were 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 
mg/kg using a standard 3+3 design.  No MTD was identified.   
 
A total of 5 expansion cohorts were then studied at 10 mg/kg comprising 
melanoma, non-small cell lung cancer, renal cell carcinoma, castration resistant 
prostate cancer and colorectal cancer.  Because signs of clinical activity were 
observed, additional cohorts of melanoma, squamous and non-squamous lung 
cancer and renal cell cancer were studied.   Five percent of patients discontinued 
treatment due to adverse events, Grade 3 or 4 treatment-related adverse events 
occurred in 14% and drug related SAEs occurred in 11%.  Most common drug 
related immune adverse events were pneumonitis, vitiligo, colitis, hepatitis, 
hypophysitis and thyroiditis.  In general, adverse events were similar in nature, 
severity and reversibility to that seen with ipilimumab, except that the incidence 
appeared to be less and pneumonitis was not observed with a significant frequency 
in studies with ipilimumab.  There was no evidence that pneumonitis was more 
common in lung cancer or any other particular histology.  There were 3 deaths 
associated with pneumonitis, two in patients with lung cancer and one in a patient 
with colorectal cancer. 
 
Table 1. Response rates associated with histology and dose8 
Histology 
Dose 
Response rate 
(%) 
Number 
treated 
Melanoma 
0.1 mg/kg 
29 
14 
Melanoma 
0.3 mg/kg 
19 
16 
Melanoma 
1 mg/kg 
30 
27 
Melanoma 
3 mg/kg 
41 
17 
Melanoma 
10 mg/kg 
20 
20 
Melanoma 
All 
28 
94 
Lung cancer 
1 mg/kg 
6 
18 
Lung cancer 
3 mg/kg 
32 
19 
Lung cancer 
10 mg/kg 
18 
39 
Lung cancer 
All 
18 
76 
Renal cell cancer 
1 mg/kg 
24 
17 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 14 
 
Renal cell cancer 
10 mg/kg 
31 
16 
Renal cell cancer 
All 
27 
33 
 
A substantial fraction of patients with objective responses who were followed for 
one year after initiation of therapy showed a prolonged duration of response (8/14 
with lung cancer had responses lasting at least 24 weeks, 13/26 with melanoma 
had responses lasting at least one year and 5/8 with renal cancer had responses 
lasting at least one year).   
 
In July 2013, Hamid et al reported results of a Phase I trial of lambrolizumab 
(previously MK-3475) a humanized IgG4 mAb that blocks PD-1.  The drug was 
administered to 135 patients with advanced melanoma at a dose of 2 mg/kg or 10 
mg/kg every 2-3 weeks.  Using RECIST, a 38% response rate was observed 
combining all dose levels with a higher response rate (52%) in patients that 
received 10 mg/kg every 2 weeks. Overall, 77% of patients had a reduction in 
tumor burden during the study.  Responses were durable in the majority of patients.  
Most common adverse events were fatigue, rash, pruritus and diarrhea and most 
were low grade.  Patients (13%) with higher grade events (grades 3-5), included 
pneumonitis in 4%, which indirectly led to the death of one patient, a 96 year old 
man.  Two cases of grade 3 renal failure were observed as well, both of which 
improved with discontinuation of therapy plus glucocorticoids.  The 
pharmacokinetics showed linear relationships with dose and the half-life of the 
agent was judged to be 2-3 weeks.  Biopsy of lesions from responding patients 
showed dense infiltration with CD8+ cytotoxic lymphocytes.  There is an ongoing 
trial randomizing dosing between 10 mg/kg administered every 3 vs every 2 weeks. 
 
Brahmer et al. reported results of anti-PD-L1 blocking antibody therapy in 207 
patients with a variety of cancers.22 The agent is an IgG4 subtype antibody, and 
therefore it is presumed that its effects would be mediated by blockade of PD-
1/PD-L1 interactions, rather than by induction of ADCC or complement mediated 
cytotoxicity.  Results were similar to that observed with anti-PD1.  Objective 
response rates were observed in 6-17% of patient groups including melanoma, 
renal cell cancer and non-small cell lung cancer.  Several patients also showed 
prolonged stabilization of disease and grade 3 or 4 toxic effects occurred in 9% of 
patients, and were primarily autoimmune in nature. No significant antitumor 
activity was not observed in cohorts of patients (n=16 patients each) with ovarian 
cancer, colorectal cancer, pancreatic cancer, breast cancer or gastric cancer. 
 
As of June 2017, single agent nivolumab has been FDA approved for adults with 
locally advanced or metastatic urothelial carcinoma, hepatocellular carcinoma, 
microsatellite instability-high or mismatch repair deficient metastatic colorectal 
cancer, head and neck cancer, Hodgkin lymphoma, metastatic renal cell 
carcinoma, advanced lung cancer and melanoma. 
 
Results of nivolumab administered in combination with ipilimumab for stage III 
or IV measurable, unresectable melanoma have recently been reported.10  At the 
maximum tolerated combination dose (1 mg/kg anti-PD1 plus 3 mg/kg ipilimumab 
every three weeks administered concurrently), 53% of patients had an objective 
response, all with tumor reduction of 80% or more.  Adverse effects observed with 
the combination therapy were qualitatively similar to those observed with 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 15 
 
ipilimumab or nivolumab monotherapy, although at an increased rate; 53% of 
patients experienced Grade 3 or 4 AEs compared to ipilimumab alone (20% of 
patients) or nivolumab alone (15% of patients).10  Sequential administration 
resulted in a lower response rate and lower toxicity rate.  With regard to biomarkers 
previously associated with responses to anti-CTLA4 or anti-PD1, investigators 
evaluated PD-L1 expression in tumors and absolute lymphocyte counts and looked 
for relationships with response.  In patients treated concurrently, 6/13 patients with 
PD-L1+ tumors responded whereas 9/22 patients with PD-L1– tumors responded 
(P>0.99 by Fisher’s exact).  Interestingly however, in the sequential group, 4/8 
patients whose tumors were PD-L1+ responded whereas only 1/13 who had PD-
L1- tumors responded.  Absolute lymphocyte counts at weeks 5-7 were not 
associated with response in this study.  In summary, the combination anti-CTLA4 
plus anti-PD1 administered concurrently induces impressive durable response 
rates in metastatic melanoma which are higher than that reported with any previous 
therapy.  Given that this is a non-randomized study however, the results must be 
interpreted with caution. 
 
Nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) has been FDA 
approved for adults with BRAF wild-type melanoma. Approval was based on data 
from CheckMate 069 trial which randomized patients with previously untreated, 
unresectable stage III or IV melanoma to receive nivolumab (1 mg/kg) plus 
ipilimumab (3 mg/kg) vs. ipilimumab (3 mg/kg) plus placebo. Patients treated on 
the nivolumab plus ipilimumab received the combination every 3 weeks x 4 doses 
then received nivolumab single agent 3 mg/kg every 2 weeks. Treatment-related 
grade 3−4 adverse events were reported in 51 (54%) of 94 patients who received 
nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received 
ipilimumab alone. The most common treatment-related grade 3−4 adverse events 
were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten 
[11%]) in the combination group and diarrhea (five [11%] of 46 patients) and 
hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3−4 
treatment-related adverse events were reported in 34 (36%) of 94 patients who 
received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, 
and diarrhea in five [5%]) compared with four (9%) of 46 patients who received 
ipilimumab alone (including diarrhea in two [4%] of 46 patients, colitis in one 
[2%], and hypophysitis in one [2%]) The 2-year overall survival was 63.8% (95% 
CI 53.3% (.6) for those assigned to nivolumab plus ipilimumab and 53.6% (95% 
CI 38.1% (.8) for those assigned to ipilimumab alone.23  
 
 
Pharmacology/Pharmacokinetic Studies 
Pharmacokinetic studies in adults in the Topalian study showed a median time to 
peak concentration of 1-4 hours after the start of the one hour infusion and a dose 
proportion increase in peak concentration and area under the curve with increasing 
dose across the dose range 0.1 mg/kg-10 mg/kg.8 Half-life is 2-4 weeks, similar to 
other therapeutic antibodies. Minimum concentrations 15 days after the first dose 
3 mg/kg of Nivolumab from 34 adults treated on CA209003 are shown in Table 2. 
Based upon this, the pediatric trial will seek to target a minimum exposure of 10 
mcg/ml. 
Table 2. Trough Nivolumab 
Concentrations in Adults  

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 16 
 
Percentile 
Cmin 
(mcg/ml) 
Min 
6.9 
5 
8.9 
10 
11.0 
15 
11.3 
20 
12.4 
25 
13.0 
30 
14.3 
35 
15.0 
40 
17.0 
45 
17.2 
50 
17.6 
55 
18.0 
60 
19.9 
65 
21.0 
70 
22.1 
75 
24.1 
80 
24.5 
85 
25.4 
90 
28.6 
95 
31.2 
Max 
38.1 
 
Pharmacodynamic analysis of PD-1 receptor occupancy revealed 64-70% occupancy 
across the range of dose levels tested.  Tumors were analyzed for PD-L1 expression from 
archival samples in 42 patients.  Of these, samples from 25 patients showed PD-L1 
expression by immunohistochemical analysis (cutoff for positivity being > 5% of cells 
expressing PD-L1).  Responses were observed in 9/25 patients with PD-L1 expression by 
IHC, whereas 0/17 patients without PD-L1 expression showed antitumor responses with 
anti-PD1 therapy.  More recent data from Grosso and colleagues assessed objective 
response rates to nivolumab in patients with melanoma using a cutoff of 5% PD-L1 
expression.  In this study, 14% of patients with PD-L1 negative tumors had objective 
antitumor responses compared to 41% of patients with PD-L1+ tumors. 24  
 
In summary, anti-PD1 mAbs demonstrate response rates of 30-50% in patients with 
melanoma and 20-30% in patients with renal cell carcinoma and non-small cell lung 
cancer.  Toxicities associated with checkpoint inhibition are primarily limited to 
autoimmune reactions.  These occur in approximately 30% of adults and children treated 
with anti-CTLA4, but in <10% of patients treated with anti-PD1.  Thus, compared to anti-

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 17 
 
CTLA4, anti-PD1 based checkpoint inhibitors demonstrate more potent antitumor effects 
across a wider range of histologies, with less toxicity.  Preliminary studies in adults have 
demonstrated higher response rates in patients with tumors expressing of the PD-L1, the 
major ligand for PD1, although antitumor responses have also been seen in patients with 
PD-L1 negative tumors.  Thus, there is currently no accurate biomarker to predict tumor 
response to anti-PD1 therapy.  In a single arm, non-randomized study, combination therapy 
with anti-PD1 plus anti-CTLA4 resulted in higher response rates for metastatic melanoma 
than observed with either agent alone, with a similar toxicity profile to that observed with 
anti-CLTA4 mAb therapy.10  Preclinical studies have demonstrated antitumor effects of 
anti-PD1 in a murine model of rhabdomyosarcoma, but there is currently limited 
information about PD-L1 expression in pediatric tumors.  
 
2.4 
Pediatric Studies 
 
Prior Experience in Children  
A pediatric Phase I trial of ipilimumab, sponsored by CTEP and led by the 
Pediatric Oncology Branch of the NCI is nearing completion.  Ipilimumab was 
administered to patients 2-21years old with refractory solid tumors. Dose cohorts 
included 1, 3, 5, and 10 mg/kg IV in a standard 3 + 3 design with 4 doses of 
induction therapy every 3 weeks followed by maintenance every 3 months until 
disease progression or unacceptable toxicity. Tumors were measured after 6 
weeks, 12 weeks, and then every 3 months.  Thirty patients with pediatric solid 
tumors (melanoma n=10, osteosarcoma n=8, soft tissue sarcomas n=7, renal 
malignancies n=3 and neuroblastoma n=2) have been enrolled.   Subjects >12 years 
of tolerated the highest dose of 10 mg/kg tested.  For subjects < 12 years of age, 3 
mg/kg was tolerated without DLT, however DLT was observed in 2 subjects < 12 
years treated at 10 mg/kg. In children < 12 years, the MTD was 5mg/kg.  Grade 
3/4 immune related adverse events (IrAE) included colitis (3) transaminitis (2), 
autoimmune thyroiditis (1), pancreatitis (1), and hypophysitis (1).  Except for a 
lesser incidence of rash, this frequency and spectrum of IrAE appears similar to 
that observed in adults treated with ipilimumab.  IrAE developed as early as week 
1 and as late as 36 weeks, but the majority occurred in the first three 
weeks.  Confirmed stable disease (stable disease at both 6 and 12 week scans) was 
the best response in 5 patients with melanoma, clear cell sarcoma or osteosarcoma, 
with a duration of 3 -18 months. Pharmacokinetics revealed no significant 
differences related to age and the exposure to ipilimumab in children was 
essentially the same as that for adults given the equivalent mg/kg dose. Although 
this study raises the prospect that younger children may have lesser tolerance to 
anti-CTLA4 therapy as compared to adolescents, this is based upon very small 
numbers and may not be truly related to differences in biology. 
 
We have demonstrated tolerability of the combination at nivolumab 3 mg/kg and 
ipilimumab 1 mg/kg in Part C. An open question remains if the combination dosing 
is optimal as delivered in Part D. Reports have suggested improved efficacy at a 
higher ipilimumab dose. Antonia et al. demonstrated tolerability and potential 
survival benefit in patients treated with 1 mg/kg nivolumab in combination with 3 
mg/kg ipilimumab in patients with small cell lung cancer.25  Other studies at this 
dose combination are ongoing. In order to test this dose combination, we will test 
in Part E and limit to children with rhabdomyosarcoma or Ewing 
sarcoma/Peripheral PNET. The rationale for including children with 
rhabdomyosarcoma is that in Part D, out of all the histologic cohorts treated with 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 18 
 
combination, we observed one PR to the combination at the Part D dose in a patient 
with rhabdomyosarcoma. Thus, we will test the combination of nivolumab (1 
mg/kg) with ipilimumab (3 mg/kg) to determine if the increased dose of 
ipilimumab demonstrates improved efficacy in a cohort of pediatric patients with 
rhabdomyosarcoma or Ewing sarcoma/Peripheral PNET. 
 
2.5 
Overview of Proposed Pediatric Study 
Initially the study opened with 3 parts (Part A, Part B, and Part C) and has been amended 
to add parts D and E. 
 
Part A will aim to define the recommended phase 2 dose (RP2D), which is a tolerable dose 
of nivolumab that provides systemic exposure similar to that achieved by the RP2D in 
adults. The goal of Part A will be to enroll at least 6 children with recurrent or refractory 
solid tumors, excluding CNS tumors.  Patients enrolled on Part A must have measurable 
or evaluable disease.  Part A will enroll at 3 mg/kg nivolumab every 14 days until disease 
progression or until toxicity requires treatment discontinuation.  A cycle will be considered 
28 days (2 doses) and the DLT monitoring period will be 28 days. Patients will be 
monitored for toxicity using standard CTCAE v.5 criteria. If DLT is observed in 2 or 
greater patients, the dose will be de-escalated to 1 mg/kg every 2 weeks and an additional 
cohort will be evaluated for toxicity and exposure at that dose level.  
 
Part A will seek to ascertain that children treated at the 3 mg/kg dose (or 1 mg/kg dose if 
de-escalation occurs) do not experience significantly less drug exposure than adults treated 
at the 3 mg/kg dose level. Table 2 demonstrates the 95% confidence interval for nivolumab 
Cmin after the first dose is approximately 10-30 mcg/ml. Therefore, Cmin levels for 
patients treated in Part A will be evaluated prior to initiation of Part B. If at least 5 of 6 
patients achieve a Cmin of at least 10 mcg/ml, we will conclude that children are not 
experiencing significantly less exposure than adults treated at the same dose.  If however, 
< 5 of 6 patients achieve a Cmin of at least 10 mcg/ml, consideration will be given to a 
protocol amendment to test a higher dose level in Part A.  Note that Cmin levels > 30 
mcg/ml will not, in and of itself result in a change in protocol design, unless excess toxicity 
is observed. 
 
Except for patients with neuroblastoma and MIBG only disease, response assessment will 
use standard RECIST criteria.  Determination of progression will use target selection and 
single dimension measurements according to RECIST criteria. Patients will be removed 
from study if tumor size increases from baseline in target lesions selected according to 
RECIST criteria.  However, because a minority of subjects treated with immunotherapy 
may derive clinical benefit despite initial evidence of progressive disease (e.g. 
pseudoprogression) patients will be allowed to remain on study if the magnitude of increase 
in tumor size is <40% and the bulleted criteria below are met.  Patients who develop a new 
lesion while on study are eligible to remain on study if they meet the criteria bulleted below 
and the sum of the total tumor burden remains < 40% according to RECIST criteria.  These 
are adapted from similar criteria already in place in trials of checkpoint inhibitors in adults 
with cancer and have been utilized in the Phase I trial of ipilimumab in children.  Additional 
criteria required in order to allow a patient to remain on study despite an increase in tumor 
size of > 20% but < 40% are the following: 
• 
In the judgment of the treating clinician, the patient does not show evidence for 
rapid disease progression and/or the patient has shown evidence for clinical 
benefit.    

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 19 
 
• 
There is no decrease in performance status. 
• 
The patient is tolerating the study drug and has not experienced a DLT. 
• 
Continued treatment with nivolumab alone or in combination with ipilimumab will 
not delay an imminent intervention required to prevent a serious complications 
(e.g. CNS metastases which require radiation therapy or surgery). 
For patients who remain on study despite increase in tumor size of > 20%, imaging to 
include target lesions must occur following every cycle if clinically indicated, and the same 
radiographic and clinical criteria must be met in order to remain on study.  If tumor size 
subsequently diminishes to < 20% increase from baseline, the patient may be followed 
according to the standard protocol guidelines which will involve less frequent imaging.  
The decision to continue treatment beyond radiographic evidence for disease progression 
should be discussed with the Study Chair and/or her designee and documented in the study 
record. 
 
Response for patients with MIBG only neuroblastoma will be assessed according to 
Section 12.4.2.   
 
Once a RP2D is identified in Part A, an expansion cohort of up to 6 additional patients will 
be treated at the nivolumab monotherapy RP2D to acquire PK data in a representative 
number of young patients (i.e. 6 patients < 12 years of age and 6 patients ≥ 12 years).  
 
Twelve evaluable patients were enrolled to Part A (June 2017).  None had dose limiting 
toxicity, the RP2D of single agent nivolumab was determined to be 3 mg/kg IV q14 days.  
Pharmacokinetic parameters were similar to adults. In children (n=11), the nivolumab 
Cmax  (n=11) was 63.2 ± 15.7 mg/mL, half-life was 10.7±1.8 days and clearance  was 
0.196 ± 0.075 mL/h/kg.26 
 
Part B and Part C will open simultaneously. Part B will evaluate the activity of nivolumab 
at its RP2D in expanded cohorts with the goal of enrolling at least 10 patients per tumor 
type: neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Hodgkin 
lymphoma, and non-Hodgkin lymphoma. Measurable disease is required for enrollment on 
Parts B1-B6, measurable or evaluable disease is required for Part B7 (melanoma) and 
MIBG evaluable disease without measurable disease in patients with neuroblastoma (Part 
B8). Patients aged 1-30 years may enroll on Parts B1-B6, B8; patients < 18 years may 
enroll on Part B7. The primary objective of Part B is to identify histologic subtypes where 
there is a signal for anti-tumor activity, using a Simon’s optimal two-stage design, with the 
exception of Part B7, which will serve as a non-statistical access cohort (without minimum 
or maximum accrual limits) for the rare diagnosis of melanoma, to remain open to 
enrollment until Parts B1-B6, B8 are complete. Note that patients who have an initial 
increase in target lesions but eventually show a response according to RECIST criteria will 
be considered responders for the purpose of defining response in Cohort B. Parameters for 
response and progression are measured in relation to baseline measurements. 
 
Preliminary data from Part B (June 2017, nivolumab 3 mg/kg  every 14 days) for  
osteosarcoma (n=10), Ewing sarcoma (n=10), and rhabdomyosarcoma (n=10) was 
presented at ASCO 2017.26 There were no objective responses. Enrollment to first stage of 
Hodgkin lymphoma, neuroblastoma measurable disease, and neuroblastoma MIBG 
evaluable disease cohorts is completed and response assessment pending. 
 
Part C will aim to enroll at least 15 patients with the same eligibility criteria required for 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 20 
 
enrollment on Part A, with the goal of identifying the MTD or RP2D of the combination 
of nivolumab plus ipilimumab. The first dose level will be nivolumab at 1 mg/kg and 
ipilimumab at 1 mg/kg with the goal of enrolling at least 3 patients at this dose level, with 
both agents administered every three weeks x 4 followed by nivolumab 3 mg/kg every 2 
weeks until disease progression or toxicity.  The second dose level will be nivolumab at 3 
mg/kg and ipilimumab at 1 mg/kg on the same schedule, with the goal of enrolling at least 
12 patients at this dose level. An expansion cohort of up to 6 additional patients will be 
treated at the nivolumab/ipilimumab combination RP2D to acquire PK data in a 
representative number of young patients (i.e. 6 patients < 12 years of age and 6 patients ≥ 
12 years in Part C).  If dose level 1 is not tolerated due to toxicity there will be no de-
escalated dose studied. 
 
Except for patients with neuroblastoma and MIBG only disease, response assessment will 
use standard RECIST, with the caveats regarding pseudo-progression noted above.   
Patients with primary brain tumors or active CNS metastases will be excluded from this 
trial due to concerns regarding pseudo-progression in the CNS. Patients with a history of 
CNS metastases that have been previously treated may enroll if sequential imaging shows 
no evidence for active disease. Patients with extra axial disease [e.g. skull (bone) metastasis 
that do not invade the dura] may enroll if there is no evidence for CNS edema associated 
with the lesion. Patients on systemic corticosteroids and/or with a history of autoimmunity 
or previous allogeneic stem cell transplant will also be excluded. Management of 
autoimmune toxicities will be guided by algorithms (Appendix VIII) developed for 
nivolumab in adults and for ipilimumab in children with cancer, where autoimmune 
toxicity was also observed. 
 
In Part C (June 2017) of the study, five evaluable patients enrolled at dose level 1 
(nivolumab 1 mg/kg) in combination with ipilimumab (1 mg/kg), none had dose limiting 
toxicity. At dose level 2, nivolumab (3 mg/kg) in combination with ipilimumab (1 mg/kg), 
twelve patients were evaluable and one had grade 2 creatinine elevation that met criteria 
for dose limiting toxicity. Part C has demonstrated that nivolumab (3 mg/kg) in 
combination with ipilimumab (1 mg/kg) is tolerated in children and adolescents.26 
 
2.6 
Rationale for Inclusion of Melanoma Cohort (Amendment #2B) 
With Amendment #2A, a non-statistical cohort for melanoma patients was added. 
Nivolumab is approved for metastatic or unresectable melanoma based upon an objective 
response rate of 32% and a duration of response greater than 6 months in approximately 
one third of responders. Currently, there is no treatment FDA approved for pediatric 
patients with melanoma.  Other agents approved for adult melanoma include interferon 
alpha, anti-CTLA4 (ipilimumab), BRAF inhibitors (vemurafenib, dabrafenib), and a MEK 
inhibitor (trametinib) approved for combination therapy with BRAF inhibitors.  Notably, 
BRAF inhibitors require a BRAF mutation for activity and this occurs in only 
approximately 50% of pediatric and adult melanomas.  Furthermore, responses to BRAF 
inhibition have been short lived. A Phase 2 trial of BRAF inhibition in pediatric melanoma 
has been initiated but has not been completed.  A Phase 1 trial of ipilimumab was 
completed in children and enrolled 11 patients with melanoma, but there were no objective 
responses and substantial autoimmune toxicity was observed.27 Interferon alpha has a low 
response rate in adult melanoma and significant side effects.  Thus, there are currently 
limited options for children with metastatic or unresectable melanoma.  It is important that 
information be gleaned on the efficacy and toxicity of nivolumab in the pediatric melanoma 
population given the likelihood that children with melanoma will be offered this agent.  
Although the rarity of the disease limits the likelihood that a statistically complete cohort 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 21 
 
can be achieved, enrollment of even limited numbers of patients could potential provide 
important information regarding the activity and tolerability of nivolumab in pediatric 
melanoma. 
 
2.7 
Rationale for Inclusion of Neuroblastoma- MIBG Evaluable Cohort (Amendment 
#2C) 
Anti-GD2 mAb therapy is the only immunotherapy with demonstrated antitumor activity 
in solid tumors of childhood. An unconjugated chimeric anti-GD2 mAb (ch14.18) 
demonstrated significant improvements in event free and overall survival when 
administered to patients following autologous stem cell transplantation.2 Importantly 
however, this same therapy demonstrated very limited evidence for antitumor activity in a 
Phase I trial when it was tested in patients with neuroblastoma measurable with standard 
radiographic imaging.28 Similarly, an anti-GD2 mAb conjugated with IL-2 (hu14.18-IL2) 
showed very limited activity in patients with radiographically measurable neuroblastoma.29  
However, when the agent was tested in a Phase II trial enrolling both a radiographically 
measurable strata and a limited disease burden strata, 0/13 patients with disease measurable 
using standard radiographic criteria showed antitumor response following treatment with 
hu14.18-IL2, whereas 5/23 patients enrolled in the non-radiographically measurable cohort 
experienced complete responses to this immunotherapy.30 All responders to hu14.18-IL2 
were patients with limited disease burden. Preclinical data demonstrates evidence for an 
immunosuppressive microenvironment that may be responsible for limited benefit of 
immune based therapies for neuroblastoma in the setting of bulk disease.31 Based upon 
these data, there is reason to hypothesize that immunotherapy for neuroblastoma may be 
more effective if undertaken in the setting of limited disease burdens. In an effort to capture 
a neuroblastoma cohort with more limited disease burden in this study of nivolumab, we 
will enroll patients with MIBG evaluable lesions (without measurable disease by RECIST), 
which is expected to accrue patients with more limited disease burdens than patients who 
will be enrolled on the neuroblastoma cohort comprising patients with radiographically 
measurable disease.  Standard response criteria are already validated for MIBG only 
neuroblastoma and will be used to measured response for this cohort. 
 
2.8 
Incidence and Proposed Management of Pleural Effusions in Patients Treated with 
Nivolumab 
As of October 22, 42 patients have been accrued to ADVL1412 and 5 cases of pleural 
effusion were reported. All involved patients with sarcoma (osteosarcoma n=2, 
rhabdomyosarcoma n=1, Ewing sarcoma n=1, epithelioid sarcoma n=1).  Four patients 
received nivolumab alone whereas one patient received a combination of nivolumab and 
ipilimumab. In all cases, the effusion was associated with radiographic evidence of 
enlargement of the underlying lung mass(es) suggesting disease progression.  Five of five 
patients for whom data is available did have baseline pleural disease associated with the 
malignancy, although twenty six other patients enrolled on ADVL1412 also had pleural 
disease at the time of enrollment and did not develop evidence of pleural effusion. In two 
cases pleural fluid was studied for the presence of tumor cells, and tumor cells were not 
identified, although one case was a bloody effusion. Two cases were treated with comfort 
measures only based upon the premise that the pleural effusion represented disease 
progression. These were associated with patient deaths, which were not attributed to the 
study drug. Based upon this experience, the possibility that the pleural effusions may be 
associated with nivolumab ± ipilumumab and could represent an inflammatory response 
was considered. The protocol has been modified in Section 6.8 to recommend aggressive 
supportive care for all patients who present with pleural effusion and a trial of 
corticosteroids for patients who present with pleural effusions of Grade 2 or greater.   

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 22 
 
 
2.9 
Rationale for Inclusion of Part D (Amendment #4) 
Part C of the study has demonstrated that nivolumab (3 mg/kg) in combination with 
ipilumumab (1 mg/kg) is tolerated in children and adolescents. As of June, 2016, some 
disease specific cohorts included in Part B, specifically the sarcoma subtypes have met first 
stage accrual or are near to accrual to the initial stage of the Simon’s optimal two-stage  
(osteosarcoma, rhabdomyosarcoma, Ewing’s sarcoma). As recently presented in abstract 
form, single agent PD-1 blockade with pembrolizumab has shown little activity in 
osteosarcoma and Ewing’s sarcoma.32 In melanoma, response rates to combination 
nivolumab/ipilimumab are higher in melanoma than with single agent nivolumab; 
therefore, it is important to determine if the combination regimen might show activity in 
pediatric solid tumors.  Hence, for select disease cohorts which will not progress beyond 
the initial stage in Part B due to lack of objective responses to single agent nivolumab, we 
will evaluate the combination of nivolumab with ipilumimab using the RP2D of nivolumab 
3 mg/kg and ipilumimab 1mg/kg at the same schedule as utilized in Part C. 
 
As of April 2018, 46 patients have been treated with the combination of nivolumab (3 
mg/kg) and ipilimumab (1 mg/kg) either on Part C or Part D of ADVL1412. The 
combination and doses have been well tolerated. 
2.10 
Rationale for Inclusion of relapsed lymphoma patients post-allogeneic transplant 
(AMD#4) 
Given the promising data in adults treated with nivolumab for relapsed or refractory 
lymphoma (NHL and Hodgkin’s disease)33 and the May 2016 FDA approval of nivolumab 
for patients with Hodgkin’s Disease, we propose to extend eligibility for patients with 
lymphoma to include those who have previously received an allogeneic stem cell 
transplant.  For patients with an available donor, allo-SCT is commonly administered in 
the relapse setting. Thus exclusion of these patients is likely to provide a significant 
limitation to enrollment for the lymphoma disease specific arms.34 Reports have 
demonstrated safety of targeting PD-1 in the post allo-SCT setting.35,36  Given these reports 
of safety, we will extend eligibility to include lymphoma patients meet the following 
criteria:  at least 100 days post allo-SCT, no evidence for GVHD at the time of enrollment 
and no requirement for immunosuppression.   
 
Depending on the response to single agent Nivolumab as seen in cohort B6 (non-Hodgkin 
lymphoma), it is possible that a cohort D5 will open which will administer a combination 
of ipilimumab and nivolumab in the post-allogeneic transplant setting. This combination 
of checkpoint therapy has not previously been used within 180 days of allogeneic SCT. 
Both agents have been used as single agents in the post-allogeneic SCT setting, ipilimumab 
has shown safety and efficacy in this setting at higher dosing levels (3 mg/kg and 10 
mg/kg).37 
 
As of April 2018, ten evaluable patients with Hodgkin lymphoma have enrolled to part B 
(single agent nivolumab) and several have shown reduction in the size of tumors following 
treatment with nivolumab.  Formal evaluation of response rate is ongoing and some 
patients remain on study.  However, based upon this data and data from a pediatric study 
evaluating pembrolizumab in Hodgkin lymphoma as well as reports of children treated off-
study, it appears clear that nivolumab as a single agent, has activity in pediatric Hodgkin 
lymphoma. Thus far, there is no evidence that activity in children or adolescents is distinct 
from that observed in adults.33 Future studies are planned to incorporate nivolumab into 
multiagent regimens for pediatric Hodgkin lymphoma. For this reason, we plan to close 
the Hodgkin lymphoma strata on this trial and refer those patients to other open trials. 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 23 
 
 
2.11 
Rationale for Inclusion of Part E (Amendment #8B) 
Nivolumab in combination with ipilimumab remains an open question. We have 
demonstrated tolerability with the combination at nivolumab 3 mg/kg and ipilimumab 1 
mg/kg. An open question remains if the dosing in this combination, as delivered in Part D 
is optimal as the FDA approved dose for metastatic melanoma employs a higher dose of 
ipilimumab (3 mg/kg) with nivolumab (1 mg/kg).38 Similarly, Antonia et al. demonstrated 
tolerability and potential survival benefit in patients treated with 1 mg/kg nivolumab in 
combination with 3 mg/kg ipilimumab in patients with small cell lung cancer and testing 
with this dosing regimen is ongoing in advanced small cell lung cancer.25  Furthermore, in 
urothelial carcinoma, ipilimumab 3 mg/kg with nivolumab 1 mg/kg appears to be equally 
safe and more effective than an ipilimumab 1 mg/kg with nivolumab 3 mg/kg regimen.39 
 
In contrast, the higher dose of ipilimumab (3 mg/kg) with 1 mg/kg nivolumab exceeded 
the DLT in adults with advanced non-small cell lung cancer40. Similarly, the FDA approved 
dosing regimen for combination therapy in renal cell cancer is ipilimumab 1 mg/kg and 
nivolumab 3 mg/kg, Thus, the optimal dosing regimen for combination therapies may vary 
with disease and patient population treated.  
 
The response rate of nivolumab (3 mg/kg) alone and nivolumab (3 mg/kg) in combination 
with ipilimumab (1 mg/kg) has been low in this pediatric study providing rationale to study 
a different dose combination in Part E. Part D (nivolumab 3 mg/kg and ipilimumab 1 
mg/kg) will close to accrual with this amendment. To determine if the increased dose of 
ipilimumab demonstrates efficacy in pediatric solid tumor histologies, we will launch Part 
E to look for a signal of efficacy with the regimen of ipilimumab 3 mg/kg plus nivolumab 
1 mg/kg.  Part E will look for evidence of a response in patients with rhabdomyosarcoma 
(E3) or Ewing sarcoma/Peripheral PNET (E4). A 10+10 Simon two-stage design will be 
used for Part E. All patients enrolled into Parts E3 or E4 will be combined into a single 
cohort for evaluation of response and toxicity. Assuming that the study does not close due 
to toxicity, enrollment will include at least 4 rhabdomyosarcoma patients and 4 Ewing 
sarcoma/Peripheral PNET patients in stage 1. If the study continues to stage 2, then the 
overall study will include at least 8 patients in each of the two disease cohorts. If at least 
one Cycle 1 dose limiting toxicity occurs among the first 10 patients or 4 dose limiting 
toxicities among 20 patients, then the study will close and conclude that the dose level is 
too toxic.  Otherwise, the study will plan to enroll a total of 20 response-evaluable pediatric 
patients.   
 
Ipilimumab at 3 mg/kg as single agent has been tested in pediatric patients and found to be 
tolerable.41 Data from Part A and Part C of this study have demonstrated tolerability and 
safety of both single agent nivolumab at 3 mg/kg, also when used in combination with 1 
mg/kg of ipilimumab. Thus, we anticipate the combination regimen of ipilimumab 3 mg/kg 
and nivolumab 1 mg/kg to be well tolerated.  
 
2.12 
Rationale for Secondary Aims 1.2.3-1.2.5 (Amendment #8B) 
Clinical response to targeted checkpoint inhibitors has been associated with upregulation 
of the target protein on the tumor tissue.42,43 Mazjner et al. performed a large survey of 
primary pediatric tumor samples (400+) for presence of tumor infiltrating immune cells 
and expression of PD-L1 on the tumor cells themselves.44,45 This survey included primary 
samples comprising multiple tumors including osteosarcoma, Ewing sarcoma, 
rhabdomyosarcoma, neuroblastoma, soft tissue sarcomas, non-Hodgkin’s lymphoma, 
Wilms tumor, and brain tumors in pediatric patients. Seventy-two percent of tissue sections 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 24 
 
did stain positive for the presence of tumor infiltrating lymphocytes (TILs) and 20% 
positive for macrophages. The role of tumor infiltrating T-cells and their subsets has been 
well established in solid tumors. Thus, we will use immunohistochemistry on diagnostic 
tissue submitted to assess presence of TILs for patients enrolled on study. 
Clinical success with checkpoint inhibitors has been associated with the degree of genetic 
instability that occurs due to mutations in tumors resulting in expression of unique 
neoantigens which can be recognized by the immune system. Neoantigens are peptides not 
normally found in healthy cells since they result from somatic alterations only present in 
the tumor 46. It has been shown that a higher level of mutations or neoantigens is associated 
with higher response rates by check–point inhibitors supporting the immunosuppression 
mediated by the PD-1 pathway. Indeed, checkpoint inhibition as a therapeutic approach 
has been most successful in tumors with high burdens of non-synonymous somatic 
mutations including melanoma, non-small cell lung cancer, renal cell carcinoma and 
bladder cancer. 47 By contrast, pediatric tumors and in general hematological malignancies 
are relatively genomically stable and driven by single translocations or gene amplifications 
(e.g. myc-n in neuroblastoma). Thus, these tumors may be less responsive to checkpoint 
inhibition due to a lower number of antigenic peptides which to mount an immune 
response. However, the mutation burden and its correlation with checkpoint inhibition in 
pediatric hematological malignancies needs to be studied further. To address tumor 
mutational burden, we will perform FoundationOneCDx testing, to determine the presence 
of somatic mutations and determine if there is an association with response to nivolumab, 
either as a single agent or in combination with ipilimumab.  
 
Adults treated with nivolumab alone and in combination with ipilimumab show an 
induction in IFNgamma-induced cytokines in serum (personal communication with BMS).  
This study will generate cytokine data that could be used to compare adult and pediatric 
populations with respect to a functional parameter of immune system-related effects (e.g. 
such as induction of IFNgamma-induced cytokines) of nivolumab alone and in 
combination with ipilimumab.   
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Oncology Patient Enrollment Network (OPEN), a web-based registration 
system available on a 24/7 basis. It is integrated with the NCI Cancer Trials Support Unit (CTSU) 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
position in the RAVE database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account (check at < https://ctepcore.nci.nih.gov/iam/index.jsp >). This is the same account 
(user id and password) used for credentialing in the CTSU members' web site (refer to Appendix 
X for CTEP and CTSU registration procedures). To perform registrations in OPEN, the site user 
must have been assigned the 'Registrar' role on the relevant Group or CTSU roster. 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. Registrars must hold a minimum of an AP registration type.   
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise 
System for regulatory and roster data and, upon enrollment, initializes the patient position in the 
Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 25 
 
crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in OPEN, the 
IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on the site’s IRB 
approval.   
  
 
3.1 
Current Study Status  
Investigators should refer to the COG website to determine if the study is currently open 
for accrual.  If the study is listed as active, investigators should then access the Studies 
Requiring Reservations page to ensure that a reservation for the study is available. To 
access the Studies Requiring Reservations page:  
1. Log in to https://open.ctsu.org/open/ 
2.  Click the Slot Reservation Tab. The Site Patient page opens.  
3.  Click the Report Tab. The Slot Reservation Report opens. Available Slots are 
detailed per study strata. 
 
3.2 
IRB Approval 
NCI Pediatric CIRB or local IRB approval of this study must be obtained by a site prior to 
enrolling patients. Sites must submit CIRB/IRB approvals to the NCI’s Cancer Trials 
Support Unit (CTSU) Regulatory Office and allow 3 business days for processing. 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 (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 Regulatory Tab. 
 
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.  
 
Submitting Regulatory Documents:   
 
Submit required forms and documents 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 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
For general (non-regulatory) questions, call the CTSU General Helpdesk at 1-888-823-
5923 or contact CTSU by email at ctsucontact@westat.com. 
 
Study centers can check the status of their registration packets by accessing the Site 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 26 
 
Registration Status page on the CTSU Member’s Website under the Regulatory Tab. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory 
Office.) 
 
 
 
3.3 
Patient Registration in the COG Registry 
Prior to enrollment on 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. 
 
3.4 
Reservation and Contact Requirements 
Once a slot-reservation confirmation is obtained after making a reservation in OPEN, the 
Study Chair or Vice Chair should be notified and site staff may then proceed to enroll 
patients to this study. (The patient will need a COG patient ID number in order to obtain a 
reservation). Patients must be enrolled within 7 calendar days of making a reservation.  
 
Reservations may be obtained 24-hours a day through the OPEN website.  
 
3.5 
Informed Consent/Assent  
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. 
 
3.6 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through one of the following mechanisms: a) the COG screening protocol, b) an IRB-
approved institutional screening protocol or c) the study-specific protocol.  Documentation 
of the informed consent for screening will be maintained in the patient’s research chart. 
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
3.7 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment. 
 
3.8 
Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into RAVE. The report must 
include the associated study number and COG patient registration and accession numbers. 
Personal identifiers, including the patient’s name and initials must be removed from the 
institutional pathology report prior to submission. 
 
3.9 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Patients who give informed consent for the protocol in order to undergo 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 27
screening for eligibility are not considered enrolled and should not be enrolled until the 
screening is completed and they are determined to meet all eligibility criteria. Study 
enrollment is accomplished by going to the CTSU OPEN (Oncology Patient Enrollment 
Network) https://open.ctsu.org/open/. For questions, please contact the CTSU OPEN 
helpdesk at https://www.ctsu.org/CTSUContact.aspx.  Patients must be enrolled before 
treatment begins.  The date protocol therapy is projected to start must be no later than five 
(5) calendar days after the date of study enrollment. Patients must not receive any 
protocol therapy prior to enrollment.
3.10
Dose Assignment
The dose level will be assigned via OPEN at the time of study enrollment.
4.0
PATIENT ELIGIBILITY
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 older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum  creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies must be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging
if necessary).
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.  
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01).  All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the 
time of audit.
4.1
Inclusion Criteria
Age:  
4.1.1.1 Parts A & C:  Patients must be ≥ 12 months and < 18 years of age at the 
time of study enrollment.
4.1.1.2 Parts B1-B6, B8, D1-D6, E3, E4: Patients must be ≥ 12 months and 30
years of age at the time of study enrollment.
4.1.1.3 Part B7: Patients must be ≥ 12 months and < 18 years of age at the time 
of study enrollment.
Diagnosis: Patients must have had histologic verification of malignancy at 
original diagnosis or relapse. 
4.1.2.1 Parts A & C: Patients with recurrent or refractory solid tumors, without
CNS tumors or known CNS metastases are eligible. Note: CNS imaging 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 28
for patients without a known history of CNS disease is only required if 
clinically indicated.
4.1.2.2 Part B1: Patients with relapsed or refractory neuroblastoma
Part B2: Patients with relapsed or refractory osteosarcoma
Part B3: Patients with relapsed or refractory rhabdomyosarcoma
Part B4: Patients with relapsed or refractory Ewing Sarcoma or 
Peripheral PNET
Part B5: Patients with relapsed or refractory Hodgkin Lymphoma
Part B6: Patients with relapsed or refractory Non-Hodgkin Lymphoma
Part B7: Patients with unresectable melanoma or metastatic melanoma 
or relapsed melanoma or refractory melanoma
Part B8: Patients with relapsed or refractory neuroblastoma (MIBG 
evaluable disease without RECIST measurable lesion)
Once the dose-escalation portion of Part A is completed, cohorts that are 
open concurrently for eligible patients (including Parts B and C and 
potential PK expansion cohorts) may be selected at the treating physician’s 
discretion pending slot availability. In the event a disease group cohort in 
Part B is completed after the initial stage of Simon’s optimal two-stage 
design (Section 11.4), for selected disease cohorts (Section 4.1.2.3), a 
corresponding cohort in the same disease group for select disease types 
will be open in Part D:
4.1.2.3 Part D1: Patients with relapsed or refractory neuroblastoma
Part D2: Patients with relapsed or refractory osteosarcoma
Part D3: Patients with relapsed or refractory rhabdomyosarcoma
Part D4: Patients with relapsed or refractory Ewing Sarcoma or 
Peripheral PNET
Part D5: Patients with relapsed or refractory Non-Hodgkin Lymphoma
Part D6: Patients with relapsed or refractory neuroblastoma (MIBG 
evaluable disease without RECIST measurable lesion)
4.1.2.4 Part E3: Patients with relapsed or refractory rhabdomyosarcoma
Part E4: Patients with relapsed or refractory Ewing Sarcoma or 
Peripheral PNET
Disease Status: 
4.1.3.1 Parts A & C: Patients must have either measurable or evaluable disease 
(see Sections 12.2 and 12.3 for definitions). 
4.1.3.2 Parts B, D, & E:  Patients must have measurable disease (see Section 12.2 
for definitions) for Parts B1-B6, D1-D5, E3 and E4. Melanoma patients in 
Part B7 must have either measurable or evaluable disease. Neuroblastoma 
patients in Parts B8 and D6 must be evaluable for MIBG response without 
evidence of RECIST measurable lesions (see Section 12.4 for definitions).
Therapeutic Options: Patient’s current disease state must be one for which 
there is no known curative therapy or therapy proven to prolong survival with 
an acceptable quality of life.
Performance Level:  Karnofsky 50% for patients > 16 years of age and 
Lansky 60 for patients 16 years of age (See Appendix I).  Patients who are 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 29
unable to walk because of paralysis, but who are up in a wheelchair, will be 
considered ambulatory for the purpose of assessing the performance score.
Prior Therapy
4.1.6.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the defined eligibility criteria are met, e.g. blood count criteria, 
the patient is considered to have recovered adequately.
a.
Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See DVL homepage for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment.
i.
At least 21 days after the last dose of cytotoxic or
myelosuppressive 
chemotherapy 
(42 
days
if 
prior 
nitrosourea).
b.
Hematopoietic growth factors: At least 14 days after the last dose of a 
long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-
acting growth factor.  For agents that have known adverse events 
occurring beyond 7 days after administration, this period must be 
extended beyond the time during which adverse events are known to 
occur.  The duration of this interval must be discussed with the study 
chair. 
c.
Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts):  At least 7 days after 
the last dose of agent.  See DVL homepage for commercial and Phase 
1 investigational agent classifications. For agents not listed, the 
duration of this interval must be discussed with the study chair and the 
study-assigned Research Coordinator prior to enrollment.
d.
Interleukins, Interferons and Cytokines (other than Hematopoetic 
Growth Factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than Hematopoetic Growth Factors)
e.
Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1.
f.
XRT/External Beam Irradiation including Protons:  ≥ 14 days after
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
50% of the pelvis; ≥ 42 days if other substantial BM radiation.
g.
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 
131I-
MIBG): ≥ 42 days must have elapsed since systemically administered 
radiopharmaceutical therapy.
h.
Cellular Therapy: ≥ 42 days must have elapsed since the completion 
of any type of cellular therapy (e.g. modified T cells, NK cells, 
dendritic cells, etc.).
i.
Patients must not have received prior exposure to nivolumab. For 
patients enrolled in Parts C, D, and E patients must not have received 
prior nivolumab or ipilimumab.
Organ Function Requirements

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 30
4.1.7.1 Adequate Bone Marrow Function Defined as:
a.
For patients with solid tumors without known bone marrow 
involvement:
-
Peripheral absolute neutrophil count (ANC) 750/mm3
-
Platelet count 75,000/mm3 (transfusion independent, defined as 
not receiving platelet transfusions for at least 7 days prior to 
enrollment)
b.
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.7.1.a
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity. At least 5 of every 
cohort of 6 patients with a solid tumor must be evaluable for 
hematologic toxicity, for Parts A and C. If dose-limiting 
hematologic toxicity is observed on either Part A or C, all 
subsequent patients enrolled must be evaluable for hematologic 
toxicity on that Part.
4.1.7.2 Adequate Renal Function Defined as:
-
Creatinine clearance or radioisotope GFR 70 ml/min/1.73 m2 or
-
A serum creatinine based on age/gender as follows:
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
1 to < 2 years
0.6
0.6
2 to < 6 years
0.8
0.8
6 to < 10 years
1
1
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC.
4.1.7.3 Adequate Liver Function Defined as:
•
Bilirubin (sum of conjugated + unconjugated) 1.5 x upper limit of 
normal (ULN) for age 
•
SGPT (ALT) 135 U/L.  For the purpose of this study, the ULN for 
SGPT is 45 U/L. 
4.1.7.4 Adequate Pulmonary Function Defined as:
•
No evidence of dyspnea at rest, no exercise intolerance due to 
pulmonary insufficiency, and a pulse oximetry > 92% while breathing 
room air. 
4.1.7.5 Adequate Pancreatic Function Defined as:
•
Serum lipase ≤ ULN at baseline. Patients with glucose intolerance 
should be on a stable regimen and be monitored.
Informed Consent: All patients and/or their parents or legally authorized 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 31
representatives must sign a written informed consent. Assent, when 
appropriate, will be obtained according to institutional guidelines.
Tissue blocks or slides must be sent for all patients per Section 8.6. If tissue 
blocks or slides are unavailable, the study chair must be notified prior to 
enrollment.
4.2
Exclusion Criteria
Pregnancy or Breast-Feeding
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal and teratogenic adverse events as there is yet no available information 
regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained 
in girls who are post-menarchal. Women of childbearing potential (WOCBP) 
receiving nivolumab will be instructed to adhere to contraception for a period of 5 
months after the last dose of nivolumab. Men receiving nivolumab and who are 
sexually active with WOCBP will be instructed to adhere to contraception for a 
period of 7 months after the last dose of nivolumab.
Concomitant Medications
4.2.2.1 Corticosteroids:  Patients requiring daily systemic corticosteroids are not 
eligible.  Patients must not have received systemic corticosteroids within 
7 days prior to enrollment. If used to modify immune adverse events
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid. Note: Use of topical or inhaled corticosteroids will not 
render a patient ineligible.
4.2.2.2 Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible.
4.2.2.3 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible.
Patients with CNS tumors or known CNS metastases will be excluded from 
this trial due to concerns regarding pseudo-progression in the CNS.  Patients 
with a history of CNS metastases that have been previously treated may enroll 
if sequential imaging shows not evidence for active disease. Patients with extra 
axial disease [e.g. skull (bone) metastasis that do not invade the dura] may 
enroll if there is no evidence for CNS edema associated with the lesion.
Patients with a history of any Grade autoimmune disorder are not eligible. 
Asymptomatic laboratory abnormalities (e.g. ANA, rheumatoid factor, altered 
thyroid function studies) will not render a patient ineligible in the absence of a 
diagnosis of an autoimmune disorder.
Patients with ≥ Grade 2 hypothyroidism due to history of autoimmunity are not 
eligible. Note: Hypothyroidism due to previous irradiation or thyroidectomy 
will not impact eligibility.
Infection:  Patients who have an uncontrolled infection are not eligible.
Patients with a history of CHF or are at risk because of underlying 
cardiovascular disease or exposure to cardiotoxic drugs must have adequate 
cardiac function as clinically indicated:

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 32
-  QTC ≤480 msec;
-  Shortening fraction of  ≥ 27% by echocardiogram or ejection fraction 
of ≥ 50% by gated radionuclide study 
Patients with known HIV or hepatitis B or C are excluded.
Patients who have received prior solid organ transplantation are not eligible.
Patient who have received allotransplantation are not eligible.
Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible.
Patients who have received prior anti-PD1 directed therapy (mAb or small 
molecule) are not eligible.
Parts C, D, and E: Patients who have received prior ipilimumab are not 
eligible.
5.0
TREATMENT PROGRAM
5.1
Overview of Treatment Plan
This trial will consist of Parts A-E as described below. Once the dose-escalation portion of 
Part A is completed, cohorts that are open concurrently for eligible patients (including Parts 
B and C and potential PK expansion cohorts) may be selected at the treating physician’s 
discretion pending slot availability. Part B will be completed for all cohorts after the initial 
stage of Simon’s optimal two-stage design (Section 11.4). Upon opening Part E to accrual, 
no additional patients will be enrolled to Part D. 
Once enrolled, patients continue on the part of the study assigned at enrollment until they 
meet criteria in Section 10.1 or Section 10.2. 
Pre-medication is not required as infusional reactions are rare, but anaphylactic precautions 
should be observed during each infusion of nivolumab. If ≥ Grade 2 infusional reaction 
occurs, the infusion should be stopped and supportive care given as per institutional 
guidelines. See Section 6.3 for management and dose modification guidelines for 
infusional reactions. Investigators are advised to monitor for fever, chills, shakes, itching,
rash, hypertension or hypotension, or difficulty breathing during and immediately after
administration of nivolumab.
Drug doses should be adjusted based on the patient’s actual weight in kilograms measured 
within 7 days prior to the beginning of each cycle.  
Part A (COMPLETED)
Nivolumab of 3 mg/kg IV infused over 60 minutes every 14 days. A cycle will be 
considered 28 days. If Dose Level 1 is not tolerable, then the 3 mg/kg dose will be 
deescalated to 1 mg/kg and a similar cohort of patients will be evaluated for 
tolerability at this dose. Note: In the event that dose-limiting immune-related 
toxicities are observed in two patients enrolled on Part A that would potentially 
define the MTD as less than the adult RP2D, a review by COG, CTEP, and BMS 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 33
will be scheduled before proceeding with dosing changes.
Dose Level
Nivolumab (mg/kg) IV over 60 min.
Day(s) of Administration 
-1
1 
1, 15
   1* 
3
1, 15
*Starting dose
Update: The single-agent recommended Phase 2 dose of Part A was 
determined to be 3 mg/kg nivolumab. 
Part B (COMPLETED)
Part B will evaluate the activity of nivolumab at its RP2D in expanded cohorts 
for patients with neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing 
sarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma. In the melanoma cohort 
(Part B7), toxicities and disease response will be reported descriptively within the 
confines of a Phase 1/2 study.
Dose Level
Nivolumab (mg/kg) IV over 60 min.
Day(s) of Administration 
   1
3
1, 15
Part C (COMPLETED)
Part C will enroll all histologies with the goal of identifying the MTD or RP2D 
of the combination of nivolumab and ipilimumab. The combination of nivolumab 
and ipilimumab will be administered every 3 weeks X 4 followed by nivolumab 
given every 2 weeks until off protocol criteria in Section 10.1 are met. Note that 
cycle length is 21 days for the first 4 cycles of Part C, whereas reverts to 28 
days for subsequent cycles which comprises two doses of nivolumab, and is 
the same regimen used in Part A and B.
Dose Level
Cycles 1-4
Cycles 5+
1
Nivolumab (IV over 60 min)
1 mg/kg on Day 1
Ipilimumab (IV over 90 min)
1 mg/kg on Day 1
Nivolumab (IV over 60 min)
3 mg/kg on Days 1 and 15
2
Nivolumab (IV over 60 min)
3 mg/kg on Day 1
Ipilimumab (IV over 90 min)
1 mg/kg on Day 1
Nivolumab (IV over 60 min)
3 mg/kg on Days 1 and 15
Infusion of ipilimumab (over 90 minutes) should be initiated no sooner than 30 
minutes after completion of the nivolumab infusion.
Vital signs (temperature, pulse, blood pressure and respirations) will be monitored 
closely baseline then every 15 minutes x 2, then every 30 minutes x 3 beginning at 
the initiation of administration of ipilimumab infusion. Patients who develop 
symptoms or signs of hypotension (≥ 25% decrease in systolic or diastolic blood 
pressures from baseline) that are temporally related to ipilimumab infusion will 
receive additional IV fluids as appropriate until the signs and symptoms resolve. 
During cycle 1, patients must remain for observation for a total of 6 hours following 
completion of ipilimumab. The post administration observation period may be 
extended to 24 hours and the patient admitted if clinically indicated.  If the patient 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 34
tolerates the first infusion of ipilimumab without incident, the observation period 
may be reduced to 90 minutes following completion of the drug infusion with 
subsequent cycles. Any patient who develops Grade 3 or 4 anaphylaxis felt to be 
primarily related to administration of ipilimumab will be removed from protocol 
therapy.
Protocol therapy will continue to be administered until patient meets one of the off
protocol criteria in Section 10.1.
Update: The recommended Phase 2 dose of nivolumab in combination 
with ipilimumab from Part C was determined to be 3 mg/kg nivolumab 
and 1 mg/kg ipilimumab. 
Part D (COMPLETED)
If criteria for accrual to Part D are met, the combination of nivolumab and 
ipilimumab will be administered every 3 weeks X 4 followed by nivolumab 
given every 2 weeks until off protocol criteria in Section 10.1 are met. Note that 
cycle length is 21 days for the first 4 cycles of Part D, whereas reverts to 28 
days for subsequent cycles which comprises two doses of nivolumab, and is 
the same regimen used in Part A and B.
Dose Level
Cycles 1-4
Cycles 5+
1
Nivolumab (IV over 60 min)
3 mg/kg on Day 1
Ipilimumab (IV over 90 min)
1 mg/kg on Day 1
Nivolumab (IV over 60 min)
3 mg/kg on Days 1 and 15
Infusion of ipilimumab (over 90 minutes) should be initiated no sooner than 30 
minutes after completion of the nivolumab infusion.
Vital signs (temperature, pulse, blood pressure and respirations) will be monitored 
closely baseline then every 15 minutes x 2, then every 30 minutes x 3 beginning at 
the initiation of administration of ipilimumab infusion. Patients who develop 
symptoms or signs of hypotension (≥ 25% decrease in systolic or diastolic blood 
pressures from baseline) that are temporally related to ipilimumab infusion will 
receive additional IV fluids as appropriate until the signs and symptoms resolve. 
During cycle 1, patients must remain for observation for a total of 6 hours following 
completion of ipilimumab. The post administration observation period may be 
extended to 24 hours and the patient admitted if clinically indicated.  If the patient 
tolerates the first infusion of ipilimumab without incident, the observation period 
may be reduced to 90 minutes following completion of the drug infusion with 
subsequent cycles. Any patient who develops Grade 3 or 4 anaphylaxis felt to be 
primarily related to administration of ipilimumab will be removed from protocol 
therapy.
Part E
The combination of nivolumab 1 mg/kg and ipilimumab 3 mg/kg will be 
administered every 3 weeks X 4 followed by nivolumab 3 mg/kg administered
every 2 weeks until off protocol criteria in Section 10.1 are met. Note that cycle 
length is 21 days for the first 4 cycles of Part E; in cycle 5 and for subsequent 
cycles, cycle length will be 28 days and nivolumab 3 mg/kg will be administered 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 35 
 
on days 1 and 15 of each cycle. 
 
Dose Level 
Cycles 1-4 (21-day Cycles) 
Cycles 5+ (28-day Cycles) 
1  
Nivolumab (IV over 30 min) 
1 mg/kg on Day 1 
 
Ipilimumab (IV over 90 min) 
3 mg/kg on Day 1 
Nivolumab (IV over 30 min) 
3 mg/kg on Days 1 and 15 
 
 
Infusion of ipilimumab (over 90 minutes) should be initiated no sooner than 30 
minutes after completion of the nivolumab infusion. If nivolumab therapy is 
withheld, ipilimumab should also be withheld. 
 
Vital signs (temperature, pulse, blood pressure and respirations) will be monitored 
closely baseline then every 15 minutes x 2, then every 30 minutes x 3 beginning at 
the initiation of administration of ipilimumab infusion. Patients who develop 
symptoms or signs of hypotension (≥ 25% decrease in systolic or diastolic blood 
pressures from baseline) that are temporally related to ipilimumab infusion will 
receive additional IV fluids as appropriate until the signs and symptoms resolve. 
During cycle 1, patients must remain for observation for a total of 6 hours 
following completion of ipilimumab. The post administration observation period 
may be extended to 24 hours and the patient admitted if clinically indicated.  If the 
patient tolerates the first infusion of ipilimumab without incident, the observation 
period may be reduced to 90 minutes following completion of the drug infusion 
with subsequent cycles. Any patient who develops Grade 3 or 4 anaphylaxis felt 
to be primarily related to administration of ipilimumab will be removed from 
protocol therapy. 
5.2 
Protocol therapy will continue to be administered until patient meets one of the off 
protocol criteria in Section 10.1.Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days for Parts A and B (and either every 21 days or 28 
days for Parts C, D, and E) if the patient has again met the parameters as defined in the 
eligibility section, Section 4.0, has not met any of the criteria for removal from therapy 
per Section 10.1, and has not experienced a dose-limiting toxicity.  A delay of up to 7 
days from the date of the next scheduled treatment dose may be allowed.  Please note the 
following exceptions: 
• 
Patients may continue on to the next cycle if Pancreatic Function is ≤ Grade 1 
(See Section 6.5) 
• 
Patients who experience pleural effusion may continue onto the next cycle upon 
resolution as per Section 6.8. 
 
5.3 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electron
ic_applications/ctc.htm. Any suspected or confirmed dose-limiting toxicity should be 
reported immediately (within 24 hours) to the Study Chair. 
 
5.4 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably, or definitely 
attributable to protocol therapy. DLT definitions will be the same for all parts.  The DLT 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 36
observation period for the purposes of dose-escalation in Part C or dose de-escalation in 
Part A will be the first cycle of therapy.  Toxicities with subsequent cycles will be 
monitored carefully and if significant numbers of delayed toxicities are observed,
consideration will be given to a protocol amendment to focus on delayed toxicities in 
assessing the MTD.
Non-Hematological DLT:
•
Any Grade 3 or Grade 4 non-hematological toxicity attributable to protocol 
therapy with the specific exclusion of:
a.
Grade 3 ALT that returns to levels that meet initial eligibility 
criteria or baseline within 7 days and does not require systemic 
immunosuppression. Note: For the purposes of this study the 
ULN for ALT is defined as 45 U/L. Adverse event grades will be 
based on increases above the upper limit of normal, regardless of 
the subject’s baseline. See Appendix IX for toxicity grading table.
b.
Grade 3 liver enzyme elevation, including AST/GGT that returns 
to baseline within 7 days and does not require systemic 
immunosuppression. 
c.
Grade 3 or 4 serum electrolyte or mineral abnormalities 
responsive to supplementation. 
d.
Grade 3 or 4 amylase or lipase abnormalities that are not 
associated with diabetes mellitus (DM), associated liver or gall 
bladder inflammation clinical manifestations of pancreatitis and 
which decrease to ≤Grade 2 within 7 days.  
e.
Grade 3 rash/oral lesions that resolves to Grade ≤ 1 within 7 days
f.
Fever greater than 40°C of ≤ 24 hr duration
g.
Grade 3 fatigue that resolves to Grade ≤ 2 within 7 days
h.
Grade 3 creatinine increased that resolves to Grade ≤ 1 or baseline
within 7 days
i.
Grade 3 pleural effusion that resolves per Section 6.8
•
Grade 2 fever that does not resolve to Grade ≤ 1 within 7 days
•
Grade 2 uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 prior to next scheduled dose
•
Grade 2 non-hematological toxicity requiring systemic immunosuppressive 
therapy, including but not limited to, autoimmunity of the lung, heart, 
kidney, bowel, CNS, pituitary or eye, with the specific exclusion of:
a.
Grade 2 pleural effusion that resolves per Section 6.8
b.
Drugs will be held for grade 2 cardiac dysfunction pending 
evaluation. 
•
Grade 2 endocrine toxicity requiring hormone replacement, with the 
exception of Grade 2 hypothyroidism, thyroiditis and thyroid dysfunction 
adequately managed with thyroid hormone replacement (see Section 6.11)
•
Grade 2 adrenal insufficiency
•
Parts A and B: Grade 2 colitis or Grade 2 diarrhea attributable to protocol 
therapy that persists for > 7 days will be considered a DLT.
•
Parts C, D, and E: Grade 2 colitis or Grade 2 diarrhea attributable to protocol 
therapy of any duration will be considered a DLT.
•
Any non-hematological toxicity requiring > 7 days delay in therapy will be 
considered a DLT

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 37
•
Note: Allergic reactions that necessitate discontinuation of study drug will 
not be considered a dose-limiting toxicity.
Hematological DLT: 
In patients evaluable for hematological toxicity (see Section 4.1.7.1) DLT is 
defined as:
•
Grade 4 thrombocytopenia (platelet count < 25,000/mm3) or Grade 4 
neutropenia lasting at least five days.
O
Note: Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity. Any grade lymphopenia will not be considered DLT.
6.0
DOSE MODIFICATIONS FOR ADVERSE EVENTS
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor.
6.1
Dose Modifications for Hematological Toxicity
Patients who experience dose-limiting hematological toxicity as defined in Section 5.4.2
will be removed from protocol therapy.
6.2
Dose Modifications for Non-Hematological Toxicity
Patients who have any dose-limiting non-hematological toxicity as defined in Section 5.4.1
will be removed from protocol therapy, except as outlined in Sections 6.3-6.12 below.
6.3
Dose Modifications for Infusion-Related Reactions
For patients who have allergic or acute infusion reactions to nivolumab or ipilimumab, 
therapy modifications based on grade should be as follows.
Grade (CTCAE v.5)
Infusion Reaction
Action
Grade 1
• Monitor patient until recovery from symptoms; infusion rate 
may be slowed.
• If the infusion is interrupted, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may 
be increased to 100% of the original infusion rate. Monitor 
patient closely.
The following prophylactic premedications are recommended 
for future infusions: diphenhydramine 1 mg/kg with max 50 mg 
(or equivalent) and/or acetaminophen 10-15 mg/kg (max 1000 
mg) at least 30 minutes before additional nivolumab or 
ipilimumab administrations, slowing infusion rate as above.
Grade 2
• Stop infusion, begin an IV infusion of normal saline, and 
treat the subject with diphenhydramine 1 mg/kg with max 
50 mg IV (or equivalent) and/or acetaminophen 10-15 
mg/kg (max 1000 mg); remain at bedside and monitor 
patient until resolution of symptoms. Corticosteroid or 
bronchodilator therapy may also be administered as 
appropriate.
• If the infusion is interrupted, then restart the infusion at 
50% of the original infusion rate when symptoms resolve; 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 38 
 
if no further complications ensue after 30 minutes, the rate 
may be increased to 100% of the original infusion rate. 
Monitor patient closely. 
•  If symptoms recur, then no further nivolumab or 
ipilimumab will be administered at that visit. Administer 
diphenhydramine 1 mg/kg with max 50 mg IV (or 
equivalent), and remain at bedside and monitor the patient 
until resolution of symptoms.  
 
The following prophylactic premedications are recommended 
for future infusions: diphenhydramine 1 mg/kg with max 50 
mg IV (or equivalent) and acetaminophen (10-15 mg/kg, max 
1000 mg) should be administered at least 30 minutes before 
additional nivolumab or ipilimumab administrations. If 
clinically indicated, corticosteroids (recommended dose: 1-2 
mg/kg/day methylprednisolone IV or equivalent) may be used. 
Grade 3 or 4 
 
• Immediately 
discontinue 
infusion 
of 
nivolumab/ 
ipilimumab.  
• Begin an IV infusion of normal saline, and treat the subject 
as follows. Recommend bronchodilators, epinephrine 0.2 to 
1 mg of a 1:1,000 solution for subcutaneous administration 
or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for 
IV administration, and/or diphenhydramine 1 mg/kg with 
max 50 mg IV with 1-2 mg/kg/day methylprednisolone IV 
(or equivalent), as needed. 
• Patient should be monitored until the investigator is 
comfortable that the symptoms will not recur. 
• Nivolumab/ipilimumab will be permanently discontinued. 
 
Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor 
patient until recovery from symptoms. In the case of late-
occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritis within 1 week after treatment), 
symptomatic treatment may be given (e.g., oral antihistamine, 
or corticosteroids).  
 
Please note that late occurring events including isolated fever 
and fatigue may represent the presentation of systemic 
inflammation. Please evaluate accordingly. 
 
6.4 
Dose Modifications for Skin Rash and Oral Lesions  
Skin Rash 
and Oral 
Lesions 
Management/Next Dose of  Nivolumab ± Ipilimumab 
≤ Grade 1 
No change in dose* 
Grade 2 
Continue protocol therapy*; Topical steroids do not require protocol therapy 
discontinuation. If prolonged symptoms require systemic corticosteroids, 
decisions regarding whether protocol therapy may be reinstituted following 
weaning of immunosuppression must be made in consultation with Protocol 
Chair/Vice-Chair and DVL Leadership.   

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 39
Skin Rash 
and Oral 
Lesions
Management/Next Dose of Nivolumab ± Ipilimumab
Grade 3
Hold* until ≤ Grade 1; if resolves within 7 days, then resume at same dose 
level. Topical steroids do not require protocol therapy discontinuation. If 
prolonged symptoms require systemic corticosteroids, decisions regarding 
whether protocol therapy may be reinstituted following weaning of 
immunosuppression must be made in consultation with Protocol Chair/Vice-
Chair and DVL Leadership.  
Grade 4
Discontinue therapy, Systemic corticosteroids indicated.
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson 
syndrome, TEN, and autoimmune bullous disease including oral lesions of bullous 
pemphigus/pemphagoid. Pruritus may occur with or without skin rash and should be treated 
symptomatically if there is no associated liver or GI toxicity. Note skin rash typically 
occurs early and may be followed by additional events particularly during steroids tapering.  
Recommended management: See Skin AE Management Algorithm
BMS Recommended Skin Adverse Management Algorithm
These suggested management guidelines are taken from the BMS algorithms 
provided in the Investigator’s Brochure.
Toxicity 
(CTCAE v.5)
Management
Follow-up
Grade 1/2 
Rash
• Symptomatic therapy 
(e.g. antihistamines, 
topical steroids)
• Continue protocol 
therapy 
If persists > 1-2 weeks or recurs:
• Consider skin biopsy
• Hold protocol therapy
• Consider 0.5-1 mg/kg/day 
methylprednisolone IV or oral equivalent
• Once improving, taper steroids over at 
least 1 month 
• Consider prophylactic antibiotics for 
opportunistic infections
If worsens:
Treat as Grade 3/4
Grade 3/4 
Rash
• Hold infusion
• Consider skin biopsy
• Dermatology consult
• 0.5-1 mg/kg/day 
methylprednisolone IV 
or IV equivalent
If improves to Grade 1:
• Taper steroids over at least 1 month,
• Add prophylactic antibiotics for 
opportunistic infections
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching 
to the equivalent dose of oral corticosteroids.
6.5
Dose modifications for Hepatic/Pancreatic Adverse Events
Liver Function Elevation
Management/Next Dose of Nivolumab ± Ipilimumab
≤ Grade 1
Continue protocol therapy
Grade 2
Hold until baseline. If resolves within 7 days, resume at same 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 40
Liver Function Elevation
Management/Next Dose of Nivolumab ± Ipilimumab
dose level. 
Grade 3
Off protocol therapy unless DLT exception in Section 5.4.1
is met.
Grade 4
Off protocol therapy unless DLT exception in Section 5.4.1
is met.
See Appendix IX for values that represent thresholds between CTCAE grades. 
Continued treatment of active immune mediated hepatitis may exacerbate ongoing 
inflammation. Holding drug to evaluate LFT changes and early treatment are 
recommended.  
LFT changes may occur during steroid tapers from other events and may occur together 
with other GI events including cholecystitis/pancreatitis.
Recommended management:  see for Hepatitic AE  management algorithm
Pancreatitis;
Amylase/Lipase 
Management/Next Dose of Nivolumab ± Ipilimumab
≤ Grade 1
Continue protocol therapy
Grade 2 Amylase
Continue protocol therapy
Grade 2 Pancreatitis/Lipase Hold until resolution to ≤ Grade 1; Resume at same dose level 
if asymptomatic
Grade 3
Off protocol therapy unless DLT exception in Section 5.4.1
is met.
Grade 4
Off protocol therapy
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as DM 
and DKA.  Lipase elevation may occur during the period of steroid withdrawal and with 
other immune mediated events or associated with colitis, hepatitis, and patients who have 
asymptomatic lipase elevation typically have self-limited course and may be retreated.
For treatment management of symptomatic pancreatitis please follow the Hepatic Adverse 
Event Management Algorithm below
BMS Recommended Hepatic Adverse Event Management Algorithm 
These suggested management guidelines are taken from the BMS algorithms 
provided in the Investigator’s Brochure.
Consider imaging for obstruction.
Toxicity 
(CTCAE v.5)
Management
Follow-up
Grade 1*
AST or ALT, 
and/or bilirubin 
increased
• Continue protocol 
therapy
• Continue routine LFT monitoring per 
Table 8.1
If worsens:
• Treat as Grade 2 or 3/4

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 41 
 
Toxicity 
(CTCAE v.5) 
Management 
Follow-up 
Grade 2*  
AST or ALT, 
and/or bilirubin 
increased 
• Hold infusion 
• Increase LFT 
monitoring to every 3 
days 
If improves to baseline: 
• Continue routine LFT monitoring per 
Table 8.1 
• Resume protocol therapy 
 
If elevations persist >5-7 days or 
worsen: 
• 0.5-1 mg/kg/day methylprednisolone 
IV or oral equivalent 
• When LFT returns to grade 1 or 
baseline, taper steroids over at least 1 
month 
• Consider prophylactic antibiotics for 
opportunistic infections 
 
Grade 3 or 4*  
AST or ALT, 
and/or bilirubin 
increased 
• Discontinue protocol 
therapy 
• Increase LFT 
monitoring to every 
1-2 days  
• 1-2 mg/kg/day 
methylprednisolone 
IV or oral 
equivalent** 
• Add prophylactic 
antibiotics for 
opportunistic 
infections 
• Consult 
gastroenterologist 
If improves to Grade 2: 
• Taper steroids over at least 1 month 
 
If does not improve in > 3-5 days, 
worsens or rebounds: 
• Add mycophenolate mofetil 600 
mg/m2/dose (max 1 g/dose) BID 
• If no response within an additional 3-5 
days, consider other 
immunosuppressants per local 
guidelines 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower 
bioavailability of oral corticosteroids should be taken into account when switching to the equivalent 
dose of oral corticosteroids. 
 
*See Appendix IX for values that represent thresholds between CTCAE grades.  
 
** The recommended starting dose for Grade 4 Hepatitis is 2 mg/kg/day methylprednisolone IV. 
 
6.6 
Dose modifications for Gastrointestinal Adverse Events 
 
Diarrhea/ 
Colitis  
Management/Next Dose of Nivolumab± Ipilimumab 
≤ Grade 1 
Continue protocol therapy 
Grade 2 
For Part A and B (Nivolumab alone), may observe and treat 
symptomatically for 7 days.  If persists > 7d, then off protocol therapy.  
For Parts C, D, and E any grade 2 diarrhea/colitis results in 
discontinuation of protocol therapy. 
Grade 3 
Off protocol therapy 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 42
Diarrhea/ 
Colitis 
Management/Next Dose of Nivolumab± Ipilimumab
Grade 4
Off protocol therapy
Patients who require steroids should be taken off study treatment. 
Please evaluate pituitary function prior to starting steroids if possible without 
compromising acute care.  
Evaluation for all patients for additional causes includes C. diff, acute and self-limited 
infectious and foodborne illness, ischemic bowel, diverticulitis, and IBD.
Recommended management:  see GI AE management Algorithm below
Other GI N-V
Management/Next Dose of Nivolumab ± Ipilimumab
≤ Grade 1
No change in dose. 
Grade 2
Hold pending evaluation for gastritis duodenitis and other immune 
adverse events or other causes.  Resume at same dose level if resolution 
to ≤ Grade 1 within 7 days.  
Grade 3
Hold pending evaluation until ≤ Grade 1.  Resume at same dose level. If 
symptoms do not resolve within 7 days with symptomatic treatment  
patients should go off protocol therapy
Grade 4
Off protocol therapy
Patients with grade 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events.  
BMS Recommended Gastrointestinal Adverse Event Management Algorithm
These suggested management guidelines are taken from the BMS algorithms 
provided in the Investigator’s Brochure.
Opiates/narcotics may mask symptoms of perforation. Infliximab should not be 
used in cases of perforation or sepsis.
Toxicity 
(CTCAE v.5)
Management
Follow-up
Grade 1
Diarrhea or
Colitis
• Continue protocol 
therapy
• Symptomatic treatment
• Close monitoring for worsening 
symptoms
• Educate patient to report worsening 
immediately
If worsens:
• Treat as Grade 2 or 3/4
Grade 2 
Diarrhea or
Colitis 
• Part A or B (Nivolumab 
alone) symptomatic 
management.  If persists 
for > 7 days, discontinue 
protocol therapy.
• Part C, D, or E
discontinue protocol 
therapy Symptomatic 
treatment
If persists > 5-7 days or recurs:
• 0.5-1 mg/kg/day methylprednisolone 
or oral equivalent
• When symptoms improve to grade 1, 
taper steroids over at least 1 month
• Consider prophylactic antibiotics for 
opportunistic infections
If worsens or persists > 3-5 days with 
oral steroids:
• Treat as Grade 3 or 4

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 43
Toxicity 
(CTCAE v.5)
Management
Follow-up
Grade 3 or 4 
Diarrhea or
Colitis 
• Discontinue protocol 
therapy
• 1 to 2 mg/kg/day 
methylprednisolone IV 
or IV equivalent
• Add antibiotics for 
opportunistic infections
• Consider lower 
endoscopy
If improves:
• Continue steroids until grade 1, then 
taper over at least 1 month
If persists > 3-5 days or recurs after 
improvement:
• Add infliximab 5 mg/kg (if no 
contraindication). Note: Infliximab 
should not be used in cases of 
perforation or sepsis
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
6.7
Dose Modifications for Pneumonitis
Pneumonitis
Management/Next Dose of Nivolumab ± Ipilimumab
≤ Grade 1
Consider delay in protocol therapy. Resume no change in dose after 
pulmonary and/or ID consultation 
Grade 2
Hold dose pending evaluation and resolution to baseline. Resume no change 
in dose after pulmonary and/or ID consultation if lymphocytic pneumonitis 
is excluded. 
Grade 3
Off protocol therapy
Grade 4
Off protocol therapy
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who 
do not respond to antibiotics and have no causal organism identified including influenza.  
Most patients with respiratory failure or hypoxia will be treated with steroids.  
Bronchoscopy may be required and analysis of lavage fluid for lymphocytic predominance 
may be helpful.  Patients with new lung nodules should be evaluated for sarcoid like 
granuloma.  Please consider recommending seasonal influenza killed vaccine for all 
patients.
Recommended management:  See Pulmonary Adverse Event Management Algorithm for 
Pneumonitis below
BMS Recommended Pulmonary Adverse Event Management Algorithm for 
Pneumonitis
These suggested management guidelines are taken from the BMS algorithms 
provided in the Investigator’s Brochure.
Evaluate with imaging and pulmonary consultation.

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 44 
 
Toxicity 
(CTCAE v.5) 
Management 
Follow-up 
Grade 1 
Pneumonitis 
• Consider delay of 
protocol therapy 
• Monitor for symptoms 
ever 2-3 days 
• Consider Pulmonary and 
ID consults 
• Re-image at least every 3 weeks 
 
If worsens: 
• Treat as Grade 2 or 3/4 
Grade 2  
Pneumonitis 
• Hold infusion 
• Pulmonary and ID 
consults 
• Monitor symptoms daily, 
consider hospitalization 
• 1 to 2 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• Consider bronchoscopy, 
lung biopsy 
• Re-image every 1-3 days 
 
If improves: 
• When symptoms return near baseline, 
taper steroids over at least 1 month 
• Consider prophylactic antibiotics 
 
If not improving after 2 weeks or 
worsening: 
• Treat as Grade 3 or 4 
Grade 3 or 4  
Pneumonitis 
• Discontinue protocol 
therapy 
• Hospitalize 
• Pulmonary and ID 
consults 
• 2-4 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
• Add prophylactic 
antibiotics for 
opportunistic infections 
• Consider bronchoscopy, 
lung biopsy 
If improves to baseline: 
• Taper steroids over at least 6 weeks 
 
If not improving after 48 hours or 
worsening: 
• Add additional immunosuppression 
(e.g. infliximab, cyclophosphamide, 
IVIG, or mycophenolate mofetil) 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching 
to the equivalent dose of oral corticosteroids. 
 
6.8 
Dose Modification and Adverse Event Management Algorithm for Pleural Effusion 
and Ascites 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 45 
 
Pleural 
effusion 
or ascites 
 
Non-life-
threatening 
(Grade < 4) 
 pleural effusion 
or ascites    
• Treat with appropriate supportive care, which may include: non-
investigational 
diuretics, 
thoracentesis, 
chest 
tube 
drainage, 
paracentesis or pleurodesis. 
• For grade 1 pleural effusion or Grade 1 or 2 ascites, monitor with 
physical exam and consider additional imaging. 
• For grade ≥ 2 pleural effusion or grade 3 ascites, initiate 
methylprednisolone (2 mg/kg/day IV) or oral equivalent with attempt 
to taper over 7-10 days after a minimum of 24 hours of treatment. 
• If chest tube drainage, pleurodesis or paracentesis is required, protocol 
therapy should be held until at least two days after the procedure or 
chest tube removal and the patient’s condition is stable. 
• If pleural effusion or ascites resolves or is managed to achieve grade ≤ 
1 and steroids are discontinued, protocol therapy may proceed without 
dose reduction. If pleural effusion or ascites is not resolved/managed 
to grade ≤ 1 and steroids are not discontinued within 28 days of next 
scheduled dose of nivolumab or ipilimumab, discontinue protocol 
therapy. 
Grade 4 or Life 
threatening 
pleural 
effusion 
or ascites 
• Institute emergency measures per institutional guidelines  
• Initiate methylprednisolone 2 mg/kg/day IV or oral equivalent with 
plan to taper as tolerated. 
• Permanently discontinue protocol therapy 
 
 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 46
6.9
Dose Modifications for Fatigue
Fatigue 
Management/Next Dose of Nivolumab ± Ipilimumab
≤ Grade 1
No change in dose.
Grade 2
No change in dose
Grade 3
Hold until ≤ Grade 2.  If resolves within 7 days, resume at same dose level
Fatigue is the most common adverse event associated with immune checkpoint therapy.  
Grade 2 or greater fatigue should be evaluated for associated or underlying organ 
involvement including pituitary, thyroid, and hepatic, or muscle (CPK) inflammation
6.10
Dose Modifications for Neurologic Adverse Events
Neurologic 
events 
Management/Next Dose of Nivolumab ± Ipilimumab
≤ Grade 1
Continue protocol therapy* 
Grade 2
Hold until resolution to baseline.* Resume with no change in dose.*
Grade 3
Off protocol therapy
Grade 4
Off protocol therapy 
*Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy 
(other than peripheral n. VII), GB syndrome, myasthenia gravis should be taken off 
protocol therapy.  
Recommended management:  See Neurologic Adverse Event Management Algorithm 
below
BMS Recommended Neurologic Adverse Event Management Algorithm 
These suggested management guidelines are taken from the BMS algorithms 
provided in the Investigator’s Brochure.
Toxicity 
(CTCAE v.5)
Management
Follow-up
Grade 1 
Neurological 
Toxicity
• Continue protocol therapy
• Continue to monitor the patient
If worsens:
• Treat as Grade 2 or 3/4
Grade 2*
Neurological 
Toxicity
• Hold infusion
• Treat symptoms per local 
guidelines
• Consider 0.5 to 1 
mg/kg/day 
methylprednisolone IV or 
oral equivalent
If improves to baseline:
• within 7 days resume protocol therapy, 
if persists >7 days discontinue protocol 
therapy
If worsens:
• Treat as Grade 3/4

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 47
Toxicity 
(CTCAE v.5)
Management
Follow-up
Grade 3/4 
Neurological 
Toxicity**
• Discontinue protocol 
therapy
• Obtain neurology consult
• Treat symptoms per local 
guidelines
• 1-2 mg/kg/day 
methylprednisolone IV or 
IV equivalent
• Add prophylactic 
antibiotics for 
opportunistic infections
If improves to Grade 2:
• Taper steroids over at least 1 month
If worsens or atypical presentation:
• Consider IVIG or other 
immunosuppressive therapies per local 
guidelines
* Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy 
(other than peripheral n. VII), GB syndrome, myasthenia gravis should be taken off 
protocol therapy.  
** With the exception of decreased tendon reflex (DTR); any grade of DTR does not 
require a dose modification.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching 
to the equivalent dose of oral corticosteroids.
6.11
Dose Modifications for Endocrine Adverse Events
Endocrine 
Hypophysitis; 
Adrenal 
Insufficiency 
Management/Next Dose of Nivolumab ± Ipilimumab
≤ Grade 1
Continue protocol therapy; See Endocrine Management Algorithm
Grade 2
Off protocol therapy if DLT criteria in Section 5.4.1 is met.
Grade 3
Off protocol therapy
Grade 4
Off protocol therapy
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, 
but including severe headache or enlarged pituitary on MRI should be considered grade 3 
events.  Isolated thyroid or testosterone deficiency may be treated as grade 2 if there are no 
other associated deficiencies and adrenal function is monitored. 
Please evaluate pituitary function before beginning steroid therapy or replacement therapy 
of any kind. 
Recommended management: See Endocrine Management Algorithm 
BMS Recommended Endocrine Adverse Event Management Algorithm
These suggested management guidelines are taken from the BMS algorithms 
provided in the Investigator’s Brochure.
Consider visual field testing, endocrinology consultation, and imaging.

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 48 
 
Toxicity 
(CTCAE v.5) 
Management 
Follow-up 
Asymptomatic 
TSH elevation  
• Continue protocol therapy 
• If TSH < 0.5 x LLN, or TSH > 
2X ULN, or consistently out of 
range in 2 subsequent 
measurements: include fT4 at 
subsequent cycles as clinically 
indicated 
• Consider endocrinology consult 
 
Symptomatic 
Endocrinopathy 
• Evaluate endocrine function 
• Consider pituitary scan 
 
Symptomatic with abnormal 
lab/pituitary scan: 
• Hold infusion 
• 1-2 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
• Initiate appropriate hormone 
therapy 
 
No abnormal lab/pituitary MRI 
scan but symptoms persist: 
• Repeat labs in 1-3 weeks/ MRI 
in 1 month 
If improves (with or without 
hormone replacement): 
• Taper steroids over at least 1 
month 
• Consider prophylactic 
antibiotics for opportunistic 
infections 
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component 
Suspicion of 
adrenal crisis 
(e.g. severe 
dehydration, 
hypotension, 
shock out of 
proportion to 
current illness)  
• Discontinue protocol therapy 
• Rule out sepsis 
• Stress dose of IV steroids with 
mineralocorticoid activity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out, then 
treat as above for symptomatic 
endocrinopathy 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching 
to the equivalent dose of oral corticosteroids. 
 
6.12 
Dose Modifications for Fever 
Fever  
Management/Next Dose of Nivolumab ± Ipilimumab 
≤ Grade 1 
Continue protocol therapy 
Grade 2 
Hold until ≤ Grade 1.  If resolves to ≤ Grade 1 within 7 days, resume at 
same dose level. If fever does not resolve to ≤ Grade 1 within 7 days, 
discontinue protocol therapy. 
Grade 3 
Hold until ≤ Grade 1.  If resolves to ≤ Grade 1 within 24 hours, resume 
at same dose level. If fever does not resolve to ≤ Grade 1 within 24 hours, 
discontinue protocol therapy. 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 49
Fever 
Management/Next Dose of Nivolumab ± Ipilimumab
Grade 4
Off protocol therapy
Patients with fever should be evaluated as clinically appropriate. Patients may experience 
isolated fever during infusion reactions or up to several days after infusion. Evaluation over 
the course of 1-2 weeks should be done for other autoimmune events that may present as 
fever 
6.13
Dose Modifications for Renal Adverse Events
Dose modifications for renal adverse events will be per Section 6.2 if DLT definition is 
met.  Refer to algorithm below for recommended management guidelines.
BMS Recommended Renal Adverse Event Management Algorithm
These suggested management guidelines are taken from the BMS algorithms 
provided in the Investigator’s Brochure.
Toxicity 
(CTCAE v.5)
Management
Follow-up
Grade 1 
Creatinine 
Increased
• Continue protocol 
therapy
If worsens:
• Treat as Grade 2/3 or 4
Grade 2 or 3
Creatinine 
Increased
• Hold infusion
• Monitor creatinine 
every 2-3 days
• 0.5-1 mg/kg/day 
methylprednisolone or 
oral equivalent
• Consider renal biopsy
If improves to Grade 1 or baseline:
• Taper steroids over at least 1 month
• Consider prophylactic antibiotics for 
opportunistic infections.
If elevations persists > 7 days or 
worsen:
• Treat as Grade 4
Grade 4 
Creatinine 
Increased
• Discontinue protocol 
therapy
• Monitor creatinine 
weekly
• 1 to 2 mg/kg/day 
methylprednisolone IV 
or IV equivalent
• Consult nephrologist
• Consider renal biopsy
If improves to Grade 1:
• Taper steroids over at least 1 month 
and add prophylactic antibiotics for 
opportunistic infections
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower 
bioavailability of oral corticosteroids should be taken into account when switching to the equivalent 
dose of oral corticosteroids.

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 50 
 
6.14 
Dose Modifications for Nivolumab + Ipilimumab Cardiac Toxicities  
 
 
Cardiac 
Toxicities *   
Nivolumab + Ipilimumab Cardiac Toxicities  
≤  Grade 1  
Hold dose pending evaluation and observation.**  
Evaluate for signs and symptoms of CHF, ischemia, 
arrhythmia or myositis.  Obtain history EKG, CK (for 
concomitant myositis), CK-MB.  Repeat troponin, CK and 
EKG 2-3 days.  If troponin and labs normalize may 
resume therapy.   If labs worsen or symptoms develop then 
treat as below.  Hold pending evaluation.  
Grade ≥ 2 
with 
suspected 
myocarditis 
Hold dose.**  Admit to hospital.  Cardiology consult.  
Rule out MI and other causes of cardiac disease.  Cardiac 
Monitoring.  Cardiac Echo.  Consider cardiac MRI and 
cardiac biopsy.  Initiate high dose methylprednisolone.  If 
no improvement within 24 hours, add either infliximab, 
ATG or tacrolimus. Resume therapy if there is a return to 
baseline and myocarditis is excluded or considered 
unlikely. 
Grade ≥ 2 
with 
confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to 
nearest Cardiac Transplant Unit).  Treat as above.  
Consider high dose methylprednisolone   
Add antithymocyte globulin (ATG) or tacrolimus if no 
improvement.   Off treatment. 
 
 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated 
according as “other event”   
Note:  The optimal treatment regimen for immune mediated myocarditis 
has not been established.  Since this toxicity has caused patient deaths, an 
aggressive approach is recommended.   
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. Specific supportive care measures for 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 51 
 
management of autoimmune reactions are detailed below: 
 
Skin Related Toxicity 
For skin-related Grade 3 autoimmune toxicity lasting > 7 days or Grade 4 
autoimmune toxicity, including severe generalized pruritis or rash, symptomatic 
treatment will be given and patients will be removed from protocol therapy. 
Therapy will be as clinically indicated and may include local skin care, 
antihistamines, or corticosteroids (which can be local/topical or systemic). The use 
of topical corticosteroids for grades 1 -3 dermatitis will be allowed, and will not 
require patients to be removed from study.  In the case of late-occurring 
hypersensitivity symptoms (e.g., appearance within one week after treatment of a 
localized or generalized pruritis), symptomatic treatment may be given (e.g., oral 
antihistamine, topical steroids for the skin).  A dermatologist should evaluate 
persistent (lasting >7 days) and/or severe rashes or pruritus. A biopsy should be 
performed if appropriate and photos should be obtained. 
 
Ocular Toxicity 
Patients who report any new visual symptom, ocular findings on exam, or change 
in vision should be immediately referred to an ophthalmologist. Ophthalmologic 
evaluation should include but will not be limited to examination of the conjunctiva, 
anterior and posterior chambers and retina, normal and dilated slit-lamp 
examination. The patient will be treated as deemed appropriate by the 
ophthalmologist, including peri-ocular steroid injections or steroid eye drops if 
necessary.  
 
Gastrointestinal Toxicity 
Any patient experiencing diarrhea (which may be defined as watery stool, or 
increase in the frequency stools above grade 1 with urgency or nocturnal bowel 
movement, or melena or hematochezia) should be further evaluated for etiology 
that should include a search for an infectious etiology, C. Difficile colitis and other 
alternative infections as clinically indicated. Consideration should be given to 
discontinuing medications known to exacerbate colitis. Grade 2 or greater diarrhea 
attributable to protocol therapy is considered a DLT as outlined in Section 5.4.1. 
It is recommended that colitis or enterocolitis of Grade 1 be evaluated as above for 
other non-immune mediated causes, then monitored closely and treated 
symptomatically without steroids, including a trial of loperamide may be used.  For 
Grade ≥ 2 colitis or enterocolitis, recommendations include endoscopy.  Even if 
colonoscopy does not reveal gross findings of colitis, biopsies should be performed 
and strong consideration should be given to upper endoscopy and biopsies. Patients 
with gross or biopsy proven colitis or enteritis should receive IV steroids 
(recommend 1 mg/kg methylprednisone daily x 7 days) followed by a minimum 
30 day taper.  In patients with Grade 3 or 4 enterocolitis that does not respond to 
high dose steroids after 7 days, further therapies should be administered as 
clinically indicated in consultation with gastroenterology subspecialists. 
 
Concern for immune-mediated liver toxicity may be elicited following LFT 
elevation of 3 fold over baseline and/or right upper quadrant abdominal pain or 
unexplained nausea or vomiting.  Other etiologies for transaminitis should be 
considered and evaluated and may include but are not limited to neoplastic, 
concurrent medications, viral hepatitis, and other toxic etiologies.  Evaluation for 
autoimmune etiologies may be evaluated by ANA, pANC, and anti-smooth muscle 
antibody tests as well as hepatology consultation with possible biopsy. 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 52 
 
Pancreatitis has rarely been associated with checkpoint inhibitors and should be 
considered in cases of abdominal pain associated with elevations of amylase and 
lipase. Treatment of pancreatitis should be supportive and may include 
consultation with gastroenterology subspecialists.  
 
Endocrine Toxicity 
Patients experiencing symptoms such as fatigue, myalgias, impotence, mental 
status changes, constipation, or other symptoms thought to be associated with 
endocrine abnormalities should be evaluated for thyroid, pituitary, or adrenal 
endocrinopathies and an endocrinologist should be consulted.  
 
Patients with Grade 2 hypothyroidism should be evaluated by an endocrinologist 
for further management. Patients with Grade 2 hypothyroidism or Grade 2 
hyperthyroidism adequately managed with thyroid hormone replacement or 
thyroid suppression may continue on protocol therapy. Patients with Grade 3 or 
greater hypothyroidism will be considered to have had a dose-limiting toxicity. 
These patients should be managed according to Section 6.11 and evaluation by an 
endocrinologist is recommended for further management. Patients who enter the 
study on thyroid replacement or suppression should have their thyroid medication 
adjusted to maintain TSH in the normal range. 
 
Auto Immune or Immune System Disorders Effecting Other Organ Systems  
Patients experiencing symptoms that may be associated with autoimmune or 
immune mediated adverse events possibly, probably or definitely related to 
protocol therapy should be evaluated and monitored closely.  These may include 
but are not limited to  pneumonitis, sarcoid-like granuloma and neurologic events 
including hypophysitis, encephalitis, aseptic meningitis, and cranial neuropathy 
especially nVII. Consideration should be given to subspecialty consultation 
particularly if systemic immune suppression is considered. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. Patients MUST 
NOT receive prophylactic myeloid growth factor in the first cycle of therapy. The Study 
Chair should be notified before growth factors are initiated. 
 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 53 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
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 
(see Section 4.0) 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 older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum  creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies must 
be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 
 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
X 
Pregnancy Test1 
X 
 
 
CBC, differential, platelets 
X 
Weekly 2 
Weekly3 
Urinalysis 
X 
 
X 
Electrolytes including Ca++, Cl, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT*, AST*, bilirubin 
X 
Weekly 
X 
Amylase, lipase, CRP 
X 
 
X 
TSH4 
X 
End of Cycle 1 
X 
Tumor Disease Evaluation- Parts A and B 
X 
End of Cycle 1 
End of cycle 2, then q 
3 cycles 5 
Tumor Disease Evaluation- Parts C, D, and 
E 
X 
End of Cycle 2 
End of cycle 4, then q 
3 cycles 5 
Pulse Oximetry 
X 
 
With Tumor Disease 
Evaluation 
Pharmacokinetics6 (Required) 
X 
X7 
X 
Vaccine Antibody and Cytokine Studies8 
(Optional) 
X 
X 
X 
Anti-Drug Antibody (ADA)9 (Required) 
X 
X 
X 
Tumor Tissue (Required, if available) 
X10 
 
X11 
EKG12, ECHO12, 13 
X 
Clinically Indicated  
CPK and Troponin  13 
X 
Clinically Indicated 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
* 
For the purpose of this study, the ULN for SGOT (AST) is 50 U/L and the ULN for SGPT (ALT) is 45 
U/L. 
1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment. Men and 
women must be willing to adhere to effective contraception during the study and for 5 months after the 
last dose of nivolumab for women of childbearing potential and 7 months after the last dose of nivolumab 
for men sexually active with women of childbearing potential.  Abstinence is an acceptable method of 
birth control. 
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 54
3
If patients develop Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until recovery 
to Grade 3
4
Free T4 should also be measured for patients with an abnormal TSH level. Guidance on the management 
of patients who develop hypothyroidism is included in Section 7.3.4.
5
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR.  Please note that if the institutional investigator determines that the patient has 
progressed based on clinical or laboratory evidence, he/she may opt not to confirm this finding 
radiographically.  If tumor growth is > 20% but < 40%, imaging to include target lesions must occur 
every cycle if clinically indicated, or if “pseudoprogression” appears based on inflammatory response, 
and the same radiographic and clinical criteria must be met in order to remain on study (See Section 
12.2.1).
6
See Section 8.3.2 and Appendix III for timing of PK studies.
7
Patients who are removed from therapy during Cycle 1 after receiving the dose of nivolumab on Day
15 should have their last PK sample collected on Day 28 of Cycle 1.
8
See Section 8.4.2 and Appendix IV for timing of vaccine antibody and section 8.8.2 and Appendix VII
for timing of cytokine studies.
9
See Section 8.5.2 and Appendix V for timing of ADA studies.
10
See Section 8.6 and Appendix VI for instructions for submitting tumor specimens. If tissue blocks or 
slides are unavailable, the study chair must be notified prior to study enrollment.
11
In the event a subject requires a biopsy for surgery and tumor tissue is removed, tissue will be requested 
for PD-L1 and CD8 Expression analysis (required, if available).
12       12-lead EKG and ECHO to be obtained at baseline, in patients with a history of CHF or at risk because 
of underlying cardiovascular disease or exposure to cardiotoxic drugs Refer to section 4.2.7
13       For patients with evidence of myocardial infarction (MI), cardiomyopathy, myositis, congestive heart 
failure (CHF) while on study, cardiac evaluations should be performed including lab tests, cardiology 
consultations as clinically indicated, including EKG, CPK, troponin, ECHO cardiogram. A CK-MB test 
may be used as a follow-up test to an elevated CK in order to determine whether the increase is due to 
heart damage or skeletal muscle damage. Refer to section 6.1.4, 5.4.1
Required Observations Following Completion of Protocol Therapy
The following studies are required until the patient is off study as defined in 
Section 10.2. 
STUDIES TO BE 
OBTAINED
~100 Days 
After Last dose
of Nivolumab
Every 6 months up to 
24 Months 
Annually up to 60 
Months
History
X
X
X
Physical exam with vital 
signs
X
X
X
CBC, differential, platelets
X
X
X
Tumor disease evaluation
X
X
X
Treatment with stem cell 
transplant
X
X
X
Evidence of or history of 
GVHD
X
X
X
8.2
Radiology Studies
Central Radiology Review for Response:  
Patients who respond (CR, PR) to therapy, have pseudoprogression or have long 
term stable disease (SD) (≥ 6 cycles) on protocol therapy will be centrally 
reviewed. The response of MIBG lesions will also be assessed by central review 
(See Section 12.4). COG Operations Center will notify the Imaging Center of any 
patient requiring central review. The Imaging Center will then request that the 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 55
treating institution forward the requested images for central review. The central 
image evaluation results will be entered into RAVE for review by the COG 
Operations Center and for data analysis. 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the ImageInBox.  
COG institutions that are not connected via the ImageInBox can send the images 
on hard copy film, CD ROM, USB flash drive or by FTP. Submitted imaging 
studies should be clearly marked with the COG patient ID, study number 
(ADVL1412) and date and shipped to Syed Aamer at the address below:
Syed Aamer, MBBS, CRP
Administrator, Imaging Research Center
Children’s Hospital Los Angeles 
4650 Sunset Boulevard, MS # 81
Los Angeles, CA 90027
Phone: (323) 361-3898
Fax:
(323) 361-3054
8.3
Pharmacokinetics (Required)
Analysis
Serum samples will be collected for pharmacokinetic evaluation of nivolumab and/ 
or ipilimumab by validated immunoassay by PPD - Pharmaceutical Product 
Development, LLC. PK parameters will include Cmax, Cmin, Tmax, AUC(TAU)
and AUC (0-21).
Sampling Schedule 
Blood samples will be obtained prior to drug administration and as outlined in 
Appendix IIIA for Parts A and B, and Appendix IIIB for Parts C, D, and E.
Sample Collection and Handling Instructions
Blood samples (2 ml for parts A and B and 2 x 2ml for parts C, D, and E) will be 
collected in SST Vacutainer tubes at a site distant from the infusion for 
pharmacokinetic evaluation. Samples cannot be drawn from the 2nd lumen of a 
multi-lumen catheter through which drug is being administered. Record the exact 
time that the sample is drawn along with the exact time that the drug is 
administered (including drug start and stop times).
1.For timepoints where both PK and ADA samples are collected, an 8.5mL 
SST tube is used. 
2.For timepoints where only a PK sample is collected, the 4mL SST tube is 
used.
Sample Processing Instructions: 
1.
Immediately after collection, gently invert each blood sample 5-10 times 
and allow blood to clot for 30-45 minutes at room temperature (tube 
standing upright).
2.
Centrifuge samples at room temperature for 10 minutes (swing out) or 15 
minutes (fixed) at 1100-1300 x g until clot and serum are well separated.
3.
Aliquot according to the following:
a.
PK-only timepoints- transfer all serum into one appropriately 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 56
labeled 2 mL screw-capped polypropylene tube
b.
PK and ADA- transfer serum equally into two appropriately 
labeled 3 mL screw-capped polypropylene tubes
4.
Store the serum samples immediately (within 1 hour of collection) at 
approximately -20°C or -70°C (preferred) until they are shipped on dry ice 
to the address in Section 8.3.6.
Sample Labeling
Each tube must be labeled with the patient’s study registration number, the 
study I.D., and the date and time the sample was drawn.  Data should be 
recorded on the Pharmacokinetic Study Form, which must accompany the 
sample(s).
Sample Shipping Instructions: 
Samples may be batched and shipped on dry ice at the end of each cycle
(Monday, Tuesday, or Wednesday) to:
Richard Catlyn
PPD - Pharmaceutical Product Development, LLC
2244 Dabney Road, Richmond, VA. 23230-3323
Tel: (804) 977-8344
Email: Richard.catlyn@ppdi.com
Fax: (804) 977-8112
Shipment notification with tracking number should be sent to Maria Edwards along 
with a copy of the PK Study form (Appendix III-A or Appendix III-B).
8.4
Vaccinated Antibody Studies (optional)
Analysis
In consenting patients, PD analysis will be done by Covance on serum samples 
for retrospective analysis of changes in antibody titers to previously vaccinated 
antigens following treatment with nivolumab alone and in combination with 
ipilimumab.
Sampling Schedule
Blood samples will be obtained prior to drug administration and as outlined in 
Appendix IV.
Sample Collection and Handling Instructions
Blood samples (2 ml) will be collected in 4 mL SST Vacutainer tubes at a site 
distant from the infusion. Samples cannot be drawn from the 2nd lumen of a 
multi-lumen catheter through which drug is being administered. Record the exact 
time that the sample is drawn along with the exact time that the drug is 
administered (including drug start and stop times).
Sample Processing and Shipping Instructions: 
1.
Immediately after collection, gently invert each blood sample 5-10 times 
and allow blood to clot for 30-45 minutes at room temperature (tube 
standing upright).
2.
Centrifuge samples at room temperature for 10 minutes (swing out) or 15 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 57
minutes (fixed) at 1100-1300 x g until clot and serum are well separated.
3.
Transfer all serum into one appropriately labeled 2 mL screw-capped 
polypropylene tube
4.
Store the serum samples immediately (within 1 hour of collection) at 
approximately -20°C or -70°C (preferred) until shipment.
Refer to the guidelines provided for sample shipping instructions.
Vaccinated Antibody Sample Shipping Instructions:
Samples may be batched and shipped on dry ice at the end of each cycle 
(Monday, Tuesday, or Wednesday) to:
Covance Central Laboratory Services
CenterlinX Receiving-Dock17
8211 SciCor Drive
Indianapolis, IN 46214
Email: monitoringUS@covance.com
Phone: 317-271-1200
Shipment notification with tracking number should be sent to Covance along 
with a copy of the Vaccinated Antibody Study form (Appendix IV).
Sample Labeling
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on 
the Vaccinated Antibody Study Form, which must accompany the sample(s).
8.5
Anti-drug antibody (ADA) analysis (Required)
Analysis: ADA analysis will be done by PPD - Pharmaceutical Product 
Development, LLC using an ELISA assay.
Sampling Schedule
Blood samples will be obtained as outlined in Appendix V.
Sample Collection and Handling Instructions
Blood samples (2 ml) will be collected in SST Vacutainer tubes at a site distant 
from the infusion. Samples cannot be drawn from the 2nd lumen of a multi-lumen 
catheter through which drug is being administered. Record the exact time that the 
sample is drawn along with the exact time that the drug is administered 
(including drug start and stop times).
1.
For timepoints where both PK and ADA samples are collected, an 8.5
mL SST tube is used. 
2.
For timepoints where only an ADA sample is collected, the 4 mL SST 
tube is used.
Sample Processing Instructions: 
1.
Immediately after collection, gently invert each blood sample 5-10 times 
and allow blood to clot for 30-45 minutes at room temperature (tube 
standing upright).

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 58
2.
Centrifuge samples at room temperature for 10 minutes (swing out) or 15 
minutes (fixed) at 1100-1300 x g until clot and serum are well separated.
3.
Aliquot according to the following:
a.
ADA-only timepoints- transfer all serum into one appropriately 
labeled 2 mL screw-capped polypropylene tube
b.
PK and ADA- transfer serum equally into two appropriately 
labeled 3 mL screw-capped polypropylene tubes
4.
Store the serum samples immediately (within 1 hour of collection) at 
approximately -20°C or -70°C (preferred) until they are shipped on dry ice
to the address in Section 8.5.6.
Sample Labeling
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on 
the Anti-drug Antibody (ADA) Study Form, which must accompany the 
sample(s).
Sample Shipping Instructions: 
Samples may be batched and shipped on dry ice at the end of each cycle (Monday, 
Tuesday, or Wednesday) to:
Richard Catlyn
PPD - Pharmaceutical Product Development, LLC
2244 Dabney Road, Richmond, VA. 23230-3323
Tel: (804) 977-8344
Email: Richard.catlyn@ppdi.com
Fax: (804) 977-8112
Shipment notification with tracking number should be sent to Richard Catlyn along 
with a copy of the ADA Study form (Appendix V).
8.6
Tumor Assessment PD-L1 and CD8 (required, if available)
Description of Studies
Tumor PD-L1 and CD8 expression will be performed by immunohistochemistry.
Archival tumor tissue should be submitted for all patients.  If a patient does not 
have tissue available, the study chair must be notified prior to enrollment.
Sampling Schedule (See Appendix VI)
•
Archival tumor tissue (Archival Formalin-Fixed Paraffin-Embedded 
(FFPE)) will be requested to be sent when available (15 slides requested, 
see Appendix VI for more information). 
•
In the event a subject requires a biopsy for surgery and tumor tissue is 
removed, tissue will be requested for PD-L1 and CD8 expression analysis 
(optional). Tumor biopsies will not be performed solely for research 
purposes.
Sample Labeling
Each specimen must be labeled with the patient’s study registration number, the 
study I.D., and must be accompanied by a pathology report.  Data should be 
recorded on the Tissue Studies Form, which must accompany the sample(s).

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 59
Sample Shipping Instructions: Tissue samples will be shipped to Mosaic 
Laboratories:
Attn: Lisa Dauffenbach
Mosaic Laboratories
12 Spectrum Pointe Drive
Lake Forest, CA 92630
Phone: (949) 472-8855
Shipment notification with tracking number should be sent to Lisa Dauffenbach 
(ldauffenbach@mosaiclabs.com) along with a copy of the Tissue Studies Form 
(Appendix VI). Please note: PD-L1, CD8, and FoundationOneCDx Tumor 
Assessments may be batched and shipped together.
8.7
Tumor Assessment FoundationOneCDx (Optional): Part E
Description of Studies
Genomic analysis of tumors will be performed by Foundation Medicine to 
explore immune related gene expression and its association with antitumor 
response (optional).
Sampling Schedule 
8.7.2.1 Archival tumor tissue (Archival Formalin-Fixed Paraffin-Embedded 
(FFPE)) will be requested to be sent when available (15 slides requested, 
or paraffin-embedded block; see Appendix VI for more information). 
Sample Labeling
Each specimen must be labeled with the patient’s study registration number, the 
study I.D., and must be accompanied by a pathology report.  Data should be 
recorded on the Tissue Studies Form, which must accompany the sample(s).
Sample Shipping Instructions: Tissue samples will be shipped to Mosaic 
Laboratories:
Attn: Lisa Dauffenbach
Mosaic Laboratories
12 Spectrum Pointe Drive
Lake Forest, CA 92630
Phone: (949) 472-8855
Shipment notification with tracking number should be sent to Lisa Dauffenbach 
(ldauffenbach@mosaiclabs.com) along with a copy of the Tissue Studies Form 
(Appendix VI). Please note: PD-L1, CD8, and FoundationOneCDx Tumor 
Assessments may be batched and shipped together.
8.8
Cytokine studies (optional)
Analysis
In consenting patients, PD analysis will be performed by Myriad RBM on serum 
samples for retrospective analysis of changes in cytokines following treatment 
with nivolumab alone and in combination with ipilimumab.

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 60
Sampling Schedule
Blood samples will be obtained prior to drug administration and as 
outlined in Appendix VII.
Sample Collection and Handling Instructions
Blood samples (2 ml) will be collected in 4 mL SST Vacutainer tubes at a site 
distant from the infusion. Samples cannot be drawn from the 2nd lumen of a 
multi-lumen catheter through which drug is being administered. Record the 
exact time that the sample is drawn along with the exact time that the drug is 
administered (including drug start and stop times).
Sample Processing and Shipping Instructions: 
1.
Immediately after collection, gently invert each blood sample 5-10 times 
and allow blood to clot for 30-45 minutes at room temperature (tube 
standing upright).
2.
Centrifuge samples at room temperature for 10 minutes (swing out) or 15 
minutes (fixed) at 1100-1300 x g until clot and serum are well separated.
3.
Transfer all serum into one appropriately labeled 2 mL screw-capped 
polypropylene tube
4.
Store the serum samples immediately (within 1 hour of collection) at 
approximately -20°C or -70°C (preferred) until shipment.
Sample Labeling
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on 
the Cytokine Study Form, which must accompany the sample(s).
Cytokine Sample Shipping Instructions: 
Samples may be batched and shipped on dry ice at the end of each cycle (Monday, 
Tuesday, or Wednesday) to:
Bristol-Myers Squibb
BMS Biorepository
Attn: Karl Kammerhoff and/or designee
Room K1421
Route 206 & Provinceline Road
Princeton, NJ 08543
609-818-6398
bmsbiorepository@bms.com 
Shipment notification with tracking number should be sent to BMS Biorepository 
and the study research coordinator via email, along with a copy of the Cytokine
Study form (Appendix VII).
9.0
AGENT INFORMATION
9.1
Nivolumab
(BMS-936558, MDX1106, ONO-4538, anti-PD-1, OpdivoTM) NSC#748726,
Structure and molecular weight 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 61
Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 
2 identical heavy chains consisting of 440 amino acids and 2 identical light chains.  
Molecular weight is 146,221 daltons.  
Supplied by:
Nivolumab will be supplied by Bristol-Myers Squibb (BMS) and distributed by 
the DCTD, NCI. Do NOT use commercially available supply.
Formulation
The agent is a clear to opalescent, colorless to pale yellow liquid, with light (few) 
particulates may be present.  It is available in a 100 mg/10 mL vial containing a
sterile, non-pyrogenic, single-use, isotonic aqueous solution formulated at 10 
mg/mL in sodium citrate dihydrate, sodium chloride, mannitol, diethylenetriamine 
pentacetic acid (pentetic acid) and polysorbate 80 (Tween® 80), and water for 
injection. Dilute solutions of hydrochloric acid and/or sodium hydroxide may be 
used for pH adjustment (pH 5.5-6.5). A small amount of overfill (0.7 mL) is 
included with each vial to account for VNS (vial, needle, syringe) loss.  The 10 
mL type I flint glass vials are stoppered with fluoropolymer film-laminated rubber 
stoppers and sealed with aluminum seals.
Storage
Nivolumab vials for injection must be stored at 2-8C (36-46F) and protected 
from light, freezing and shaking. Unopened vials can be stored at room 
temperature (up to 25C, 77F) and room light for up to 48 hours.
If a storage temperature excursion is identified, promptly return Nivolumab to 2°C-
8°C and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.
Solution Preparation
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose. When the dose is based on 
patient weight (i.e., mg/kg), nivolumab injection can be infused undiluted or 
diluted to protein concentrations as low as 0.35 mg/mL. When the dose is fixed 
(e.g., 240 mg flat dose), nivolumab injection can be infused undiluted or diluted 
so as not to exceed a total infusion volume of 160 mL. For patients weighing less 
than 40 kilograms (kg), the total volume of infusion must not exceed 4 mL per kg 
of patient weight. During drug product preparation and handling, vigorous mixing 
or shaking is to be avoided.
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin 
containers and infusion sets, and glass bottles.
Stability
Shelf life surveillance of the intact vials is ongoing.
The administration of undiluted and diluted nivolumab must be completed within 
24 hours of preparation. If not used immediately, the infusion solution of 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 62
nivolumab injection prepared for dosing may be stored for up to 24 hours in a 
refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the total 24 hours 
can be at room temperature (up to 25°C, 77°F) and under room light. The 
maximum 8-hour period under room temperature and room light conditions for 
nivolumab injection in IV bag includes the product administration period (30
minutes). 
CAUTION: The single-use vials of nivolumab for injection do not contain 
preservatives or bacteriostatic agents and should be prepared as soon as possible 
prior to administration using aseptic technique. It is advised that the product be 
discarded 8 hours after initial entry.
Administration
See Treatment and Dose Modifications sections of the protocol.
Nivolumab should be administered as an intravenous infusion over 30 minutes 
through a 0.2 to 1.2 micron pore size, low-protein binding (polyethersulfone 
membrane) in-line filter.  Nivolumab is not to be administered as an IV push or 
bolus injection. Do not administer other medications through the same IV line. 
Flush IV line at the end of the infusion.
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin 
containers and infusion sets, and glass bottles. 
When administered in combination with ipilimumab, infuse nivolumab first 
followed by ipilimumab on the same day. Use separate infusion set and filters for 
each infusion. 
Potential drug interactions
No formal pharmacokinetic drug-drug interaction studies have been conducted 
with nivolumab. The indirect drug-drug interaction potential of nivolumab was 
assessed using systemic cytokine modulation data for cytokines known to 
modulate CYP enzymes. There were no meaningful changes in cytokines known 
to have indirect effects on CYP enzymes across all dose levels of nivolumab. This 
lack of cytokine modulation suggests that nivolumab has no or low potential for 
modulating CYP enzymes, thereby indicating a low risk of therapeutic protein-
drug interaction.
Patient Care Implications
Adverse events were observed in animal reproduction studies. Nivolumab may be 
expected to cross the placenta; effects to the fetus may be greater in the second and 
third trimesters. Based on its mechanism of action, nivolumab is expected to cause 
fetal harm if used during pregnancy. Women of childbearing potential (WOCBP) 
receiving nivolumab must continue contraception for a period of 5 months after 
the last dose of nivolumab. Men receiving nivolumab and who are sexually active 
with WOCBP must continue contraception for a period of 7 months after the last 
dose of nivolumab.
It is not known if nivolumab is present in breast milk. Due to the potential for 
serious adverse reactions in the breastfed infant, the manufacturer recommends to 
discontinue breastfeeding during treatment.

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 63
Nivolumab Toxicities
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/a
eguidelines.pdf for further clarification. Frequency is provided based on 2069 
patients. Below is the CAEPR for BMS-936558 (Nivolumab, MDX-1106).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required.
Version 2.3, June 18, 20181
Adverse Events with Possible 
Relationship to BMS-936558 (Nivolumab, MDX-1106)
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 2)
CARDIAC DISORDERS
Cardiac 
disorders 
-
Other 
(cardiomyopathy)
Myocarditis
Pericardial tamponade2
Pericarditis
ENDOCRINE DISORDERS
Adrenal insufficiency3
Hypophysitis3
Hyperthyroidism3
Hypothyroidism3
EYE DISORDERS
Blurred vision 
Dry eye
Eye disorders - Other (diplopia) 3
Eye disorders - Other (Graves 
ophthalmopathy) 3
Eye disorders -
Other (optic 
neuritis retrobulbar) 3
Uveitis
GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal pain (Gr 2)
Colitis3
Colonic perforation3
Diarrhea
Diarrhea (Gr 3)
Dry mouth
Dry mouth (Gr 2)

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 64 
 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Gastritis 
  
 
 
 Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5 
  
 
 
Immune system disorders - Other 
(GVHD 
in 
the 
setting 
of 
allotransplant) 3, 6  
  
 
 
Immune system disorders - Other 
(sarcoid granuloma) 3  
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased3 
 
 Alanine 
aminotransferase 
increased3 (Gr 3)  
 
Aspartate aminotransferase 
increased3 
 
 Aspartate 
aminotransferase 
increased3 (Gr 3)  
 
Blood bilirubin increased3 
 
 Blood bilirubin increased348484847 
(Gr 2)  
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count decreased  
 Lymphocyte count decreased (Gr 
2) 
  
Neutrophil count decreased  
  
 
Platelet count decreased 
 
  
 
Serum amylase increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism 
and 
nutrition 
disorders 
- 
Other 
(diabetes 
mellitus with ketoacidosis) 3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and connective 
tissue 
disorder 
- 
Other 
(polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 65 
 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - Other 
(demyelination 
myasthenic 
syndrome) 
  
 
 
Nervous system disorders - Other 
(encephalitis) 3 
  
 
 
Nervous system disorders - Other 
(meningoencephalitis) 
  
 
 
Nervous system disorders - Other 
(meningoradiculitis) 3 
  
 
 
Nervous system disorders - Other 
(myasthenic syndrome) 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy 
  
 
 
Reversible 
posterior 
leukoencephalopathy syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, 
thoracic 
and 
mediastinal disorders - Other 
(bronchiolitis 
obliterans 
with 
organizing pneumonia) 3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2)  
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 2)  
 
 
Skin and subcutaneous disorders 
-Other (bullous pemphigoid)  
  
 
Skin 
and 
subcutaneous 
disorders - Other (Sweet’s 
Syndrome) 3 
 
  
 
Skin hypopigmentation3 
 
  
 
 
 Stevens-Johnson syndrome 
  
 
 
 Toxic epidermal necrolysis 
  
 
 
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. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3BMS-936558 (Nivolumab, MDX-1106) being a member of class of agents involved in the inhibition of 
“immune checkpoints”, may result in severe and possibly fatal immune-mediated adverse events probably 
due to T-cell activation and proliferation.  This may result in autoimmune disorders that can include (but are 
not limited to) autoimmune hemolytic anemia, acquired anti-factor VIII immune response, autoimmune 
aseptic meningitis, autoimmune hepatitis, autoimmune nephritis, autoimmune neuropathy, autoimmune 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 66 
 
thyroiditis, bullous pemphigoid, exacerbation of Churg-Strauss Syndrome, drug rash with eosinophilia 
systemic symptoms [DRESS] syndrome, facial nerve disorder (facial nerve paralysis), limbic encephalitis, 
hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders 
(e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, 
thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia gravis, polymyositis, and 
Guillain-Barre syndrome. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying 
fever and pancytopenia. 
 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in 
patients receiving allo stem cell transplant (SCT) after receiving BMS-936558 (Nivolumab, MDX-1106).  
These complications may occur despite intervening therapy between receiving BMS-936558 (Nivolumab, 
MDX-1106) and allo-SCT. 
 
7Infusion reactions, including high-grade hypersensitivity reactions which have been observed following 
administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or 
hypotension, or difficulty breathing during and immediately after administration of nivolumab. 
 
 
Adverse events reported on BMS-936558 (Nivolumab, MDX-1106) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that BMS-936558 
(Nivolumab, MDX-1106) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; Ventricular 
arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; Gastrointestinal disorders 
- Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; 
Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis  
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune thrombotic 
microangiopathy); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper respiratory 
infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - Other 
(protein total decreased); Lymphocyte count increased; Weight loss  
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Musculoskeletal and 
connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal and connective tissue disorder 
- Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other (tubulointerstitial 
nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; Dyspnea; 
Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain of skin; 
Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other (rosacea) 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 67
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis
Note: BMS-936558 (Nivolumab, MDX-1106) 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.
Agent Ordering and Agent Accountability
NCI supplied agents may be requested by eligible participating Investigators (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), NCI Biosketch, Agent Shipment
Form, and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP supplied investigational agents for the study 
should be ordered under the name of one lead participating investigator at that 
institution.
Clinical Drug Request and Investigator Brochure Availability
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password and active person registration status. For questions 
about drug orders, transfers, returns, or accountability call or email PMB anytime.
Refer to the PMB’s website for specific policies and guidelines related to agent 
management. Questions about IB access may be directed to the PMB IB 
coordinator via email.
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. Questions about IB access may be directed to the PMB IB 
coordinator via email.
Agent Inventory Records
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents received 
from the PMB using the appropriate NCI Investigational Agent (Drug)
Accountability Record (DARF) available on the CTEP forms page. Store and 
maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol.
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov
• PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm    
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/  
• CTEP Identity and Access Management (IAM) account: 
  
https://ctepcore.nci.nih.gov/iam/

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 68
• 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)
• Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/
9.2
Ipilimumab
(MDX-010, anti-CTLA-4 antibody, YervoyTM) NSC#732442,
Description
Ipilimumab is a fully human immunoglobulin (IgG1) specific for human CTLA-
4 antigen (CD152). It consists of 4 polypeptide chains, 2 identical heavy chains 
with 447 amino acids and 2 identical light chains consisting of 215 amino acids. 
Current NCI sponsored protocols utilize ipilimumab produced and formulated 
from a transfectoma, Chinese hamster ovary [CHO] cell line. Ipilimumab 
monoclonal antibody is specific for the CTLA-4 antigen (CD152) expressed on a 
subset of activated T-cells. CTLA-4 interaction with the B7 molecule, one of its 
ligands expressed on professional antigen presenting cells, can down-regulate a T-
cell response. Ipilimumab is thought to act by blocking the interaction of CTLA-4 
with the B7 ligand, resulting in a blockade of the inhibitory effect of T-cell 
activation that is created by the CTLA-4/B7 interaction.
Supplied by:
Ipilimumab is an investigational agent provided by Bristol-Myers Squibb and 
supplied to investigators by the Division of Cancer Treatment and Diagnosis 
(DCTD), Cancer Therapy Evaluation Program (CTEP), National Cancer Institute 
(NCI). Do NOT use commercially available supply.
Formulation
Ipilimumab injection is supplied as 200 mg/40 mL (5 mg/mL), formulated as a clear 
to slightly opalescent, colorless to pale yellow, sterile, isotonic aqueous solution (pH 
of 7) that may contains particles. Each vial contains a small amount of overfill. All 
vials are Type 1 flint glass vials with gray butyl stoppers and aluminum seals. Inactive 
ingredients include sodium chloride, TRIS-hydrochloride, diethylenetriamine 
pentacetic acid, mannitol, polysorbate 80, sodium hydroxide, hydrochloric acid, 
water for injection, and a small amount of nitrogen as a processing agent.  
Storage
Store intact vials of ipilimumab refrigerated at 2-8 °C (36-46°F). Protect from 
light. DO NOT FREEZE OR SHAKE. The formulation contains no preservatives.  
If a storage temperature excursion is identified, promptly return ipilimumab to 2°C-
8°C and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 69
Solution Preparation
Ipilimumab may be dispensed undiluted or further diluted in 0.9% NaCl Injection, 
USP or 5% Dextrose Injection, USP to a concentration between 1 mg/mL and 4 
mg/mL.  Ipilimumab is stable in polyvinyl chloride (PVC), non-PVC/non DEHP (di-
(2-ethylhexyl) phthalate) IV bag or glass container. Ipilimumab diluted between 1 
mg/mL and 4 mg/mL is stable in polypropylene syringes. Mix GENTLY by 
inverting several times. Do not shake.  Vials of ipilimumab for injection do not 
contain preservatives; the product should be prepared as soon as possible prior to 
administration using aseptic technique.
Stability
Shelf-life surveillance of the intact vials is ongoing. Prepared solutions of
ipilimumab undiluted (5 mg/mL) or diluted with 0.9% sodium chloride are stable
for up to 24 hours refrigerated (2 – 8° C) or at room temperature (under room light).
Administration
See Treatment and Dose Modifications sections of the protocol.
Ipilimumab is administered as a 90-minute intravenous infusion using a
volumetric pump and a PVC IV infusion set with an in-line, sterile, non-pyrogenic, 
low-protein-binding filter (0.2 micron to 1.2 micron).  Do NOT administer as an
intravenous push
or
bolus. For administration by syringe pump, the 
concentration of Ipilimumab must be within the range of 1 mg/mL and 4 
mg/mL.
When administered in combination with nivolumab, infuse nivolumab first 
followed by ipilimumab on the same day. Use separate infusion set and filters for 
each infusion. 
Ipilimumab Toxicities
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/aegui
delines.pdf for further clarification. Frequency is provided based on 2678 
patients. Below is the CAEPR for Ipilimumab (MDX-010).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required.
Version 2.10, March 29, 201949

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 70 
 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Blood 
and 
lymphatic 
system 
disorders 
- 
Other 
(acquired 
hemophilia) 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Myocarditis50 
  
 
 
Pericardial effusion 
  
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency50 
 
  
 
Hyperthyroidism50 
 
  
 
Hypophysitis50 
 
  
 
Hypopituitarism50 
 
  
 
Hypothyroidism50 
 
  
 
Testosterone deficiency50 
 
  
EYE DISORDERS 
  
 
Eye disorders - Other (episcleritis)50  
  
 
Uveitis50 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis50 
 
 Colitis50 (Gr 3) 
 
 
Colonic perforation51 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Enterocolitis 
 
  
 
Esophagitis 
 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Pancreatitis50 
 
  
 
Vomiting 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
 
General 
disorders 
and 
administration site conditions - 
Other 
(Systemic 
inflammatory 
response syndrome [SIRS]) 
  
 
 
Multi-organ failure 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary 
disorders 
- 
Other 
(hepatitis)50 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Autoimmune disorder50 
 
  
 
 
Immune system disorders - Other 
(GVHD 
in 
the 
setting 
of 
allotransplant)52 
  

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 71 
 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
INFECTIONS AND INFESTATIONS 
  
 
 
 Infections and infestations 
- 
Other (aseptic meningitis)50 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
  
 
Aspartate 
aminotransferase 
increased 
 
  
 
 
Lymphocyte count decreased 
  
 
Neutrophil count decreased 
 
  
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
 
Metabolism 
and 
nutrition 
disorders - Other (exacerbation of 
pre-existing diabetes mellitus) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Arthritis 
 
  
 
 
Generalized muscle weakness 
  
 
Musculoskeletal 
and 
connective 
tissue 
disorder 
- 
Other 
(polymyositis)50 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Ataxia 
  
 
Facial nerve disorder50 
 
  
 
Guillain-Barre syndrome50 
 
  
 
Headache 
 
  
 
Myasthenia gravis50 
 
  
 
 
Nervous system disorders - Other 
(immune-mediated 
encephalitis)50 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy 
  
 
Trigeminal nerve disorder 
 
  
PSYCHIATRIC DISORDERS 
  
 
 
Psychiatric disorders - Other 
(mental status changes) 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Renal and urinary disorders - Other 
(granulomatous 
tubulointerstitial 
nephritis) 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis 
 
  
 
 
Respiratory failure 
  

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 72 
 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Respiratory, 
thoracic 
and 
mediastinal disorders - Other 
(bronchiolitis 
obliterans 
with 
organizing pneumonia) 
  
 
 
Respiratory, 
thoracic 
and 
mediastinal disorders - Other 
(lung infiltration) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
Skin 
and 
subcutaneous 
tissue 
disorders 
- 
Other 
(Sweet's 
Syndrome) 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-cell 
activation and proliferation.  These can include (but are not limited to) autoimmune hemolytic anemia, 
acquired anti-factor VIII immune response, autoimmune aseptic meningitis, autoimmune hepatitis, 
autoimmune thyroiditis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic 
colitis, endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, and adrenal insufficiency), ocular manifestations (e.g., uveitis, iritis, 
conjunctivitis, blepharitis, and episcleritis), sarcoid granuloma, myasthenia gravis, polymyositis, and 
Guillain-Barre syndrome.  The majority of these reactions manifested early during treatment; however, a 
minority occurred weeks to months after discontinuation of ipilimumab especially with the initiation of 
additional treatments. 
 
3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in association with 
subsequent IL-2 therapy. 
 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients receving allo 
stem cell transplant (SCT) after receiving Ipilimumab (MDX-010).  These complications may occur despite 
intervening therapy between receiving Ipilimumab (MDX-010) and allo-SCT. 
 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 
 
6Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal 
hemorrhage, 
Oral 
hemorrhage, 
Pancreatic 
hemorrhage, 
Rectal 
hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 73
DISORDERS SOC.
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.
Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that Ipilimumab (MDX-010) caused the adverse 
event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders -
Other (pure red cell aplasia)50; Febrile neutropenia
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy
EYE DISORDERS - Extraocular muscle paresis53; Eye disorders - Other (retinal pigment changes)
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; Gastrointestinal disorders -
Other (gastroenteritis); Gastrointestinal hemorrhage54; Proctitis
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac 
chest pain
HEPATOBILIARY DISORDERS - Hepatic failure50
IMMUNE SYSTEM DISORDERS - Allergic reaction
INFECTIONS AND INFESTATIONS - Infection55
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase increased; 
Platelet count decreased; Serum amylase increased; White blood cell decreased
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint range of motion 
decreased; Myalgia; Pain in extremity
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Seizure
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia
RENAL AND URINARY DISORDERS - Proteinuria
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Cough; Dyspnea; 
Laryngospasm
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Skin 
hypopigmentation
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal arteritis)
Note: Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) 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.
Agent Ordering and Agent Accountability
NCI supplied agents may be requested by the eligible participating 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), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP supplied investigational agents for the study should 
be ordered under the name of one lead participating investigator at that institution.
Clinical Drug Request and Investigator Brochure Availability

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 74
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a “current” 
password, and active person registration status. For questions about drug orders, transfers, 
returns, or accountability call or email PMB anytime. Refer to the PMB’s website for 
specific policies and guidelines related to agent management. Questions about IB access 
may be directed to the PMB IB coordinator via email.
The current versions of the IBs for the agents will also be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing (OAOP) application. 
Questions about IB access may be directed to the PMB IB coordinator via email. 
Agent Inventory Records
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) 
available on the CTEP forms page. Store and maintain separate NCI Investigational Agent 
Accountability Records for each agent, strength, formulation and ordering investigator on 
this protocol.
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov
• PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm    
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP
• CTEP Identity and Access Management (IAM) account: 
    https://ctepcore.nci.nih.gov/iam/
• CTEP Associate Registration and IAM account help:
ctepreghelp@ctep.nci.nih.gov
• PMB email: PMBAfterHours@mail.nih.gov
• PMB phone and hours of service: (240) 276-6575 
Monday through Friday between 8:30 am and 4:30 pm (ET)
• PMB IB Coordinator: IBcoordinator@mail.nih.gov
• Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/
10.0
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
10.1
Criteria for Removal from Protocol Therapy 
a)
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease of greater than 40% increase from baseline target 
lesions selected according to RECIST criteria (See Section 12.0).
b)
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease > 12 weeks after start of protocol therapy.
c)
Adverse Events requiring removal from protocol therapy (See Sections 5.4 and 6.0).
d)
Immune adverse events requiring removal from protocol therapy (See Section 5.4

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 75 
 
and Section 6.0) which in the opinion of the treating physician are consistent with 
acute or chronic GVHD requiring systemic immunosuppression. 
e) 
Refusal of further protocol therapy by patient/parent/guardian 
f) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
g) 
Physician determines it is not in the patient’s best interest. 
h) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of protocol therapy (See Section 8.1). 
i) 
Study is terminated by Sponsor. 
j) 
Pregnancy 
 
Patients who are removed from protocol therapy during cycle 1 (Part A and B) or 
during cycles 1 and 2 (Parts C, D, or E) should continue to have the required 
observations in Section 8.1 until the originally planned end of the cycle or until all 
adverse events have resolved per Section 13.4.4, whichever happens LATER. The 
only exception is with documentation of the patient’s withdrawal of consent. Patients 
who are removed from protocol therapy in subsequent cycles should have the 
necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed as described in Section 8.1.1 until 
they meet the criteria for Off Study (see below). Ongoing adverse events, or adverse events 
that emerge after the patient is removed from protocol therapy, but within 100 days of the 
last dose of investigational agent, must be followed and reported via RAVE and CTEP-
AERS (if applicable). Serious adverse events that occur during the follow-up period (more 
than 30 days after the last administration of investigational agent) and have an attribution 
of possible, probable, or definite require reporting per Footnote 1 of Table A.  Follow-up 
data will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
 
a) 
100 days after the last dose of the investigational agent (Patients on Part A or C that 
are not enrolled at the MTD; Patients on Part E). 
b) 
The fifth anniversary of the date the patient was enrolled on this study (All patients 
enrolled at the determined MTD)  
c) 
Death 
d) 
Lost to follow-up 
e) 
Withdrawal of consent for any further required observations or data submission. 
f) 
Enrollment onto another COG therapeutic (anti-cancer) study  
g) 
Patient did not receive protocol treatment after study enrollment 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
Part A:  Phase 1 (single agent) - patients with solid tumors, excluding brain and CNS 
tumors 
Part B:  Patients with relapsed or refractory neuroblastoma (B1) 
 
Patients with relapsed or refractory osteosarcoma (B2) 
 
Patients with relapsed or refractory rhabdomyosarcoma (B3) 
 
Patients with relapsed or refractory Ewing Sarcoma or Peripheral PNET (B4) 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 76 
 
Patients with relapsed or refractory Hodgkin Lymphoma (B5) 
Patients with relapsed or refractory Non-Hodgkin Lymphoma (B6) 
Patients with unresectable melanoma or metastatic melanoma or relapsed 
melanoma or refractory melanoma (B7) 
Patients with relapsed or refractory neuroblastoma (MIBG evaluable without 
RECIST evaluable disease) (B8) 
Part C:  Phase 1 (combination) - patients with solid tumors, excluding brain and CNS 
tumors  
Part D:  Patients with relapsed or refractory neuroblastoma (D1) 
 
Patients with relapsed or refractory osteosarcoma (D2) 
Patients with relapsed or refractory rhabdomyosarcoma (D3) 
Patients with relapsed or refractory Ewing Sarcoma or Peripheral PNET (D4) 
Patients with relapsed or refractory Non-Hodgkin Lymphoma (D5) 
Patients with relapsed or refractory neuroblastoma (MIBG evaluable without 
RECIST evaluable disease) (D6) 
Part E: Patients with relapsed or refractory rhabdomyosarcoma (E3) 
 
Patients with relapsed or refractory Ewing Sarcoma or Peripheral PNET (E4) 
 
Part 
Minimum 
Maximum 
Estimated Duration 
A 
4 
36 (20% inevaluable) 
2-36 months  
B 
60 
170 (10% inevaluable) 
1-2.75 years 
C 
2 
36 (20% inevaluable 
2-36 months 
D 
 
 0 
110 (10% inevaluable) 
1-2.75 years 
E 
2 
23 (10% inevaluable) 
1-23 months 
 
Part A will enroll a minimum of 2 evaluable patients at each dose level for determination 
of MTD/Recommended Phase 2 dose (RP2D) of single agent nivolumab. Once the MTD 
or recommended Phase 2 dose has been defined in Part A, Parts B and C will open 
concurrently. Part C will enroll a minimum of 2 evaluable patients at each dose level for 
determination of MTD/Recommended Phase 2 dose (RP2D) of the combination nivolumab 
plus ipilumumab.  Up to 6 additional patients with relapsed/refractory solid tumors without 
restrictions on heme evaluability may be enrolled at the RP2D determined in Part A and 
Part C to acquire PK data in a representative number of young patients (i.e. patients < 12 
years old) at the MTD/RP2D in each Part.  Once the dose-escalation portion of Part A is 
completed, cohorts that are open concurrently for eligible patients (including Parts B and 
C and potential PK expansion cohorts) may be selected at the treating physician’s 
discretion pending slot availability. 
 
The single-agent recommended Phase 2 dose of Part A was determined to be 3 
mg/kg nivolumab.  
 
The recommended Phase 2 dose of nivolumab in combination with ipilimumab 
from Part C was determined to be 3 mg/kg nivolumab and 1 mg/kg ipilimumab.  
 
In the event a cohort in a given disease group in Part B is completed after Stage 1, a 
corresponding cohort in the same disease group will open for select disease types in Part 
D at the RP2D determined in Part C. 
 
A minimum of 4 patients will be enrolled in Part A, and a maximum of 36 patients are 
possible. A maximum of 36 patients could occur in the unlikely scenario that each dose 
level is expanded to 12 patients per Section 11.2.2, and a 20% inevaluable rate occurs. A 
minimum of 2 patients will be enrolled in Part C, and a maximum of 36 patients is possible 
similar to Part A. Review of the enrollment rate into previous COG new agent studies 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 77 
 
indicates that 1-2 patients per month are available, which will permit completion of Part A 
within 11-22 months and Part C within 14-29 months.  
 
Review of patient accrual onto recent Phase 2 solid tumor studies indicates the following 
entry rates for the various tumors under study can be achieved for Parts B, D and E: 
 
Disease Group/Part 
 
 
Patients/ Year 
Neuroblastoma  
 
 
10-12 
Osteosarcoma  
 
 
10-12 
Rhabdomyosarcoma 
 
 
8-10 
Ewing Sarcoma  
 
 
10-12 
Hodgkin Lymphoma 
 
 
10-12 
Non-Hodgkin Lymphoma 
 
10-12 
Melanoma 
 
 
 
3-4 
 
A minimum of 10 evaluable patients per disease group will be enrolled in Parts B1-B6 and 
B8 and Parts D1-6. A maximum 22 per disease group will be enrolled in these cohorts. A 
non-statistical access cohort for the rare diagnosis of melanoma (Part B7) will remain open 
to enrollment until Parts B1-B6, B8 and Parts D1-6 are complete. If at any time after 
enrollment of three patients, cycle 1 DLT occurs in ≥ 33% in the melanoma cohort, 
enrollment to that cohort will be closed. There will be no required minimum or maximum 
accrual limits for Part B7; however, given the accrual rate of 3-4 patients/year a minimum 
of 0 evaluable patients and a maximum of 16 patients is anticipated to enroll in this disease 
group assuming the maximum study duration of 4 years. The maximum enrollment 
assumes a 10% inevaluable rate. Therefore, a minimum of 60 patients and a maximum of 
170 patients will be enrolled in Part B. A maximum of 110 patients will be enrolled in Part 
D. 
 
As cohort D5 investigates the combination of nivolumab and ipilimumab in patients who 
may be post-allogeneic BMT, if at any time after 3 enrollments, acute or chronic GVHD 
requiring systemic immunosuppression occurs in ≥ 33% of patients, the strata will be 
closed to accrual. 
 
A minimum of 6 children < 12 years of age and at least 6 children ≥ 12 years of age will 
be evaluated for tolerability and systemic exposure of single agent nivolumab RP2D in 
Parts A and B.  If less than 6 patients < 12 years of age are enrolled upon completion of 
accrual to Part B, additional children (any histology) will be added to Part A studied to 
reach the 6 patient minimum. 
 
Update: As of Amendment #8 a total of 132 patients have been enrolled: 
Part A:  13 patients 
Part B:  B1: 10 patients 
 
B2: 10 patients 
 
B3: 11 patients 
 
B4: 10 patients 
 
B5: 12 patients 
 
B6: 10 patients 
 
B7: 1 patient 
 
B8: 8 patients 
Part C:  18 patients 
Part D:  D2: 10 patients 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 78
D3: 10 patients
D4: 9 patients
A total 132 patients have enrolled into ADVL1412 to date. A minimum of 3 evaluable 
patients will be enrolled in Part E, and a maximum of 23 patients will be enrolled overall. 
The maximum enrollment assumes a 10% inevaluable rate, and this part of the study is 
anticipated to be completed within 2-23 months. Therefore, the maximum number of 
patients for the entire study is expected to be 155 with amendment 8, and this entire 
protocol will have been completed within 5.5 years.
11.2
Definitions
Evaluable For Adverse Events
For all parts of the study, any patient who receives at least one dose of the study 
drug(s) and who experiences a dose-limiting toxicity is considered evaluable for 
Adverse Events. In addition, for the dose-escalation portions (Parts A and C), 
during Cycle 1, patients must have the appropriate toxicity monitoring studies 
performed to be considered evaluable for dose limiting toxicity. In Parts A and C, 
patients who do not have DLT and do not receive at least 85% of the prescribed 
dose within the first 28 days (the DLT observation period) for reasons other than
toxicities (e.g. progressive disease) will not be considered evaluable for toxicity
and will be replaced.
Maximum Tolerated Dose
•
The MTD will be the maximum dose at which fewer than one-third of 
patients experience DLT (See Section 5.4) during Cycle 1 of therapy. 
•
In the unlikely event that two DLTs observed out of 6 evaluable patients are 
different classes of Adverse Effects (e.g. hepatotoxicity and 
myelosuppression), AND all of the following conditions are met, expansion 
of the cohort to 12 patients will be considered: 
• One of the DLTs does not appear to be dose-related
• The Adverse Effects are readily reversible
• The study chair, DVL statistician, DVL committee chair or vice chair, 
and IND sponsor all agree that expansion of the cohort is acceptable
If fewer than 1/3 of patients in the expanded cohort experience dose-
limiting toxicities, the dose escalation can proceed.
•
The DLTs observed in the pharmacokinetic (PK) expansion cohort will be 
counted towards the total number of DLTs observed at the MTD during the 
dose escalation portion of the study. If ≥ 1/3 of the cohort of patients at the 
MTD (during the dose escalation plus the PK expansion) experience DLT 
then the MTD will be exceeded. 
Evaluability for Response
Any patient who is enrolled who meets eligibility criteria for Parts B, D or E and 
receives at least one dose of protocol therapy will be considered evaluable for 
response provided: (1) the patient demonstrates progressive disease or death while 
on protocol therapy (note: if the institutional investigator determines that the 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 79 
 
patient has progressed based on clinical or laboratory evidence, he/she may opt not 
to confirm this finding radiographically); or (2) the patient is observed on protocol 
therapy for at least one cycle and the tumor is not removed surgically prior to the 
time complete response or partial response is confirmed, or (3) the patient 
demonstrates a complete or partial response as confirmed according to protocol 
criteria. Patients who demonstrate a complete or partial response confirmed by 
central review will be considered to have experienced a response for the 
application of the rule given in Section 11.4. Two objective status determinations 
are required to confirm best response (Section 12.6). All other patients will be 
considered non-responders. All patients considered to have a response (CR or PR) 
must have imaging studies reviewed centrally at the COG. Centers will be notified 
by the COG about requests for scans of patients with stable disease. See Section 
8.2 regarding image submission instructions. The central review by COG will be 
provided as the final reviewed assessment of response when such becomes 
available. Patients inevaluable for response will be considered for replacement. 
  
11.3 
Determination of Recommended Phase 2 Dose for Nivolumab as a Single Agent (Part 
A): 
− Part A will evaluate a single dose level (3 mg/kg). If 1 or fewer of 6 evaluable patients 
experience DLT and at least 5/6 of patients achieve a Cmin of at least 10 mcg/ml, the 
3 mg/kg dose level will be the RP2D and we will conclude that children are not 
experiencing significantly less exposure than adults treated at the same dose.  If 
however, < 5 of 6 patients achieve a Cmin of at least 10 mcg/ml, consideration will be 
given to a protocol amendment to test a higher dose level in Part A.  Note that Cmin 
levels > 30 mcg/ml will not, in and of itself result in a change in protocol design, unless 
excess toxicity is observed. 
− If 2 or more of the 6 patients experience DLT at the 3 mg/kg dose level, then the MTD 
has been exceeded and the 1 mg/kg dose level will be evaluated. If 1 or fewer of 6 
patients experience DLT at the 1 mg/kg dose level and at least 5/6 of patients achieve 
a Cmin of at least 10 mcg/ml, then this dose level will be the RP2D. Once the RP2D 
for nivolumab as a single agent is determined, Part B and Part C will open 
simultaneously.  
 
Update: The single-agent recommended Phase 2 dose of Part A was determined to 
be 3 mg/kg nivolumab.  
  
11.4 
Phase 2 Evaluation of Nivolumab (for Part B): 
 
Study Design 
The best response of disease to nivolumab will be examined separately for each of 
the tumor strata: neuroblastoma, osteosarcoma, rhabdomyosarcoma, ewing 
sarcoma, Hodgkin lymphoma, and non-Hodgkin lymphoma with the goal of 
enrolling at least evaluable 10 patients per tumor type. Given the activity seen in 
adult patients with melanoma, an additional non-statistical cohort for patients with 
unresectable, metastatic, relapsed or refractory melanoma will be open to accrual 
as Part B7 to preliminarily define the antitumor effects of nivolumab within the 
confines of a phase 1/2 study and will remain open for enrollment until Parts B1-
B6, B8 are complete. Given the rarity of the disease in the pediatric population the 
study will not remain open to complete this cohort if all other strata have completed 
accrual. If at any time after enrollment of three patients, cycle 1 DLT occurs in ≥ 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 80 
 
33% in the melanoma cohort, enrollment to that cohort will be closed. If at least 
12 patients are treated at Part B7, evaluation of accrual rate and toxicities may be 
discussed with the sponsor to determine if any changes in study design are 
required. The following Simon’s optimal two stage design56 will be used for Parts 
B1-B6, B8. 
 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 10 patients 
0 
Terminate 
the 
stratum: 
agent 
ineffective 
1 or more 
Inconclusive result, continue stratum 
(proceed to stage 2) 
 
Stage 2: Enter 10 additional 
patients 
2 or less      
Terminate 
the 
stratum: 
agent 
ineffective 
3 or more 
Terminate the stratum: agent effective 
 
In the event that a cohort in a given disease group in Part B is completed after Stage 
1 because no responses are observed, a cohort in the same disease group will open 
to up to 10 evaluable patients in Part D, at the RP2D of nivolumab in combination 
with ipilimumab as determined in Part C: 3 mg/kg nivolumab and 1 mg/kg 
ipilimumab (See Section 11.6). 
 
Nivolumab will not be considered of sufficient interest for further evaluation in a 
disease category if the true response rate is 5% and of sufficient activity if the true 
response rate is 25%. If nivolumab has a true response rate of 5%, the rule 
described above will identify it of sufficient activity for further study with 
probability 0.07 (type I error), and the trial will have an expected sample size of 
14 with 60% probability of early termination.  If nivolumab has a true response 
rate of 25%, the rule described above will identify it of sufficient activity for 
further study with probability 0.88 (power against the alternative hypothesis P = 
0.25). 
 
Children with a target diagnosis and measurable or MIBG evaluable disease who 
are enrolled on Part A and receive the RP2D will be considered evaluable for 
disease response in Part B.  
 
If cycle 1 DLT occurs in ≥ 33% of evaluable patients in a cohort of Part B with at 
least 3 evaluable patients, the maximum tolerated dose will have been exceeded 
in this tumor type and the cohort will be closed to further enrollment. 
 
Response in all patients with solid tumors will be determined according to 
RECIST as defined in the protocol as either complete response (CR), partial 
response (PR), stable disease (SD) or progressive disease (PD), or as described in 
Section 12.0 for other categories of responses assessment, and reported as final 
results. A report on the efficacy assessment will be posted on the completed 
disease stratum as part of the semi-annual study committee meeting book report.   
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 81 
 
Method of Analysis 
Response criteria are described in Section 12.0. Response rates will be calculated 
separately for each of the tumor strata as the percent of patients whose best 
response is a CR or PR and confidence intervals will be constructed according to 
the method of Chang.57  A responder is defined as a patient who achieves a best 
confirmed response (as defined in Section 12.6) of PR or CR on the study and 
includes pseudo-progressive disease. Response is defined relative to baseline 
disease. 
 
11.5 
Dose Escalation and Determination of Recommended Phase 2 Dose for Nivolumab 
plus Ipilimumab (Part C): 
The rolling six phase 1 trial design will be used for the conduct of Part C of this study.49  
Two to six patients can be concurrently enrolled onto a dose level, dependent upon (1) the 
number of patients enrolled at the current dose level, (2) the number of patients who have 
experienced DLT at the current dose level, and (3) the number of patients entered but with 
tolerability data pending at the current dose level.  Accrual is suspended when a cohort of 
six has enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the 
cohort, the number of DLTs observed, and the number of participants at risk for developing 
a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, 
when three participants are enrolled onto a dose cohort, if toxicity data is available for all 
three when the fourth participant entered and there are no DLTs, the dose is escalated and 
the fourth participant is enrolled to the subsequent dose level. If data is not yet available 
for one or more of the first three participants and no DLT has been observed, or if one DLT 
has been observed, the new participant is entered at the same dose level. Lastly, if two or 
more DLTs have been observed, the dose level is de-escalated. This process is repeated for 
participants five and six. In place of suspending accrual after every three participants, 
accrual is only suspended when a cohort of six is filled. When participants are inevaluable 
for toxicity, they are replaced with the next available participant if escalation or de-
escalation rules have not been fulfilled at the time the next available participant is enrolled 
onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose 
level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study 
is suspended to accrual: 
 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
3 
0 
3 
0 
Escalate** 
 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
 
4 
0 
4 
0 
Escalate** 
 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 82
5
1
0, 1, 2, 3 or 4
0, 1, 2, 3 or 4
Same dose level
5
0
5
0
Escalate**
5
≥ 2
0, 1, 2 or 3
0, 1, 2 or 3
De-escalate*
6
0
0, 1, 2, 3, or 4
2, 3, 4, 5 or 6
Suspend
6
1
0, 1, 2, 3 or 4
0, 1, 2, 3 or 4
Suspend
6
0 or 1
5 or 6
0 or 1
Escalate**
6
≥ 2
0, 1, 2, 3 or 4
0, 1, 2, 3 or 4
De-escalate*
* If six patients already entered at next lower dose level, the MTD has been defined. If the lowest 
dose level is not tolerated, that part will close to accrual and discussed with sponsor.
**If final dose level has been reached, the recommended dose has been reached.
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
the MTD has been exceeded and dose escalation will be stopped (see Section 11.2.2 for 
exception to rule).
In addition to determination of the MTD, a descriptive summary of all toxicities will be 
reported.
11.6
Phase 2 Evaluation of Nivolumab (3 mg/kg) in Combination with Ipilimumab (1 
mg/kg) (for Part D):
In the event that a cohort in a given disease group in Part B is completed after Stage 1 
because no responses are observed, a corresponding cohort will open in the same disease 
group for select disease types to an initial cohort of up to 10 evaluable patients in Part D, 
at the RP2D of nivolumab in combination with ipilimumab as determined in Part C: 3 
mg/kg nivolumab and 1 mg/kg ipilimumab.
Study Design
The best response of disease to nivolumab in combination with ipilimumab will be 
examined separately for each of the tumor strata that are expanded from Part B.
The following Simon’s optimal two stage design56 will be used for Parts D1-6.
Cumulative Number 
of Responses
Decision
Stage 1: Enter 10 patients
0
Terminate 
the 
stratum: 
agent 
ineffective
1 or more
Inconclusive result, continue stratum 
(proceed to stage 2)
Stage 2: Enter 10 additional 
patients
2 or less     
Terminate 
the 
stratum: 
agent 
ineffective
3 or more
Terminate the stratum: agent effective
Nivolumab in combination with ipilimumab will not be considered of sufficient 
interest for further evaluation in a disease category if the true response rate is 5% 
and of sufficient activity if the true response rate is 25%. If nivolumab in 
combination with ipilimumab has a true response rate of 5%, the rule described 
above will identify it of sufficient activity for further study with probability 0.07 
(type I error), and the trial will have an expected sample size of 14 with 60% 
probability of early termination.  If nivolumab in combination with ipilimumab has 
a true response rate of 25%, the rule described above will identify it of sufficient 
activity for further study with probability 0.88 (power against the alternative 
hypothesis P = 0.25).

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 83
Children with a target diagnosis and measurable or MIBG evaluable disease who 
are enrolled on Part C and receive the RP2D will be considered evaluable for 
disease response in Part D. The number of patients needed to evaluate any cohort 
in part D would therefore be reduced by the number of patients treated and 
evaluable for response in part C,
If cycle 1 DLT occurs in ≥ 33% of evaluable patients in a cohort of Part D with at 
least 3 evaluable patients, the maximum tolerated dose will have been exceeded 
in this tumor type and the cohort will be closed to further enrollment.
Response in all patients with solid tumors will be determined according to 
RECIST as defined in the protocol as either complete response (CR), partial 
response (PR), stable disease (SD) or progressive disease (PD), or as described in 
Section 12.0 for other categories of responses assessment, and reported as final 
results. A report on the efficacy assessment will be posted on the completed 
disease stratum as part of the semi-annual study committee meeting book report.  
Method of Analysis
Response criteria are described in Section 12.0. Response rates will be calculated
separately for each of the tumor strata as the percent of patients whose best 
response is a CR or PR and confidence intervals will be constructed according to 
the method of Chang.57  A responder is defined as a patient who achieves a best 
confirmed response (as defined in Section 12.6) of PR or CR on the study and 
includes pseudo-progressive disease. Response is defined relative to baseline 
disease.
11.7
Phase 2 Evaluation of Nivolumab (1 mg/kg) in Combination with Ipilimumab 
(3 mg/kg) (for Part E):
Study Design
The Simon’s optimal two stage design47 will be used for Part E to assess response 
in rhabdomyosarcoma (E3) and Ewing/Peripheral PNET pediatric patients (E4). 
All patients enrolled into either E3 or E4 will be combined for assessment of 
response and toxicity. Assuming that the study does not stop early for dose limiting 
toxicity, a total of 10 response-evaluable patients will be enrolled into Stage 1. 
This will include at least 4 patients each in parts E3 and E4. If at least 1 response 
is observed among 10 evaluable patients, then stage 2 will open for enrollment. A 
total of 10 more response-evaluable patients will then be enrolled into Stage 2 
including at least 4 more patients each in parts E3 and E4. Otherwise, the study 
will close with stage 1 and the study will conclude that the agent does not elicit 
sufficient response. 
The following Simon’s optimal two-stage design will be used to assess response 
in Part E. 
Cumulative Number 
of Responses
Decision
Stage 1: Enter 10 patients
0
Terminate 
the 
stratum: 
agent 
ineffective
1 or more
Inconclusive result, continue stratum 

ADVL1412
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY.
Version Date: 03/30/2020
Page 84
(proceed to stage 2)
Stage 2: Enter 10 additional 
patients
2 or less     
Terminate 
the 
stratum: 
agent 
ineffective
3 or more
Terminate the stratum: agent effective
The combination of Nivolumab (1 mg/kg) and Ipilimumab (3mg/kg) will not be 
considered of sufficient interest for further evaluation among Rhabdomyosarcoma 
and Ewing/Peripheral PNET patients if the true response rate is ≤ 5% and of 
sufficient activity if the true response rate is ≥25%. If this combination has a true 
response rate of 5%, the rule described above will identify it of sufficient activity 
for further study with probability 0.07 (type I error), and the trial will have an 
expected sample size of 14 with 60% probability of early termination. If the 
combination has a true response rate of 25%, the rule described above will identify 
it of sufficient activity for further study with probability 0.88 (power against the 
alternative hypothesis P = 0.25). A maximum of 23 patients will be enrolled into 
Part E allowing for 10% inevaluability.
If at least one Cycle 1 dose limiting toxicity occurs among the first 10 patients or 
4 patients with dose limiting toxicities among 20 patients, then the study will close 
and conclude that the dose level is too toxic. This rule will provide >=89% power 
to terminate the study in stage 1 and >=90% power overall to terminate the study 
due to excessive Cycle 1 toxicity when the true cycle 1 toxicity is >=20%. 
Otherwise, the study will continue per the 10+10 Simon two-stage design. The 
overall type 1 error rate for this rule is 40% if the true Cycle 1 toxicity is 0.05 and 
66% if the true toxicity is 0.10.
All grade 3, 4, and 5 toxicity attributed to protocol therapy will reviewed weekly 
by the study committee and discussed during the scheduled monthly sponsor calls
in order to determine the need for any changes. Consideration to open the second 
stage will be discussed by all approved parties (i.e. DSMC, NCI) following the 
release of the aggregated data for all events. 
Method of Analysis
Response criteria are described in Section 12.0. Response rates will be calculated
for the combined cohort as the percent of patients whose best response is a CR or 
PR and confidence intervals will be constructed according to the method of 
Chang.48  A responder is defined as a patient who achieves a best confirmed 
response (as defined in Section 12.6) of PR or CR on the study and includes 
pseudo-progressive disease. Response is defined relative to baseline disease.
11.8
Inclusion of Children, Women and Minorities
The study is open to all participants regardless of gender or ethnicity.  Review of accrual 
to past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase 1 trial which will accrue a limited number of 
patients, a balance must be struck between patient safety considerations and limitations on 
the number of individuals exposed to potentially toxic or ineffective treatments on the one 
hand and the need to explore gender, racial, and ethnic aspects of clinical research on the 
other. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 85 
 
accrual may be expanded or additional studies may be performed to investigate those 
differences more fully.   
 
11.9 
Pharmacokinetic and Correlative Studies and Response Analysis 
 
A descriptive analysis of pharmacokinetic (PK) parameters of nivolumab will be performed 
to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The 
PK parameters will be summarized with simple summary statistics, including means, 
medians, ranges, and standard deviations (if numbers and distribution permit).   
 
While the primary aim of this study is to define the recommended phase 2 dose of 
nivolumab (or nivolumab plus ipilimumab), patients will have disease evaluations 
performed as indicated in Section 8.1.  Disease response will be assessed according to 
RECIST criteria for patients with solid tumors, and will be reported descriptively.   
 
In addition, Part B will evaluate the activity of nivolumab in expanded cohorts of patients 
with neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Hodgkin 
lymphoma, non-Hodgkin lymphoma. In the melanoma cohort (Part B7), toxicities and 
disease response will be reported descriptively. 
 
Pharmacodynamic studies will evaluate the degree of PD1 occupancy rate on peripheral 
blood T cells pre- and post-therapy using flow cytometry.  Anti-drug antibody analyses 
will be measured by Bristol-Myers Squibb.  
 
PD-L1 expression will be analyzed in an exploratory fashion, both using a binary scale and 
using a continuous scale to evaluate whether there are correlations between PD-L1 
expression and antitumor effects. 
 
Biomarkers, including those identified in the secondary objectives, will be evaluated for 
association with outcome, overall and by tumor type. All of these analyses will be 
descriptive and exploratory and hypotheses generating in nature. 
 
12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
12.2 
Response Criteria for Patients with Solid Tumors  
See the table in section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained at the end of the subsequent cycle 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  Key points are that 5 target lesions are identified and that changes in the largest 
diameter (unidimensional measurement) of the tumor lesions but the shortest diameter of 
malignant lymph nodes are used in the RECIST v 1.1 criteria. 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 86 
 
 
Exceptions for Delayed Response (‘pseudoprogression’) 
Patients in whom the magnitude of increase in tumor size is >20% but <40%, may 
remain on study for up to 12 weeks after start of protocol therapy if the following 
criteria are met. Lesions < 10 mm will not be considered new lesions; new lesions 
≥ 10 mm of longest diameter must be included in the total tumor burden.   
• 
In the judgment of the treating clinician, the patient does not show evidence 
for rapid disease progression or the patient has shown evidence for clinical 
benefit.    
• 
There is no decrease in performance status. 
• 
The patient is tolerating the study drug and there has been no DLT. 
• 
Continued treatment with nivolumab alone or in combination with 
ipilimumab will not delay an imminent intervention required to prevent a 
serious complications (e.g. CNS metastases which require radiation therapy 
or surgery). 
 
For patients who remain on study despite increase in tumor size > 20%, imaging 
to include target lesions must occur every cycle if clinically indicated, or if 
“pseudoprogression” appears based on inflammatory response, or sarcoid 
granuloma is present, and the same radiographic and clinical criteria must be met 
in order to remain on study.  If tumor size subsequently diminishes to < 20% 
increase from baseline, the patient may be followed according to the standard 
protocol guidelines which will involve less frequent imaging.  The decision to 
continue treatment beyond radiographic evidence for disease progression should 
be discussed with the study PI, and if needed, the sponsor, and documented in the 
study record. 
 
Definitions 
 
12.2.2.1 Evaluable for objective response:  
Eligible patients who receive at least one dose of protocol therapy will 
be considered evaluable for response. Evaluable patients who 
demonstrate a complete or partial response confirmed by central review 
before receiving non-protocol anti-cancer therapy will be considered a 
responder. All other evaluable patients will be considered non-
responders. 
 
12.2.2.2 Evaluable Non-Target Disease Response:  
Eligible patients who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease and have received 
at least one dose of protocol therapy will be considered evaluable for 
non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
  
 
Disease Parameters 
 
12.2.3.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥10 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 87 
 
mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
12.2.3.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed 
by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
12.2.3.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥ 10 to <15 mm short axis), are considered non-measurable disease.  
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
12.2.3.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion that can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
12.2.3.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 88 
 
calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
12.2.4.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and 10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
12.2.4.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable.  
 
12.2.4.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
12.2.4.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.2.4.5 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
12.2.4.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.2.4.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 89 
 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.2.5.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progression. See Section 12.2.1 
for exception). Note: in presence of SD or PR in 
target disease but unequivocal progression in 
non-target or non-measurable disease, the patient 
has PD if there is an overall level of substantial 
worsening in non-target disease such that the 
overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 90 
 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
12.2.5.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions (. See 
Section 12.2.1 for exception) and/or unequivocal 
progression of existing non-target lesions.  
Unequivocal progression should not normally 
trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect. Best response is determined as outlined in Section 
12.6 from a sequence of overall response assessments. 
 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately measured 
in at least one dimension.  Such lesions may be evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers or other reliable 
measures.  
 
Complete Response 
Disappearance of all evaluable disease. 
 
Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
 
Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), 
or Progressive Disease. 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 91 
 
 
Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. See Section 12.2.1 for exception. 
 
Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.6 from a sequence of overall response assessments. 
 
 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.4.1 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
12.4.2 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions  
 
12.4.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2.1 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 92 
 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
12.4.4 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Table 5 in Section 12.6. 
 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
Bone Marrow Involvement  
Bone marrow obtained within 28 days prior to study enrollment with tumor cells 
seen on routine morphology (not by immunohistochemical staining only) of 
bilateral aspirate or biopsy on one bone marrow sample. 
 
Bone Marrow responses are determined by H&E Staining of bilateral bone marrow 
biopsies and aspirates. 
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
Patients who enroll with neuroblastoma in bone marrow 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 93 
 
by morphology have progressive disease if there is a 
doubling in the amount of tumor in the marrow AND a 
minimum of 25% tumor in bone marrow by morphology. 
(For example, a patient entering with 5% tumor in marrow 
by morphology must increase to ≥ 25% tumor to have 
progressive disease; a patient entering with 30% tumor 
must increase to > 60%). 
 
Patients who enroll without evidence of neuroblastoma in 
bone marrow will be defined as having progressive 
disease if tumor is detected in 2 consecutive bone marrow 
biopsies or aspirations done at least 21 days apart. 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.6. 
 
 
12.6 
Best Response 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 28 days Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once ≥ 
28 days from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 94 
 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 3.  Sequences of overall response assessments with corresponding best 
response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
Table 4: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
Table 5: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly identified lesion by 
CT/MRI that occurs during therapy would be considered progressive disease. 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 95 
 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the data collection packet 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); 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. 
 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 5.0. All 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 96 
 
appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
Step 2:  Grade the adverse event using the NCI CTCAE v.5.0. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
Note:  This includes all events that occur within 30 days of the last dose of protocol 
treatment.  Any event that occurs during the follow-up period (See Section 
10.2) more than 30 days after the last dose of treatment and is attributed 
(possibly, probably, or definitely) to the agent(s) must also be reported 
according to the instructions in the table below. Attribution categories are 
as follows: Unrelated, Unlikely, Possible, Probable, and Definite. 
 
Table A: Phase 1 and Early Phase 2 Studies:  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, 2 
 
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) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
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 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 97 
 
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. 
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 AE, 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 learning of the AE. 
1Serious adverse events that occur during the follow up period (See Section 10.2) 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 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
 
Effective Date:  May 5, 2011 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
Additional Instructions or Exceptions to Expedited Reporting Requirements for Phase 1 Trials Utilizing an 
Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not clearly due 
to progressive disease must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP 
IND agent per the timelines outlined in the table above. 
 
• 
Adverse events associated with study drug overdose are to be reported via CTEP-AERS. 
 
• 
Lymphopenia, does not require expedited reporting, unless it is associated with hospitalization. 
 
• 
All cases of Graft versus host disease (GVDH) while patient is on study should be reported via 
CTEP AERS regardless of attribution to protocol therapy. This includes reporting during extended 
follow up periods 
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), does 
not require expedited reporting, unless it is associated with hospitalization. 
 
Category 
Adverse Events 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 98 
 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
 
• Grade 1 and 2 adverse events listed in the table below do not require expedited reporting via CTEP-
AERS, unless it is associated with hospitalization. 
Category 
Adverse Events 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
GASTROINTESTINAL DISORDERS 
Constipation 
GASTROINTESTINAL DISORDERS 
Dry Mouth 
GASTROINTESTINAL DISORDERS 
Nausea 
GASTROINTESTINAL DISORDERS 
Vomiting 
GENERAL DISORDERS AND 
ADMINISTRATION SITE CONDITIONS 
Chills 
INVESTIGATIONS 
Alanine aminotransferase increased 
INVESTIGATIONS 
Aspartate aminotransferase increased 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
METABOLISM AND NUTRITION DISORDERS 
Dehydration 
MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS 
Arthralgia 
MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS 
Arthritis 
NERVOUS SYSTEM DISORDERS 
Headache 
RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS 
Dyspnea 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Urticaria 
 
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.8 and in 
Section 9.2.9 of the protocol.   
 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that resolves and then recurs 
during a subsequent cycle does not require CTEP-AERS reporting unless (1) the Grade increases; or (2) 
hospitalization is associated with the recurring AE. 
 
13.2 
When to Report an Event in an Expedited Manner  
 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable) and by telephone call to the Study Chair. Once internet 
connectivity is restored, a 24-hour notification phoned in must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS, accessed via the 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 99 
 
CTEP home page 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.h
tm. 
 
13.3 
Expedited Reporting Methods  
 
CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the NCI’s Adverse Event 
Reporting System that can be found at   
https://ctepcore.nci.nih.gov/ctepaers/pages/task   
 
A CTEP-AERS report must be submitted electronically via the system at 
https://ctepcore.nci.nih.gov/ctepaers/pages/task. If prompted to enter a sponsor 
email address, please type in: PEPCTNAERS@childrensoncologygroup.org 
 
Send supporting documentation to the NCI by fax (fax# 301-897-7404) and by 
email to the ADVL1412 study assigned Research Coordinator.  ALWAYS 
include the ticket number on all faxed and emailed documents. 
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG data 
submission forms and do not alter the guidelines for CTEP-AERS reporting. 
 
If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than Grade 1, whichever level is higher (note that the resolution 
date may therefore be different from the date at which the grade of the AE 
decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
13.5 
Other Recipients of Adverse Event Reports 
 
Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the data 
form packet (See Section 14.1). 
 
COG will forward reports and supporting documentation to the Study Chair, to 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 100 
 
the FDA (when COG holds the IND) and to the pharmaceutical company (for 
industry sponsored trials). 
 
Adverse events determined to be reportable must also be reported according to 
the local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
13.6 
Reporting Secondary AML/MDS 
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients on NCI-sponsored trials following their chemotherapy for cancer must be 
reported to the Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation 
Program (CTEP) via CTEP-AERS and included as part of the second malignant neoplasm 
reporting requirements for this protocol (see data submission packet).  Submit the 
completed CTEP-AERS report within 14 days of an AML/MDS diagnosis occurring after 
treatment for cancer on NCI-sponsored trials. 
 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via AdEERS. Three options are available to describe 
the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified. 
 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and emailed to the 
ADVL1412 COG Study Assigned Research Coordinator along with any additional medical 
information. The potential risk of exposure of the fetus to the investigational agent should 
be documented in the “Description of Event” section of the CTEP-AERS report. 
 
 
Pregnancy 
• 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 101 
 
(Pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” System Organ Class (SOC). 
 
• 
Pregnancy should 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. 
 
Pregnancy Loss (Fetal Death) 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
 
• 
Any pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
Death Neonatal 
• 
Neonatal death, defined in CTCAE as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least 
possibly due to the investigational agent/intervention, should be reported 
expeditiously. 
 
• 
A neonatal death should be reported expeditiously as Grade 4 ”Death 
neonatal” under the “General disorders and administration” SOC when 
the death is the result of a patient pregnancy or pregnancy in partners 
of men on study 
 
• 
Do NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
Pregnancy should be followed up until the outcome of the pregnancy is known at 
intervals deemed appropriate by her physicians. The “Pregnancy Information 
Form” should be used for all necessary follow-ups. This form is available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf.  
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information: e.g., Roadmaps, Pathology Reports, Surgical 
Reports. These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the data form packet. 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 102 
 
See separate Data Form Packet, which includes submission schedule. 
 
14.2 
Access to Rave for Data Submission/ Data Reporting 
Data collection for this study will be done through the Medidata Rave clinical data 
management system.  Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS).  To access Rave via iMedidata, the site user must have an active CTEP-
IAM account (check at < https://ctepcore.nci.nih.gov/iam >) and the appropriate Rave 
role (Rave CRA, Read-Only, Site Investigator) on either the COG or PEP-CTN roster at 
the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata.  To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page.  Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed.  Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will also receive a separate invitation 
from iMedidata to activate their account.  Account activation instructions are located on 
the CTSU website, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on iMedidata/Rave 
is available on the CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ 
or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com, or by email to the COG Study Assigned Data Manager. 
 
14.3 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, July 31 
and October 31. Instructions for submitting data using the CDUS can be found on the CTEP 
website: http://ctep.cancer.gov/reporting/cdus.html.  This is not a responsibility of institutions 
participating in this trial. 
 
14.4 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 103 
 
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 investigational 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 investigational 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 
NIH, 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 investigational 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 investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected , used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP for immediate delivery to Collaborator(s) for advisory review and comment 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 104 
 
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. 
 
 
14.5 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the PEP-CTN scientific 
committee; and a member from the NCI. The DSMC meets at least every 6 months 
to review current study results, as well as data available to the DSMC from other 
related studies. Approximately 6 weeks before each meeting of the Phase 1 and 2 
DSMC, study chairs will be responsible for working with the study statistician to 
prepare study reports for review by the DSMC. The DSMC will provide 
recommendations to the COG PEP-CTN Chair and the Group Chair for each study 
reviewed to change the study or to continue the study unchanged. Data and Safety 
Committee reports for institutional review boards can be prepared using the public 
data monitoring report as posted on the COG Web site. 
 
Monitoring by the Study Chair and Developmental Therapeutics Leadership  
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the COG 
PEP-CTN Chair, Vice Chair and Statistician on a weekly conference call. 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 105 
 
REFERENCES 
1. 
Kantoff PW, Higano CS, Shore ND, et al: Sipuleucel-T immunotherapy for castration-resistant 
prostate cancer. N Engl J Med 363:411-22, 2010 
2. 
Yu AL, Gilman AL, Ozkaynak MF, et al: Anti-GD2 antibody with GM-CSF, interleukin-2, and 
isotretinoin for neuroblastoma. N Engl J Med 363:1324-34, 2010 
3. 
Grupp SA, Kalos M, Barrett D, et al: Chimeric antigen receptor-modified T cells for acute 
lymphoid leukemia. N Engl J Med 368:1509-18, 2013 
4. 
Brentjens RJ, Davila ML, Riviere I, et al: CD19-targeted T cells rapidly induce molecular 
remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 
5:177ra38, 2013 
5. 
Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al: T cells expressing CD19 chimeric antigen 
receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-
escalation trial. Lancet, 2014 
6. 
Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in 
leukemia. N Engl J Med 371:1507-17, 2014 
7. 
Mullard A: New checkpoint inhibitors ride the immunotherapy tsunami. Nat Rev Drug Discov 
12:489-92, 2013 
8. 
Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med 366:2443-54, 2012 
9. 
Hamid O, Robert C, Daud A, et al: Safety and tumor responses with lambrolizumab (anti-PD-1) 
in melanoma. N Engl J Med 369:134-44, 2013 
10. 
Wolchok JD, Kluger H, Callahan MK, et al: Nivolumab plus ipilimumab in advanced melanoma. 
N Engl J Med 369:122-33, 2013 
11. 
Weber J: Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol 37:430-9, 2010 
12. 
Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with 
metastatic melanoma. N Engl J Med 363:711-23, 2010 
13. 
Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated 
metastatic melanoma. N Engl J Med 364:2517-26, 2011 
14. 
Ascierto PA, Marincola FM, Ribas A: Anti-CTLA4 monoclonal antibodies: the past and the 
future in clinical application. J Transl Med 9:196, 2011 
15. 
Barber DL, Wherry EJ, Masopust D, et al: Restoring function in exhausted CD8 T cells during 
chronic viral infection. Nature 439:682-7, 2006 
16. 
Dong H, Strome SE, Salomao DR, et al: Tumor-associated B7-H1 promotes T-cell apoptosis: a 
potential mechanism of immune evasion. Nat Med 8:793-800, 2002 
17. 
Iwai Y, Ishida M, Tanaka Y, et al: Involvement of PD-L1 on tumor cells in the escape from host 
immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 
99:12293-7, 2002 
18. 
Woo SR, Turnis ME, Goldberg MV, et al: Immune inhibitory molecules LAG-3 and PD-1 
synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72:917-
27, 2012 
19. 
Highfill SL, Cui Y, Giles AJ, et al: Disruption of CXCR2-mediated MDSC tumor trafficking 
enhances anti-PD1 efficacy. Sci Transl Med 6:237ra67, 2014 
20. 
Zhou Q, Munger ME, Highfill SL, et al: Program death-1 signaling and regulatory T cells 
collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced 
acute myeloid leukemia. Blood 116:2484-93, 2010 
21. 
Fridman WH, Pagès F, Sautès-Fridman C, et al: The immune contexture in human tumours: 
impact on clinical outcome. Nature Reviews Cancer 12:298-306, 2012 
22. 
Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in patients 
with advanced cancer. N Engl J Med 366:2455-65, 2012 
23. 
Hodi FS, Chesney J, Pavlick AC, et al: Combined nivolumab and ipilimumab versus ipilimumab 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 106 
 
alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, 
randomised, controlled, phase 2 trial. The Lancet Oncology 17:1558-1568 
24. 
Grosso JF, Horak CE, Inzunza HD, et al: Association of Tumor PD-L1 Expression and Immune 
Biomarkers With Clinical Activity 
in Patients With Advanced Solid Tumors Treated With Nivolumab, American Society of Clinical 
Oncology. Chicago, IL, 2013 
25. 
Antonia SJ, López-Martin JA, Bendell J, et al: Nivolumab alone and nivolumab plus ipilimumab 
in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. 
The Lancet Oncology 17:883-895 
26. 
Kara Davis EF, et al: ADVL1412: Initial results of a phase I/II study of nivolumab and 
ipilimumab in pediatric patients with relapsed/refractory solid tumors—A COG study. Journal of 
Clincal Oncolcology 35, 2017 
27. 
Melinda S. Merchant KB, Leonard H. Wexler, Carlos Rodriguez-Galindo and Crystal Mackall: 
Ipilimumab: First results of a phase I trial in pediatric patients with advanced solid tumors. . 
Journal of Clinical Oncology, 2012 ASCO Annual Meeting Abstracts Vol 30, No 15_suppl (May 
20 Supplement), 2012: 9545, 2012 
28. 
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 
29. 
Osenga KL, Hank JA, Albertini MR, et al: A phase I clinical trial of the hu14.18-IL2 (EMD 
273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a 
study of the Children's Oncology Group. Clin Cancer Res 12:1750-9, 2006 
30. 
Shusterman S, London WB, Gillies SD, et al: Antitumor activity of hu14.18-IL2 in patients with 
relapsed/refractory neuroblastoma: a Children's Oncology Group (COG) phase II study. J Clin 
Oncol 28:4969-75, 2010 
31. 
Mussai F, Egan S, Hunter S, et al: Neuroblastoma Arginase Activity Creates an 
Immunosuppressive Microenvironment That Impairs Autologous and Engineered Immunity. 
Cancer Res 75:3043-53, 2015 
32. 
Tawbi HA-H, Burgess MA, Crowley J, et al: Safety and efficacy of PD-1 blockade using 
pembrolizumab in patients with advanced soft tissue (STS) and bone sarcomas (BS): Results of 
SARC028--A multicenter phase II study. ASCO Meeting Abstracts 34:11006, 2016 
33. 
Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or 
refractory Hodgkin's lymphoma. N Engl J Med 372:311-9, 2015 
34. 
Alinari L, Blum KA: How I treat relapsed classical Hodgkin lymphoma after autologous stem cell 
transplant. Blood 127:287-95, 2016 
35. 
Villasboas JC, Ansell SM, Witzig TE: Targeting the PD-1 pathway in patients with relapsed 
classic Hodgkin lymphoma following allogeneic stem cell transplant is safe and effective. 
Oncotarget, 2016 
36. 
Yared JA, Hardy N, Singh Z, et al: Major clinical response to nivolumab in relapsed/refractory 
Hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant, 2016 
37. 
Davids MS, Kim HT, Bachireddy P, et al: Ipilimumab for Patients with Relapse after Allogeneic 
Transplantation. N Engl J Med 375:143-53, 2016 
38. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. New England Journal of Medicine 373:23-34, 2015 
39. 
Sharma P: Efficacy and safety of nivolumab plus ipilimumab in previously treated metastatic 
urothelial carcinoma: First results from the phase I/II CheckMate 032 study. SITC Annual 
meeting, 2016 
40. 
Hellmann MD, Rizvi NA, Goldman JW, et al: Nivolumab plus ipilimumab as first-line treatment 
for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, 
multicohort study. The Lancet Oncology 18:31-41 
41. 
Merchant MS, Wright M, Baird K, et al: Phase 1 Clinical Trial of Ipilimumab In Pediatric 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 107 
 
Patients With Advanced Solid Tumors. Clinical cancer research : an official journal of the 
American Association for Cancer Research 22:1364-1370, 2016 
42. 
Topalian SL, Hodi FS, Brahmer JR, et al: Safety, Activity, and Immune Correlates of Anti–PD-1 
Antibody in Cancer. New England Journal of Medicine 366:2443-2454, 2012 
43. 
Taube JM, Klein A, Brahmer JR, et al: Association of PD-1, PD-1 ligands, and other features of 
the tumor immune microenvironment with response to anti-PD-1 therapy. Clinical cancer 
research : an official journal of the American Association for Cancer Research 20:5064-5074, 
2014 
44. 
Majzner RG, Simon JS, Grosso JF, et al: Assessment of programmed death-ligand 1 expression 
and tumor-associated immune cells in pediatric cancer tissues. Cancer:n/a-n/a 
45. 
Aoki T, Hino M, Koh K, et al: Low Frequency of Programmed Death Ligand 1 Expression in 
Pediatric Cancers. Pediatric Blood & Cancer 63:1461-1464, 2016 
46. 
Schumacher TN, Schreiber RD: Neoantigens in cancer immunotherapy. Science 348:69-74, 2015 
47. 
Hause RJ, Pritchard CC, Shendure J, et al: Classification and characterization of microsatellite 
instability across 18 cancer types. Nat Med 22:1342-1350, 2016 
48. 
BMS-936558 (Nivolumab, MDX-1106) being a member of class of agents involved in the 
inhibition of “immune checkpoints”, may result in severe and possibly fatal immune-mediated 
adverse events probably due to T-cell activation and proliferation.  This may result in 
autoimmune disorders that can include (but are not limited to) autoimmune hemolytic anemia, 
acquired anti-factor VIII immune response, autoimmune aseptic meningitis, autoimmune 
hepatitis, autoimmune nephritis, autoimmune neuropathy, autoimmune thyroiditis, bullous 
pemphigoid, exacerbation of Churg-Strauss Syndrome, drug rash with eosinophilia systemic 
symptoms [DRESS] syndrome, facial nerve disorder (facial nerve paralysis), limbic encephalitis, 
hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine 
disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, 
myasthenia gravis, polymyositis, and Guillain-Barre syndrome.,  
49. 
This 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.,  
50. 
Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-cell 
activation and proliferation.  These can include (but are not limited to) autoimmune hemolytic 
anemia, acquired anti-factor VIII immune response, autoimmune aseptic meningitis, autoimmune 
hepatitis, autoimmune thyroiditis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and 
hemorrhagic colitis, endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, 
hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal insufficiency), ocular 
manifestations (e.g., uveitis, iritis, conjunctivitis, blepharitis, and episcleritis), sarcoid granuloma, 
myasthenia gravis, polymyositis, and Guillain-Barre syndrome.  The majority of these reactions 
manifested early during treatment; however, a minority occurred weeks to months after 
discontinuation of ipilimumab especially with the initiation of additional treatments.,  
51. 
Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in 
association with subsequent IL-2 therapy.,  
52. 
Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients 
receving allo stem cell transplant (SCT) after receiving Ipilimumab (MDX-010).  These 
complications may occur despite intervening therapy between receiving Ipilimumab (MDX-010) 
and allo-SCT.,  
53. 
In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia 
gravis).  
54. 
Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 108 
 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, 
Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under 
the GASTROINTESTINAL DISORDERS SOC.,  
55. 
Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.,  
56. 
Simon R: Optimal two-stage designs for phase II clinical trials.Control Clin Trials. Controlled 
Clinical Trials 10(1):1-10, 1989 
57. 
MN C: Improved confidence intervals for a binomial parameter following a group sequential 
phase II  
clinical trial. Stat Med 23 2817-26, 2004 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 109 
 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 110 
 
APPENDIX II: CORRELATIVE STUDIES GUIDE  
 
PARTS A and B: 
Correlative Study 
Appx. 
Tube Type 
Blood 
Volume 
per 
Sample 
Cycle 1 
Volume 
Pharmacokinetics 
IIIA;  
SST Vacutainer 
2 mL 
14 mL 
Anti-Drug Antibody (ADA) Studies 
V 
SST Vacutainer 
2 mL 
2 mL 
Vaccinated Antibody Studies 
IV 
SST Vacutainer 
2 mL 
2 mL 
Total Blood Volume in Cycle 1 
 
18 mL 
Tumor Tissue 
VI 
 
 
 
PARTS C, D AND E: 
Correlative Study 
Appx. 
Tube Type 
Blood 
Volume 
per 
Sample 
Cycle 1 
Volume 
Pharmacokinetics 
IIIB 
SST Vacutainer 
4 mL 
8 mL 
Anti-Drug Antibody (ADA) Studies 
V 
SST Vacutainer 
4 mL 
4 mL 
Vaccinated Antibody Studies 
IV 
SST Vacutainer 
2 mL 
2 mL 
Cytokine Studies 
VII 
SST Vacutainer 
2 mL 
4mL 
Total Blood Volume in Cycle 1:  
Parts C, D and E 
 
18 mL 
Tumor Tissue 
VI 
 
 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 111 
 
APPENDIX IIIA:  PHARMACOKINETIC STUDY FORM (PARTS A AND B) 
 
COG Pt ID # _______________ 
ACC # _______________ 
Part of Study # _______________ 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|    Dose Level: _______mg/kg   Dose Administered: ______mg 
 
 
 
Serum samples (2 mL) will be collected for pharmacokinetic studies at a site distant from the infusion, prior to and at the end of 
infusion (EOI) on Days 1 and 15 of Cycle 1, and prior to and at EOI on Day 1 of Cycle 2. Samples cannot be drawn from the 2nd 
lumen of a multi-lumen catheter through which drug is being administered. Additional samples will be also obtained on Days 2, 
4, and 8 of Cycles 1 and 2 as indicated below. Record the exact date and time each sample is drawn and the start and stop time 
of the nivolumab infusion.  
Blood 
Sample 
No. 
Time Point 
Scheduled Sample Collection 
Time 
Scheduled  
Nivolumab  
Time Point 
Actual Date 
Sample Collected 
or Dose Given 
Actual Time Sample 
Collected or Dose 
Given (24-hr clock) 
1^ 
Cycle 1, Day 1 
Prior to Cycle 1, Day 1 infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
___/___/___ 
Start: |__|__|:|__|__| 
Stop: |__|__|:|__|__| 
2 
Cycle 1, Day 1 
Immediately following EOI 
 
___/___/___ 
|__|__| : |__|__| 
3 
Cycle 1, Day 2 
24 (±2) hrs after EOI 
 
___/___/___ 
|__|__| : |__|__| 
4 
Cycle 1, Day 4 
72 (±2) hrs after EOI 
 
___/___/___ 
|__|__| : |__|__| 
5 
Cycle 1, Day 8 
Any time point 
 
___/___/___ 
|__|__| : |__|__| 
6 
Cycle 1, Day 15 
Prior to Cycle 1, Day 15 infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, Day 15 
___/___/___ 
Start: |__|__|:|__|__| 
Stop: |__|__|:|__|__| 
7 
Cycle 1, Day 15 
Immediately following EOI 
 
___/___/___ 
|__|__| : |__|__| 
8^ 
Cycle 2, Day 1* 
Prior to Cycle 2, Day 1 infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 2, Day 1 
___/___/___ 
Start: |__|__|:|__|__| 
Stop: |__|__|:|__|__| 
9 
Cycle 2, Day 1 
Immediately following EOI 
 
___/___/___ 
|__|__| : |__|__| 
10 
Cycle 2, Day 2 
24 (±2) hrs after EOI 
 
___/___/___ 
|__|__| : |__|__| 
11 
Cycle 2, Day 4 
72 (±2) hrs after EOI 
 
___/___/___ 
|__|__| : |__|__| 
12 
Cycle 2, Day 8 
Any time point 
 
___/___/___ 
|__|__| : |__|__| 
13^ 
Cycle 4, Day 1 
Prior to Cycle 4, Day 1 infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
*  Patients who are removed from therapy during Cycle 1 after receiving the dose of nivolumab on Day 15 should have this sample 
collected on Day 28 of Cycle 1. 
^ Note serum samples (2 mL) for ADA analysis will also be collected at these timepoints.  
  
Sample Processing Procedures: One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. Refer to Section 
8.3 for instructions on packaging and shipping PK samples.  
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ______________________________________________                    Date: __________________________ 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 112 
 
APPENDIX IIIB:  PHARMACOKINETIC STUDY FORM (PARTS C, D AND E) 
 
COG Pt ID # _______________ 
ACC # _______________ 
Part of Study # _______________ 
Please do not write patient names on this form or on samples.  
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|     
 
Nivolumab: _______mg/kg   Dose Administered: ______mg Ipilimumab: ______mg/kg  Dose Administered: ______mg 
 
Serum samples (4 mL per sample aliquoted into two 4ml SST tubes) will be collected for pharmacokinetic studies at a site distant from the infusion, prior 
to the nivolumab infusion and at the end of the ipilimumab infusion (EOI) on Day 1 of Cycles 1-4.  Samples cannot be drawn from the 2nd lumen of a 
multi-lumen catheter through which drug is being administered. Record the exact date and time each sample is drawn and the start and stop time of the 
nivolumab infusion.  
Blood 
Sample 
No. 
Time Point 
Scheduled Sample Collection 
Time 
Scheduled 
Infusion  Time 
Point  
Actual Date 
Sample 
Collected or 
Dose Given 
Actual Time Dose Given  
(24-hr clock) 
Actual Time 
Sample 
Collected (24-hr 
clock) 
1^ 
Cycle 1, Day 1 
Within 30 min prior to start 
of nivolumab infusion 
 
___/___/___ 
 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
___/___/___ 
Nivolumab       Start: |__|__| : |__|__| 
 
 
 
___/___/___ 
Nivolumab       Stop: |__|__| : |__|__| 
 
 
 
___/___/___ 
 Ipilimumab      Start: |__|__|:|__|__| 
 
2 
Cycle 1, Day 1 
Immediately prior to 
ipilimumab EOIa (3 hr from 
start of nivolumab infusion) 
 
___/___/___ 
 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
___/___/___ 
Ipilimumab     Stop: |__|__|:|__|__| 
 
3^ 
Cycle 2, Day 1 
Within 30 min prior to start 
of nivolumab infusion 
 
___/___/___ 
 
|__|__| : |__|__| 
 
Cycle 2, Day 1 
___/___/___ 
Nivolumab       Start: |__|__| : |__|__| 
 
 
 
___/___/___ 
Nivolumab       Stop: |__|__| : |__|__| 
 
 
 
___/___/___ 
Ipilimumab      Start: |__|__|:|__|__| 
 
4 
Cycle 2, Day 1 
Immediately prior to 
ipilimumab EOIa  (3 hr from 
start of nivolumab infusion) 
 
___/___/___ 
 
|__|__| : |__|__| 
 
Cycle 2, Day 1 
___/___/___ 
Ipilimumab     Stop: |__|__|:|__|__| 
 
5^ 
Cycle 3, Day 1 
Within 30 min prior to start 
of nivolumab infusion 
 
___/___/___ 
 
|__|__| : |__|__| 
 
Cycle 3, Day 1 
___/___/___ 
Nivolumab       Start: |__|__| : |__|__| 
 
 
 
___/___/___ 
Nivolumab       Stop: |__|__| : |__|__| 
 
 
 
___/___/___ 
Ipilimumab      Start: |__|__|:|__|__| 
 
6 
Cycle 3, Day 1 
Immediately prior to 
ipilimumab EOIa  (3 hr from 
start of nivolumab infusion) 
 
___/___/___ 
 
|__|__| : |__|__| 
 
Cycle 3, Day 1 
___/___/___ 
Ipilimumab     Stop: |__|__|:|__|__| 
 
7^ 
Cycle 4, Day 1 
Within 30 min prior to start 
of nivolumab infusion 
 
___/___/___ 
 
|__|__| : |__|__| 
 
Cycle 4, Day 1 
___/___/___ 
Nivolumab       Start: |__|__| : |__|__| 
 
 
 
___/___/___ 
Nivolumab       Stop: |__|__| : |__|__| 
 
 
 
___/___/___ 
Ipilimumab      Start: |__|__|:|__|__| 
 
8 
Cycle 4, Day 1 
Immediately prior to 
ipilimumab EOIa  (3 hr from 
start of Nivolumab infusion) 
 
___/___/___ 
 
|__|__| : |__|__| 
 
Cycle 4, Day 1 
___/___/___ 
Ipilimumab     Stop: |__|__|:|__|__| 
 
a. EOI: This sample should be taken immediately prior to stopping the ipilimumab infusion. In the event of a delay beyond 1 hr, the 
sample should be taken at the END of the infusion.  
^ Note serum samples (4 mL) for ADA analysis will also be collected at these timepoints.  
 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 113 
 
Sample Processing Procedures: One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. Refer to Section 
8.3 for instructions on packaging and shipping PK samples.  
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ______________________________________________                    Date: __________________________ 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 114 
 
 
APPENDIX IV: VACCINATED ANTIBODY STUDY FORM 
 
COG Pt ID # _______________ 
ACC # _______________      Gender: _______       Age: _________ 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|  
   Part of Study # _______________ 
 
Dose Level: _______mg/kg 
Weight: ________ kg  Nivolumab Dose Administered: ______mg  
 
 
Serum samples (2 mL) will be collected in consenting patients at baseline and prior to Cycle 2, Day 1 nivolumab infusion. 
Record the exact date and time each sample is drawn. Refer to Section 8.4 for processing instructions. 
Blood 
Sample 
No. 
Time Point 
Scheduled Sample Collection Time 
Scheduled  
Nivolumab  
Time Point 
Actual Date 
Sample Collected 
or Dose Given 
Actual Time Sample 
Collected or Dose 
Given (24-hr clock) 
1 
Cycle 1, Day 1 
Prior to Cycle 1, Day 1 nivolumab infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
___/___/___ 
Start: |__|__|:|__|__| 
Stop: |__|__|:|__|__| 
2* 
Cycle 2, Day 1 
Prior to Cycle 2, Day 1 nivolumab infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
* Patients who are removed from therapy during Cycle 1 should have this sample collected on Day 28 (or Day 21) of 
Cycle 1. 
 
One copy of this Vaccinated Antibody Study Form should uploaded into RAVE. Refer to the provided guidelines for instructions 
on shipping these samples. 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form 
below: 
 
Signature: ______________________________________________                    Date: _________________________ 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 115 
 
APPENDIX V: ANTI-DRUG ANTIBODY (ADA) STUDY FORM 
 
COG Pt ID # _______________ 
ACC # _______________ 
Part of Study # _______________ 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|  
    
  
Dose Level: _______mg/kg 
Weight: ______ kg         Nivolumab Dose Administered: ______mg  
 
 
In Parts A and B, serum samples (2 mL) will be collected in all patients prior to Day 1 nivolumab infusion in 
each cycle. Record the exact date and time each sample is drawn. In Parts C, D, and E serum samples (4 mL) 
will be collected in all patients prior to Day 1 nivolumab infusion in each cycle for ADA assessment of both 
Nivolumab and Ipilimumab. 
 
Cycle  
Scheduled Sample Collection 
Time 
Actual Date 
Sample 
Collected  
Actual Time 
Sample Collected 
Cycle # 1 
Prior to Day 1 nivolumab infusion 
___/___/___ |__|__| : |__|__| 
 
Subsequent Cycles: 
Cycle  
Scheduled Sample Collection 
Time 
Actual Date 
Sample 
Collected  
Actual Time 
Sample Collected 
Cycle#______ 
Prior to Day 1 nivolumab infusion 
___/___/___ |__|__| : |__|__| 
 
 
One copy of this ADA Study Form should be uploaded into RAVE 
Refer to Section 8.5 for instructions on packaging and shipping ADA samples.  
 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form 
below: 
 
Signature: ______________________________________________                    Date: __________________________ 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 116 
 
APPENDIX VI: TISSUE STUDIES FORM 
 
COG Pt ID # _______________ 
ACC # ______________ Date:________     Part of Study # ____  
(Please do not write patient names on this form or on samples) 
 
Sample Labeling: 
Samples should be labeled with the following information: 
Protocol number:    ADVL1412 
Institution:        _________________                                      E3: Rhabdomyosarcoma 
Patient ID #:     _________________                                      E4: Ewing’s Sarcoma 
Accession #:     _________________  
Sample Date:    _________________ 
Anatomical Site of Acquired Tissue:  __________________ 
Tissue obtained at (check one option below): 
Diagnosis            Relapse         Subsequent Resection/Biopsy 
 
Tissue sample is from a: 
    Resection     or       Biopsy 
Shipment of Tumor Tissue: 
Tissue is requested from original diagnosis, relapse, or any subsequent resection or biopsy prior to treatment with 
nivolumab. Archived tissue samples should be in the form of a paraffin-embedded tissue block or at least 5 unstained 
slides (15 requested, 5 required) from the tissue block accompanied by a copy of the pathology report. Fine needle 
aspirate samples or other cytology samples are not acceptable and tumor samples obtained from bone metastases are 
generally not considered acceptable. 
 
All blocks or slides must be labeled with the patient’s study registration number (COG Patient ID #), the study I.D. 
(ADVL1412), and the sample collection date. Data should be recorded on this Tissue Studies Form, which must 
accompany the sample(s) to the address provided in Section 8.6.3.  
 
1. If sending paraffin block (PREFERRED): 
a. 
Place appropriate sample ID label on back of cassette 
b. Place labeled cassette in a Zipper lock bag  
c. 
Paraffin blocks are shipped to the lab at ambient temperature. It is acceptable to send blocks 
refrigerated if sending blocks and slides together. 
 
2. If sending slides: 
If slides will be cut from tissue block, they must be cut within one week of shipment. Recommended thickness 
of tissue sections for slides is 4 microns. Positively charged slides are required (Superfrost Plus is 
recommended). After cutting, the slides should be kept in refrigerator (2-5°C). 
a. 
Place slides in the plastic slide holder and place sample ID label provided on the slide holder 
b. Place the slide holder in the Zipper lock bag and eliminate as much air (and therefore moisture) as 
possible prior to sealing the Zip-lock bag 
c. 
Slides are shipped to the lab at refrigerated temperature on a cold gel pack. It is acceptable to send 
blocks refrigerated if sending blocks and slides together. 
 
One copy of this form should be uploaded into RAVE.   
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this 
form below: 
 
Signature: _______________________________               Date:__________________________________ 
(site personnel who collected samples) 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 117 
 
APPENDIX VII: CYTOKINE STUDY FORM 
 
COG Pt ID # _______________ 
ACC # _______________      Gender: _______       Age: _________ 
 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|  
   Part of Study # _______________ 
 
Dose Level: _______mg/kg 
Weight: ________ kg  Nivolumab Dose Administered: ______mg  
 
 
Blood samples (2 mL) will be collected in consenting patients at baseline and prior to Cycle 2, Day 1 nivolumab infusion. 
Record the exact date and time each sample is drawn. Refer to Section 8.8 for processing instructions. 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Sample Collection Time 
Scheduled  
Nivolumab  
Time Point 
Actual Date 
Sample Collected 
or Dose Given 
Actual Time 
Sample Collected 
or Dose Given (24-
hr clock) 
1 
Cycle 1, Day 1 
Prior to Cycle 1, Day 1 nivolumab infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
___/___/___ 
Start: |__|__|:|__|__| 
Stop: |__|__|:|__|__| 
2* 
Cycle 2, Day 1 
Prior to Cycle 2, Day 1 nivolumab infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
* Patients who are removed from therapy during Cycle 1 should have this sample collected on Day 28 (or Day 21) of 
Cycle 1. 
 
One copy of this Cytokine Study Form should uploaded into RAVE. Refer to the provided guidelines for instructions on shipping 
these samples. 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form 
below: 
 
Signature: ______________________________________________                    Date: _________________________ 
 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 118 
 
APPENDIX VIII: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
The use of the following medications should be avoided during protocol therapy if reasonable 
alternatives exist. This is not an inclusive list. Because the lists of these agents are constantly 
changing, it is important to regularly consult frequently updated medical references. For the most 
current list of medications, please refer to the following reference: 
Woosley, RL and Romero, KA, www.Crediblemeds.org, QTdrugs List, Accession Date 
December 2nd, 2016, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ  85755 
 
 
Medications that prolong QTc 
Amiodarone 
Flecainide 
Anagrelide 
Fluconazole 
Arsenic trioxide 
Haloperidol 
Azithromycin 
Ibutilide 
Chloroquine 
Methadone 
Chlorpromazine 
Moxifloxacin 
Ciprofloxacin 
Ondansetron 
Citalopram 
Pentamidine 
Clarithromycin 
Pimozide 
Disopyramide 
Procainamide 
Dofetilide 
Propofol 
Domperidone 
Quinidine  
Droperidol 
Sevoflurane 
Dronedarone 
Sotalol 
Erythromycin 
Thioridazine  
Escitalopram 
Vandetanib  
 
 
Medications that MAY prolong QTc 
Aripiprazole 
Lapatinib 
Bortezomib 
Lenvatinib 
Bosutinib 
Leuprolide 
Ceritinib 
Mirtazapine 
Clomipramine 
Nicardipine 
Crizotinib 
Nilotinib 
Dabrafenib 
Olanzapine 
Dasatinib 
Osimertinib 
Degarelix 
Pazopanib 
Desipramine 
Promethazine 
Dolasetron 
Risperidone 
Eribulin mesylate 
Sorafenib 
Famotidine 
Sunitinib 
Foscarnet 
Tacrolimus 
Gemifloxacin 
Vemurafenib 
Granisetron 
Venlafaxine 
Isradipine 
Vorinostat 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 119 
 
APPENDIX IX: TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
>ULN - ≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3.0 x ULN 
Grade 3: 
> 3.0 x ULN -10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
ALT: For the purpose of this study, the ULN for ALT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
> 45 U/L - ≤ 135 U/L 
Grade 2: 
136 U/L – 225 U/L 
Grade 3: 
226 U/L - 900 U/L 
Grade 4: 
> 900 U/L 
 
AST: For the purpose of this study, the ULN for AST is 50 U/L regardless of baseline. 
 
Grade 1: 
> 50 U/L- ≤ 150 U/L 
Grade 2: 
151 U/L -250 U/L 
Grade 3: 
251 U/L -1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN - 5.0 x ULN 
Grade 3: 
> 5.0- x ULN 20.0 x ULN 
Grade 4: 
> 20.0 x ULN 
 
 
 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 120 
 
APPENDIX X: CTEP AND CTSU REGISTRATION PROCEDURES 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually.  To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type 
of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined in the table 
below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI 
Biosketch 
(education, 
training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list all 
clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the RCR Help 
Desk by email at < RCRHelpDesk@nih.gov >. 
 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 

 
 
ADVL1412 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
 
 
 
 
Version Date: 03/30/2020 
 
Page 121 
 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and 
submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory criteria 
including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not required 
to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the CIRB, IRB 
approval information is received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via IRBManager 
to indicate their intent to open the study locally.  The CIRB’s approval of the SSW is then communicated 
to the CTSU Regulatory Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the Signatory Institution are 
participating in the study. 
 
Requirements for ADVL1412 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-signed 
CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
For applicable studies with a radiation and/or imaging (RTI) component, the enrolling site must be 
aligned to a RTI provider.  To manage provider associations access the Provider Association tab on 
the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove 
associated providers.  Sites must be linked to at least one IROC credentialed provider to participate on 
trials with an RT component. Enrolling sites are responsible for ensuring that the appropriate 
agreements are in place with their RTI provider, and that appropriate IRB approvals are in place.   
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab →Regulatory 
Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 in order to receive further instruction and support.