Phase Ib /II Clinical Trial of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Subjects With High Grade Primary CNS Malignancies
Phase: PHASE2
Conditions: Various Advanced Cancer
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CA209908
IND Number:
119,590
EUDRACT Number
2016-004441-82
Date
12-Dec-2016
Revised Date:
11-Sep-2017
Clinical Protocol CA209908
Phase Ib /II Clinical Trial of Nivolumab Monotherapy and Nivolumab in Combination with 
Ipilimumab in Pediatric Subjects with High Grade Primary CNS Malignancies 
CheckMate908: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 908
Revised Protocol 01
Medical Monitor
Lewis Strauss, MD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (e.g., amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
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confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, e.g., a Contract Research 
Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 01
11-Sep-2017
To clarify protocol text based on local reviews and 
investigator feedback. 
Original Protocol
12-Dec-2016
Not Applicable
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OVERALL RATIONALE FOR THE REVISED PROTOCOL 01
The purpose of this amendment is to clarify protocol text based on local reviews and investigator 
feedback.
These changes affect all participants and should be implemented after IRB approval. 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 01
Section & Title
Description of Change
Section 1, Synopsis, Study 
Population; Section 6.1, 
Inclusion Criteria, Criterion 
2.a; Section 5.1.1, Overall 
Design
Added that patients must 
have received Standard of 
Care therapy and that no 
potentially-curative therapy is 
available.
Section 1, Synopsis, Study 
Population; Section 6.1, 
Inclusion Criteria, Criterion 
2.a.
Indicated for Cohort 1 “but 
no chemotherapy” and 
changed “thalamic” to 
“midline”; for Cohort 2, 
changed “supratentorial” to 
“non-brainstem”; for Cohort 
3, added “and chemotherapy 
(regardless of age)”; for 
Cohort 4, added “(regardless 
of age)
Section 2, Schedule of 
Activities, Table 2.-1, 
Screening Procedural Outline 
Removed pregnancy test at 
screening because a 
pregnancy test prior to the 
first dose is already required. 
Section 2, Schedule of 
Activities, Table 2.-1, 
Screening Procedural 
Outline; Table 2.-2, 
Nivolumab Monotherapy 
[Module A] Procedural 
Outline (CA209908); Table 
2.-3, Nivolumab + 
Ipilimumab combination 
[Module B] Procedural 
Outline (CA209908); Table 
2.-4, Follow-up Procedural 
Outline (CA209908); 
 
Guidance on whether Spine 
MRI and CSF cytopathology 
are expected at baseline or 
on-study.
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 01
Section & Title
Description of Change
Section 2, Schedule of 
Activities, Table 2.-2, 
Nivolumab Monotherapy 
[Module A] Procedural 
Outline (CA209908); Table 
2.-3, Nivolumab + 
Ipilimumab combination 
[Module B] Procedural 
Outline (CA209908); Table 
2.-4, Follow-up Procedural 
Outline (CA209908
Increased interval of MRI 
scans from Q8 week to Q12 
week after 1 year on study.
Section 3.1.2, Checkpoint 
Inhibitors for CNS Tumors; 
Section 3.1.3, Checkpoint 
Inhibitors in Pediatric 
Participants
Updated information on trials
of nivolumab or nivolumab 
plus ipilimumab in adults 
with GBM and in children 
with non-CNS tumors
Section 3.2.1, Indications to 
be Studied
Included rationale for 
eligibility of Cohort 1 after 
initial RT rather than at 
progression
Section 3.2.4, Nivolumab 
Combined with Ipilimumab
Updated to focus text 
specifically on CNS tumors
Synopsis, Overall Design; 
Section 5.1, Overall Design; 
Section 10.1 Sample Size 
Determination 
Indicated that target number 
of participants is 
approximate, subject to 
recommendation of Study 
Steering Committee
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 01
Section & Title
Description of Change
Section 5.1.2, Safety Lead In
Indicated that SSC may 
recommend to proceed with
Expansion phase if 0 DLT is 
observed in the first 5 (of 6) 
in Cohort 1 or the first 7 (of 
10) participants in Cohort 2 
Section 5.1.3, Definition of 
Dose-limiting Toxicity 
Clarified definition of “DLT-
evaluable” to include subjects 
who delay or discontinue 
treatment due to related AE.
Section 5.1.5, Follow-up 
Phase; Section 5.3, End of 
Study Definition
Added a sentence regarding 
the length of follow-up.
Section 5.1.6.1, Data 
Monitoring Committee; 
Section 5.1.6.2 ,Study 
Steering Committee
Indicated that any major 
recommendation of one 
committee would be 
communicated to the other
Section 5.1.6.2, Study 
Steering Committee
Added a condition that 
accrual may be kept open to 
study a sub-population
Section 5.5.1, Nivolumab
Expanded the justification for 
dose of nivolumab
Section 6.1, Inclusion 
Criteria, Criterion 2.f.
Criterion has been modified 
minimum intervals from last 
prior therapy and added 
cautions for selected prior 
therapy and moved to
criterion 2.j
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 01
Section & Title
Description of Change
Table 6.2-1
Added maximum permitted 
creatinine values in SI 
(umol/L) units
Section 6.2, Exclusion 
Criteria, criterion 4.e; Section 
7.4.1, Dose Delay Criteria; 
Section 8.1.1, 
Discontinuation of 
Nivolumab due to Toxicity 
[Module A or B]; Section 
9.2.7, Potential Drug Induced 
Liver Injury (DILI)
Defined “fixed” ULN for 
AST and ALT.
Section 8.1.1, 
Discontinuation of 
Nivolumab Due to Toxicity 
[Module A or B]
Grade 3 Neurologic toxicity 
has been added as a 
discontinuation criteria.
Section 8.1.2, 
Discontinuation of 
Combination treatment due to 
Toxicity [Module B]
Added a criterion regarding 
select Grade 2 drug-related 
events; Restart of nivolumab 
after ipilimumab 
discontinuation for AE may 
be permitted
Section 9.1, Efficacy 
Assessments
Added additional guidance 
for investigators regarding 
imaging, including reference 
to RAPNO proposal. 
Clarified that lumbar 
puncture for CSF is done only 
if clinically indicated.
Section 9.1.1, Imaging 
Assessment for the Study
Provided extensive additional 
details on MRI assessments, 
including related to potential 
leptomeningeal dissemination
Section 9.2.2, Method of 
Detecting AEs and SAEs
Deleted prohibition against 
staff asking participant or 
family questions about 
specific AEs.
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 01
Section & Title
Description of Change
Section 9.4.1, Physical 
Examinations
Defined neurologic 
examination as part of 
physical exam.
Section 9.5, 
Pharmacokinetics, Table 9.5-
1, Pharmacokinetics and 
Anti-Drug Antibody 
Sampling Schedule for 
Nivolumab; Table 9.5-2, 
Pharmacokinetic and Anti-
Drug Antibody Sampling 
Schedule for Nivolumab in 
Combination with 
Ipilimumab
Clarified that lumbar 
puncture for CSF is done only 
if clinically indicated. 
Section 10.1, Sample Size 
Determination 
Provided additional detail on 
the formula used to calculate 
the sample size.
Section 10.3.5, Interim 
Analyses
Provided additional details 
regarding the interim 
analyses.
All
Minor formatting corrections, 
cross-references, and edits to 
improve clarity.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR THE REVISED PROTOCOL 01 ............................. 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 01............................ 
TABLE OF CONTENTS .............................................................................................. 
1. SYNOPSIS ................................................................................................................ 
2. SCHEDULE OF ACTIVITIES................................................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. OBJECTIVES AND ENDPOINTS .......................................................................... 
5. STUDY DESIGN...................................................................................................... 
5.1 Overall Designs ................................................................................................. 
5.1.1 Screening Period ...................................................................................... 
5.1.2 Safety Lead-in .......................................................................................... 
5.1.3 Definition of Dose-Limiting Toxicity ....................................................... 
5.1.4 Expansion ................................................................................................. 
5.1.5 Follow-Up Phase ..................................................................................... 
5.1.6 Data Monitoring Committee and Other External Committees ................ 
5.1.6.1 Data Monitoring Committee ........................................................... 
5.1.6.2 Study Steering Committee ............................................................... 
5.1.6.3 Blinded Independent Central Review Committee ........................... 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
 
 
 
 
 
 
 
6. STUDY POPULATION ........................................................................................... 
6.1 Inclusion Criteria .............................................................................................. 
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6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7. TREATMENT .......................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.1.1 Module A (Nivolumab Monotherapy): ..................................................... 
7.1.2 Module B (Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Combination): ... 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Dose Delay Criteria ................................................................................. 
7.4.2 Criteria to Resume Treatment .................................................................. 
7.4.3 Treatment of Related Infusion Reactions ................................................. 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance ...................................................................................... 
 
 
 
 
 
7.8 Treatment After the End of the Study ............................................................... 
8. DISCONTINUATION CRITERIA .......................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Discontinuation of Nivolumab Due to Toxicity [Module A or B] ............ 
8.1.2 Discontinuation of Combination treatment due to Toxicity [Module B] . 
8.1.3 Post Study Drug Study Follow-up............................................................ 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9. STUDY ASSESSMENTS AND PROCEDURES .................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.1.2 Suspected Progression ............................................................................. 
9.1.3 Assessment of Response ........................................................................... 
9.1.4 Results of Central Radiology Assessments .............................................. 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
 
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9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital signs................................................................................................. 
9.4.3 Electrocardiograms ................................................................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
9.4.5 Imaging Safety Assessment ...................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
10. STATISTICAL CONSIDERATIONS ................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
 
 
10.3.5 Interim Analyses ..................................................................................... 
 
12. APPENDICES ........................................................................................................ 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 6 KARNOFSKY AND LANSKY CRITERIA ........................................ 
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1.
SYNOPSIS
Protocol Title: Phase Ib /II Clinical Trial of Nivolumab Monotherapy and Nivolumab in 
Combination with Ipilimumab in Pediatric Subjects with High Grade Primary CNS 
Malignancies 
Study Phase:
1b/2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Population:
Male and female, age 6 months and 22 years old at the time of enrollment, and meeting one 
of the following CNS tumor type criteria:
Participants must have received standard of care therapy, and there must not be potentially-
curative treatment available, in one of the following:
1) A newly diagnosed DIPG that has been treated with radiation therapy (RT) but no 
chemotherapy. Diagnosis of DIPG must be confirmed either based on MRI criteria or 
histology. (Cohort 1)
a) Eligibility includes diffuse midline glioma with demonstrated H3K27M mutation
b) Biopsy is not required for DIPG
c) Enrollment can occur during radiation therapy or up to 4 weeks after end of RT
2) A histologically confirmed recurrent or progressive non-brainstem HGG previously treated 
with surgical resection and RT (with or without chemotherapy). (Cohort 2)
3) A histologically confirmed medulloblastoma that has relapsed or is resistant to at least one 
line of prior therapy including surgery, RT, and chemotherapy (regardless of age) (Cohort 3)
4) A histologically confirmed ependymoma that has relapsed or is resistant to at least one line 
of prior therapy including surgical resection and RT (regardless of age). (Cohort 4)
5) A histologically-confirmed high grade CNS malignancy “other than above” which is 
recurrent or progressive after at least one line of prior therapy, including for example: 
choroid plexus carcinoma, germ cell tumor, anaplastic pleomorphic xanthoastrocytoma, 
pineoblastoma, 
AT/RT, 
embryonal 
tumor
with 
multilayered 
rosettes 
(ETMR; 
C19MC-altered) that has relapsed or is resistant to at least one line of prior therapy. (Cohort 
5) 
Note: Participants with any of the above subtypes of high grade CNS tumors are eligible for 
the safety lead in phase, See Study Design (Section 5.1).
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Objectives and Endpoints:
Objectives
Endpoints
PRIMARY
Safety Lead In
To estimate the safety and tolerability of study treatment in pediatric
participants with primaryhigh- grade CNS tumors.
Incidence of DLTs, SAEs, and
AEs leading to discontinuation.
Expansion
To estimate the OS in pediatric participants with newly
diagnosed DIPG. (Cohort 1)
OS
To estimate the PFS in pediatric participants with recurrent or 
progressive HGG. (Cohort 2)
PFS

To estimate the PFS in pediatric participants with relapsed or 
resistant medulloblastoma. (Cohort 3)
PFS

To estimate the PFS in pediatric participants with relapsed or 
resistant ependymoma. (Cohort 4)
PFS

To estimate the PFS in pediatric participants with recurrent or 
progressive other rare CNS tumors (including pineoblastoma,
AT/RT, embryonic CNS tumors) (Cohort 5)
PFS
SECONDARY
Safety Lead In

To describe any observed anti-tumor activity of study treatment in 
pediatric primary high grade CNS tumors.
Secondary endpoints are the same 
as in the expansion phase.
Expansion

To estimate the safety of study therapy in pediatric participants with
newly diagnosed DIPG, recurrent or progressive HGG, recurrent or 
progressive medulloblastoma, recurrent or progressive ependymoma and
recurrent or progressive other primary rare CNS tumors.
Incidence of AEs, SAEs, drug-
related AEs, AEs leading to 
discontinuation, and death. 
Incidence of laboratory 
abnormalities.

To estimate the PFS and OSr in pediatric participants with newly
diagnosed DIPG. (Cohort 1)
PFS, OS(12)

To estimate the PFSr, OS, and OSr and in pediatric participants with
recurrent or progressive HGG. (Cohort 2)
PFS(6), OS, OS(12)

To estimate the PFSr, OS, and OSr in pediatric participants with
recurrent or progressive medulloblastoma. (Cohort 3)
PFS(6), OS, OS(12)

To estimate the PFSr, OS, and OSr in pediatric participants with
recurrent or progressive ependymoma. (Cohort 4)
PFS(6), OS, OS(12)

To estimate the PFSr and OS and in pediatric participants with
recurrent or progressive other rare CNS tumors (including
pineoblastoma, AT/RT, other embryonic CNS tumors). (Cohort 5)
PFS(6), OS 
 
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Objectives
Endpoints

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; AT/RT = atypical teratoid rhabdoid tumor; CNS = central nervous system; DIPG = diffuse 
intrinsic pontine glioma; DLT = dose limiting toxicity; DOR = duration of response; HGG = high grade glioma; 
ORR = objective response rate; OS = overall survival; OSr = overall survival rate; PD = pharmacodynamic; PFS 
= progression free survival; PFSr = progression free survival rate; PK = pharmacokinetics; SAE = serious adverse 
event.
Overall Design:
CA209908 is an open-label, sequential-arm Phase 1b/2 clinical trial of nivolumab monotherapy 
and of nivolumab plus ipilimumab in pediatric participants with high grade primary CNS 
malignancies. 
Cohorts are defined by tumor type (histology):
Cohort 1: N = 22 participants with newly-diagnosed DIPG, including midline glioma with 
H3K27M
Cohort 2: N = 15 participants with recurrent or progressive non-brainstem HGG, regardless of 
mutation status, including glioblastoma
Cohort 3: N = 15 participants with relapsed or resistant medulloblastoma 
Cohort 4: N = 10 participants with relapsed or resistant ependymoma
Cohort 5: N = 18 participants with other recurrent subtypes of high-grade CNS malignancy 
(eg, pineoblastoma, AT/RT, germ cell tumor, and others)
The above intended target numbers for each Module are approximate. 
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Treatments are defined by Module:
Module A: nivolumab 3 mg/kg every 2 weeks, as monotherapy, and 
Module B: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, every 3 weeks for 4 doses followed by 
nivolumab 3 mg/kg every 2 weeks.
Enrollment to Module A will open in parallel for all cohorts. The first 6 participants in Cohort 1 
who are treated and DLT evaluable will be evaluated for safety before additional participants are
treated in that cohort. Separately, the first 10 participants treated and DLT evaluable in the 
recurrent disease Cohorts 2-5 (combined) will be evaluated for safety before additional 
participants are treated (see Schema in Figure 5.1-1) in those Cohorts. At regularly-scheduled 
teleconferences, the Study Steering Committee (SSC) will review safety, assess potential DLTs, 
and make recommendations regarding reopening of enrollment.
Based on determination of adequate safety, enrollment will re-open for evaluation of efficacy to 
complete the planned number of participants for each cohort in Module A expansion. 
Participants evaluated in the safety lead-in will be included for evaluation of efficacy (ie, the 
6 participants with DIPG evaluated for safety in Cohort 1 are included in the 22 planned 
participants).
Enrollment will begin in Module B, by cohort, based on completion of planned accrual in 
Module A or a decision of the SSC (see Section 5.1.6.2); therefore, accrual will not open in 
parallel for Module B. Investigators will be informed when Module B is open. For Module B, the 
first 10 participants treated and DLT evaluable in all cohorts combined will be evaluated for 
safety by the SSC before additional participants are enrolled (see Schema in Figure 5.1-1) after 
which cohorts will be re-opened for full accrual in the expansion.
Participants will be closely monitored for AEs throughout the study using clinical and laboratory 
evaluations (see Sections 2 and 9 for details). The SSC (see Section 5.1.6.2) will meet regularly 
during the study to ensure that participant safety is carefully monitored.
Tumor progression or response endpoints will be assessed using Radiologic Assessment in 
Neuro-Oncology criteria (RANO) 2010 described in Section 9.1.3, as assessed by Investigator.
Blood samples will be obtained prior to and post drug administration for PK and biomarkers. The 
PK sampling schedule for monotherapy and combination therapy are provided in Table 9.5-1 and 
Table 9.5-2, respectively. 
After discontinuation of study treatment, all participants will be followed for safety, tumor 
progression, and OS (see Section 5.1.4).
Number of Participants:
Enrolled 176-200
(88-100
for nivolumab
monotherapy; 88-100
for nivolumab
+ 
ipilimumab combination)
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Treated 
160 (80
for nivolumab monotherapy; 80
for nivolumab + ipilimumab 
combination)
Screen Failure Rate 10-25%
Cohorts A1 and B1: Sample sizes of 22 participants for each of the Cohorts A1 and B1
in DIPG is based on comparison of OS against an historical control of median OS 
9 months, assuming 80% power, 1-sided alpha of 10%, target median OS of 15 months, 
and a one-sample log rank test. All distributions are assumed to be exponential; assume 
12 months for accrual and 24 months for follow-up.
Cohorts A2 and B2: Sample sizes of 15 participants for each of the Cohorts A2 and B2
in HGG is based on an historical PFS(6) of 18%, one-year accrual, one year follow-up, a 
target PFS(6) of 38% providing 80% power using a one-sided Type 1 error of 10%, 
assuming an exponential distribution.
Cohort A3 and B3: Sample sizes of 15 participants for each of the cohorts is based on 
comparison of PFS against an historical control of PFS rate at 4 months of .18, assuming 
80% power, 1-sided alpha of 10%, target PFS rate at 4 months of .38, and a one-sample 
log rank test. All distributions are assumed to be exponential; assume 12 months for 
accrual and 12 months follow-up.
Cohort A4 and B4: Sample sizes of 10 participants for each of the cohorts is based on 
comparison of PFS against an historical control of median PFS of 2.1 months, assuming 
80% power, 1-sided alpha of 10%, target median PFS of 4.4 months, and a one-sample 
log rank test. All distributions are assumed to be exponential; assume 12 months for 
accrual and 12 months follow-up.
Cohort A5 and B5: Sample sizes of 18 participants for each of the Cohorts A5 and B5 is 
not based on statistical considerations as these cohorts contain various tumor types. 
However, if the disease control rate at 12 months is 30%, 18 patients provide 21% 
precision for the estimate.
Treatment Arms and Duration:
Study treatment:
Study Drug for CA209908
Medication 
Potency 
IP/Non-IP 
Nivolumab
(BMS-936558-01) Solution for 
Injectiona
100 mg (10 mg/mL)
IP
Ipilimumab
(BMS-734016)
Solution for Injection
200 mg (5 mg/mL)
IP
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a May be labeled as either “BMS-936558-01” or “Nivolumab”
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Figure 1-1:
Overall Study Design Schematic
A2 Recurrent High-Grade 
Glioma/Glioblastoma
A1 Newly-diagnosed 
Pontine Glioma, post-RT
A3 Recurrent 
Medulloblastoma
A4 Recurrent Ependymoma
A5 Recurrent High-Grade 
Other Histologies
Notes: 
•
Cohorts are indicated by tumor type; Study Treatments are indicated as A = nivolumab and B = nivolumab + ipilimumab
•
Safety is evaluated across cohorts (indicated as “lead-in”), prior to expansion
•
Efficacy is evaluated by cohort (indicated as Expansion), including lead-in population
•
Module B opens, by cohort, when corresponding Module A is completed or upon decision of Steering Committee
Safety 
lead-in
N = 10
N = 6
B2 Recurrent High-Grade 
Glioma/Glioblastoma
B1 Newly-diagnosed 
Pontine Glioma, post-RT
B3 Recurrent 
Medulloblastoma
B4 Recurrent 
Ependymoma
B5 Recurrent High-Grade 
Other Histologies
Expansion
N = 15
N = 15
N = 22
Safety 
lead-in
Expansion
N = 15
N = 22
Efficacy analysis
Safety analysis
N = 10
N = 18
N = 10
N = 15
N = 18
N = 10
Efficacy analysis
Safety analysis
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2.
SCHEDULE OF ACTIVITIES
Screening assessments for this study are summarized in Table 2.-1, On-treatment procedures for 
Module A in Table 2.-2 and for Module B in Table 2.-3, and Follow-Up procedures for both 
Modules A and B in Table 2.-4. Schematics for Treatment and Key Assessments are provided in 
Figure 2.-1 and Figure 2.-2 for Modules A and B, respectively. Detailed schedules for 
pharmacokinetic (PK) and immunogenicity sampling are provided (Modules A and B, 
respectively) in Table 9.5-1 and Table 9.5-2 and for biomarker sampling in Table 9.8-2 and
Table 9.8-3.
Additional diagnostic procedures and laboratory tests not required by protocol should be 
performed as clinically-indicated; these results may be included in study data. Any clinically-
appropriate intervention should be done, regardless of protocol requirement, for optimal 
management of each study participant.
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Table 2.-1:
Screening Procedural Outline (CA209908)
Procedurea
Screening
Visit
Notes
Informed Consent
X
Register in Interactive Response System to obtain participant number; then again prior to 
treatment start if fully eligible (see instructions provided in manual)
Inclusion/Exclusion Criteria
X
Must be confirmed prior to treatment
Medical History
X
Tumor Sample Submission
X
Tumor tissue, either FFPE block or a minimum of 20 slides from recent surgery if performed; 
archival tissue is required if no recent surgery done. (See Section 6.1; not required for DIPG)
Sample should be sent with an institutional pathology report. Additional molecular information 
will be collected.
Physical Examination (including vital signs 
& performance status)
X
Include BP, HR, RR, temperature, and neurological exam at screening and within 72 hours prior 
to treatment 
Within 14 days prior to treatment: Height, weight, and Lansky play score (LPS) for 16 years or 
Karnofsky performance scale (KPS) for > 16 years of age.
Assessment of Signs and Symptoms
X
Within 14 days prior to treatment assignment.
Steroid Dose Documentation
X
Within 14 days prior to treatment assignment.
Serious Adverse Events Assessment
X
See Appendix 3.
Laboratory Tests
X
Within 14 days prior to treatment: CBC w/differential; Chemistry panel (see Section 9.4.4).
Within 28 days prior to treatment: Thyroid panel and Hepatitis B/C serology (see Section 9.4.4).
Screening/Baseline Tumor Assessment
X
Contrast-enhanced MRI must be performed within 21 days prior to study treatment (see Imaging 
Manual). Complete MRI of the spine performed per clinical indication. See Section 9.1.1.
CSF cytopathology per clinical indication up to 7 days before treatment start. See Section 9.8.1.
In Cohort 1, MRI must be performed after RT and prior to study treatment; prior diagnostic
MRI scan also will be collected. 
a Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations. If a participant is 
referred from another institution, assessments that were completed at the referring institution can be used as the screening assessments. 
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Table 2.-2:
Nivolumab Monotherapy [Module-A] Procedural Outline (CA209908)
Procedure
Cycle 1 and 
subsequent cyclesa
Notesb
(Cycle duration = 2 weeks unless treatment is delayed)
Targeted Physical Examination, Vital 
Signs, Weight and Performance Status
X
To be performed within 72 hours of dosing. Physical and neurologic exam at C1D1 and as 
clinically indicated. See Section 9.4.1. VS (BP, HR, RR and temperature, weight) within 
72 hours prior to dose. Lansky play score (LPS) for 16 years or Karnofsky performance 
scale (KPS) for > 16 years.
Adverse Event assessment
Continuously
Record at each visit. Assessed using NCI CTCAE v. 4.
Laboratory Tests
X
Within 72 hours prior to each dose. Include CBC w/differential, ALT, AST, T-Bili, BUN 
or serum urea, creatinine, Na, K, Cl, glucose.
TSH every 6 weeks with reflexive Free T4 and Free T3 if TSH abnormal.
Laboratory tests do not need to be repeated on C1D1 if done within 14 days prior to dose. 
Pregnancy Test (WOCBP only)
X
Serum or urine (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to first dose then at least once every 4 weeks (1 week) regardless of delays.
Tumor Assessment
X 
(See note)
Contrast enhanced MRI after 6 & 12 wks (1 week) then Q 8 wks (1 week) X 4, then 
Q 12 wks (1 week), or earlier if clinically indicated. NOTE: Post-RT MRI required in 
Cohort 1. MRI of the spine also performed per clinical indication. See Section 9.1.1.
Tumor Tissue, on-study sample
X
(See note)
If biopsy or resection is performed at suspected progression, tumor sample (block or slides) 
should be submitted to central laboratory. (See Section 9.8.5)
 
Dispense Study Drug
X
First dose within 3 calendar days of treatment assignment. 
a If dose is delayed, the procedures scheduled for that same time point (except tumor assessments which should follow the specified schedule) should also be 
delayed to coincide with when that time point’s dosing actually occurs.
b Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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Figure 2.-1:
Module A Treatment and Key Assessments
Module A: Treatment & Key Assessments
PK
ADA
Biomarkers
X
1
3
7
13
15
17
19
21
25
29
week
MRI scan
5
11
9
MRI scan: pre-study, q6 wk x 2, then q8 wk
Nivolumab
PK: pre-dose & EOI; ADA samples
Biomarker samples; see Table for detail
X
Tumor sample; and if surgery on-study or at PD
This Figure is for overall guidance, and 
does not include (eg) treatment delay, 
unscheduled assessments, etc.
Thyroid Fn
CBC & Chems
Local lab tests, repeat as clinically indicated
Treatment 
[cycle]
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Table 2.-3:
Nivolumab + Ipilimumab combination [Module B] Procedural Outline (CA209908)
Procedure
Cycles 1-4a
(Cycle = 3 weeks)
Cycle 5 and beyonda
(Cycle = 2 weeks)
Notesb
Targeted Physical Examination, 
Vital Signs, Weight and 
Performance Status
X
X
To be performed within 72 hours of dosing. Physical and neurologic exam
at C1D1 and as clinically indicated. See Section 9.4.1, VS (BP, HR, RR 
and temperature, weight) within 72 hours prior to dose. Lansky play score 
(LPS) for 16 years or Karnofsky performance scale (KPS) for > 16 years.
Adverse Events Assessment
Continuously
Record at each visit using NCI CTCAE v. 4.
Laboratory Tests
X
X
Within 72 hours prior to each dose. Include CBC w/differential, ALT, AST, 
T-Bili, BUN or serum urea, creatinine, Na, K, Cl, glucose, amylase, and 
lipase.
TSH every 6 weeks with reflexive Free T4 and Free T3 if TSH is abnormal.
Laboratory tests do not need to be repeated on C1D1 if done within 14 days 
prior to dose.
Pregnancy Test (WOCBP only)
X
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG) within 24 hours prior to first dose then at least once every 
4 weeks (1 week) regardless of dose delays.
12-Lead ECG
X
X
Only as clinically indicated.
Tumor Assessment
X (See note)
Contrast enhanced MRI after 6 & 12 weeks (1 week) then Q 8 weeks (
1 week) X 4, then Q 12 weeks, (1 week) or earlier if clinically indicated. 
Post-RT MRI required in Cohort 1. MRI of the spine also performed per 
clinical indication. See Section 9.1.1.
 
Dispense Study Drug
X (combination)
X (monotherapy)
First dose within 3 calendar days of treatment assignment.
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a If a dose is delayed, the procedures for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs, except 
tumor assessments which should follow the specified schedule. Cycle 5 begins 3 weeks after Cycle 4
b Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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Figure 2.-2:
Module B Treatment and Key Assessments
Module B: Treatment & Key Assessments
Treatment 
[cycle]
1
4
7
10
13
15
17
19
21
25
29
week
MRI scan
PK
ADA
Biomarkers
Tumor Tissue X
Thyroid Fn
CBC & Chems
Ipilimumab
MRI scan: pre-study, q6 wk x 2, then q8 wk
Nivolumab
PK: pre-dose & EOI; ADA samples
Biomarker samples; see Table for detail
X
Tumor sample; and if surgery on-study or at PD
Local lab tests, repeat as clinically indicated
This Figure is for overall guidance, and 
does not include (eg) treatment delay, 
unscheduled assessments, etc.
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Table 2.-4:
Follow-up Procedural Outline (CA209908)
Procedure
Follow-up Visits 1 & 2a
Survival Visitsb
Notesc
Targeted Physical Examination
X
Adverse Events Assessment
X
X
Drug-related adverse events will be followed until resolved or 
returned to baseline. See Section 9.2.3.
Serious Adverse Events Assessment
X
Laboratory Tests
X
CBC w/differential, LFTs, T. Bili, BUN, creatinine, Na, K, Cl, 
glucose and TSH for follow-up #1, repeat labs at follow-up #2 if 
study drug-related toxicity persists.
Pregnancy Test WOCBP only
X
Serum or Urine.
Survival Status
X
X
Every 3 months (clinic visit or telephone contact), during Survival 
phase, include documentation of subsequent chemotherapy.
Tumor Assessment
X
X
Participants who did not progress while on study treatment should 
continue MRI follow-up according to the schedule in Table 2.-2 and
Table 2.-3, or earlier if clinically indicated, regardless of subsequent
therapy. MRI of the spine and CSF cytopathology also performed 
per clinical indication.
Tumor tissue, on-study sample
X
X
If biopsy or surgical resection is performed at suspected progression, 
a tumor sample (block or slides) should be submitted to central 
laboratory.
a Participants must be followed for at least 100 days after last dose of study treatment. Follow-up visit #1 should occur 30 days from the last dose (7 days) or 
can be performed on the date of discontinuation if that date is greater than 42 days from the last dose. Follow-up #2 occurs approximately 100 days (7 days)
after the last dose of study treatment. Both follow-up visits should be conducted in person.
b Survival visits to occur every 3 months (14 days) from Follow-up visit 2. May be conducted in person or by telephone. BMS may request that survival data 
be collected on all treated participant s outside of the 3 month specified window. At the time of this request each participant will be contacted to determine 
their survival status unless the participant has withdrawn consent for all contact.
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c Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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4.
OBJECTIVES AND ENDPOINTS
Table 4.-1:
Objectives and Endpoints
Objectives
Endpoints
PRIMARY
Safety Lead In
To estimate the safety and tolerability of study treatment in pediatric
participants with primary high-grade CNS tumors.
Incidence of DLTs, SAEs, and AEs 
leading to discontinuation.
Expansion
To estimate the OS in pediatric participants with newly
diagnosed DIPG. (Cohort 1)
OS
To estimate the PFS in pediatric participants with recurrent or 
progressive HGG. (Cohort 2)
PFS

To estimate the PFS in pediatric participants with relapsed or 
resistant medulloblastoma. (Cohort 3)
PFS

To estimate the PFS in pediatric participants with relapsed 
or resistant ependymoma. (Cohort 4)
PFS

To estimate the PFS in pediatric participants with recurrent
or progressive other rare CNS tumors (including
pineoblastoma, AT/RT, embryonic CNS tumors) (Cohort 5)
PFS
SECONDARY
Safety Lead In

To describe any observed anti-tumor activity of study treatment in 
pediatric primary high-grade CNS tumors.
Secondary endpoints are the same as 
in the expansion phase.
Expansion

To estimate the safety of study therapy in pediatric participants with
newly diagnosed primary DIPG, recurrent or progressive HGG,
recurrent or progressive primarymedulloblastoma, recurrent or 
progressive primary ependymoma and recurrent or progressive other 
primary rare CNS tumors.
Incidence of AEs, SAEs, drug-
related AEs, AEs leading to 
discontinuation, and death. 
Incidence of laboratory 
abnormalities.

To estimate the PFS and OSr in pediatric participants with newly
diagnosed DIPG. (Cohort 1)
PFS, OS(12)

To estimate the PFSr, OS, and OSr and in pediatric participants with
recurrent or progressive HGG. (Cohort 2)
PFS(6), OS, OS(12)

To estimate the PFSr, OS, and OSr in pediatric participants with
recurrent or progressive medulloblastoma. (Cohort 3)
PFS(6), OS, OS(12)

To estimate the PFSr, OS, and OSr in pediatric participants with
recurrent or progressive ependymoma. (Cohort 4)
PFS(6), OS, OS(12)

To estimate the PFSr and OS and in pediatric participants with
recurrent or progressive other rare CNS tumors (including
pineoblastoma, AT/RT, other embryonic CNS tumors). (Cohort 5)
PFS(6), OS 
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Table 4.-1:
Objectives and Endpoints
Objectives
Endpoints
EXPLORATORY
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; AT/RT = atypical teratoid rhabdoid tumor; CNS = central nervous system; DIPG = diffuse 
intrinsic pontine glioma; DLT = dose limited toxicity; DOR = duration of response; HGG = high grade glioma; 
ORR = objective response rate; OS = overall survival; OSr = overall survival rate; PD = pharmacodynamic; PFS 
= progression-free survival; PFSr = progression-free survival rate; PK = pharmacokinetics; SAE = serious 
adverse event.
5.
STUDY DESIGN
5.1
Overall Designs
CA209908 is an open-label, sequential-arm Phase 1b/2 clinical trial of nivolumab monotherapy 
and of nivolumab plus ipilimumab in pediatric participants with high-grade primary CNS 
malignancies. 
Cohorts are defined by tumor type (histology):
Cohort 1: N = 22 participants with newly-diagnosed DIPG, including midline glioma with 
H3K27M mutation
Cohort 2: N = 15 participants with recurrent or progressive non-brainstem HGG, regardless of 
mutation status, including glioblastoma
Cohort 3: N = 15 participants with relapsed or resistant medulloblastoma 
Cohort 4: N = 10 participants with relapsed or resistant ependymoma
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Cohort 5: N = 18 participants with other recurrent subtypes of high-grade CNS malignancy 
(eg, pineoblastoma, AT/RT, germ cell tumor, and others)
The above intended target numbers for each Module are approximate. 
Molecular phenotype analyses will be performed according to institutional standard. Details on 
the molecular subtype of the individual tumors will be reported when they become available.
Treatments are defined by Module:
Module A: nivolumab 3 mg/kg every 2 weeks, as monotherapy, and 
Module B: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, every 3 weeks for 4 doses followed by 
nivolumab 3 mg/kg every 2 weeks.
Enrollment to Module A will open in parallel for all cohorts. The first 6 participants in Cohort 1
who are treated and DLT evaluable will be evaluated for safety before additional participants are 
treated in that Cohort. Separately, the first 10 participants treated and DLT evaluable in the
recurrent disease Cohorts 2-5 (combined) will be evaluated for safety before additional 
participants are treated (see Schema in Figure 5.1-1) in those Cohorts. At regularly-scheduled 
teleconferences, the Study Steering Committee (SSC) will review safety, assess potential DLTs, 
and make recommendations regarding reopening of enrollment. See additional details in Section 
5.1.2.
Based on determination of adequate safety, enrollment will re-open for evaluation of efficacy to 
complete the planned number of participants for each cohort in Module A expansion. 
Participants evaluated in the safety lead-in will be included for evaluation of efficacy (ie, the 
6 participants with DIPG evaluated for safety in Cohort 1 are included in the 22 planned 
participants).
Enrollment will begin in Module B, by cohort, based on completion of planned accrual in 
Module A or a decision of the SSC (see Section 5.1.6.2); therefore, accrual will not open in 
parallel for all cohorts into Module B. Investigators will be informed when Module B is open. 
For Module B, the first 10 participants treated and DLT evaluable in all cohorts combined will 
be evaluated for safety by the SCC before additional participants are enrolled in all cohorts 
combined will be evaluated for safety by the SSC before additional participants are enrolled (see 
Schema in Figure 5.1-1) after which cohorts will be re-opened for full accrual in the expansion. 
(NOTE: An individual participant may not enroll in more than one Module.)
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Figure 5.1-1:
Overall Study Design Schematic
A2 Recurrent High-Grade 
Glioma/Glioblastoma
A1 Newly-diagnosed 
Pontine Glioma, post-RT
A3 Recurrent 
Medulloblastoma
A4 Recurrent Ependymoma
A5 Recurrent High-Grade 
Other Histologies
Notes: 
•
Cohorts are indicated by tumor type; Study Treatments are indicated as A = nivolumab and B = nivolumab + ipilimumab
•
Safety is evaluated across cohorts (indicated as “lead-in”), prior to expansion
•
Efficacy is evaluated by cohort (indicated as Expansion), including lead-in population
•
Module B opens, by cohort, when corresponding Module A is completed or upon decision of Steering Committee
Safety 
lead-in
N = 10
N = 6
B2 Recurrent High-Grade 
Glioma/Glioblastoma
B1 Newly-diagnosed 
Pontine Glioma, post-RT
B3 Recurrent 
Medulloblastoma
B4 Recurrent 
Ependymoma
B5 Recurrent High-Grade 
Other Histologies
Expansion
N = 15
N = 15
N = 22
Safety 
lead-in
Expansion
N = 15
N = 22
Efficacy analysis
Safety analysis
N = 10
N = 18
N = 10
N = 15
N = 18
N = 10
Efficacy analysis
Safety analysis
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Participants will be closely monitored for AEs throughout the study using clinical and laboratory 
evaluations (see Sections 2 and 9 for details). The SSC (see Section 5.1.6.2) will meet regularly 
during the study to ensure that participant safety is carefully monitored.
Tumor progression or response endpoints will be assessed using Radiologic Assessment in 
Neuro-Oncology criteria (RANO) 2010 described in Section 9.1.3, as assessed by Investigator.
Blood samples will be obtained prior to and post drug administration for PK and biomarkers. The 
PK sampling schedule for monotherapy and combination therapy are provided in Table 9.5-1 and 
Table 9.5-2, respectively. 
After discontinuation of study treatment, all participants will be followed for safety, tumor 
progression, and survival (see Section 5.1.5).
5.1.1
Screening Period
Screening procedures are provided in Table 2.-1. Procedures which are standard of care may be 
performed prior to Informed Consent. See Section 7.2 for Treatment Assignment.
Participants in Cohort 1 may be enrolled at any time from diagnosis until 4 weeks after 
completion of RT. (RT is not specified by protocol, but is considered standard of care.) For 
participants in Cohort 1, study treatment must be initiated within a maximum of 6 weeks 
post-RT. The screening period for participants in Cohorts 2-5 may be up to 4 weeks as needed. 
For all Cohorts, study treatment should begin within 3 days after assignment of study treatment. 
All molecular information about the tumor will be entered on the case report form when it 
becomes available (not required for treatment start). Testing for genetic or molecular features
(eg, H3K27M mutation, BRAF mutation, RELA-fusion, etc) is not performed centrally but will 
be performed according to institutional procedures. 
5.1.2
Safety Lead-in
A safety lead-in will be implemented because nivolumab, as monotherapy or immediately after 
RT or in combination with ipilimumab, has not been studied in pediatric participants with CNS 
tumors.
In Module A, 6 participants with newly-diagnosed DIPG (Cohort 1) will be evaluated for safety 
of nivolumab administered following RT and 10 participants with recurrent CNS tumors will be 
evaluated for safety of nivolumab monotherapy. Tolerability and safety of the treatment will be 
determined after these participants have completed 3 doses and a minimum of 6 weeks on study
or discontinued due to dose-limiting toxicity (DLT; see Section 5.1.3). Safety evaluation will be 
conducted based on criteria described in Sections 9.2 and 9.4. Enrollment will proceed to 
expansion for Module A only if not more than 2 DLTs are observed in Cohort 1, and separately 
only if not more than 3 DLTs are observed among the 10 participants in Cohorts 2-5. If no DLTs 
are observed in the first 5 (of 6) participants in Cohort 1 or in the first 8 (of 10) participants in 
Cohorts 2-5, then after review by the SSC, enrollment to corresponding Expansion phase may 
proceed. Participants who discontinue study treatment prior to 3 doses for reasons other than 
drug-related toxicities are not evaluable for DLT and will be replaced.
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If exactly 2 DLTs are observed in Cohort 1 or exactly 3 DLTs are observed in Cohorts 2-5, the 
SSC will make a determination as to continuation of enrollment based on the nature, severity,
and reversibility of the AEs observed. In this circumstance, enrollment will be stopped until the 
DMC has agreed.
In Module B, 10 participants from any Cohort (ie, those for which Module A has closed) will be 
evaluated for safety of nivolumab in combination with ipilimumab. Tolerability and safety of the 
treatment will be determined after these participants have completed 2 doses and observed for a 
minimum of 6 weeks or discontinued due to DLT. Safety evaluation will be conducted based on 
criteria described in Sections 9.2 and 9.4. If not more than 3 DLTs are observed among the 
10 participants in Cohorts 1-5, enrollment will proceed into expansion for Module B. 
Participants who are not evaluable for DLT will be replaced. The same condition as noted above 
will be implemented if exactly 3 DLTs are observed in this safety population.
The SSC will review safety information in order to determine closure and re-opening of 
enrollment by Cohort. Safety and tolerability beyond initial dosing may also be taken into 
consideration.
5.1.3
Definition of Dose-Limiting Toxicity
A dose limiting toxicity (DLT) is defined as a drug-related AE occurring in the first 6 weeks of 
study treatment. A participant will be considered evaluable for a DLT if study treatment was 
delayed > 2 weeks or was discontinued due to a related AE, or if planned study treatment 
(3 doses of nivolumab in Module A, 2 doses of nivolumab plus ipilimumab in Module B) was 
administered and safety evaluation after 6 weeks on study is available to the SSC. Participants 
who discontinue treatment for a reason other than toxicity (ie, without DLT) are not evaluable 
for DLT and will be replaced in enrollment. 
The Sponsor and SSC will determine whether a toxicity qualifies as DLT. In addition, the SSC 
may consider AEs occurring after 6 weeks of study in assessment of overall tolerability.
DLTs will be assessed separately for Cohort 1 because the anatomic location of DIPG and the 
administration of study treatment shortly after RT may create additional risks of 
immune-treatment effect. The frequency of DLTs will be assessed as a group for participants 
with recurrent or progressive CNS tumors (Cohorts 2-5). 
The following drug-related AEs will be considered DLT:

Any Grade 3 clinical toxicity including:

Grade 3 non-neurologic AE of any duration

Grade 3 neurologic AE consistent with immune-treatment effect (ie, associated with 
tumor location, but not consistent with progressive disease) and not resolved to Grade 0-1 
within 14 days despite appropriate treatment

Grade 2 uveitis (eg, with eye pain or blurred vision) that does not respond to topical 
therapy (ie, improved to Grade 0-1 within 14 days) or requires systemic treatment

Exception: fever or vomiting lasting < 72 hours is not a DLT
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Any Grade 3 laboratory value not resolved to Grade 0-1 within 14 days, except

Elevation of AST, ALT or total bilirubin of any duration

DILI (AST or ALT >3 x ULN with total bilirubin >2 x ULN) of any duration

Any Grade 4 laboratory value, except the following are not DLT

lipase or amylase without associated symptoms

lymphocytopenia

electrolyte abnormality lasting < 72 hours

Any IMAE, regardless of Grade, which requires discontinuation of study treatment 
(eg, pneumonitis, hypersensitivity reaction, acute kidney injury) will be a DLT.
5.1.4
Expansion
After acceptable safety has been established in the safety lead-in, enrollment will continue in the 
expansion.
In Modules A and B, study therapy (see Section 7.1) will be administered to the total numbers of 
participants per Cohort given in Section 5.1. Participants evaluable for efficacy who were treated
in the safety lead-in will be included in the total number planned for expansion.
5.1.5
Follow-Up Phase
The follow-up phase begins when the decision is made to discontinue a participant from study 
treatment (see Section 8.1), including for AEs, for maximum clinical benefit (investigator 
decision), for participant request, disease progression, or another reason.
Participants will be evaluated for AEs with visits at 30 days (7 days) from the last dose of 
study drug or can be performed on the date of discontinuation if that date is greater than 42 days 
from the last dose. Follow-up visit #2 occurs approximately 100 days (7 days) after last dose of 
drug; for details, see Table 2.-4 and Section 9.2. All AEs must be documented for a minimum of 
100 days after discontinuation, but drug-related toxicities should continue be followed until they 
resolve, return to baseline, or are deemed irreversible. 
Participants who discontinue treatment for a reason other than disease progression will continue 
to undergo tumor assessments according to the schedule in Table 2.-2 and Table 2.-3, or earlier if 
clinically indicated, regardless of subsequent therapy. Introduction of anti-tumor therapy in the 
absence of progression is strongly discouraged.
Regardless of subsequent therapy, a minimum observation time of 3 years is planned for long-
term survivors.
5.1.6
Data Monitoring Committee and Other External Committees
Three independent committees will be utilized: a SSC, a data monitoring committee (DMC) and 
a Blinded Independent Central Review Committee (BICR).
5.1.6.1
Data Monitoring Committee
A Data Monitoring Committee will be established to provide oversight of safety and to provide 
advice to the sponsor regarding actions the committee deems necessary for the continuing 
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protection of participants. The DMC will be charged with assessing such actions in light of an 
acceptable benefit/risk profile for nivolumab. The DMC will act in an advisory capacity to BMS 
and will monitor participant safety and evaluate the available efficacy data for the study. The 
oncology therapeutic area of BMS has primary responsibility for design and conduct of the 
study. The DMC will meet at least every 6 months or more frequently as needed on an ad hoc 
basis. Information regarding DMC membership, responsibilities, and procedures are detailed in 
the DMC charter. The DMC will be informed should a safety signal emerge and may convene an 
ad-hoc meeting on its own initiative. Any major recommendation of the SSC will be 
communicated to the DMC. When required, adjudicated events will be submitted to the DMC 
and Health Authorities for review. The DMC will review all available data (safety and efficacy) 
data at each meeting. At the conclusion of each DMC meeting, the committee will provide the 
sponsor with a recommendation to continue, modify or terminate the study protocol based upon 
their review. Ultimately, decisions regarding the study protocol will be made by the sponsor in 
conjunction with advice from the SSC and the DMC.
5.1.6.2
Study Steering Committee 
A SSC will be utilized. The SSC will be comprised of subject matter experts, with chairman 
representation from each of the Cooperative Groups (eg, COG and ITCC). They will provide 
guidance for study design and input as needed throughout the course of the study including 
oversight of safety and efficacy considerations, study conduct, and risk-benefit ratio in protocol 
CA209-908
(See Section 10.3.5).
Any
major recommendation of the DMC will be 
communicated to the SSC.
The Steering committee may recommend to: 
1) Terminate or continue accrual to any cohort for safety or efficacy reasons, and overall 
clinical risk/benefit considerations. 
a) a test for futility, as defined in Section 10.3.5
b) any of Cohorts 2-5 may be stopped at discretion of Steering Committee; for example, a 
cohort would be considered for closure if 0/9 evaluable participants experience an 
objective response
c) keep accrual open beyond the stated target number of participants in any Cohort, for 
example, in order to study a sub-population with preliminary evidence of benefit
(requires Amendment)
d) proceed to Expansion phase based on safety criteria (Section 5.1.2) 
2) Open a newly-diagnosed HGG cohort, contingent on safety and preliminary efficacy in 
recurrent HGG, or another cohort based on new information (requires Amendment)
3) Implement any clinically-indicated safety modifications (eg, prolonging infusion duration) to 
be effective immediately, pending distribution of an Amendment.
Following review, the SSC will recommend continuation, modification, or discontinuation of this 
study based on reported safety and efficacy data.
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5.1.6.3
Blinded Independent Central Review Committee
The clinical management of participants during the study protocol will be based upon local 
radiologic tumor measurements and the investigator-assessed RANO response criteria described 
in Section 9.1.3. Radiologic imaging from this study will also be transmitted to a centralized 
imaging core lab for storage and sponsor access. Imaging will be analyzed for PFS and response 
by a BICR as determined by the sponsor. Details of the BICR responsibilities and procedures 
will be specified in the Blinded Independent Central Review charter.
5.2
Number of Participants
A complete description of the sample size is provided in Section 10.1. Up to 200 participants are 
planned to be enrolled and screened, with up to 100 in Module A and 100 in Module B to include 
up to 80 participants treated per module.
5.3
End of Study Definition
This study will consist of safety lead in and expansion; and 3 periods: screening, treatment, and 
follow-up. The start of the trial is defined as the first visit for the first screened participant. The 
end of the trial is defined as the last scheduled procedure shown in the Schedule of Activities in 
Section 2 for the last participant. Study completion is defined as the final date on which data for 
the primary endpoint is expected to be collected. Follow-up for a minimum of 3 years (from 
study entry) is planned, if applicable.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Prior to study participation, written informed consent from participants, or in the case of 
minors, written permission (informed consent) from parents (both, if required by local 
law), guardians, or legally acceptable representatives must be obtained according to local 
laws and regulations.
b) Assent from minor participants should be obtained per local laws and regulations and 
should be documented in accordance with local requirements.
c) Written informed consent and HIPAA authorization (applies to covered entities in the 
USA only) obtained from the participant/legal representative prior to performing any 
protocol-related procedures, including screening evaluations
d) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study, including disease assessment by 
contrast enhanced MRI.
2) Type of Participant and Target Disease Characteristics
a) Participants must have received standard of care therapy, and there must be no 
potentially-curative treatment available, in one of the following Cohorts:
i)
A newly diagnosed DIPG that has been treated with radiation therapy (RT) but no 
chemotherapy. Diagnosis of DIPG must be confirmed either based on MRI criteria or 
histology. (Cohort 1)
(1). Eligibility includes diffuse midline glioma with demonstrated H3K27M mutation
(2). Biopsy is not required for DIPG
(3). Enrollment can occur during radiation therapy or up to 4 weeks after end of RT
ii) A histologically confirmed recurrent or progressive non-brainstem HGG previously
treated with surgical resection and RT (with or without chemotherapy). (Cohort 2)
iii) A histologically confirmed medulloblastoma that has relapsed or is resistant to at least 
one line of prior therapy including surgery, RT, and chemotherapy (regardless of 
age). (Cohort 3)
iv) A histologically confirmed ependymoma that has relapsed or is resistant to at least 
one line of prior therapy including surgical resection and RT (regardless of age).
(Cohort 4)
v) A histologically-confirmed high grade CNS malignancy “other than above” which is 
recurrent or progressive after at least one line of prior therapy, including for example: 
choroid 
plexus 
carcinoma, 
germ 
cell 
tumor, 
anaplastic 
pleomorphic 
xanthoastrocytoma, pineoblastoma, AT/RT, embryonal tumor with multilayered 
rosettes (ETMR; C19MC-altered) that has relapsed or is resistant to at least one line 
of prior therapy. (Cohort 5) 
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b) An interval of at least 12 weeks after the end of prior radiation therapy is required unless 
there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement 
on MRI outside of the radiotherapy treatment field (applies only to Cohorts 2-5).
c) Lansky play score (LPS) for 16 years of age or Karnofsky performance scale (KPS) for 
> 16 years of age assessed within two weeks of enrollment must be 60. Participants 
who are unable to walk because of neurologic deficits, but who are up in a wheelchair, 
will be considered ambulatory for the purpose of assessing the performance score 
(Appendix 6)
d) A tumor sample must be available for submission to central laboratory [not required for 
DIPG (Cohort 1)]. 
i)
If surgery was performed at time of recurrence, prior to study entry, a tumor sample 
from this resection should be submitted. 
ii) If no re-operation was performed, archival tumor from the most recent previous
resection should be submitted.
iii) Tumor sample must be submitted within 30 days after treatment assignment
iv) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor 
tissue sections (recent: cut within 3 months), with an associated pathology report,
must be submitted for inclusion.
e) Substantial recovery (ie, no ongoing safety issues) from surgical resection prior to first 
dose of study therapy.
f)
Revised as per Revised Protocol 02. Please refer to criterion 2j: An interval of 4 weeks 
(or 5 half-lives of a targeted therapies with short half-life) after the last administration of 
any other treatment for CNS malignancies (6 weeks for nitrosoureas). The interval from 
most recent bevacizumab must be 5 weeks. The interval from most recent biological agent 
must be 7 days or 5 half-lives, whichever is longer.
g) Able to taper steroids, preferably discontinue. Participants must be receiving not more 
than 0.05 mg/kg dexamethasone per day (or equivalent) for intracranial mass effect at 
study entry.
h) Participants who have received high-dose chemotherapy with autologous hematopoietic 
cell transplantation must be at least 6 months post-hematopoietic cell transplantation and 
they must have a CD4 count of at least 200.
i)
Participant re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been treated). If 
re-enrolled, the participant must be re-consented.
j)
A minimum interval of 21 days after any prior therapy, including chemotherapy or 
biologic agents, and at least 48 hours after any intrathecal therapy. Caution should be 
used for blood counts recovery after prior alkylating agent and for possible rebound 
edema after prior bevacizumab; in such cases, a longer interval may be needed.
3) Age and Reproductive Status
a) Males and Females, ages 6 months to < 22 years old at the time of enrollment
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b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]) within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of study treatment with nivolumab and 5 months after the last dose of study treatment 
[ie, 30 days (duration of ovulatory cycle) plus the time required for the investigational 
drug to undergo approximately five half-lives.]
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 
7 months after the last dose of study treatment [ie, 90 days (duration of sperm turnover) 
plus the time required for the investigational drug to undergo approximately 5 half-lives.]
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
but still must undergo pregnancy testing as described in this section. 
Investigators shall counsel WOCBP, and male participants who are sexually active with 
WOCBP, on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy. At a minimum, contraceptive counseling should be provided at the time of assent or 
consent. Investigators shall advise on the use of highly effective methods of contraception, 
(Appendix 4) which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Participants with an active, known, or suspected autoimmune disease. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll.
b) Participants with a concurrent condition requiring systemic treatment with either 
corticosteroids (> 0.25 mg/kg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days of start of study treatment. Inhaled or topical steroids, and 
adrenal replacement steroid doses > 0.25 mg/kg daily prednisone equivalent, are 
permitted in the absence of active autoimmune disease.
c) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally.
d) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the participant to receive protocol therapy, or interfere with the 
interpretation of study results.
e) Participants who cannot undergo magnetic resonance imaging (MRI) with contrast 
enhancement.
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2) Target Disease Exclusions
a) Unable to taper steroids due to ongoing mass effect; a maximum dexamethasone dose of 
0.05 mg/kg/day is allowed, but preferably have been discontinued. 
b) Participants with low-grade gliomas or tumors of unknown malignant potential are not 
eligible
c) Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan.
d) Participants with bulky tumor on imaging are ineligible; bulky tumor is defined as:
i)
Tumor with any evidence of uncal herniation or severe midline shift
ii) Tumor with diameter of > 6 cm in one dimension on T1 contrast-enhanced MRI
iii) Tumor that in the opinion of the investigator, shows significant mass effect. (Contact 
BMS medical monitor for questions.)
3) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways.
b) Prior allogeneic hematopoietic cell transplantation unless MM approval in advance.
c) Participants who are receiving any other anti-cancer or investigational drug therapy or 
non-palliative radiation therapy are ineligible.
4) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1000/μL
c) Platelets < 75 x 103/μL (or transfusion-dependent)
d) Hemoglobin < 9.0 g/dL (can be transfused)
e) Serum creatinine > 1.5 x upper limit of normal based on age/gender as follows:
Table 6.2-1:
Age/Gender Serum Creatinine Limits
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
mg/dL
umol/L (SI)
mg/dL
umol/L (SI)
1 to < 2 years
0.6
53
0.6
53
2 to < 6 years
0.8
71
0.8
71
6 to < 10 years
1
88
1
88
10 to < 13 years
1.2
106
1.2
106
13 to < 16 years
1.5
133
1.4
124
16 years
1.7
150
1.4
124
Note: the threshold values in this table were derived from the Schwartz formula for estimating GFR,60 utilizing 
child length and stature data published by the US Centers for Disease Control and Prevention.
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f)
AST/ALT: > 3.0 x ULN. For the purposes of this trial, a fixed ULN = 45 will be used for 
AST and ALT.
g) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 x ULN).
h) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
5) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
b) History of severe hypersensitivity reaction to any monoclonal antibody.
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to 
continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is 
required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered into study treatment (second IRT visit entry). A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and 
to respond to queries from regulatory authorities. Minimal information includes date of consent, 
demography, screen failure details, eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / has 
not been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value).
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The most current result prior to first dose of study treatment is the value by which study 
inclusion will be assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2.-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7.
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
treatment allocation.
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

Nivolumab

Ipilimumab
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
In this protocol, nivolumab and ipilimumab are investigational products. Radiotherapy (prior to 
treatment start in Cohort 1) is not an investigational product, even if given after enrollment.
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products.
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Table 7.-1:
Study treatments for CA209908
Product 
Description / 
Class and 
Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage 
Conditions
(per label)
Nivolumab
Solution for 
Injectiona
100 mg 
(10 mg/mL)
IP
Open label
10 mL Vial (5 or 10 
vials /carton)
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles.
Store at 2 to 8C. 
Protect from light 
and freezing
Ipilimumab 
Solution for 
Injection
200 mg
(5 mg/mL)
IP
Open-label
40  mL vial (4 vials per 
carton)
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
Store at 2 to 8°C. 
Protect from light 
and freezing.
a Nivolumab is labeled as BMS-936558-01 Solution for Injection
7.1
Treatments Administered
Dosing calculations should be based on the actual body weight assessed at baseline. It is not 
necessary to recalculate subsequent doses if the participant weight is within 10% of the weight 
used to calculate the previous dose. All doses should be rounded up to the nearest milligram per 
institutional standard.
Participants should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, participants should be managed according 
to Section 7.4.3.
Doses of nivolumab may be interrupted during infusion (see Section 7.4.3), delayed (see 
Section 7.4.1), or discontinued (see Section 8.1) depending on how the participant tolerates 
treatment. Dosing visits (cycles) are not skipped or omitted, but they may be delayed. There will 
be no dose escalations or reductions of nivolumab allowed. Premedications are not 
recommended for the first dose of nivolumab. Nivolumab and ipilimumab may be administered 
within 3 days before or after the scheduled dose. 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/4 mL (10 mg/mL) nivolumab 
injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding in-line filter at the protocol-specified doses. It is not to be administered as an 
IV push or bolus injection; any programmable infusion pump may be used. Nivolumab injection 
can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 
5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. Instructions for 
dilution and infusion of nivolumab injection may be provided in the clinical protocol, or 
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pharmacy binder. Care must be taken to assure sterility of the prepared solution as the product 
does not contain any antimicrobial preservative or bacteriostatic agent. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
Ipilimumab injection can be used for IV administration with or without dilution after transferring 
to a PVC, non-PVC/non-DEHP or glass container and is stable for 24 hours at 2-8°C or room 
temperature/room light (RT/RL). For ipilimumab preparation and storage instructions, refer to 
ipilimumab IB and Section 7.1.2.
When study drugs (nivolumab and ipilimumab) are to be administered on the same day, 
nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a saline 
flush or D5W flush to clear the line of nivolumab before starting the ipilimumab infusion. The 
second infusion will always be the ipilimumab study drug and will start after the infusion line 
has been flushed, filters changed, and participant has been observed to ensure no infusion 
reaction has occurred. The time in between infusions is expected to be approximately 30 minutes 
but may be more or less depending on the situation.
Separate infusion bags and filters should be used when administering nivolumab and ipilimumab 
on the same day.
Care must be taken to assure sterility of the prepared solutions, since the drug product does not 
contain any antimicrobial preservatives or bacteriostatic agents. At the end of the infusion, flush 
the line with a sufficient quantity of normal saline or 5% dextrose solution.
This study consists of 2 modules:
7.1.1
Module A (Nivolumab Monotherapy):
Participants in Module A will receive nivolumab at a dose of 3 mg/kg as a 30-minute IV 
infusion, on Day 1 of each treatment cycle every 2 weeks. Participants should begin study 
treatment within 3 calendar days of treatment assignment (ie, second IRT visit entry). 
Participants in Cohort 1 will begin treatment within 6 weeks after the end of RT.
The selection and timing of dose for each participant is as follows:
Table 7.1.1-1:
Selection and Timing of Dose for Module A (Nivolumab 
Monotherapy)
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
Nivolumab
3 mg/kg
Every 2 weeks
IV
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7.1.2
Module B (Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Combination):
First 4 Cycles:
Participants should receive nivolumab at a dose of 3 mg/kg as a 30-minute IV infusion, followed 
30 minutes after by ipilimumab at a dose of 1 mg/kg as a 30 minutes IV infusion on Day 1 of 
each treatment cycle every 3 weeks, for 4 doses, until progression, unacceptable toxicity, 
withdrawal of consent, or the study ends, whichever occurs first. Participants should begin study 
treatment within 3 calendar days of treatment assignment (ie, second IRT visit entry). 
Participants in Cohort 1 will begin treatment within 6 weeks after the end of RT.
When study drugs (nivolumab and ipilimumab) are to be administered on the same day, 
nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a 
normal saline or D5W flush to clear the line of nivolumab before starting the ipilimumab 
infusion. The second infusion will always be the ipilimumab study drug and will start after the 
infusion line has been flushed, filters changed and participant has been observed to ensure no 
infusion reaction has occurred. The time in between infusions is expected to be approximately 
30 minutes but may be more or less depending on the situation.
Ipilimumab is to be administered as a 30 minute IV infusion, using a volumetric pump with a 
0.2 to 1.2 micron in-line filter at the protocol-specified dose. The drug can be diluted with 0.9% 
normal saline or 5% Dextrose Injection to concentrations between 1 mg/mL and 4 mg/mL. It is 
not to be administered as an IV push or bolus injections. Care must be taken to assure sterility of 
the prepared solutions, since the drug product does not contain any antimicrobial preservatives or 
bacteriostatic agents. At the end of the infusion, flush the line with a sufficient quantity of 
normal saline or 5% dextrose solution.
The selection and timing of dose for each participant is as follows:
Table 7.1.2-1:
Selection and Timing of Dose for Module B (Nivolumab and 
Ipilimumab Combination) - First 4 cycles
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
Nivolumab
3 mg/kg
Every 3 weeks
IV
Ipilimumab
1 mg/kg
Every 3 weeks
IV
Cycle 5 and beyond:
Participants should receive nivolumab at a dose of 3 mg/kg as a 30-minute IV infusion, on Day 1 
of each treatment cycle every 2 weeks, starting 3 weeks after the fourth dose of the combination.
The selection and timing of dose for each participant is as follows:
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Table 7.1.2-2:
Selection and Timing of Dose for Module B (Nivolumab and 
Ipilimumab Combination) - Cycle 5 and Beyond
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
Nivolumab
3 mg/kg
Every 2 weeks
IV
7.2
Method of Treatment Assignment
This is an open-label study. All participants will be assigned to treatment using an Interactive 
Response Technology (IRT). Before the study is initiated, each user will receive log in 
information and directions on how to access the IRT.
The first call to IRT will be made in order to enroll a participant and should be made as soon as 
possible after informed consent has been obtained. An identification number will be assigned and 
should be used in all subsequent communications.
The second call to IRT will be made when eligibility has been established and the participant is 
ready to begin study treatment. Subsequent assignments of study drug are also managed via IRT.
7.3
Blinding
This is an open-label study; blinding procedures are not applicable.
7.4
Dosage Modification
Dose modifications related to management of specific AEs are described further in Appendix 5.
7.4.1
Dose Delay Criteria
Premedications are not recommended for the first dose of nivolumab.
Participants should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, participants should be managed according 
to Section 9.2.9.
Doses of nivolumab and ipilimumab may be interrupted, delayed, or discontinued depending on 
how well the participant tolerates the treatment. Dosing visits are not skipped, only delayed. 
Tumor assessments for all participants should continue as per protocol even if dosing is delayed. 
During Module B (nivolumab and ipilimumab combination), both nivolumab and ipilimumab 
should be delayed at the same time. There will be no dose escalations or reductions of nivolumab 
allowed.
For the purposes of this trial, a fixed ULN = 45 will be used for AST and ALT. 
Nivolumab administration should be delayed for the following:

Grade 2 non-skin, drug-related adverse event, with the exception of fatigue

Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities

Grade 3 skin, drug-related adverse event
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
Grade 3 drug-related laboratory abnormality, with the following exceptions: 

Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay

Grade 3 AST, ALT, Total Bilirubin will require dose discontinuation (see 
Section 9.2.7)

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
7.4.2
Criteria to Resume Treatment
Participants who require delay of nivolumab or ipilimumab should be re-evaluated weekly or 
more frequently if clinically indicated and resume nivolumab dosing when re-treatment criteria 
are met.
Participants may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade 1 or baseline value, with the following exceptions:

Participants may resume treatment in the presence of Grade 2 fatigue

Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity

For participants with Grade 2 AST, ALT, or TBILI elevations, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete.

Participants with combined Grade 2 AST/ALT AND TBILI values meeting discontinuation 
parameters should have treatment permanently discontinued. 

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor.
Adrenal insufficiency requires discontinuation regardless of control with hormone replacement.
If nivolumab treatment is delayed for any reason, ipilimumab must also be delayed until the 
participant has appropriately recovered and is able to resume the combination treatment on the 
first day of the subsequent cycle.
7.4.3
Treatment of Related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, each 
is unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the BMS Study 
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Medical Monitor and reported as an SAE if it meets the criteria. Infusion reactions should be 
graded according to NCI CTCAE (Version 4) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):

Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(as pediatric equivalent per kg or weight based pediatric equivalent, at investigator 
discretion) and/or acetaminophen/paracetamol appropriate for age/weight at least 30 minutes 
before additional nivolumab administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but 
responds 
promptly 
to 
symptomatic 
treatment 
(eg, 
antihistamines, 
non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic 
medications indicated for 24 hours):

Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the participant with diphenhydramine 50 mg IV (as pediatric equivalent per kg or weight 
based pediatric equivalent, at investigator discretion) and/or acetaminophen/paracetamol 
appropriate for age/weight; remain at bedside and monitor participant until resolution of 
symptoms. Corticosteroid and/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; if no further complications ensue after 30 minutes, the 
rate may be increased to 100% of the original infusion rate. Monitor participant closely. If 
symptoms recur, then no further nivolumab or ipilimumab will be administered at that visit.

For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or pediatric equivalent per kg, at investigator’s discretion) and/or 
acetaminophen/paracetamol appropriate for age/weight should be administered at least 30 
minutes before nivolumab infusions. If necessary, corticosteroids (up to 25 mg of 
hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae (eg, renal 
impairment, pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory support 
indicated):

Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of 
normal saline and treat the participant as follows: Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1000 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 50 mg IV 
(or pediatric equivalent per kg, at investigator’s discretion) with methylprednisolone 100 mg 
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IV (or weight-based equivalent), as needed. Participant should be monitored until the 
Investigator is comfortable that the symptoms will not recur. Study drug will be permanently 
discontinued. Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor participant until recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites 
by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
For details on prepared drug storage and use time of nivolumab and ipilimumab under room 
temperature/light and refrigeration, please refer to the nivolumab IB47 section for 
“Recommended Storage and Use Conditions” and/or pharmacy manual.

Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2 and Study Pharmacy Manual.
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not Applicable.
7.6
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as by the participant’s 
medical record and Case Report Form (CRF).
 
 
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7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment. Study treatment will be provided via an 
extension of the study, a rollover study requiring approval by responsible health authority and 
ethics committee or through another mechanism at the discretion of BMS.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the 
following occur: a) the study is terminated due to safety concerns; b) the development of the
nivolumab is terminated for other reasons, including but not limited to lack of efficacy and/or not 
meeting the study objectives; c) the participant can obtain medication from a government 
sponsored or private health program. In all cases BMS will follow local regulations.
8.
DISCONTINUATION CRITERIA
Tumor assessments should continue as per protocol even if dosing is delayed. Periodic study 
visits to assess safety and laboratory studies should also continue every 6 weeks or more 
frequently if clinically indicated during such dosing delays.
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Confirmed radiologic disease progression or investigator-assessed clinical progression as 
described in Section 9.1.2

Toxicity as specified below and in Section 9.2

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
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consent for any further contact with him/her or persons previously authorized by participant 
to provide this information (See Section 8.2)

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the participant.

Maximum clinical benefit as assessed by Investigator

Pregnancy (as specified in Section 9.2.5)

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of 
this event. In most cases, the study drug will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for participant safety). Please contact the Sponsor or 
designee within 24 hours of awareness of the pregnancy. If the investigator determines a possible 
favorable benefit/risk ratio that warrants continuation of study drug, a discussion between the 
investigator and the Sponsor or designee must occur.
Discontinuation of the study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined (in the algorithm below) OR 
(in Appendix 5) or if the investigator believes that it is in best interest of the participant.
Refer to the Schedule of Activities for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed
All participants who discontinue study treatment should comply with protocol specified follow-
up procedures as outlined in Section 2. The only exception to this requirement is when a 
participant withdraws consent for all study procedures including post-treatment study follow-up 
or loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records and reported
page.
8.1.1
Discontinuation of Nivolumab Due to Toxicity [Module A or B] 
For the purposes of this trial, a fixed ULN = 45 will be used for AST and ALT.
Nivolumab treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
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
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the 
following exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, 
bronchospasm, neurologic toxicity, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm,
neurologic toxicity,
hypersensitivity reaction, myocarditis or infusion reaction of any duration requires 
discontinuation

Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement.

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation
Grade 3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN (see 
Section 9.2.7)

Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:

Grade 4 neutropenia 7 days

Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset

Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.

Any event that leads to delay in dosing lasting > 6 weeks for nivolumab monotherapy from 
the previous dose requires discontinuation, with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. 

Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the BMS 
medical monitor must be consulted.
* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
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8.1.2
Discontinuation of Combination treatment due to Toxicity [Module B]
Additional criteria apply to participants in Module B; the criteria above for nivolumab apply to 
both Modules. To the extent possible, assessment for discontinuation of nivolumab should be 
made separately from the assessment made for discontinuation of ipilimumab. Although there is 
overlap among the discontinuation criteria, if discontinuation criteria are met for ipilimumab but 
not for nivolumab, treatment with nivolumab may continue if ipilimumab is discontinued. After 
discussion with the Medical Monitor, nivolumab monotherapy may continue if ipilimumab is 
discontinued. If a participant in Module B meets criteria for discontinuation and investigator is
unable to determine whether the event is related to both or one study drug, the participant should 
discontinue both nivolumab and ipilimumab, and be taken off the treatment phase of the study.
At investigator discretion, with approval of BMS medical monitor, participant may discontinue 
ipilimumab and (after recovery of AEs) may restart nivolumab monotherapy.
Nivolumab and Ipilimumab treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, or recurs with the 
following exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-
related uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, 
and endocrinopathies:

Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reaction, myocarditis, or infusion reaction of any 
duration requires discontinuation

Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation:
o
Grade 3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
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
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:

Grade 4 neutropenia 7 days

Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset

Grade 4 drug-related endocrinopathy: adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.

Any event that leads to delay in dosing during combination therapy lasting > 8 weeks 
(Module B) from the previous dose requires discontinuation, with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. 

Dosing delays lasting > 8 weeks for combination therapy from the previous dose that 
occur for non-drug-related reasons may be allowed if approved by the BMS medical 
monitor.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the BMS 
medical monitor must be consulted. 
8.1.3
Post Study Drug Study Follow-up
For follow-up of AEs and SAEs after discontinuation of study treatment, see Section 9.2.
OS and PFS are key endpoints of this study. Post study follow-up is of critical importance and is 
essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed for collection of progression and/or 
survival information according to Section 5.1.5, ie, until disease progression and at least 3 years 
for survival (as applicable). 
BMS may request that survival data be collected on all treated participants outside of the 
protocol defined window (Table 2.-1, Table 2.-2, Table 2.-3, and Table 2.-4). At the time of this 
request, each participant will be contacted to determine their survival status unless the participant 
has withdrawn consent for all contacts or is lost to follow-up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures. The only exception to this 
is when a participant specifically withdraws consent for any further contact with him/her or 
persons previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
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
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

Withdrawal of consent may be requested by participants, parents, guardians, or legally 
acceptable representatives, in accordance with local regulations. The wishes of minor 
participants to withdraw their assent should also be respected.
8.3
Lost to Follow-Up

All reasonable efforts must be made to locate participants to determine and report their 
ongoing status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical 
records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If investigator’s use of third-party representative to assist in the follow-up portion of the 
study has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 

The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.

If after all attempts, the participant remains lost to follow-up, then the last known alive date 
as determined by the investigator should be reported and documented in the participant’s 
medical records.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities. 

Protocol waivers or exemptions are not allowed.

All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before treatment start. The investigator will maintain a 
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screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, tachypnea) or symptoms (eg. dyspnea, 
cough, fever) consistent with possible pulmonary adverse events, the participant should be 
immediately evaluated to rule out pulmonary toxicity, according to the suspected pulmonary 
toxicity management algorithm Appendix 5.47
Some of the assessments referred to in this section may not be captured as data in the eCRF. 
They are intended to be used as safety monitoring by the treating physician. Additional testing or
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
Efficacy will be based on imaging assessments (Section 9.1.1) supplemented by clinical 
neurologic examination and performance status as well as additional considerations as applicable 
eg, steroid requirement, CSF cytopathology. Consensus Recommendations for imaging of brain
tumors61 should be followed. Additional sequences, based on the clinical setting, should be 
included at the discretion of the neuroradiologist.
Study endpoints of response or progression will be based on widely-accepted RANO criteria 
(See Section 9.1.3); in pediatric tumors, however, interpretation by an experienced 
neuroradiologist is essential. For tumors with a propensity to disseminate in the leptomeninges, 
guidance contained in paper entitled Response Assessment in Medulloblastoma and 
Leptomeningeal Seeding Tumors: Recommendations from the Response Assessment in Pediatric 
Neuro-Oncology Committee by Warren et al54 should be considered, particularly with respect to 
imaging and cytopathologic parameters. The expectations stated in Schedule of Activities and 
Section 9.1.1 are generally applicable, but investigators have discretion to modify the frequency 
of spine MRI and CSF cytopathology based on individual circumstances.
In addition, consideration may be given to the recent iRANO proposal.62 As these proposed 
criteria have not yet been widely applied, they may be considered as an exploratory endpoint.
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9.1.1
Imaging Assessment for the Study
All participants will undergo contrast enhanced brain MRI at the time points specified in Table 
2.-1, Table 2.-2, Table 2.-3, and Table 2.-4. An Imaging Manual will be provided. Screening 
MRI may be performed prior to informed consent, as part of standard care. Adequate quality of 
the baseline evaluation must be assured by the PI prior to treatment start and repeat imaging 
performed if not adequate. However, it is not necessary that the MRI machine be “qualified” (by 
imaging CRO) for the screening evaluation. 
For Inclusion of Cohorts 2-5, if first recurrence of the CNS tumor is documented by MRI, an 
interval of at least 12 weeks after the end of prior radiation therapy is required unless there is 
either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancing mass on MRI 
outside of the radiotherapy treatment field. 
Evaluation of the leptomeninges is standard in many pediatric CNS malignancies and should be 
performed as clinically indicated. In Cohorts 3 and 5, a baseline MRI spine and CSF 
cytopathology are expected, unless clinically contraindicated. In Cohorts 2 and 4, baseline MRI 
spine and CSF cytopathology may be obtained based on clinical judgment; these are not 
expected in Cohort 1.
On treatment and follow up MRIs should occur on the following schedule: Q6W x 2 
assessments, then Q8W x 4, and then Q12W (1 week). The expected timing of tumor 
assessments is therefore at Weeks 7, 13, 21, 29, 37, 45, and subsequently every 12 weeks. 
Investigators may obtain more frequent follow-up MRI scans as medically indicated. Local 
radiologic assessment of tumor measurements will be used during the study for clinical 
management and investigator-assessed disease progression. MRI scans should continue on the 
indicated schedule regardless of treatment delay.
If baseline MRI spine showed metastatic deposits, then it should be repeated at the same 
intervals as the MRI of brain, ie regular tumor assessments indicated in Table 2.-2, Table 2.-3, 
and Table 2.-4, ordinarily at the same imaging session. Frequency of MRI spine is at the 
investigator’s discretion. If the baseline is negative, then less frequent re-assessment may be 
appropriate depending on the individual circumstances. All imaging assessments of sites of 
disease should be submitted (Section 5.1.6.3) to the central imaging laboratory.
If baseline CSF cytopathology is positive, then it should be repeated approximately every 
8 weeks during study, as clinically indicated.
Participants who are unable (due to existent medical condition, ie, pacemaker or ICD device) or 
unwilling to have a contrast enhanced MRI of the brain at baseline are excluded from the study. 
Participants who become unable to undergo MRI imaging after the start of participation in the 
study may continue in the study for assessment of overall survival as long as there is no safety 
issue which would require monitoring by MRI.
Study-related MRI imaging of the brain will be performed per the frequency specified above. 
Investigators may obtain additional MRI scans as medically indicated. For other locally 
performed imaging, it is the local imaging facility’s responsibility to determine, based on 
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participant attributes (eg, allergy history, diabetic history, and renal status), the appropriate 
imaging modality, and contrast regimen for each participant. Imaging contraindications and 
contrast risks should be considered in this assessment. Participants with severe renal 
insufficiency (ie, estimated glomerular filtration rate < 30 mL/min/1.73 m2) are at increased risk 
of nephrogenic systemic fibrosis. MRI contrast should not be given to this participant population, 
who should be excluded from the study. In addition, participants with surgically implanted 
devices (pacemaker, deep brain stimulator, metallic implants, etc) incompatible with MRI should 
not undergo such imaging techniques. The local imaging facility and investigator should 
determine the appropriate precautions or guidelines that should be instituted for participants with 
tattoos, body piercings, or other body art.
The ultimate decision to perform MRI in an individual participant in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee. 
Study sites will retain local access to the imaging results for safety and efficacy reading 
purposes. The study investigator will review the local MRI results as clinically appropriate to 
ensure that any potentially emergent clinical situations are addressed in a timely fashion. 
Clinically significant radiologic findings or changes from baseline scans will be coded as AEs or 
SAEs according to the criteria described in Section 9.2. Any additional or incidental radiographic 
findings of potential clinical relevance that are not directly associated with the objectives of the 
protocol should be evaluated and handled by the Study Investigator as per standard 
medical/clinical judgment.
Sites will be trained in image acquisition parameters, the submission process, and application of 
RANO criteria63 prior to scanning the first study participant. These guidelines will be outlined in 
a separate Site Imaging Manual provided by the imaging core lab. Investigators will assess PFS, 
ORR and DOR based on RANO criteria. 
All radiologic imaging from this study will be transmitted to a centralized imaging core lab for 
storage and sponsor access. At Sponsor request, BICR will assess PFS in all Cohorts and ORR in 
participants with measurable disease.
9.1.2
Suspected Progression
In order to distinguish potential treatment effects (or “pseudo-progression”), from progressive 
disease and thus to minimize premature discontinuation of treatment, participants who initially 
meet radiologic criteria for disease progression, but are tolerating study drug, may continue 
receiving study drug until confirmation of progression. If the follow-up assessment confirms that 
progression has occurred, the date of progression will be the date at which progression was first 
determined. If the follow-up assessment does not confirm progression, then the original time 
point response will be assessed as SD. If possible, MRI perfusion images should also be 
obtained. 
If a determination cannot be made after a 6 to 8 week interval, then treatment may continue until 
either progression is confirmed or regression is observed, consistent with either 
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pseudoprogression (in Cohort 1) or immune-treatment effect. There is no time limit for 
confirmation of progression. The BMS Medical Monitor should be consulted.
Suspected disease progression within 12 weeks after the end of RT must be confirmed (per 
RANO) by subsequent MRI performed approximately 6-8 weeks after the initial radiological 
assessment of progression. Prior to 12 weeks after RT, progression can only be defined using 
diagnostic imaging if there is new enhancement outside of the radiation field (beyond the high-
dose region or 80% isodose line) or if there is unequivocal evidence of viable tumor on 
histopathologic sampling.63 Note: in the absence of radiographic or histologic confirmation of 
progression, clinical decline alone is not sufficient for definition of progressive disease.
9.1.3
Assessment of Response
Response will be assessed using RANO 2010 criteria.63 Table 9.1.3-1 describes the radiological 
and clinical criteria that will be used for determining tumor response. Table 9.1.3-2 describes the 
criteria used for assessing eligibility (for Cohorts 2-5), based on time from prior RT (See 
Section 6.1). Table 9.1.3-3 describes the criteria will be used for assessing BOR. All measurable 
and non-measurable lesions must be assessed using the same techniques as at baseline.
Participants who have no lesion measuring 1 cm on 2 perpendicular diameters on baseline MRI 
cannot have a complete or partial response and will be followed only for recurrence. Similarly, 
participants with DIPG in Cohort 1 (ie, in the post-RT period) will be considered to have non-
measureable disease. These participants will be considered non-evaluable for BOR analysis, but 
their disease status will be assessed (SD or PD) at each tumor assessment, and they will be 
included in analysis of PFS and OS. If no signs of progression are observed by MRI, the 
radiologic assessment will be categorized as SD. The appearance of any new lesion consistent 
with tumor will be categorized as PD.
The assessments that will contribute to evaluation of PD include response assessments recorded 
between the date of first dose of study therapy and the first to occur of the following:
1) The date of objectively documented progression per RANO criteria
2) The date of subsequent therapy, or
3) The date of pathology results from diagnostic surgical resection
4) The date of clinical progression
The minimum duration between baseline scan and first on-study scan in order to determine BOR 
of SD is at least 5 weeks on study. If the minimum time is not met when SD is otherwise the best 
time point response, the participant’s best response will depend on the subsequent assessments. 
For example, a participant who has SD at a time point < 6 weeks and PD at a second assessment, 
will have a best response of PD.
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Table 9.1.3-1:
RANO Criteria for Time-point Response Assessment Incorporating 
MRI and Clinical Factors
Response
Criteria
CR
Requires all of the following: complete disappearance of all enhancing measurable and 
nonmeasurable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; 
participants must be off corticosteroids (or on physiologic replacement doses only); and stable or 
improved clinically. Note: Participants with nonmeasurable disease only cannot have a complete 
response; the best response possible is stable disease.
PR
Requires all of the following: 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasurable 
disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower 
dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the 
scan evaluation should be no greater than the dose at time of baseline scan; and stable or 
improved clinically. Note: Participants with nonmeasurable disease only cannot have a partial 
response; the best response possible is stable disease.
SD
Requires all of the following: does not qualify for complete response, partial response, or 
progression; stable nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan. In the event that the corticosteroid dose was increased for new 
symptoms and signs without confirmation of disease progression on neuroimaging, and 
subsequent follow-up imaging shows that this increase in corticosteroids was required because of 
disease progression, the last scan considered to show stable disease will be the scan obtained 
when the corticosteroid dose was equivalent to the baseline dose.
PD
Defined by any of the following: 25% increase in sum of the products of perpendicular 
diameters of enhancing lesions compared with the smallest tumor measurement obtained either at 
baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids (Stable 
doses of corticosteroids include participants not on corticosteroids); significant increase in 
T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with 
baseline scan or best response after initiation of therapy* not caused by comorbid events (eg, 
radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or 
other treatment effects); any new lesion; clear clinical deterioration not attributable to other 
causes apart from the tumor (eg, seizures, medication adverse effects, complications of therapy, 
cerebrovascular events, infection, and so on) or changes in corticosteroid dose; failure to return 
for evaluation as a result of death or deteriorating condition; or clear progression of 
nonmeasurable disease.
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Table 9.1.3-2:
Criteria for Determining First Progression Depending on Time 
after Radiotherapy 
First Progression
Definitiona
Progressive disease < 12
weeks after completion 
of radiotherapy
Progression can only be defined using diagnostic imaging if there is new 
enhancement outside of the radiation field (beyond the high-dose region or 80% 
isodose line) or if there is unequivocal evidence of viable tumor or histopathologic 
sampling (eg, solid tumor areas [ie, > 70% tumor cell nuclei in areas], high or 
progressive increase in MIB-1 proliferation index compared with prior biopsy, or 
evidence for histologic progression or increased anaplasia in tumor). Note: Given the 
difficulty of differentiating true progression from pseudoprogression, clinical decline 
alone, in the absence of radiographic or histologic confirmation of progression, will 
not be sufficient for definition of progressive disease in the first 12 weeks after 
completion of radiotherapy.
Progressive disease 12 
weeks after completion
of radiotherapy
1. New contrast-enhancing lesion outside of radiation field on decreasing, stable, or 
increasing doses of corticosteroids.
2. Increase by 25% in the sum of the products of perpendicular diameters between 
the first post radiotherapy scan, or a subsequent scan with smaller tumor size, and the 
scan at 12 weeks or later on stable or increasing doses of corticosteroids.
3. Clinical deterioration not attributable to concurrent medication or comorbid 
conditions is sufficient to declare progression on current treatment but not for entry 
onto a clinical trial for recurrence.
4. For participants receiving antiangiogenic therapy, significant increase in T2/FLAIR 
non-enhancing lesion may also be considered progressive disease. The increased 
T2/FLAIR must have occurred with the participant on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of 
therapy and not be a result of comorbid events (eg, effects of radiation therapy, 
demyelination, ischemic injury, infection, seizures, postoperative changes, or other 
treatment effects).
a Wen PY, Macdonald DR, Reardon DA, et al. Updated Response Assessment Criteria for High-Grade Gliomas: 
Response Assessment in Neuro-Oncology Working Group; J Clin Oncol. 2010 Apr 10; 28(11):1963-72.
Table 9.1.3-3:
Assessment of Best Overall Response
Best Overall Response
Criteriaa
CR
CR observed in assessments 4 weeks apart per RANO
PR
PR observed in assessments 4 weeks apart per RANO
SD 
Note: To qualify for SD there 
must be a minimum on-
treatment period of 6 weeks.)
SD observed and does not qualify for CR or PR 
or 
Suspected PD followed with histologic results not confirming PD, and no CR, 
PR or SD observed 
Not Evaluable (NE)
Insufficient data to determine disease progression or response
PD
No CR, PR, or SD prior to PD
a Wen PY, Macdonald DR, Reardon DA, et al. Updated Response Assessment Criteria for High-Grade Gliomas: 
Response Assessment in Neuro-Oncology Working Group; J Clin Oncol. 2010 Apr 10; 28(11):1963-72.
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9.1.4
Results of Central Radiology Assessments
The clinical management of participants during the study protocol and secondary outcomes 
(PFS) will be based upon local radiologic tumor measurements and the investigator-assessed 
RANO response criteria described in Section 9.1.3. Radiologic imaging from this study will be 
also be transmitted to a centralized imaging core lab for storage and for analysis by blinded 
independent central review as determined by the Sponsor. The site will be informed of quality 
issues or need for repeat scanning via queries from the core lab.
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or the study, or that caused the 
participant to discontinue before completing the study. 
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which 
were exacerbated by the induction of autoimmunity. Information supporting the assessment will 
be collected on the participant’s case report form.
Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until 
[the follow-up contact], at the timepoints specified in the Schedule of Activities (Section 2). 
Nonserious AE information should also be collected from the start of a placebo lead-in period or 
other observational period intended to establish a baseline status for the participants.
Sections 5.6.1 and 5.6.2 in the IB represent the Reference Safety Information to determine 
expectedness of serious adverse events for expedited reporting.47 Following the participant’s 
written consent (or the parent/guardian/LAR’s permission) to participate in the study, all SAEs, 
whether related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of last 
dose of study treatment. For participants who are assigned treatment but never treated, SAEs 
should be collected for 30 days from the date of treatment assignment.

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the appropriate section of the eCRF section.
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
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3.

The investigator will submit any updated SAE data to the sponsor within 24 hours of this 
being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the 
study treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AEs or/or SAEs. Inquiry about specific AEs should be guided by clinical judgment in 
the context of known adverse reactions, when appropriate for the next program or protocol. 
9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
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Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and 
FDA Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, 
Unexpected Serious Adverse Reaction) is a subset of SAEs and will be reported to the 
appropriate regulatory authorities and investigators following local and global guidelines and 
requirements.
All SAEs must be collected that occur during the screening period and within 100 days of the 
last dose of study treatment. For participants randomized/assigned to treatment and never treated 
with study drug, SAEs should be collected for 30 days from the date of treatment assignment.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please call the BMS Medical Monitor 
within 24 hours of awareness of the pregnancy.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form if permissible by local regulations.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
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It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for 
reporting details). For the purposes of this trial, a fixed ULN = 45 will be used for AST and 
ALT. 
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 x ULN, AND
2) Total bilirubin > 2 x ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
 
 
 
 
 
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9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2).
In the event of an overdose the [investigator/treating physician] should:
1) Contact the Medical Monitor immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities.
3) Document the quantity of the excess dose as well as the duration of the overdosing in the 
CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned timepoints for all safety assessments are listed in the Schedule of Activities (Section 2).
Safety assessments include AEs, physical examinations, vital signs, performance status, 
assessment of signs and symptoms, laboratory tests, and pregnancy tests as outlined in the 
Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, 
cough, fever) consistent with possible pulmonary adverse events, the participant should be 
immediately evaluated to rule out pulmonary toxicity, according to the suspected pulmonary 
toxicity management algorithm Appendix 5.47
Some of the assessments referred to in this section may not be captured as data in the eCRF. 
They are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.4.1
Physical Examinations
Refer to Schedule of Activities in Section 2.
In addition to the usual physical examination, a neurologic exam is performed routinely in a 
pediatric neuro-oncology clinic. Neurological exams are expected during Screening and at 
C1D1, and as clinically indicated. Normal institutional practice is expected. The exam includes 
observation of gait and coordination, cranial nerve function (including speech and visual fields), 
extremity strength and report of bladder/bowel function, with particular attention to any changes 
in previously-noted deficits.
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9.4.2
Vital signs
Refer to Schedule of Activities in Section 2.
9.4.3
Electrocardiograms
Refer to Schedule of Activities, Table 2.-3, for electrocardiograms for Module B. A 12-lead ECG 
should be performed during the study period only as clinically indicated.
9.4.4
Clinical Safety Laboratory Assessments

Investigators must document their review of each laboratory safety report.

See Section 2 for additional details on the assessments to be conducted.
Laboratory tests evaluated are included in Table 9.4.4-1.
Table 9.4.4-1:
Laboratory Tests
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Creatinine
Blood Urea Nitrogen (BUN)
Uric acid
Glucose
Total Protein - screening only
Albumin - screening only
Sodium
Potassium
Chloride
Calcium - screening only
Phosphorus - screening only
Lipase (Module B only)
Amylase (Module B only)
Serology (screening only)
Serum for hepatitis C antibody, hepatitis B surface antigen, (HIV-1 and -2 antibody where mandated locally)
Other Analyses
TSH (reflex to free T3 and Free T4 only if abnormal)
Pregnancy test (WOCBP only: predose, discharge).
9.4.5
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
 
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
 
 
 
 
 
 
 
 
 
 
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By applying the above methodology, the intended target number of participants (N) for cohort 1-
4 are obtained as follows:
Cohort 1: 22 participants are required (17 events) for each cohort. This assumes 80% power 
with a one sided Type 1 error of 10%, a historical median OS of 9 months (
 
 
), 1-year accrual, 2-year follow-up, and a target effect size of median OS 15 months. 
Cohort 2: 15 participants are required for each cohort. This assumes 80% power with a 
one-sided Type 1 error of 10%, a historical PFS(6) of 18% 
 
), one-year accrual, 
one-year follow-up, a target PFS(6) of 38%. An interim analysis based on PFS(6) for futility 
only will be conducted after at least 8 of the planned number of participants are enrolled with 6 
months follow-up. In addition, all other available efficacy data will be evaluated in the futility 
analysis. The method is adapted according to
Details of the futility criteria and 
simulations will be contained in the Statistical Analysis Plan (SAP).
Cohort 3: 15 participants are required for each cohort. This assumes 80% power with a 
one-sided Type 1 error of 10%, 1-year accrual and 1-year follow-up, a historical median PFS(4) 
of 18% and a target PFS(4) of 38% (see 
 
, equivalent to PFS(6) of 23%). An 
interim analysis based on PFS(6) for futility only will be conducted after at least 8 of the planned 
number of participants are enrolled with 6 months follow-up. In addition all other available 
efficacy data will be evaluated in the futility analysis.
Cohort 4: 10 participants are required for each cohort. This assumes at least 80% power with a 
one-sided Type 1 error of 10%, a historical median PFS of 2.1 months (see etoposide arm of 
 
), 1-year accrual, 1-year follow-up, and a target median PFS of 4.4 months.
Cohort 5: 18 participants are required for each cohort. Sample sizes each of the expansion 
Cohorts A5 and B5 is not based on statistical considerations as these cohorts contain various 
tumor types. However, if the disease control rate at 12 months is 30%, 18 participants provide 
21% precision for the estimate.
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10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign informed consent. This is the dataset 
for disposition.
Treated
All enrolled participants who received at least one dose of study 
drug. This is the dataset for safety evaluation.
Safety Lead-in participants
In Module A, the first 6 DLT-evaluable participants in Cohort 1 
and the first 10 DLT-evaluable participants in Cohorts 2-5; in 
Module B, the first 10 DLT-evaluable participants.
Response-evaluable 
participants
All treated participants with measurable disease at a baseline 
tumor assessment (Source: CRF).
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will 
describe the selection of participants to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. Below is a summary of planned statistical 
analyses of the primary and secondary endpoints.
10.3.1
Efficacy Analyses
The primary efficacy analyses will be performed on treated population for the final analysis. 
Details on censoring scheme on time-to-event endpoints such as OS, PFS, and DOR will be 
described in the SAP. Efficacy analysis will be performed by each cohort separately; however, 
treated participants in the safety lead-in period who meet the inclusion criteria for the 
corresponding cohort will also be included in the cohort analysis.
OS is defined as the time between the date of diagnosis and the date of death in Cohort 1 and the 
time between date of first dose and the date of death for Cohorts 2-5. A participant who has not 
died will be censored at the last known alive date. OS will be followed continuously while 
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participants are on study drug and every 3 months via in-person or phone contact during the 
survival follow-up phase of the study drug.
PFS is defined as the time from first dose to the date of the first documented tumor progression 
or death due to any cause. Participants who die without a reported prior progression will be 
considered to have progressed on the date of death. Participants who did not have disease 
progression or die will be censored at the date of last evaluable tumor assessment. Participants 
who did not have any on study tumor assessment and did not die will be censored at the first 
dose date. PFS will be determined by investigators based on RANO criteria. First tumor 
assessments will occur at week 6 and 12, and will be at every 8 weeks for the first year and then 
every 12 weeks thereafter until disease progression is documented.
ORR is defined as the number of participants whose BOR is confirmed CR or PR divided by all 
participants who are evaluable for response, ie have measurable disease at baseline. BOR is 
defined as the best response designation, as determined by investigators, recorded between the 
date of first dose and the date of objectively documented progression per RANO criteria or the 
date of subsequent therapy, whichever occurs first. All available response designations will 
contribute to the BOR assessment. For participants without documented progression or 
subsequent therapy, all available response designations will contribute to the BOR assessments.
DOR for a participant with a BOR of CR or PR, is defined as the time between the date of first 
response and the date of the first objectively documented tumor progression per RANO or death, 
whichever occurs first.
Endpoint
Statistical Analysis Methods
Primary
Cohort A1 and B1: OS
For each cohort separately, OS curve will be estimated using the Kaplan-
Meier (KM) method. The distribution of OS in all treated participants 
will be compared against the historical control of an exponential 
distribution with median OS 9 months (Cohen, Heideman, et al) using a 
one-sided one-sample log rank test when approximately 17 events have 
occurred or after each participant has been followed for at least 24 
months. Median OS and the corresponding two-sided 80% confidence 
intervals using the log-log transformation will be computed.
Cohort A2 and B2: PFS
For each cohort separately, PFS curve will be estimated using the 
Kaplan-Meier (KM) method. The distribution of PFS in all treated 
participants will be compared against the historical control of an 
exponential distribution with median PFS 2.25 months (Hwang, et al) 
using a one-sided one-sample log rank test when each participant has 
been followed for at least 12 months. Median PFS and the corresponding 
two-sided 80% confidence intervals using the log-log transformation 
will be computed.
Cohort A3 and B3: PFS
For each cohort separately, PFS curve will be estimated using the 
Kaplan-Meier (KM) method. The distribution of PFS in all treated 
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Endpoint
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participants will be compared against the historical control of an 
exponential distribution with PFS(4) equal to .18 using a one-sided one-
sample log rank test when either 15 events have occurred or each 
participant has been followed for at least 12 months. Median PFS and 
the corresponding two-sided 80% confidence intervals using the log-log 
transformation will be computed.
Cohort A4 and B4: PFS
For each cohort separately the distribution of PFS in all treated 
participants will be compared against the historical control of an 
exponential distribution with median PFS equal to 2.1 months using a 
one-sided one-sample log rank test when either 10 events have occurred 
or each participant has been followed for at least 12 months.
Cohort A5 and B5: PFS
For each cohort separately individual PFS will be listed by tumor type 
after each participant reaches 12 months follow-up. PFS curve will be 
estimated using the Kaplan-Meier (KM) method for all tumor types 
(pooled) and selected individual tumor types, if there is enough data.
Secondary
Cohort A1 and B1:
PFS, OS(12)
Cohorts A1 and B1: 
PFS is estimated by Kaplan-Meier method and the corresponding 95% 
CI for median OS will be calculated via Brookmeyer and Crowley 
methodology using log-log transformation. OS(12) will be estimated 
using the Kaplan-Meier (KM) method.
The corresponding 95% 
confidence interval for median OS will be calculated via Brookmeyer 
and 
Crowley 
methodology 
using 
log-log 
transformation 
and 
corresponding 95% confidence interval for OS(12) will be derived based 
on Greenwood formula. All secondary endpoints will be analyzed at the 
time of the primary analysis.
Cohort A2 and B2:
PFS(6), OS, OS(12)
Cohort A3 and B3:
PFS(6), OS, OS(12)
Cohort A4 and B4:
PFS(6), OS, OS(12)
Cohorts A2, A3, A4, B2, B3, B4
Secondary statistics analysis for other cohorts A2, A3, and A4, B2, B3, 
and B4 is the same as for Cohort A1 and B1 (except timepoint for OS(r) 
and PFS(r) may differ.
Cohort A5 and B5:
PFS(12), OS
Cohorts A5, B5:
OS will be listed.  OS curve will be computed using Kaplan-Meier 
method for pooled indications and selected individual indications. The 
corresponding 95% confidence interval for median OS will be calculated 
via Brookmeyer and Crowley methodology using log-log transformation 
and corresponding 95% confidence interval for PFS(12) will be derived 
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Endpoint
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based on Greenwood formula.
 
 
 
 
 
 
 
 
 
 
 
10.3.2
Safety Analyses
All safety analyses will be performed on the treated population.
Endpoint
Statistical Analysis Methods
Primary
Module A and B Safety 
Lead-in:
Incidence of AEs, SAEs, 
drug-related 
AEs, 
AEs 
leading to discontinuation, 
and death.
AEs 
will 
be 
graded 
according to CTCAE v4.03.
Incidence 
of 
laboratory 
abnormalities
Laboratory values will be 
graded 
according 
to 
CTCAE v4.03.
Module A and B Safety Lead-in:
Frequency distribution of treated participants with AE using the worst 
CTC grade. Participants will only be counted (1) once at the preferred 
term (PT) level, (2) once at the system organ class (SOC) level, and (3) 
once in the ‘Total participant’ row at their worst CTC grade, regardless 
of SOC or PT. By Cohort.
Lab shift table using the worst CTC grade per participant by Cohort.
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Endpoint
Statistical Analysis Methods
Secondary
All Cohorts A1-A5, B1-
B5:
Incidence of AEs, SAEs, 
drug-related 
AEs, 
AEs 
leading to discontinuation, 
and death.
AEs 
will 
be 
graded 
according to CTCAE v4.03.
Incidence 
of 
laboratory 
abnormalities
Laboratory values will be 
graded 
according 
to 
CTCAE v4.03.
All Cohorts A1-A5, B1-B5:
Frequency distribution of treated participants with AE using the worst 
CTC grade. Participants will only be counted (1) once at the preferred 
term (PT) level, (2) once at the system organ class (SOC) level, and (3) 
once in the ‘Total participant’ row at their worst CTC grade, regardless 
of SOC or PT. By Cohort.
Lab shift table using the worst CTC grade per participant by Cohort.
 
 
 
 
 
 
 
 
 
 
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10.3.5
Interim Analyses 
Cohorts A1 and B1: No interim analysis for futility is planned, as the Cohorts are expected to 
be fully enrolled when the OS endpoint becomes available. However, in Module A if other 
indications are stopped for futility, enrollment in Module B may be initiated based on 
recommendations of the Steering Committee.
Cohorts A2 and B2: The interim futility analysis for Cohorts A2 and B2 (HGG) will be 
conducted using PFS(6) and after at least 8 participants have been followed for 6 months. In 
addition, all other available efficacy data will be evaluated in the futility analysis.
Cohorts A3 and B3: An interim analysis based on PFS(6) for futility only will be conducted 
after at least 8 of the planned number of participants are enrolled with 6 months follow-up. In 
addition all other available efficacy data will be evaluated in the futility analysis.
Cohorts A4 and B4: No interim analysis for futility is planned as the sample size is too small.
Cohorts A5 and B5: No interim analysis for futility is planned as it is comprised of many 
diverse histologies. However, in Module A if other indications are stopped for futility enrollment 
in Module B may be initiated based on the recommendation of the Steering Committee.
For Cohorts 2 and 3: the Bayesian statistical methodology is described in Bayesian Adaptive 
Methods for Clinical Trial by Berry et al published in Chapman and Hall (2011) and is outlined 
here with adaptations from Lee and Liu A predictive probability design for phase II cancer 
clinical trials.
Cohort 4 has a smaller sample size than the other cohorts (n=10) so it is not appropriate to add an 
interim analysis for futility. For Cohorts 2 and 3: The Bayesian statistical methodology is 
described in Bayesian Adaptive Methods for Clinical Trial by Berry et al published in Chapman 
and Hall (2011) and is outlined here with adaptations from Lee and Liu REF A predictive 
probability design for phase II cancer clinical trials. Clinical Trials. 2008 5(2):93-106. 
1) Once 8 subjects have been followed for at least 6 months a Cox proportional hazards model 
will be fit to interim data and estimate of hazard rate obtained.
2) Based on memoryless property of exponential survival times will be generated for each 
subject conditional on the observed data using the estimated hazard rate and one-sample log 
rank test applied to the fully enrolled cohort. The simulated trial will be declared success if 
log rank is significant.
3) Simulations will be repeated 1000 times. The predictive probability of success is defined as 
the proportion of simulated trials that are declared success based on observed interim data.
4) If predictive probability of success is <20%, futility may be declared. The totality of data will 
be considered in any decision to stop the cohort.
Detailed simulations will be described in the Statistical Analysis Plan.
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12.
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AA
anaplastic astrocytoma
ADA
anti-drug antibodies
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT/RT
atypical teratoid/rhabdoid tumor
AUC
area under the concentration-time curve
BICR
blinded independent central review committee
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CFR
Code of Federal Regulations 
cHL
classic Hodgkins lymphoma
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
CNS
Central nervous system
CR
complete response
CRC
colorectal cancer
CRF
Case Report Form, paper or electronic
CSF
cerebrospinal fluid
CV
coefficient of variation
DILI
Drug induced liver injury
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Term
Definition
DIPG
diffuse intrinsic pontine glioma
dL
deciliter
DLT
dose limiting toxicity
DMC
Data monitoring committee
DNA
deoxyribonucleaic acid
DOR
duration of response
ECG
electrocardiogram
eCRF
electronic Case Report Form
EFS
event free survival
eg
exempli gratia (for example)
EOI
end of infusion
EOMES
eomesodermin
ESR
Expedited Safety Report
ETMR
embryonal tumor with multilayered rosettes
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FLAIR
fast fluid-attenuated inversion recovery
FSH
follicle stimulating hormone
GBM
glioblastoma
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HCV-RNA
hepatitis C virus-ribonucleic acid
HGG
high grade glioma
HIV
Human Immunodeficiency Virus
HLA
human leukocyte antigen
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Term
Definition
HR
heart rate; hazard ratio
IB
Investigator Brochure
ICD
implantable cardioverter defibrillator
ICF
informed consent form
ICH
International Conference on Harmonisation 
ICOS
inducible T cell co-stimulator
ie
id est (that is)
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IMAE
Immune-mediated adverse event
IMG
immunogenicity
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IP
investigational product
ir
immune-related
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K+
potassium
KPS
Karnofsky Performance Score
kg
kilogram
L
liter
LAM
Lactation amenorrhea method
LDH
lactate dehydrogenase
LFT(s)
liver function test(s)
LPS
Lansky Play Score
mg
milligram
MGMT
O6-methylguanylmethyltransferase
min
minute
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Term
Definition
mL
milliliter
MLR
mixed lymphocyte reaction
MRI
magnetic resonance imaging
MS
mass spectrometry
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
N
Nivolumab (BMS-936558)
Na+
sodium
NE
not evaluable
NSCLC
non-small cell lung carcinoma
OR
objective response
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease 
PD
pharmacodynamics
PD-1
Programmed cell death protein 1
PD-L1
Programmed cell death ligand 1
PFS
progression free survival
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PR
partial response
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RANO
Radiologic Assessment in Neuro-Oncology
RBC
red blood cell
RCC
Renal cell carcinoma
RT
radiotherapy
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Term
Definition
SAE
serious adverse event
SCLC
squamous cell lung carcinoma
SD
standard deviation; stable disease
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedures
SSC
study steering committee
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TCR
T cell receptor
TILs
Tumor infiltrating lymphocytes
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:

Good Clinical Practice (GCP), 

as defined by the International Council on Harmonisation (ICH)

in accordance with the ethical principles underlying European Union Directive 2001/20/EC

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 

Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines

applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant
recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:

IRB/IEC for 

Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 

Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.

Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the informed consent form approved for 
the study prior to clinical study participation. The explicit wish of a minor, who is capable of 
forming an opinion and assessing this information to refuse participation in, or to be withdrawn 
from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
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refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments nivolumab and ipilimumab (whether supplied by BMS, its vendors, 
or the site) must substantiate study treatment integrity and traceability from receipt, preparation, 
administration, and through destruction or return. Records must be made available for review at 
the request of BMS/designee or a Health Authority.
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If
Then
Supplied by BMS (or its 
vendors):
Records or logs must comply with applicable regulations and guidelines and should 
include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each participant, including unique 
participant identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (e.g., lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
Sourced by site, and not 
supplied by BMS or its 
vendors (examples include 
IP sourced from the sites 
stock or commercial 
supply, or a specialty 
pharmacy)
The investigator or designee accepts responsibility for documenting traceability and 
study drug integrity in accordance with requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.  
These records should include:

label identification number or batch number 

amount dispensed to and returned by each participant, including unique 
participant identifiers

dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
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The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
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RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS 
(including its vendors
Any unused study treatments supplied by BMS can only be 
destroyed after being inspected and reconciled by the responsible 
Study Monitor unless study treatments containers must be 
immediately destroyed as required for safety, or to meet local 
regulations (eg, cytotoxics or biologics).
If study treatments will be returned, the return will be arranged by 
the responsible Study Monitor.
Study treatments sourced by site, not 
supplied by BMS (or its vendors) 
(examples include study treatments 
sourced from the sites stock or commercial 
supply, or a specialty pharmacy)
It is the investigator’s or designee’s responsibility to dispose of all 
containers according to the institutional guidelines and procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
For this study, study treatments (those supplied by BMS or its vendors) such as full or partially 
used study treatment containers, vials, syringes cannot be destroyed on-site.
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It is however, the investigator’s or designee’s responsibility to arrange for disposal of all empty 
study treatment containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local, and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. The return of full or partially used study 
treatments supplied by BMS or its vendors will be arranged by the responsible Study Monitor.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Participant recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies: 
o
a visit to the emergency room or other hospital department < 24 hours, that does 
not result in admission (unless considered an important medical or 
life-threatening event)
o
elective surgery, planned prior to signing consent
o
admissions as per protocol for a planned medical/surgical procedure
o
routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy)
o
medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases
o
admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason)
o
admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 8.1.1 for the definition of potential DILI.) 
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Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy Surveillance 
Form (electronic or paper forms).

The preferred method for SAE data reporting collection is through the eCRF.

The paper SAE/pregnancy surveillance forms are only intended as a back-up option when 
the eCRF system is not functioning.
o
In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 years 
in the absence of other biological or physiological causes. In addition, females under the age 
of 55 years must have a serum follicle stimulating hormone (FSH) level > 40 mIU/ml to 
confirm menopause. 
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 5 months weeks after the end 
of study treatment. 
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 
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Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c

Intrauterine device (IUD)c

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence 
that the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
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Unacceptable Methods of Contraception

Male or female condom with or without spermicide.1, 2 Male and female condoms cannot 
be used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end 
of treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 7 months after the end of study treatment. 

Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 6
KARNOFSKY AND LANSKY CRITERIA
STATUS
STATUS
KARNOFSKY
LANSKY
KARNOFSKY or 
LANSKY
Normal, no complaints
Fully active, normal
100
Able to carry on normal activities; minor signs or 
symptoms of disease
Minor restrictions in 
physically strenuous 
activity
90
Normal activity with effort; some signs or symptoms of 
disease
Active, but tires more 
quickly
80
Cares for self. Unable to carry on normal activity or to do 
active work
Substantial restriction of, 
and less time spent, in play 
activity
70
Requires occasional assistance, but able to care for most of 
his needs
Out of bed, but minimal 
active play; keeps busy 
with quiet activities
60
Requires considerable assistance and frequent medical care
Gets dressed, but inactive 
much of day; no active 
play, able to participate in 
quiet play
50
Disabled. Requires special care and assistance
Mostly in bed; participates 
in some quiet activities
40
Severely disabled. Hospitalization indicated though death 
non imminent
In bed; needs assistance 
even for quiet play
30
Very sick. Hospitalization necessary. Active supportive 
treatment necessary
Often sleeping; play 
limited to passive 
activities
20
Moribund
No play; does not get out 
of bed
10
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