A Randomized, Open-Label, Phase 2 Study of Nivolumab in Combination With Ipilimumab or Nivolumab Monotherapy in Participants With Advanced or Metastatic Solid Tumors of High Tumor Mutational Burden (TMB-H)
Phase: PHASE2
Conditions: Pan Tumor
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Randomized, Open-Label, Phase 2 Study of Nivolumab in Combination with Ipilimumab or 
Nivolumab Monotherapy in Participants with Advanced or Metastatic Solid Tumors of High 
Tumor Mutational Burden (TMB-H) 
(CheckMate 848: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 848) 
 
NCT Number: NCT03668119 
Document Date (Date in which document was last revised): May 4, 2021 

Page:
1
Protocol Number:
CA209848
IND Number:
140,266
EX-US
Non-IND
EUDRACT Number:
2016-002898-35
Date:
13-Oct-2016
Revised Date: 04-May-2021
Clinical Protocol CA209848
A Randomized, Open-Label, Phase 2 Study of Nivolumab in Combination with Ipilimumab or 
Nivolumab Monotherapy in Participants with Advanced or Metastatic Solid Tumors of High 
Tumor Mutational Burden (TMB-H)
(CheckMate 848: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 848)
Protocol Amendment 04
Incorporates Administrative Letters 04, 05, 06, and 07
Clinical Scientist
Clinical Trial Physician-
Medical Monitor
Bristol-Myers Squibb Company
Bristol-Myers Squibb Company
3401 Princeton Pike
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (mobile): 
Email: 
Lawrenceville, NJ 08648
Telephone (office): 
Email:
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
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, 
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BMS-936558
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Protocol Amendment No.: 04
Date: 04-May-2021
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disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
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, eg, a Contract Research Organization 
(CRO).
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BMS-936558
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Protocol Amendment No.: 04
Date: 04-May-2021
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 04
04-May-2021
Clarified statistical analysis populations for blood tumor mutational burden
(bTMB) final analysis, tissue tumor mutational burden (tTMB) interim 
analysis, and tTMB final analysis.
Updates made to align with current nivolumab Investigator Brochure (IB)
and Bristol-Myers Squibb Company (BMS) guidelines for protocols with 
nivolumab using Common Terminology Criteria for Adverse Events
(CTCAE) v5. Updates made to treatment management algorithms for 
immuno-oncology agents.
Added safety reporting and dose modification related to severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2).
Incorporated Administrative Letters 04, 05, 06, and 07. Note: After 
Administrative Letter 07, Medical Monitor/Clinical Trial Physician 
responsibility transitioned from 
, to 
 
. Since Protocol Amendment 04 was in development, the 
personnel update was not communicated in an administrative letter. This 
responsibility has now transitioned to 
.
Administrative 
Letter 07
28-Jul-2020
The purpose of this administrative letter is to advise of a change in study 
personnel and update aligning with the BMS Medical Contacts or designee 
referenced.
Administrative 
Letter 06
18-Jun-2020
The purpose of this administrative letter is to advise of a change in study 
personnel and title update aligning with the BMS Medical Contacts or 
designee referenced.
Administrative 
Letter 05
11-Mar-2020
The purpose of this administrative letter is to advise of a change in study 
personnel and title updates.
Administrative 
Letter 04
08-Jan-2020
This letter serves to clarify and correct the Study Design Schematic of 
Revised Protocol 03. In the section referencing the Study Design Schematic, 
Synopsis, Figure 2.1 and Section 5.1, Figure 5.1-1 (Overall Design) the 
sample size is referenced incorrectly as n = 159. As part of Revised Protocol 
03, the number of randomized participants was updated to range from 
approximately 183 to 342 however was inadvertently not updated in the 
Study Design Schematic therefore this should be updated to n = 183.
Revised 
Protocol 03
14-Aug-2019
Provided clarification that pre-screening requirements on tTMB and bTMB 
results should be ≥ 10 mut/Mb (tTMB ≥ 10 mut or the new cutoff value of 
bTMB determined by the 1st interim analysis).
Clarified that Belgium and the Netherlands will not enroll adolescent 
participants and therefore all content related to pediatric/adolescents is not 
applicable for sites in those countries.
Added Section 3.2.5 on Nivolumab Clinical Pharmacology to Background
Updated the range of participants and further clarified statistical analyses
and sample size determination. 
Added standard language regarding use of CT component of a PET-CT 
scanner.
Clarified biomarker tissue collection to occur during pre-screening.
Also included updates per Administrative Letter 02, update to study 
personnel Medical Monitor and Study Director, and Administrative Letter 
03, clarified and corrected a typo in Exclusion Criteria (Section 6.2).
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Protocol Amendment No.: 04
Date: 04-May-2021
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Document
Date of Issue
Summary of Change
Made minor editorial and grammatical corrections throughout.
Administrative 
Letter 03
29-May-2019
This letter serves to clarify and correct a typo in the Exclusion Criteria of 
Revised Protocol 02.  In the section referencing Exclusion Criteria (Section 
6.2), Physical and Laboratory Test Findings, (bullet number 3) regarding the 
calculated creatinine clearance reflecting the normal range. This exclusion 
criteria is intended to exclude patients with significant renal function 
impairment as indicated by elevated serum creatinine unless creatinine 
clearance is greater than the specified values for adults and adolescents, 
respectively.
Administrative 
Letter 02
07-Mar-2019
The purpose of this administrative letter is to advise of a change in study 
personnel.
Revised 
Protocol 02
11-Dec-2018
Incorporates feedback received from FDA on the study design of 
CA209-848 and Administrative Letter 01.
Administrative 
Letter 01
10-Jul-2018
Notification that a new IND number (140,266, for tissue agnostic, pan tumor 
in TMB-H population) will be used for CA209-848 protocol.
Revised 
Protocol 01
18-May-2018
This protocol is listed a “Revised protocol 1” to remain Title 21 CFR Part 11 
compliant (FDA regulations on electronic records and electronic signatures). 
The initial protocol CA209848 was never activated as initially written. The 
study was fully revised and, therefore, there are no summary of changes to 
compare to the initial protocol.
Original 
Protocol
13-Oct-2016
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 04:
This amendment incorporates clarifications concerning the analysis populations used for the blood 
tumor mutational burden (bTMB) and tissue tumor mutational burden (tTMB) cohorts and the type 
of analysis (interim or final primary) being performed. Enrollment into the bTMB high population 
was closed in Dec-2019, as the required number of participants needed for final analysis was met.
Enrollment into the tTMB high population remained ongoing to complete enrollment for this 
participant population. Because of the varying enrollment rates, the bTMB final analysis will 
coincide with the tTMB interim efficacy analysis, leading to the need for clarification of the 
primary analysis populations for both analyses. Both of these analyses will take place after study-
wide randomization has completed.
•
The final analysis population for the primary endpoint (overall response rate [ORR] based on 
blinded independent central review [BICR] assessments) for the bTMB high population will 
be all participants in the salvage setting randomized before the study closed enrollment to this 
cohort in Dec-2019; the database cutoff (last patient last visit [LPLV]) for the analysis will be 
at least 12 months after last patient first treatment and after completion of study-wide
randomization.
•
The primary analysis population for the tTMB interim analysis (ORR based on BICR 
assessments) is limited to tTMB high participants in the salvage setting randomized at least 12 
months prior to the LPLV for the analysis to allow sufficient time to demonstrate durability of 
response. Study-wide randomization will complete prior to the LPLV for the analysis.
•
The final analysis of the primary endpoint (ORR based on BICR assessments) for the tTMB 
high population in the salvage setting will be performed at least 12 months after all tTMB high 
participants have been randomized.
Protocol Amendment 04 incorporates changes per previous Administrative Letters 04, 05, 06, and 
07, and updates to align with current Bristol Myers Squibb Company (BMS) guidelines for 
nivolumab studies (including current nivolumab Investigator Brochure [IB] version 19, addendum 
version 1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) guidance.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis: Data Monitoring 
Committee; Section 
5.1.1.1: Data Monitoring 
Committee
Added data monitoring committee (DMC) 
review of the bTMB final analysis results.
The bTMB final analysis will 
coincide with the tTMB interim 
analysis, so it was decided to have 
the DMC review both results.
Synopsis: Figure 2: Study 
Design Schematic; Section 
5.1: Overall Design; Figure 
5.1-1: Study Design 
Schematic
Corrected the number of potential 
randomized study participants.
As part of Revised Protocol 03, the 
number of randomized participants 
was updated to approximately 183 
to 342, but the Study Design 
Schematic had not previously been 
updated to reflect this change.
Protocol Amendment No.: 04
Date: 04-May-2021
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis: Key Inclusion 
Criteria
Added ‘(salvage setting)’ to criterion 1a.
Clarified that the eligible 
participant disease characteristics 
described in Inclusion Criterion 1a 
(updated in Revised Protocol 02 
dated 11-Dec-2018) represent 
salvage setting characteristics. No 
change to the actual criterion for 
eligibility.
Section 2: Schedule of 
Activities
Tables 2-1, 2-2, 2-3, 2-4, 
and 2-5
Added collection of all serious adverse 
events (SAEs) and non-serious adverse 
events (AEs) associated with SARSCoV-2 
infection.
Aligned with current BMS 
guidelines for protocol updates 
concerning SARS-CoV-2.
Section 2: Schedule of 
Activities Table 2-1; 
Section 5.1: Overall 
Design; Section 6.1:
Inclusion Criteria 2c
Added “validated CLIA” to instances of 
acceptable bTMB results
Clarification that the Foundation 
Medicine bTMB assay is validated 
by Clinical Laboratory 
Improvement Amendments (CLIA).
Section 5.4.5: Rationale for 
Two Year Duration of 
Treatment 
Deleted prior references to Keynote-010 and 
Keynote-006.
Aligned with current BMS 
guidelines for protocols with 
nivolumab, in which outdated 
background information on 
analyses of pembrolizumab 
progression rates has been 
removed.
Section 5.5.4: Clinical 
Pharmacology Summary
Updated current nivolumab 
pharmacokinetic (PK) parameters to include 
more details of nivolumab clearance in 
nivolumab monotherapy and nivolumab 
plus ipilimumab therapy and in specific 
populations, among which are those with 
renal/hepatic impairment.
Nivolumab clinical PK assessed 
using a population PK approach; 
updated to align with the current 
nivolumab  IB.
Section 5.5.5: Rationale for 
30-minute Infusion
Added current approval status for a 30-
minute infusion for nivolumab, either as 
monotherapy or in combination, and for 
ipilimumab when combined with 
nivolumab. 
Aligned with current United States 
prescribing information (USPI) for 
nivolumab and current USPI for 
ipilimumab
Section 6.1: Inclusion 
Criteria 
2) Type of Participant and 
Target Disease 
Characteristics
3) Age and Reproductive 
Status; Appendix 4: 
Women of Childbearing 
Added “(salvage setting)” to Criterion 2a.
Removed male contraception language. 
Inclusion Criterion 3e is no longer 
applicable.
In Appendix 4, the guidance for male 
participants is now designated as Not 
Applicable.
Clarified that the eligible 
participant disease characteristics
described in Inclusion Criterion 2a
(updated in Revised Protocol 02
dated 11-Dec-2018) represent 
salvage setting characteristics. 
There was no change to the actual 
criterion for eligibility.
Aligned with the current nivolumab 
IB and BMS guidelines for 
Protocol Amendment No.: 04
Date: 04-May-2021
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & 
Title
Description of Change
Brief Rationale
Potential Definitions and 
Methods of Contraception;
Appendix 4: Contraception 
Guidance for Male 
Participants with Partner(s) 
of Child Bearing Potential
protocols with nivolumab, which 
reflect the lack of nivolumab 
genotoxicity and no transmission of 
biologically relevant amounts to 
women of childbearing potential 
(WOCBP) partners.  
Section 7.1.1: Arm A or 
Arm B Rollover ۛ
Nivolumab in Combination 
with Ipilimumab; Section 
7.1.2: Arm B ۛ Nivolumab 
Monotherapy
Added “approximately” to references of 
30-minute intravenous infusions.
Added optional instructions to flush the 
intravenous line with an appropriate amount 
of diluent.
Aligned with current BMS 
guidelines for protocols with 
nivolumab.
Section 7.4.1: Dose Delay 
Criteria
Updated to align with CTCAE v5 grading, 
and added new terms (ie, Guillain-Barre, 
myasthenia gravis, 
hypophysitis/hypopituitarism).
Updated text to tabular format (Table 7.4.1-
1) and included criteria to resume and/or 
discontinue treatment. 
Added instruction to delay dosing in 
participants with SARS-CoV-2 infection.
Aligned with current nivolumab IB 
and BMS guidelines for protocols 
with nivolumab using CTCAE v5 
for safety assessments; changed to 
tabular format for greater ease of 
use.
Aligned with current BMS 
guidelines for protocol updates 
concerning SARS-CoV-2.
Section 7.4.2: Criteria to 
Resume Treatment
Updated and moved criteria to resume 
treatment following specific AEs to Table 
7.4.1-1.
Clarified that participants may resume study 
treatment following steroid taper for AE
management.
Added criteria to resume treatment 
following SARS-CoV-2 infection.
Aligned with current nivolumab IB 
and BMS guidelines for protocols 
with nivolumab.
Aligned with current BMS 
guidelines for protocol updates 
concerning SARS-CoV-2. 
Section 7.4.4: Treatment of 
Nivolumab- and 
Ipilimumab-Related 
Infusion Reactions
Made minor updates to treatment guidelines.
Aligned with current BMS 
guidelines for protocols with 
nivolumab.
Section 7.4.5: Management 
Algorithms for Immuno-
oncology Agents
Made minor updates to language 
referencing the management algorithms for 
immuno-oncology agents in Appendix 5.
Aligned with current BMS 
guidelines for protocols with 
nivolumab.
Section 7.7.1: Concomitant 
Therapy, Prohibited and/or 
Restricted Treatments;
Section 7.7.2: Permitted 
Therapy
Made minor updates to prohibited therapies 
per nivolumab program updates.
Added restrictions on administration of live 
(prohibited) or not live (permitted) SARS-
CoV-2 vaccines.
Aligned with current BMS 
guidelines for protocols with 
nivolumab.
Aligned with current BMS 
guidelines for protocol updates 
concerning SARS-CoV-2.
Protocol Amendment No.: 04
Date: 04-May-2021
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 8.1:
Discontinuation from Study 
Treatment;
Section 8.1.1: Dose 
Discontinuation in 
Nivolumab and Ipilimumab 
Combination;
Section 8.1.2: Dose 
Discontinuation in 
Nivolumab Monotherapy 
Arm
Updated and moved criteria to discontinue 
treatment following specific AEs to Table 
7.4.1-1.
Aligned with current nivolumab IB 
and BMS guidelines for protocols 
with nivolumab using CTCAE v5 
for safety assessments.
Section 9: Study 
Assessments and 
Procedures
Updated to include recommendations for 
potential cardiac or pulmonary toxicity.
Aligned with current nivolumab IB 
and BMS guidelines for protocols 
with nivolumab.
Section 9.2.1: Time Period 
and Frequency for 
Collecting AE and SAE 
Information;
Section 9.2.3: Follow-up of 
AEs and SAEs
Added instruction for collection and follow-
up of SAEs and non-serious AEs associated 
with SARS-CoV-2 infection.
Aligned with current BMS 
guidelines for protocol updates 
concerning SARS-CoV-2.
Section 9.2.5: Pregnancy
Removed instruction for reporting of 
pregnancy occurring in a female partner of a 
male study participant.
Aligned with current nivolumab IB 
and essential protocol elements, 
which reflect the lack of nivolumab 
genotoxicity and no transmission of 
biologically relevant amount to  
WOCBP partners.  
Section 9.5:
Pharmacokinetics, 
Table 9.5-1:
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule ۛ Arm A or Arm 
B Rollover ۛ Nivolumab in 
Combination with 
Ipilimumab;
Table 9.5-2:
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule Arm B ۛ
Nivolumab Monotherapy
Clarified site of blood draw and proper 
documentation of sample collection and the 
evaluation of samples for development of 
anti-drug antibody.
Revised footnote b to clarify end of 
infusion-PK sampling. 
Aligned with current BMS 
guidelines for protocols with 
nivolumab.
Section 9.10: Patient-
Reported Outcomes
Revised text to clarify that alternate 
administration modalities may be used if 
necessary.
Aligned with current BMS 
guidelines for protocol updates 
concerning SARS-CoV-2.
Protocol Amendment No.: 04
Date: 04-May-2021
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 10: Statistical 
Considerations
Added “in the salvage setting” to 
descriptions of the primary analysis 
populations.
Added “and study randomization is 
completed” to timing of the analyses.
Clarified that the primary analysis 
populations include salvage setting 
participants per inclusion criteria 
updated in Revised Protocol 02
dated 11-Dec-2018.
Clarification that the tTMB interim 
analysis and bTMB and tTMB final 
analyses will take place after study 
randomization is completed.
Section 10.1: Sample Size 
Determination; 
Section 10.2: Populations 
for Analyses
Revised text to clarify that only participants 
in the bTMB high population enrolled prior 
to the closure of the bTMB high group will 
be included in the final primary bTMB 
efficacy analysis population.
Added Table 10.2-1.
Enrollment into the bTMB high 
population was closed in Dec-2019; 
the primary bTMB efficacy 
analysis population will include all 
participants randomized into this 
group prior to its closure.
Table 10.2-1 clarifies the primary 
analysis populations and timing of 
the analyses.
Section 10.3.6: Interim 
Analyses
Revised text to clarify that the primary 
analysis population for the tTMB interim 
efficacy analysis will be limited to study 
participants in the tTMB high population 
who were randomized at least 12 months 
prior to the LPLV for the analysis.
In order to achieve the necessary 
number of study participants in the 
tTMB high population for the 
tTMB primary endpoint final 
analysis, enrollment into this 
population continued after the date
on which  criteria were met for the 
tTMB interim analysis. The 
primary analysis population for the 
interim analysis will therefore 
consist of all tTMB high 
participants randomized at least 12 
months prior to the LPLV for the 
analysis.
Section 11: References
Removed references to KEYNOTE-010 and 
KEYNOTE-006 per Section 5.4.5 update.
Added references for current nivolumab 
USPI and current ipilimumab USPI.
Aligned with current BMS 
guidelines for protocols with 
nivolumab.
Section 12: Appendix 1: 
Abbreviations and 
Trademarks
Added abbreviations.
Aligned with updated text within 
the protocol body.
Section 12: Appendix 2: 
Study Governance 
Considerations: Monitoring
Added flexible language to allow for remote 
monitoring.  
Aligned with current BMS 
guidelines for protocol updates 
concerning SARS-CoV-2.
Protocol Amendment No.: 04
Date: 04-May-2021
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 12: Appendix 5: 
Management Algorithms 
for Studies Under CTCAE 
Version 5.0
Updated treatment management algorithms 
for immuno-oncology agents.
Aligned with current nivolumab IB 
and BMS guidelines for protocols 
with nivolumab using CTCAE v5 
for safety assessments.
All
Made minor formatting and typographical 
corrections.
These changes are minor and
therefore have not been 
summarized.
Protocol Amendment No.: 04
Date: 04-May-2021
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 04: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 Rationale for Participant Population with TMB-H Tumor ...................... 
 
3.1.2 Rationale for Study in Refractory, Metastatic, or Unresectable Setting . 
 
3.1.3 Rationale for Inclusion of Adolescent Participants ................................. 
 
3.1.4 Rationale for Key Endpoints .................................................................... 
 
3.1.4.1 Rationale for Independent Central Review ..................................... 
 
3.1.4.2 Rationale for Investigator Assessed Response ................................ 
 
3.1.5 Rationale for Exploratory Biomarker Assessments ................................. 
 
3.1.6 Rationale for Outcomes Research Assessments ....................................... 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Mechanism of Action of Nivolumab ......................................................... 
 
3.2.2 Ipilimumab Mechanism of Action ............................................................ 
 
3.2.3 Nivolumab Combined with Ipilimumab and Nivolumab Monotherapy 
Clinical Activity in Adults ........................................................................... 
 
3.2.4 Nivolumab Combined with Ipilimumab and Nivolumab Monotherapy 
Clinical Activity in Adolescents .................................................................. 
 
3.2.5 Nivolumab Clinical Pharmacology .......................................................... 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
3.3.1 Adult Patients ........................................................................................... 
 
3.3.2 Adolescent Patients .................................................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
 
5.1.1.1 Data Monitoring Committee ........................................................... 
 
5.1.1.2 Blinded Independent Central Review Committee ........................... 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.4.1 TMB Cutoff and Stratification ................................................................. 
 
5.4.2 Stratification with Line of Therapy .......................................................... 
 
5.4.3 Exclusion of Melanoma, NSCLC and RCC .............................................. 
 
5.4.4 Rationale for Treatment with Nivolumab and Ipilimumab after Disease 
Progression with Nivolumab Monotherapy ................................................ 
 
5.4.5 Rationale for Two Year Duration of Treatment ....................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
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Clinical Protocol
BMS-936558
CA209848
nivolumab
Protocol Amendment No.: 04
Date: 04-May-2021
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5.5.1 Rationale for Nivolumab Monotherapy Dose Selection .......................... 
 
5.5.2 Nivolumab/Ipilimumab Combination Therapy Dose Selection and 
Duration ...................................................................................................... 
 
5.5.2.1 Population Pharmacokinetics of Nivolumab .................................. 
 
5.5.2.2 Population Pharmacokinetics of Ipilimumab ................................. 
 
5.5.2.3 Pharmacokinetics of Nivolumab and Ipilimumab ........................... 
 
5.5.3 Dose for Adolescents................................................................................ 
 
5.5.4 Clinical Pharmacology Summary ............................................................ 
 
5.5.5 Rationale for 30-minute Infusion ............................................................. 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening Period ......................................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Arm A or Arm B Rollover – Nivolumab in Combination with Ipilimumab
..................................................................................................................... 
 
7.1.2 Arm B – Nivolumab Monotherapy ........................................................... 
 
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 Nivolumab and Ipilimumab or Nivolumab Treatment beyond Disease 
Progression ................................................................................................. 
 
7.4.3.1 Treatment with nivolumab and ipilimumab after disease 
progression during treatment with nivolumab monotherapy (Arm B 
rollover) ................................................................................................ 
 
7.4.4 Treatment of Nivolumab- and Ipilimumab-Related Infusion Reactions .. 
 
7.4.5 Management Algorithms for Immuno-oncology Agents .......................... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Permitted Therapy ................................................................................... 
 
7.7.3 Palliative Local Therapy .......................................................................... 
 
7.7.4 Other Restrictions and Precautions ......................................................... 
 
7.7.5 Imaging Restriction and Precautions ...................................................... 
 
7.7.6 Surgical Resection Following Initial Response ....................................... 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Dose Discontinuation in Nivolumab and Ipilimumab Combination........ 
 
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Clinical Protocol
BMS-936558
CA209848
nivolumab
Protocol Amendment No.: 04
Date: 04-May-2021
12
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Approved
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5.0
v
Approved
1.0
v

8.1.2 Dose Discontinuation in Nivolumab Monotherapy Arm ......................... 
 
8.1.3 Post Study Treatment 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 Methods of Measurement ......................................................................... 
 
9.1.2.1 Solid tumors .................................................................................... 
 
9.1.2.2 Primary CNS Neoplasms ................................................................ 
 
9.1.3 Imaging and Clinical Assessment ............................................................ 
 
9.1.3.1 BICR Confirmation of Radiographic Progression ......................... 
 
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 Immune-mediated Adverse Events ........................................................... 
 
9.2.9 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Vital signs................................................................................................. 
 
9.4.3 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.4 Imaging Safety Assessment ...................................................................... 
 
9.5 Pharmacokinetics .............................................................................................. 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Additional Research Collection ............................................................... 
 
9.8.2 Immunogenicity Assessments ................................................................... 
 
9.8.3 Blood-based Biomarkers .......................................................................... 
 
9.8.4 Tissue-based Biomarkers ......................................................................... 
 
9.8.5 Other Assessments ................................................................................... 
 
9.9 Medical Resource Utilization and Health Economics ...................................... 
 
9.10 Patient-Reported Outcomes ............................................................................ 
 
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....................................................................................... 
 
10.3.3 Pharmacokinetics Analysis .................................................................... 
 
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Clinical Protocol
BMS-936558
CA209848
nivolumab
Protocol Amendment No.: 04
Date: 04-May-2021
13
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Approved
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10.3.4 Outcomes Research Analyses ................................................................ 
 
10.3.5 Other Analyses ....................................................................................... 
 
10.3.6 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
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 5 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0 ......................................................................................................... 
 
APPENDIX 6 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 7 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
 
APPENDIX 8 RADIOGRAPHIC ASSESSMENT FOR NEURO-ONCOLOGY 
(RANO) CRITERIA FOR HIGH-GRADE GLIOMAS ......................................... 
 
APPENDIX 9 KARNOFSKY AND LANSKY CRITERIA ........................................ 
 
APPENDIX 10 SIMULATION RESULTS.................................................................. 
 
APPENDIX 11 COUNTRY SPECIFIC AMENDMENTS .......................................... 
 
APPENDIX 12 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
 
 
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Clinical Protocol
BMS-936558
CA209848
nivolumab
Protocol Amendment No.: 04
Date: 04-May-2021
14
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title: A Randomized, Open-Label, Phase 2 Study of Nivolumab in Combination 
with Ipilimumab or Nivolumab Monotherapy in Participants with Advanced or Metastatic 
Solid Tumors of High Tumor Mutational Burden (TMB-H)
(CheckMate 848: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 848)
Study Phase: 2
Rationale: Blockade of the PD-1 pathway has proven effective in generating robust anti-tumor 
immune responses. Nivolumab, an anti-PD-1 blocking antibody, has demonstrated overall survival 
benefit in multiple tumors including non-squamous cell lung cancer, squamous cell lung cancer, 
melanoma, renal cell carcinoma and head and neck cancer. Recent data across multiple tumor types 
support the hypothesis that patients with tumors harboring increased somatic mutations due to 
DNA mismatch-repair deficiencies are more likely to respond to anti-PD-1/PD-L1 and 
anti-CTLA-4 blockade. Tumor mutational burden (TMB) refers to the total number of somatic 
mutations that exist within a tumor’s genome. A subset of these mutations may result in expressed 
proteins that are not recognized by the host’s immune system as self, and therefore has the potential 
to be immunogenic and more susceptible to an immune-mediated anti-tumor response. The 
primary goal of this study is to demonstrate the clinical activity of nivolumab in combination with 
ipilimumab in multiple tumor types based on the status of TMB.
Tumors with a high mutational burden may have a higher number of neo-antigens which, in 
principle, would be expected to be more immunogenic than tumors with comparatively low 
mutational burden.1 Therefore, high TMB has been hypothesized to correlate with improved 
efficacy in patients treated with immune-oncology (IO) therapies. This hypothesis has been 
supported by multiple publications across IO therapies, tumor types, and lines of treatment.
The available data suggest that, in addition to PD-L1, TMB is also an important predictive 
biomarker of the clinical efficacy of IO therapy. Therefore, patients of TMB-H across multiple 
solid tumors will be selected for participation in this clinical study
Study Population:
For entry into the study, the following criteria MUST be met.
Key Inclusion Criteria (See protocol Section 6.1 for full list of criteria)
1) Type of Participant and Target Disease Characteristics
a) Participants with a refractory, metastatic, or unresectable histologically or cytologically 
confirmed solid malignant tumor with TMB-H who are refractory to standard local 
therapies per local management guidelines, or for which no standard treatment per local 
management guidelines is available (salvage setting).
b) The IRT must be provided with the results of both tissue and blood TMB-H testing for 
eligible participants prior to randomization. Both results are utilized for stratification 
purposes (see Figure 1).
Protocol Amendment No.: 04
Date: 04-May-2021
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Clinical Protocol
CA209848
BMS-936558
nivolumab
Figure 1-1:
TMB Pre-Screening/Screening
i)
Participants must have either tTMB or bTMB ≥ 10 mut/Mb (tTMB ≥ 10 mut or the new 
cutoff value of bTMB determined by the 1st interim analysis)
ii) Prior results of TMB-H obtained with F1CDx assay (tissue) or bTMB-validated CLIA
assay from Foundation Medicine (blood) are acceptable for eligibility purposes. 
(1) If tTMB result is available, blood sample must be provided for central TMB testing
(2) If bTMB result is available, tissue sample must be provided for central TMB testing 
(3) If neither tTMB nor bTMB result is available, both tissue and blood samples must 
be provided for central TMB testing
iii) TMB results obtained from any other assays are not acceptable for eligibility.
c) Participants must have measurable disease for response assessment as per RECIST 1.1 for 
solid tumors other than CNS, and RANO criteria for primary CNS malignancies.
2) Age and Reproductive Status
a) Males and Females, ages of 12 years and older. Sites in Belgium and the Netherlands will 
not include adolescents and only enroll participants 18 years or older.
Exclusion Criteria (See protocol Section 6.2 for full list of criteria)
3) Prior/Concomitant Therapy
a) Participants who received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways
Protocol Amendment No.: 04
Date: 04-May-2021
16
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v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Objectives and Endpoints:
Objectives
Endpoints
Primary
•
To estimate BICR-assessed objective response rate (ORR) 
in participants of tTMB-H treated with nivolumab 
combined with ipilimumab
•
BICR-assessed ORR using RECIST 1.1, 
and Response Assessment for Neuro-
Oncology (RANO) criteria in primary CNS 
tumors 
•
To estimate BICR-assessed ORR in participants of bTMB-
H treated with nivolumab combined with ipilimumab
• BICR-assessed ORR using RECIST 1.1, and 
RANO criteria in primary CNS tumors
Secondary
•
To estimate the BICR-assessed duration of response 
(DOR) and time to response (TTR) in participants of 
tTMB-H treated with nivolumab combined with 
ipilimumab
•
BICR-assessed DOR
•
BICR-assessed TTR
•
To estimate the BICR-assessed DOR and TTR in 
participants of bTMB-H treated with nivolumab combined 
with ipilimumab
• BICR-assessed DOR
• BICR-assessed TTR
•
To evaluate the BICR-assessed ORR, DOR and TTR in 
participants of tTMB-H treated with nivolumab 
monotherapy
• BICR-assessed ORR
• BICR-assessed DOR
• BICR-assessed TTR
•
To evaluate the BICR-assessed ORR, DOR and TTR in 
participants of bTMB-H treated with nivolumab 
monotherapy
• BICR-assessed ORR
• BICR-assessed DOR
• BICR-assessed TTR
•
To evaluate Investigator-assessed ORR, DOR, TTR in 
participants of tTMB-H treated with  nivolumab combined 
with ipilimumab and nivolumab monotherapy
• Investigator-assessed ORR
• Investigator-assessed DOR
• Investigator-assessed TTR
•
To evaluate Investigator-assessed ORR, DOR, TTR in 
participants of bTMB-H treated with nivolumab combined 
with ipilimumab and nivolumab monotherapy
• Investigator-assessed ORR
• Investigator-assessed DOR
• Investigator-assessed TTR
•
To evaluate BICR-assessed and investigator-assessed 
clinical benefit rate (CBR) in participants of tTMB-H 
treated with nivolumab combined with ipilimumab and 
nivolumab monotherapy
• BICR-assessed CBR
• Investigator-assessed CBR
•
To evaluate BICR-assessed and investigator-assessed CBR 
in participants of bTMB-H treated with nivolumab 
combined with ipilimumab and nivolumab monotherapy
• BICR-assessed CBR
• Investigator-assessed CBR
•
To evaluate BICR-assessed and investigator-assessed 
progression free survival (PFS) in participants of tTMB-H 
treated with nivolumab combined with ipilimumab and 
nivolumab monotherapy
• BICR-assessed PFS
• Investigator-assessed PFS
•
To evaluate BICR-assessed and investigator-assessed PFS 
in participants of bTMB-H treated with nivolumab 
combined with ipilimumab and nivolumab monotherapy
• BICR-assessed PFS
• Investigator-assessed PFS
•
To evaluate overall survival (OS) in participants of tTMB-
H treated with nivolumab combined with ipilimumab and 
nivolumab monotherapy
• Overall survival
Protocol Amendment No.: 04
Date: 04-May-2021
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Clinical Protocol
CA209848
BMS-936558
nivolumab
Objectives
Endpoints
•
To evaluate OS in participants of bTMB-H treated with
nivolumab combined with ipilimumab and nivolumab 
monotherapy
• Overall survival
• To assess overall safety and tolerability 
• AEs, clinical laboratory values, or other 
safety biomarkers
Exploratory
•
To assess overall health status and health utility 
•
Mean change from baseline in the 3-level 
version of the EQ-5D (EQ-5D-3L) visual 
analog scale (VAS) and utility index, 
respectively
•
To assess cancer-related symptoms and quality of life 
•
Mean change from baseline in domains and 
symptoms in the 30-item European 
Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire 
(EORTC QLQ-C30).
• To characterize the pharmacokinetics of 
nivolumab/ipilimumab and explore exposure-response 
relationships with respect to safety and efficacy
•
Population pharmacokinetic parameters 
•
To assess immunogenicity of nivolumab/ipilimumab
•
Incidence of anti-nivolumab/anti-
ipilimumab antibodies
•
To characterize tumor and host biomarkers 
•
Analysis of genomic, molecular, and 
immunohistochemical profiles
•
To assess OS and BICR-assessed and investigator-
assessed ORR, DOR, PFS in all participants of TMB-H 
treated with nivolumab combined with ipilimumab and 
nivolumab monotherapy
•
OS
•
BICR-assessed ORR
•
BICR-assessed DOR 
•
BICR-assessed PFS 
•
Investigator-assessed ORR
•
Investigator-assessed DOR
•
Investigator-assessed PFS 
Overall Design:
The study will enroll participants diagnosed with select advanced or metastatic solid tumors with 
either tissue (tTMB) or blood TMB (bTMB) ≥ 10 mut/Mb (TMB-H). Both tissue and blood TMB 
will be assessed prior to randomization. 
Participants without a prior known tTMB-H status available via F1CDx assay, or a prior known 
bTMB-validated CLIA result available from Foundation Medicine, will provide consent for pre-
screening and TMB status determination, but consent for further screening procedures and study 
treatment should be deferred until TMB-H status is established. Screening process can continue 
when the participant’s status is TMB-H. 
Participants with a prior known result of tTMB-H via F1CDx assay or bTMB-H from 
Foundation Medicine may proceed immediately with full screening procedures. Both tissue and 
blood TMB will be assessed prior to randomization. Prior results of tTMB or bTMB obtained from 
Protocol Amendment No.: 04
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Clinical Protocol
CA209848
BMS-936558
nivolumab
any other assays except the ones described above are not acceptable, including prior result of tTMB 
obtained via Foundation One assay.
Once the TMB-H status is determined, this study will consist of three phases: screening, treatment, 
and follow-up. 
Efficacy will be evaluated using tumor specific response criteria, ie, RECIST 1.1 for solid tumors2
and RANO criteria3 for primary CNS tumors. 
The primary analysis of BICR-assessed ORR in participants with either bTMB-H or tTMB-H will 
be conducted after a minimum of 12 months following LPFT. This study will end when analysis 
of the primary endpoint is complete. Additional survival analysis may be conducted for up to 
5 years beyond the primary endpoint analysis.
Details regarding the assessments to be performed during these phases are outlined in Section 2
Schedule of Activities. 
The study design schematic is presented below:
Figure 1-2:
Study Design Schematic
Note: Mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent participants will 
not be included in these countries.
Physical examinations, vital sign measurements, outcome questionnaires, biomarker collection, 
and clinical laboratory evaluations will be performed at selected times throughout study 
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Date: 04-May-2021
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Clinical Protocol
CA209848
BMS-936558
nivolumab
participation. Participants will be closely monitored for AEs throughout the study. Blood samples 
will be collected for safety, pharmacokinetic (PK) and biomarker analysis. 
Participants with progressive disease while on treatment with nivolumab monotherapy may be 
allowed to be treated beyond progression with nivolumab and ipilimumab (Arm B rollover – see 
Section 7.4.3).
Number of Participants: 
The number of randomized participants will range from approximately 183 to 342 based on 1) the 
actually observed concordance between tTMB-H and bTMB-H, and 2) the new bTMB cutoff 
determined by the interim analysis should it occur. The per tumor type cap is approximately 15% 
of the total sample size.
A total of 76 TMB-evaluable subjects in the salvage setting treated with nivolumab + ipilimumab 
are required for each of the tTMB and bTMB populations. The sample size determination was not 
based on power consideration, but to provide precision on the estimation of ORR and DOR for 
TMB-high participants treated with nivolumab + ipilimumab. The following table summarizes the 
exact 95% CIs for a sample size of 76 in the nivolumab + ipilimumab arm when observed ORRs 
range from 25%-50%.
Sample size
Number of responses
Response rate
95% Confidence interval
76
19
0.25
(0.16, 0.36)
76
22
0.29
(0.19, 0.40)
76
24
0.32
(0.21, 0.43)
76
26
0.34
(0.24, 0.46)
76
28
0.37
(0.26, 0.49)
76
30
0.39
(0.28, 0.51)
76
32
0.42
(0.31, 0.54)
76
34
0.45
(0.33, 0.57)
76
36
0.47
(0.36, 0.59)
76
38
0.50
(0.38, 0.62)
Treatment Arms and Duration:
Study treatment: 
Study Drugs for CA209848
Medication
Potency
IMP/
Non-IMP
Nivolumab
(BMS-936558-01)
Solution for Injection
100 mg (10 mg/mL) and 40 mg (10 mg/mL)
IMP
Protocol Amendment No.: 04
Date: 04-May-2021
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Clinical Protocol
CA209848
BMS-936558
nivolumab
Study Drugs for CA209848
Medication
Potency
IMP/
Non-IMP
Ipilimumab
(BMS-734016) Solution for Injection
200 mg
(5 mg/mL)
IMP
Treatments Administered
The selection and timing of dose for each participant is as follows:
Selection and Timing of Dose
Treatment 
Arm
Study 
Treatment
Participant 
Age/Weight
Unit dose 
strength(s)/
Dosage level(s)
Frequency of 
Administration
Route of 
Administration
Arm A or Arm 
B rollover: 
nivolumab in 
combination 
with 
ipilimumab
Nivolumab
Adults and 
adolescents 
≥40kg
240 mg
Q2 weeks up to 
24 months
IV
Adolescents 
< 40kg
3 mg/kg
Q2 weeks up to 
24 months
IV
Ipilimumab
All participants
1 mg/kg
Q6 weeks up to 
24 months
IV
Arm B: 
nivolumab 
monotherapy
Nivolumab
Adults and 
adolescents 
≥40kg
480 mg
Q4 weeks up to 
24 months
IV
Adolescents 
< 40kg
6 mg/kg
Q4 weeks up to 
24 months
IV
Note: Mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent participants will 
not be included in these countries.
Data Monitoring Committee: Yes
To provide independent oversight of safety, efficacy, and study conduct, a data monitoring 
committee (DMC) will be instituted. The DMC will meet regularly to ensure that participant safety 
is carefully monitored. The DMC will convene additional ad hoc meetings if necessary. Following 
each meeting, the DMC will recommend continuation, modification, or discontinuation of the 
study based on observed toxicities. The DMC will review the interim analysis results and 
determine whether the cut-off value for bTMB should be adjusted for the first interim analysis and 
whether criteria for superiority are met at that time for the tTMB interim analysis; the DMC will 
also review the bTMB final analysis results. A separate DMC charter will describe the activities 
of this committee in more detail.
Blinded Independent Central Review
A Blinded Independent Central Review (BICR) committee will be formed for standardized 
response assessment. Images will be submitted to an imaging third-party vendor for central review. 
Protocol Amendment No.: 04
Date: 04-May-2021
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Clinical Protocol
CA209848
BMS-936558
nivolumab
Imaging acquisition guidelines and submission process will be outlined in the CA209848 Study 
Imaging Manual to be provided by the vendors. For tumor types which require clinical indicators 
as part of the standard response assessment, the clinical indicator data will be provided to the BICR
along with imaging data.
REFERENCES
1
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determine sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348:124 
8.
2
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.
3
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 28;1 
3059-3067. 2010.
Protocol Amendment No.: 04
Date: 04-May-2021
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5.0
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1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA209848)
Procedure
Screening Visit
Notes
Pre-screening for TMB-H
Participants must have TMB-H status (tissue and/or blood) confirmed via F1CDx assay (tissue) or bTMB-validated 
CLIA assay from Foundation Medicine (blood) prior to signing consent for other eligibility procedures (see details in
Section 6.1).
Prior TMB-H results ≥ 10 mut/Mb obtained from F1CDx assay (tissue) or bTMB-validated CLIA assay from 
Foundation Medicine (blood) are acceptable for eligibility purposes. 
Participants who do not have TMB-H status (tissue or blood) with the assays described above must sign a pre-
screening informed consent form and have tissue and / or blood samples provided for central testing. See 
details below for Biomarkers Collection.
Both tissue and blood results obtained with these assays are required prior to randomization, and both can be done 
under the pre-screening, if not previously available; as long as at least one of the results is ≥ 10 mut/Mb (tTMB ≥ 
10 mut/Mb or the new cutoff value of bTMB determined by the 1st interim analysis), the participant may sign 
the study Informed Consent Form and proceed to additional screening procedures.
Biomarkers Collection
Tumor tissue 
Refer to 
Table 9.8-1 and 
Table 9.8-2:
Biomarker 
Tissue and 
Blood Samples: 
Arm B 
Nivolumab 
Monotherapy
If prior tTMB results are submitted, the tTMB assay must have been F1CDx. 
Foundation One or any other assays are not acceptable.
For patients without prior tTMB results from F1CDx: A formalin-fixed, paraffin-embedded 
tumor tissue (FFPET) block (preferred) or 25 unstained slides of tumor tissue (archival tissue or 
fresh biopsy) is required. 10 slides are required for TMB eligibility evaluation and 15 slides are 
required for PD-L1 and other tumor-based biomarker evaluations.
For patients with prior tTMB results from F1CDx: A formalin-fixed, paraffin-embedded tumor 
tissue (FFPET) block (preferred) or 15 unstained slides of tumor tissue (archival tissue or fresh 
biopsy) is required from all participants for PD-L1 and other tumor-based biomarker evaluations. 
Fresh biopsies are preferred; however, archival samples are acceptable if obtained within 
9 months of signing the initial consent form ([pre-screening] and no additional intervening 
therapy (excluding palliative therapy) in between).
If a fresh biopsy is warranted, the participant must have a lesion that can be biopsied at an 
acceptable clinical risk as judged by the investigator in order to be eligible for the study.
Protocol Amendment No.: 04
Date: 04-May-2021
23
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA209848)
Procedure
Screening Visit
Notes
If the required number of slides are not available, the BMS Medical Monitor must be consulted 
upfront, prior to enrollment, to discuss acceptability of the tissue available. 
Collection of blood sample for TMB 
testing 
Refer to 
Table 9.8-1 and 
Table 9.8-2:
Biomarker 
Tissue and 
Blood Samples: 
Arm B 
Nivolumab 
Monotherapy
If prior bTMB-validated CLIA results are submitted, bTMB testing must have been done by 
Foundation Medicine. Any other assays are not acceptable.
A fresh blood sample must be submitted (all participants). 
Eligibility Assessments
Informed consent
X
For participants 18 years of age or older, and legal representatives of participants age between 12 
and less than 18 years old
Assent form
X
For participants ages between 12 and less than 18 years old; should be obtained per local laws and 
regulations
Inclusion/Exclusion criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first dose
Medical history
X
Including diagnostic pathology report, TMB level, dMMR, and MSI-High status (if previously 
performed), and all previous anti-cancer treatments 
Safety Assessments
Pregnancy test 
X
WOCBP only: Serum or urine (minimum sensitivity 25 IU/L or equivalent units of HCG) to be 
done at screening visit and repeated within 24 hours of first dose of study therapy
Concomitant medications
X
Within 14 days prior to first dose 
Physical examination
X
Including height and weight within 14 days prior to randomization.
Vital signs
X
Temperature, blood pressure, and heart rate within 14 days prior to randomization.
Performance Status
X
Within 14 days prior to randomization. See Appendix 6 for ECOG performance status (for 
participants ≥ 16 years old with solid tumors, Appendix 9 for Karnofsky (participants ≥ 16 years 
old with CNS as primary tumor) and Lansky (for all participants < 16 years old) 
Protocol Amendment No.: 04
Date: 04-May-2021
24
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA209848)
Procedure
Screening Visit
Notes
Assessment of signs and symptoms
X
Within 14 days prior to randomization.
Serious adverse events (SAE) 
Assessment
X
SAEs collected from time of consent.
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection collected from time of 
consent.
Electrocardiogram (ECG)
X
Within 14 days prior to randomization.
Laboratory Tests
Hematology and chemistry
X
See Section 9.4.3 Clinical Safety Laboratory Assessments 
Hepatitis B and hepatitis C testing
X
Within 28 days prior to randomization: Hepatitis B and C testing (HBsAg and anti-HCV [HCV-
RNA, if needed])
HIV Testing
X
Testing for HIV must be performed at sites where mandated locally.
Thyroid function testing
X
Thyroid panel including TSH, free T3, and free T4 within 14 days prior to randomization
Efficacy Assessments
Body Imaging 
X
For Solid Tumors: Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all 
other known and/or suspected sites of disease, within 28 days prior to date of first dose.
Brain Imaging
X
For Primary CNS Tumor: MRI of the brain without and with gadolinium-based contrast should be 
performed during screening period.
For Solid Tumors: Participants with known or suspected brain metastases, MRI of the brain 
without and with contrast is required unless participant has completed an imaging study of the 
brain within 28 days of study drug administration. CT of the brain without and with contrast can be 
performed if MRI is contraindicated. See Section 9.1.1 for further details
Other: Bone Scan
As clinically indicated per local standards. See Section 9.1.1 for further details. 
IRT/Clinical Drug Supplies
Contact IRT
X
IRT contact must occur as follows:
For participant number assignment at the time informed consent is obtained.
Within 3 days prior to dosing for study drug vial assignment.
Protocol Amendment No.: 04
Date: 04-May-2021
25
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Note: 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.
Note: Mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent participants will not be included in these countries.
Protocol Amendment No.: 04
Date: 04-May-2021
26
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-2:
On Study Assessments Treatment Phase - Arm A - Nivolumab in Combination with Ipilimumab 
(CA209848)
Procedure
Day 1
Every 2 weeks (i.e., 
every subsequent cycle 
Day 1) 
(± 3 Days)
Every 6 weeks 
(i.e. every 3 cycles 
Day 1 (± 3 Days)
Every 12 weeks 
(i.e. every 6 
cycles Day 1) 
(± 7 Days)
Notes
For the purposes of this table, a cycle 
refers to nivolumab every 2 weeks
Safety Assessments
Pregnancy test 
X
X (see note)
WOCBP only: Serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) to be done 
within 24h prior to first dose of study 
treatment, and then every 4 weeks 
(± 1 week) regardless of dosing schedule. 
Weight
X
X (see note)
X (see note)
Weight must be assessed within 72h prior 
to dosing for adolescents < 40kg, and 
every 6 weeks (i.e., every 3 cycles) for 
adults and adolescents ≥ 40kg
Physical examination and 
ECOG, Karnofsky or Lansky 
Performance Status 
X
Within 72h prior to dosing. See Appendix 
6 for ECOG performance status (for 
participants ≥ 16 years old with solid 
tumors), and Appendix 9 for Karnofsky 
(participants ≥ 16 years old with CNS as 
primary tumor) and Lansky (for all 
participants < 16 years old)
Targeted physical examination 
and ECOG, Karnofsky or 
Lansky Performance Status 
X
Must be performed within 72h prior to 
dosing and include at a minimum the 
cardiovascular, gastrointestinal, and 
pulmonary body systems. See Appendix 6 
for ECOG performance status (for 
participants ≥ 16 years old with solid 
tumors), and Appendix 9 for Karnofsky 
(participants ≥ 16 years old with CNS as 
primary tumor) and Lansky (for all 
participants < 16 years old)
Protocol Amendment No.: 04
Date: 04-May-2021
27
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-2:
On Study Assessments Treatment Phase - Arm A - Nivolumab in Combination with Ipilimumab 
(CA209848)
Procedure
Day 1
Every 2 weeks (i.e., 
every subsequent cycle 
Day 1) 
(± 3 Days)
Every 6 weeks 
(i.e. every 3 cycles 
Day 1 (± 3 Days)
Every 12 weeks 
(i.e. every 6 
cycles Day 1) 
(± 7 Days)
Notes
For the purposes of this table, a cycle 
refers to nivolumab every 2 weeks
Vital signs
X
X
Temperature, blood pressure, and heart 
rate. Must be performed prior to dosing.
Concomitant medication
Continuously
Adverse events (including 
serious and non-serious)
assessment
Continuously
Record at each visit. All AEs (SAEs or 
non-serious AEs), including those 
associated with SARS-CoV-2 infection, 
must be collected continuously throughout 
the treatment period. Adverse events and 
laboratory values will be graded according 
to the NCI-CTCAE version 5.
Laboratory Assessments
Hematology and chemistry
X
X
See Section 9.4.3 Clinical Safety 
Laboratory Assessments. Must be 
performed within 72h prior to dosing.
Thyroid function testing
X
X (see note)
Thyroid function testing should be done 
every 4 weeks (i.e., Day 1 of every other 
cycle) for the first 10 cycles, and then 
every 8 weeks until completion of study 
treatment. Must be performed within 72h 
prior to dosing.
Pharmacokinetic Assessment
See Section 9.5
Immunogenicity Assessment
See Section 9.5
Biomarker assessment
See Section 9.8
Collection of tumor tissue for 
biomarkers upon disease 
progression
See Section 9.8
If a biopsy has been performed and tissue 
is available, participants are requested to 
submit fresh tumor tissue for biomarker 
Protocol Amendment No.: 04
Date: 04-May-2021
28
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-2:
On Study Assessments Treatment Phase - Arm A - Nivolumab in Combination with Ipilimumab 
(CA209848)
Procedure
Day 1
Every 2 weeks (i.e., 
every subsequent cycle 
Day 1) 
(± 3 Days)
Every 6 weeks 
(i.e. every 3 cycles 
Day 1 (± 3 Days)
Every 12 weeks 
(i.e. every 6 
cycles Day 1) 
(± 7 Days)
Notes
For the purposes of this table, a cycle 
refers to nivolumab every 2 weeks
research. Tissue submission is optional 
and biopsy is not required by protocol.
Additional research collection
See Section 9.8.1
Efficacy Assessments
Body Imaging
X (see note)
For Solid Tumors: Tumor Assessments 
should occur every 12 weeks (± 7 days) 
until BICR confirmation of disease 
progression or treatment 
discontinuation(including treatment 
beyond progression), whichever comes 
later. 
See Section 9.1.1 for further details.
Brain Imaging
X (see note)
For Primary CNS neoplasms: MRI without 
and with contrast; should have MRI of the 
brain approximately every 12 weeks (± 7 
days) until BICR confirmation of disease 
progression or treatment 
discontinuation(including treatment 
beyond progression), whichever comes 
later. 
For Solid Tumors: Participants with a 
history of brain metastasis or symptoms 
should have a surveillance brain MRI per 
standard of care (approximately 12 weeks) 
or sooner if clinically indicated. 
See Section 9.1.1 for further details.
Protocol Amendment No.: 04
Date: 04-May-2021
29
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-2:
On Study Assessments Treatment Phase - Arm A - Nivolumab in Combination with Ipilimumab 
(CA209848)
Procedure
Day 1
Every 2 weeks (i.e., 
every subsequent cycle 
Day 1) 
(± 3 Days)
Every 6 weeks 
(i.e. every 3 cycles 
Day 1 (± 3 Days)
Every 12 weeks 
(i.e. every 6 
cycles Day 1) 
(± 7 Days)
Notes
For the purposes of this table, a cycle 
refers to nivolumab every 2 weeks
Other: Bone Scan
X (see note)
As clinically indicated per local standards. 
See Section 9.1.1 for further details.
Outcomes Research
EORTC QLQ-C30 and EQ-5D 
questionnaires
X
X
Each assessment should be completed at 
the start of the clinic visit prior to dosing 
or any study-related procedures. Only
applies to participants ≥18 years of age at 
baseline. If the dose is delayed, then PRO 
completion should also be delayed and 
synchronized with the delayed dosing.
See Section 9.10 for more details. 
Study Treatment
Contact IRT
X
X
Within 3 days prior to dosing for study 
drug vial assignment
Nivolumab 240 mg Q2W 
(adults and adolescents ≥ 
40kg)
X
X
Participants should be dosed within 3 days 
from the scheduled dose. Participants may 
be dosed no less than 12 days from the 
previous dose.
Nivolumab 3 mg/kg Q2W 
(adolescents < 40 kg)
X
X
Participants should be dosed within 3 days 
from the scheduled dose. Participants may 
be dosed no less than 12 days from the 
previous dose.
Ipilimumab 1 mg/kg Q6W (all 
participants)
X
X (see note)
Ipilimumab should be administered every 
6 weeks (i.e., every 3 cycles, Day 1). 
Participants should be dosed within 3 days 
from the scheduled dose
Note: Mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent participants will not be included in these countries.
Protocol Amendment No.: 04
Date: 04-May-2021
30
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-3:
On Study Assessments Treatment Phase - Arm B - Nivolumab Monotherapy (CA209848)
Procedure
Day 1
Every 4 weeks
(i.e. each subsequent 
cycle Day 1)
(± 3 Days)
Every 12 weeks 
(i.e. every 3 cycles 
Day 1)
(± 7 Days)
Notes
For the purposes of this table, a cycle refers to nivolumab every 
4 weeks
Safety Assessments
Pregnancy test 
X
X
WOCBP only: Serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) to be done within 24h prior to 
first dose of study treatment, and then every 4 weeks (± 1 week) 
regardless of dosing schedule. 
Weight
X
X
Weight must be assessed within 72h prior to dosing 
Physical examination 
and ECOG, Karnofsky 
or Lansky Performance 
Status
X
Within 72 hours prior to dosing. See Appendix 6 for ECOG 
performance status (for participants ≥ 16 years old with solid 
tumors), and Appendix 9 for Karnofsky (participants ≥ 16 years old 
with CNS as primary tumor) and Lansky (for all participants < 16 
years old)
Targeted physical 
examination and ECOG, 
Karnofsky or Lansky 
Performance Status
X
Targeted examination must be performed within 72 hours prior to 
dosing and include at a minimum the cardiovascular, 
gastrointestinal, and pulmonary body systems. See Appendix 6 for 
ECOG performance status (for participants ≥ 16 years old with 
solid tumors), and Appendix 9 for Karnofsky (participants ≥ 16 
years old with CNS as primary tumor) and Lansky (for all 
participants < 16 years old)
Vital signs
X
X
Temperature, blood pressure, and heart rate. Must be performed 
prior to study drug administration. 
Concomitant medication
Continuously
Adverse events 
(including serious and 
non-serious) assessment
Continuously
Record at each visit. All AEs (SAEs or non-serious AEs), including 
those associated with SARS-CoV-2 infection, must be collected 
continuously throughout the treatment period. Adverse events and 
laboratory values will be graded according to the NCI-CTCAE 
version 5.
Protocol Amendment No.: 04
Date: 04-May-2021
31
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-3:
On Study Assessments Treatment Phase - Arm B - Nivolumab Monotherapy (CA209848)
Procedure
Day 1
Every 4 weeks
(i.e. each subsequent 
cycle Day 1)
(± 3 Days)
Every 12 weeks 
(i.e. every 3 cycles 
Day 1)
(± 7 Days)
Notes
For the purposes of this table, a cycle refers to nivolumab every 
4 weeks
Laboratory Assessments
Hematology and 
chemistry
X
X
See Section 9.4.3 Clinical Safety Laboratory Assessments. Must be 
performed within 72h prior to study drug administration.
Thyroid function testing
X
X (see notes)
Thyroid function testing should be done every 4 weeks (i.e., Day 1 
of every cycle) for the first 5 cycles, and then every 8 weeks (i.e., 
Day 1 of every other cycle) until completion of study treatment.
Must be performed within 72h prior to study drug administration.
Pharmacokinetic 
Assessment
See Section 9.5
Immunogenicity 
Assessment
See Section 9.5
Biomarker assessments
See Section 9.8
Collection of tumor 
tissue for biomarkers 
upon disease progression
See Section 9.8
If a biopsy has been performed and tissue is available, participants 
are requested to submit fresh tumor tissue for biomarker research. 
Tissue submission is optional and biopsy is not required by 
protocol.
Additional research 
collection
See Section 9.8
Efficacy Assessments
Body Imaging
X
For Solid Tumors: Tumor Assessments should occur every 12 
weeks (± 7 days) until BICR confirmation of disease progression or
treatment discontinuation(including treatment beyond progression), 
whichever comes later. 
See Section 9.1.1 for further details.
Protocol Amendment No.: 04
Date: 04-May-2021
32
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-3:
On Study Assessments Treatment Phase - Arm B - Nivolumab Monotherapy (CA209848)
Procedure
Day 1
Every 4 weeks
(i.e. each subsequent 
cycle Day 1)
(± 3 Days)
Every 12 weeks 
(i.e. every 3 cycles 
Day 1)
(± 7 Days)
Notes
For the purposes of this table, a cycle refers to nivolumab every 
4 weeks
Brain Imaging
X
For Primary CNS neoplasms: MRI without and with contrast 
should have MRI of the brain approximately every 12 weeks (± 7 
days) until BICR confirmation of disease progression or treatment 
discontinuation (including treatment beyond progression), 
whichever comes later.
For solid tumor: Participants with a history of brain metastasis or 
symptoms should have a surveillance brain MRI per standard of 
care (approximately 12 weeks) or sooner if clinically indicated. 
See Section 9.1.1 for further details.
Other: Bone Scan
X
As clinically indicated per local standards. See Section 9.1.1 for 
further details.
Outcomes Assessments
EORTC QLQ-C30 and 
EQ-5D questionnaires
X
X
Each assessment should be completed at the start of the clinic 
visit prior to dosing or any study-related procedures. Only applies 
to participants ≥18 years of age at baseline. If the dose is delayed, 
then PRO completion should also be delayed and synchronized
with the delayed dosing. See Section 9.10 for more details. 
Study Treatment 
Contact IRT
X
X
Within 3 days prior to dosing for study drug vial assignment
Nivolumab 480 mg 
Q4W (adults and 
adolescents ≥ 40 kg)
X
X
Participants should be dosed within 3 days from the scheduled 
dose. The minimum interval between doses is 22 days.
Nivolumab 6 mg/kg 
Q4W (adolescents < 
40 kg)
X
X
Participants should be dosed within 3 days from the scheduled 
dose. The minimum interval between doses is 22 days.
Note: Mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent participants will not be included in these countries.
Protocol Amendment No.: 04
Date: 04-May-2021
33
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-4:
On Study Assessments Treatment Phase – Arm B Rollover – Participants Treated with Nivolumab in 
Combination with Ipilimumab After Disease Progression During Nivolumab Monotherapy (CA209848)
Procedure
Day 1
Every 2 weeks (i.e. 
every subsequent cycle 
Day 1) 
(± 3 Days)
Every 6 weeks 
(i.e. every 3 cycles 
Day 1 (± 3 Days)
Every 12 weeks 
(i.e. every 6 
cycles Day 1) 
(± 7 Days)
Notes
For the purposes of this table, a cycle 
refers to nivolumab every 2 weeks
Safety Assessments
Pregnancy test 
X
X (see note)
WOCBP only: Serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) to be done 
within 24 h prior to first dose of study 
treatment, and then every 4 weeks 
(± 1 week) regardless of dosing schedule. 
Weight
X
X (see note)
X (see note)
Weight must be assessed within 72h prior 
to dosing for adolescents < 40 kg, and 
every 6 weeks for adults and adolescents ≥ 
40 kg
Physical examination and 
ECOG, Karnofsky or Lansky 
Performance Status 
X
Within 72 hours prior to dosing. See 
Appendix 6 for ECOG performance status 
(for participants ≥ 16 years old with solid 
tumors), and Appendix 9 for Karnofsky 
(participants ≥ 16 years old with CNS as 
primary tumor) and Lansky (for all 
participants < 16 years old)
Targeted physical examination 
and ECOG, Karnofsky or 
Lansky Performance Status 
X
Targeted examination must be performed 
within 72 hours prior to dosing and 
include at a minimum the cardiovascular, 
gastrointestinal, and pulmonary body 
systems. See Appendix 6 for ECOG 
performance status (for participants ≥ 16 
years old with solid tumors), and
Appendix 9 for Karnofsky (participants ≥ 
16 years old with CNS as primary tumor) 
and Lansky (for all participants < 16 years 
old)
Protocol Amendment No.: 04
Date: 04-May-2021
34
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-4:
On Study Assessments Treatment Phase – Arm B Rollover – Participants Treated with Nivolumab in 
Combination with Ipilimumab After Disease Progression During Nivolumab Monotherapy (CA209848)
Procedure
Day 1
Every 2 weeks (i.e. 
every subsequent cycle 
Day 1) 
(± 3 Days)
Every 6 weeks 
(i.e. every 3 cycles 
Day 1 (± 3 Days)
Every 12 weeks 
(i.e. every 6 
cycles Day 1) 
(± 7 Days)
Notes
For the purposes of this table, a cycle 
refers to nivolumab every 2 weeks
Vital signs
X
X
Temperature, blood pressure, and heart 
rate. Must be performed prior to dosing. 
Concomitant medication
Continuously
Adverse events (including 
serious and non-serious) 
assessment
Continuously
Record at each visit. All AEs (SAEs or 
non-serious AEs), including those 
associated with SARS-CoV-2 infection, 
must be collected continuously throughout 
the treatment period. Adverse events and 
laboratory values will be graded according 
to the NCI-CTCAE version 5.
Laboratory Assessments
Hematology and chemistry
X
X
See Section 9.4.3 Clinical Safety 
Laboratory Assessments. Must be 
performed within 72h prior to dosing.
Thyroid function testing
X
X (see note)
Thyroid function testing should be done 
every 4 weeks (i.e., Day 1 of every other 
cycle) for the first 10 cycles, and then 
every 8 weeks until completion of study 
treatment. Must be performed within 72h 
prior to dosing.
Pharmacokinetic Assessment
See Section 9.5
Immunogenicity Assessment
See Section 9.5
Biomarker assessment
See Section 9.8
Collection of tumor tissue for 
biomarkers upon disease 
progression
See Section 9.8
If a biopsy has been performed and tissue 
is available, participants are requested to 
submit fresh tumor tissue for biomarker 
Protocol Amendment No.: 04
Date: 04-May-2021
35
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-4:
On Study Assessments Treatment Phase – Arm B Rollover – Participants Treated with Nivolumab in 
Combination with Ipilimumab After Disease Progression During Nivolumab Monotherapy (CA209848)
Procedure
Day 1
Every 2 weeks (i.e. 
every subsequent cycle 
Day 1) 
(± 3 Days)
Every 6 weeks 
(i.e. every 3 cycles 
Day 1 (± 3 Days)
Every 12 weeks 
(i.e. every 6 
cycles Day 1) 
(± 7 Days)
Notes
For the purposes of this table, a cycle 
refers to nivolumab every 2 weeks
research. Tissue submission is optional 
and biopsy is not required by protocol.
Additional research collection
See Section 9.8.1
Efficacy Assessments
Body Imaging
X (see note)
For Solid Tumors: Tumor Assessments 
should occur every 12 weeks (± 7 days) 
until BICR confirmation of disease 
progression or treatment discontinuation
(including treatment beyond progression), 
whichever comes later. 
See Section 9.1.1 for further details.
Brain Imaging
X (see note)
For Primary CNS neoplasms: MRI without 
and with contrast; should have MRI of the 
brain approximately every 12 weeks (± 7 
days) until BICR confirmation of disease 
progression or treatment discontinuation
(including treatment beyond progression), 
whichever comes later.
For solid tumors: Participants with a 
history of brain metastasis or symptoms 
should have a surveillance brain MRI per 
standard of care (approximately 12 weeks) 
or sooner if clinically indicated. 
See Section 9.1.1 for further details.
Other: Bone Scan
X (see note)
As clinically indicated per local standards. 
See Section 9.1.1 for further details.
Protocol Amendment No.: 04
Date: 04-May-2021
36
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-4:
On Study Assessments Treatment Phase – Arm B Rollover – Participants Treated with Nivolumab in 
Combination with Ipilimumab After Disease Progression During Nivolumab Monotherapy (CA209848)
Procedure
Day 1
Every 2 weeks (i.e. 
every subsequent cycle 
Day 1) 
(± 3 Days)
Every 6 weeks 
(i.e. every 3 cycles 
Day 1 (± 3 Days)
Every 12 weeks 
(i.e. every 6 
cycles Day 1) 
(± 7 Days)
Notes
For the purposes of this table, a cycle 
refers to nivolumab every 2 weeks
Outcomes Research
EORTC QLQ-C30 and EQ-5D 
questionnaires
X
X
Each assessment should be completed at 
the start of the clinic visit prior to dosing 
or any study-related procedures. Only 
applies to participants ≥ 18 years of age at 
baseline. If the dose is delayed, then PRO 
completion should also be delayed and 
synchronized with the delayed dosing.
See Section 9.10 for more details. 
Study Treatment
Contact IRT
X
X
Within 3 days prior to dosing for study 
drug vial assignment
Nivolumab 240 mg Q2W 
(adults and adolescents 
≥40kg)
X
X
Participants should be dosed within 3 days 
from the scheduled dose. Participants may 
be dosed no less than 12 days from the 
previous dose.
Nivolumab 3 mg/kg Q2W 
(adolescents < 40 kg)
X
X
Participants should be dosed within 3 days 
from the scheduled dose. Participants may 
be dosed no less than 12 days from the 
previous dose.
Ipilimumab 1mg/kg Q6W (all 
participants)
X
X (see note)
Ipilimumab should be administered every 
6 weeks (i.e., every 3 cycles, Day 1). 
Participants should be dosed within 3 days 
from the scheduled dose
Note: Mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent participants will not be included in these countries.
Protocol Amendment No.: 04
Date: 04-May-2021
37
5.0
Approved
930106993
5.0
v
Approved
1.0
v

Clinical Protocol
CA209848
BMS-936558
nivolumab
Table 2-5:
Follow-up Assessments CA209848
Procedure
Follow-up Visits 
X01 (Day 30) (± 7 Days) 
and X02 (Day 100)a
(± 7 Days) after Last Dose
Survival
Follow-up Visitsb
Every 3 months
(± 14 Days)
Notes
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include the cardiovascular, 
gastrointestinal, and pulmonary body systems and examination to 
specific malignancy. 
To assess for potential late emergent study drug related findings. 
Adverse events assessment
X
Record at each visit. All AEs and SAEs must be collected 
continuously up to 100 days after study drug discontinuation. 
SAEs that relate to any later protocol specified procedure must be 
collected.
Participants will be followed for all SAEs, non-serious AEs of 
special interest (as defined in Section 9), and all AEs (SAEs and 
non-serious AEs) associated with confirmed or suspected SARS-
CoV-2 infection until resolution, the condition stabilizes, the event 
is deemed irreversible, the participant is lost to follow-up (as 
defined in Section 8.3), or for suspected cases, until SARS-CoV-2 
infection is ruled out.
Laboratory Tests
Hematology and chemistry
X
See Section 9.4.3 Clinical Safety Laboratory Assessments
Thyroid function testing
X
TSH with reflexive free T3 and free T4 
Pharmacokinetic Assessment
See Section 9.5
Immunogenicity Assessment
See Section 9.5
Pregnancy test
X
WOCBP only: serum or urine
Outcome Research Assessment
EORTC QLQ-C30 questionnaire
X
Only participants ≥ 18 years of age at baseline. See Section 9.10
for more details.
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Table 2-5:
Follow-up Assessments CA209848
Procedure
Follow-up Visits 
X01 (Day 30) (± 7 Days) 
and X02 (Day 100)a
(± 7 Days) after Last Dose
Survival
Follow-up Visitsb
Every 3 months
(± 14 Days)
Notes
EQ-5D questionnaire
X
X
May be obtained through a telephone call or clinic visit. Only 
participants ≥ 18 years of age at baseline. See Section 9.10 for 
more details.
Efficacy Assessments
Body Imaging
X (See note)
X (See note)
Only for solid tumor participants without progression.
Tumor Assessments should occur every 12 weeks (± 7 days) from
date of first dose until BICR confirmation of disease progression 
and treatment discontinuation (including treatment beyond 
progression), whichever comes later. 
See Section 9.1 for further details.
Brain Imaging
X (See note)
X (See note)
Primary CNS neoplasms: MRI without and with contrast should 
have MRI of the brain approximately every 12 weeks (± 7 days)
until BICR confirmation of disease progression or treatment 
discontinuation (including treatment beyond progression), 
whichever comes later.
For Solid Tumors: Participants with a history of brain metastasis or 
symptoms should have a surveillance brain MRI per standard of 
care (approximately 12 weeks) or sooner if clinically indicated.
See Section 9.1 for further details.
Other: Bone Scan
X (See note)
X (See note)
As clinically indicated per local standards.
See Section 9.1 for further details.
Participant status
X
Every 3 months after X02; may be accomplished by visit or phone 
contact, to update survival information 
Collect all subsequent anti-cancer treatment.
a Participants must be followed for at least 100 days after last dose of study treatment. Follow-up visit #1 (FU1) occurs approximately 30 days (± 7 days) after the 
last dose or coinciding with the date of discontinuation (± 7 days) if date of discontinuation is greater than 30 days after last dose. Follow-up visit #2 (FU2) 
occurs approximately 100 days (± 7 days) from last dose. Both FU1 and FU2 should be conducted in person.
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b Survival Follow-up visits to occur every 3 months ± 14 days from Follow-up Visit 2. BMS may request that survival data be collected on all treated participants 
outside of the protocol 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 contacts. Survival follow-up may be conducted in person or by telephone.
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3
INTRODUCTION
Blockade of the PD-1 pathway has proven effective in generating robust anti-tumor immune 
responses. Nivolumab, an anti-PD-1 blocking antibody, has demonstrated overall survival benefit 
in multiple tumors including non-squamous cell lung cancer, squamous cell lung cancer, 
melanoma, renal cell carcinoma and head and neck cancer. Recent data across multiple tumor types 
support the hypothesis that patients with tumors harboring increased somatic mutations due to 
DNA mismatch-repair deficiencies are more likely to respond to anti-PD-1/PD-L1 and anti-CTLA-
4 blockade. Tumor mutational burden (TMB) refers to the total number of somatic mutations that 
exist within a tumor’s genome. A subset of these mutations may result in expressed proteins that 
are not recognized by the host’s immune system as self, and therefore has the potential to be 
immunogenic and more susceptible to immune-mediated anti-tumor response. The primary goal 
of this study is to demonstrate the clinical activity of nivolumab in combination with ipilimumab 
in multiple tumor types based on the status of TMB.
3.1
Study Rationale
3.1.1
Rationale for Participant Population with TMB-H Tumor 
Tumors with a high mutational burden may have a higher number of neo-antigens which, in 
principle, would be expected to be more immunogenic than tumors with comparatively low 
mutational burden.1 Therefore, high TMB has been hypothesized to correlate with improved 
efficacy in patients treated with immune-oncology (IO) therapies. This hypothesis has been 
supported by multiple publications across IO therapies, tumor types, and lines of treatment. The 
first published study of TMB as a biomarker of clinical outcomes was reported by Snyder et al, 
where high TMB (TMB-H) was found to be associated with efficacy in metastatic melanoma 
patients treated with anti-CTLA-4 therapy. Further studies by Rizvi et al reported TMB as a 
biomarker of pembrolizumab efficacy in second-line NSCLC patients.1 Additional studies of 
pembrolizumab and atezolizumab in NSCLC have been generally consistent with these results.2
Furthermore, TMB was evaluated in an exploratory post hoc analysis in the BMS-sponsored first 
line NSCLC study, CheckMate 026, which represents the first phase 3 study to demonstrate the 
impact of TMB on efficacy of a PD-1/L1 inhibitor.3 This analysis demonstrated that in patients 
with TMB-H, the ORR was numerically higher in the nivolumab arm versus the chemotherapy 
arm (47% vs 28%) and the median PFS was longer in the nivolumab arm compared to the 
chemotherapy arm (9.7 vs 5.8 mo., HR 0.62; 95% CI 0.38, 1.00). OS was notable, though similar 
(18.3 vs 18.8 mo. and 1 year OS rates of 64% vs 60%, respectively), between the arms in patients 
with TMB-H, although of note, 68% of patients in the chemotherapy arm received subsequent 
nivolumab.4 Interestingly, the ORR and mPFS rates observed in the TMB-H subgroup in the 
nivolumab arm within CheckMate 026 were similar to those reported in the first line NSCLC study 
of pembrolizumab (Keynote-024), where ORR and mPFS were 45% and 10.3 months, 
respectively, in patients with ≥ 50% PD-L1 expression treated with pembrolizumab monotherapy.5
Results from CA209227 showed that nivolumab combined with ipilimumab, as first line treatment 
in patients with metastatic NSCLC of TMB ≥10 mut/Mb, demonstrated significantly better and 
durable clinical response and progression-free survival benefit compared to chemotherapy, 
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including ORR 45.3% vs 26.9%, DOR ≥1 yr 68% vs 25%, PFS rate at 1 yr 43% vs 13%, and mPFS 
of 7.2 vs 5.4 months. Preliminary analysis on OS was also encouraging, and the clinical benefits 
are independent of PD-L1 expression. These findings further support TMB as an important, 
predictive and independent biomarker for clinical efficacy.
Recently, Yarchoan M, et al suggested a significant positive linear correlation between higher 
TMB and increased ORR after analyzing 27 tumor types/subtypes treated with anti-PD-1/PD-L1 
monotherapy, which highlights the potential strong relationship between TMB and the clinical 
activity of anti-PD-1/PD-L1 therapies across multiple cancers.6
Figure 3.1.1-1:
Correlation between Tumor Mutational Burden and Objective 
Response Rate with Anti–PD-1 or Anti–PD-L1 Therapy
Taken together, the available data suggest that, in addition to PD-L1, TMB is also an important 
predictive biomarker of the clinical efficacy of IO therapy. Therefore, patients of TMB-H across 
multiple solid tumors will be selected for participation in this clinical study.
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Prevalence of TMB-H tumor: Selected tumors and their corresponding prevalence by TMB are 
shown in the figure below: 
Figure 3.1.1-2:
Tumor Mutational Burden in Various Tumor Types
Analyzed using an algorithm developed to extract mutational signatures from catalogues of somatic mutations in 7042 
primary cancers. Source: adapted from Alexandrov LB, et al. Nature 2013;500:415-217
3.1.2
Rationale for Study in Refractory, Metastatic, or Unresectable Setting 
This trial with nivolumab in combination with ipilimumab and nivolumab monotherapy will 
include participants with refractory, metastatic or unresectable TMB-H malignancy who have been 
treated with prior non-IO therapies. In general, malignancies included in this trial are the ones that 
have no standard of care after first line therapy showing an improved benefit over best supportive 
care. The low prevalence of TMB-H in these tumor types limits the feasibility of traditional large-
scale randomized trials. As a result, a high unmet medical need exists for these patients, with no 
less expectation for immunotherapy activity.
3.1.3
Rationale for Inclusion of Adolescent Participants
The majority of pediatric patients with cancer are enrolled in clinical trials; however, enrollment
has been shown to decrease with age, and only 10% to 15% of older adolescents (ages 12 to 19) 
with cancer participate in clinical trials and is considered an unmet need. Much of the more than 
50% decrease in overall childhood cancer mortality since 1975 has been attributed to clinical trial 
participation, but survival improvements for adolescents and young adults have historically lagged 
behind the pediatric population as a whole, and decreased participation in clinical trials may
contribute to this finding. 
Lack of participation in the pediatric trials may be due to differences in tumors observed in the 
two groups, as tumors in adolescents may mirror those observed more often in adults. For trials in 
adult participants with tumor types that also occur in adolescents, adolescents are often excluded 
due to safety or regulatory concerns. Overall, this has led to a delay in the study of new therapies 
in adolescents, and most problematically, a delay in new efficacious therapies reaching this 
population. It has been recommended that adolescents be considered for trials in adult populations 
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for tumor types that are observed in adolescents and that share features common to those tumors 
that occur in adults.8,9 Thus, adolescents will be included in this study where locally permitted.
Individual countries and sites have the option of opting out of adolescent eligibility.
This section is not applicable for sites in Belgium or the Netherlands as adolescents will not be 
included in these countries.
3.1.4
Rationale for Key Endpoints
Objective response rate (ORR) assessed by a blinded independent central review committee is the 
primary endpoint of this study. ORR is a validated clinical endpoint in many tumors, and in patients 
in whom a durable tumor response is achieved can be expected to derive a survival benefit from 
therapy.10
3.1.4.1
Rationale for Independent Central Review 
The primary endpoint of ORR will be based on centrally-assessed radiologic tumor measurements 
(and additional clinical indicators, where applicable) using standard disease-specific response 
criteria. A centrally-assessed ORR will provide standardized assessment of progression and 
response using disease-specific response criteria. For this purpose, radiologic imaging from this 
study will be transmitted to an imaging core lab for analysis by a Blinded Independent Central 
Review (BICR) committee. Please see Section 9.1 and CA209848 Imaging Manual for additional 
information.
3.1.4.2
Rationale for Investigator Assessed Response
Investigator-assessed radiologic tumor measurements (and additional clinical indicators, where 
applicable) using standard disease-specific response criteria will closely reflect observed clinical 
practice responses, and will allow for real-time treatment decisions based on the most 
comprehensive, available, clinical information for the individual participant.
3.1.5
Rationale for Exploratory Biomarker Assessments 
An effective anti-tumor immune response relies on a number of interactions, beginning with the 
immune system recognizing the tumor cell as foreign. One important means of recognition is the 
expression of unique tumor-specific peptides (i.e., neoantigens) that are processed, presented via 
the major histocompatibility complex (MHC), and subsequently recognized by T cells as 
immunologic targets. This triggers an immune response driven by T-cell activation, cytokine 
production, peripheral expansion, and infiltration of effector cells that ultimately kill the tumor 
cell.
A number of factors can suppress an effective anti-tumor response, including a lack of strong 
tumor neoantigens recognized by T cells, downregulation of the MHC on cancer cells, minimal 
activation or inactivation of T cells, poor infiltration of effector cells into tumors, and the actions 
of immune checkpoint proteins (e.g., programmed cell death protein 1 [PD-1], programmed death 
ligand 1 [PD-L1], cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]) and tumor 
microenvironment modulators (e.g., regulatory T cells [TRegs] and myeloid-derived suppressor 
cells [MDSCs]), which limit the strength and duration of immune responses.
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As described by Blank et al.,11 requirements for T-cell-mediated tumor control (and targets for 
potential biomarker selection for immuno-oncology therapy) include: tumor foreignness, general 
immune status, immune cell infiltration, absence of checkpoints, absence of soluble inhibitors, 
absence of inhibitory tumor metabolism, and tumor sensitivity to immune effectors. 
Tumor PD-L1 is already an established clinically validated biomarker with available 
complementary/companion diagnostic tests for anti-PD-1/L1 therapies in several tumor types. The 
utility of tumor PD-L1 as the sole predictive biomarker is limited by the lack of an optimal cut-off 
value for PD-L1 expression that reliably selects all patients likely to benefit from immuno-
oncology therapy. For example, in SCCHN study CA209141, while improved efficacy was 
observed with increasing PD-L1 expression, durable responses were also observed in patients with 
PD-L1 non-expressing tumors.
Due to the complexity of the immune system and its response to immuno-oncology therapy, 
additional biomarkers beyond PD-L1 are being investigated to help clinicians to select therapy for 
patients most likely to benefit (e.g., those ‘immune-primed’ patients with one or more 
tumor/immune characteristics that indicate a positive response to immuno-oncology therapy) or to 
suggest alternative combinations beyond immuno-oncology therapy alone. Exploratory 
biomarkers that may be assessed in this study include but are not limited to: tumor gene expression 
profiling, PD-L2, CD8, and myeloid derived suppressor cells (MDSCs). 
3.1.6
Rationale for Outcomes Research Assessments 
The evaluation of patient-reported outcomes is an increasingly important aspect of clinical 
efficacy in oncology trials. Such data provide an understanding of the impact of treatment from 
the participant’s perspective and offer insights into patient experience that may not be captured 
through physician reporting. Additionally, generic health-related quality of life measures provide 
data needed for calculating utility values to inform health economic models.
3.2
Background
OPDIVO® (nivolumab), is a human programmed death receptor-1 (PD-1)12 blocking antibody 
approved for unresectable or metastatic melanoma, previously treated metastatic squamous non-
small cell lung cancer (NSCLC), advanced renal cell carcinoma, and classical Hodgkin lymphoma 
in the United States and in Japan for unresectable melanoma, kidney cancer, and NSCLC, and is 
in clinical development for the treatment of other malignancies. Nivolumab has also demonstrated 
clinical activity as combination therapy with ipilimumab in melanoma, NSCLC, RCC, and 
Hodgkin lymphoma. The majority of responses were durable and exceeded 6 months. 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 224,573 participants treated to date. Overall, 
the safety profile of nivolumab monotherapy is manageable and generally consistent across 
completed and ongoing clinical trials with no maximum tolerated dose (MTD) reached at any dose 
tested up to 10 mg/kg. There was no pattern in the incidence, severity, or causality of AEs to 
nivolumab dose level. Most AEs were low grade (Grade 1 - 2) with relatively few related high 
grade (Grade 3 - 4) AEs. 
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To characterize AEs of special clinical interest that are potentially associated with the use of 
nivolumab, Bristol-Myers Squibb (BMS) has identified select AEs based on the following 
principles: AEs that may differ in type, frequency, or severity from AEs caused by therapies that 
are not immuno-modulating; AEs that may require immunosuppression (e.g. corticosteroids) as 
part of their management; AEs whose early recognition and management may mitigate severe 
toxicity; AEs for which multiple event terms may be used to describe a single type of AE, thereby 
necessitating the pooling of terms for full characterization. 
Based on these principles and taking into account the types of AEs already observed across studies 
of nivolumab monotherapy, pneumonitis, interstitial nephritis, diarrhea/colitis, hepatitis, rash, 
endocrinopathies, and hypersensitivity/infusion reaction events are currently considered to be 
select AEs. The majority of these AEs have been managed successfully with supportive care and, 
in more severe cases, a combination of dose delay, permanent discontinuation, and/or initiation of 
systemic corticosteroids. 
This protocol will generate efficacy and safety data on nivolumab in combination with ipilimumab 
therapy and nivolumab monotherapy for refractory, metastatic and unresectable select tumor types 
of TMB-H (excluding melanoma, RCC, NSCLC and hematologic malignancies), some of which 
have not been previously examined in clinical trials.
3.2.1
Mechanism of Action of Nivolumab 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses. 13,14,15. 
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor (TCR).16 Collectively, these signals govern 
the balance between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA 4, ICOS, and BTLA. 17 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also been 
noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.18 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
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In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-
4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a 
cytomegalovirus (CMV) re-stimulation assay with human peripheral blood mononuclear cells 
(PBMC), the effect of nivolumab on antigen specific recall response indicates that nivolumab 
augmented IFN-γ secretion from CMV specific memory T cells in a dose-dependent manner versus 
isotype-matched control. In vivo blockade of PD-1 by a murine analog of nivolumab enhances the 
anti-tumor immune response and results in tumor rejection in several immunocompetent mouse 
tumor models (MC38, SA1/N, and PAN02).19
3.2.2
Ipilimumab Mechanism of Action
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin superfamily that competes with CD28 for B7. CTLA-4 mediated signals are 
inhibitory and turn off T cell-dependent immune responses.20 Ipilimumab is a fully human 
monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from human 
and nonhuman primates. The proposed mechanism of action for ipilimumab is interference of the 
interaction of CTLA-4 with B7 molecules on APCs, with subsequent blockade of the inhibitory 
modulation of T-cell activation promoted by the CTLA 4/B7 interaction.
3.2.3
Nivolumab Combined with Ipilimumab and Nivolumab Monotherapy 
Clinical Activity in Adults
Multiple clinical studies have evaluated nivolumab combined with ipilimumab at different doses 
and schedules. The following information describes the results of initial early phase clinical studies 
that were the basis for the nivolumab plus ipilimumab combination regimens that have been 
explored in late phase clinical development.
In the Phase 1 study CA209004, ascending doses of nivolumab have been studied concomitantly 
with ascending doses of ipilimumab in participants with unresectable or metastatic melanoma.
In each arm in this multi-arm study, ipilimumab was administered once every 3 weeks for 4 
doses with nivolumab administered once every 3 weeks for 8 doses. Starting at week 24,
ipilimumab and nivolumab were administered once every 12 weeks for 8 doses. The three
initial dose-escalation cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg + ipilimumab 3 
mg/kg; n=14), Cohort 2 (nivolumab 1.0 g/kg + ipilimumab 3 mg/kg; n =17) and Cohort 3 
(nivolumab 3.0 mg/kg + ipilimumab 3 mg/kg; n = 6). Later, the study was amended to include 
Cohort 2a which evaluated nivolumab 3 mg/kg + ipilimumab 1 mg/kg (n - 16). The primary 
objective was to assess safety/tolerability; the secondary objective was to assess preliminary 
efficacy.
Of the 52 participants evaluable for response as of the 15-Feb-2013 clinical cut-off in CA209004,
21 participants (40%) had an objective response by modified World Health Organization
(mWHO) criteria. In an additional 2 participants (4%) there was an unconfirmed objective 
response. In Cohort 1 (0.1 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 14 evaluable
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participants had an objective response by mWHO (21%), including 1 CR and 2 PRs. In Cohort
2 (1 mg/kg nivolumab + 3 mg/kg ipilimumab), 9 out of 17 (53%) evaluable participants had an
objective response by mWHO, including 3 CRs (18%) and 6 PRs (35%). In Cohort 2a (3 
mg/kg nivolumab + 1 mg/kg ipilimumab), 6 out of 15 ( 40%) response evaluable participants
had an objective response by mWHO, including 1 CR (7%) and 5 PRs (33%). In Cohort 3 (3 
mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 6 (50%) evaluable participants had an objective
response by mWHO, all 3 of which were PRs (50%).
Preliminary analysis revealed 16 of the 52 evaluable participants (31%) had > 80% reduction in
the size of target tumor lesions by the week 12 evaluation. This is compared to < 2% for 3 
mg/kg ipilimumab monotherapy based on CA184020 (N=540) and < 3% for nivolumab
monotherapy based on CA209003 (N=94, 0.1-10 mg/kg).
The following dose limiting toxicities (DLTs) were observed: in Cohort 1,Grade 3 elevated
AST/ALT (1 participant); in Cohort 2, Grade 3 uveitis (1 participant) and Grade 3 elevated
AST/ALT (1 participant) and in Cohort 3, Grade 4 elevated lipase (2 participants) and Grade 3
elevated lipase (1 participant). Based on these data, Cohort 2 was identified as the maximum
tolerated dose (MTD) and Cohort 3 exceeded the MTD.
A total of 53 melanoma participants were treated with nivolumab combined with ipilimumab in
CA209004 across Cohorts 1, 2, 2a, and 3. At least 1 adverse event (AE) regardless of causality
has been reported in 98% of participants treated. The most common (reported at 10% incidence)
treatment related AEs (any Grade 93%; Grade 3-4 53%:) are rash (55%; 4%), pruritus (47%;
0%), vitiligo (11%; 0%), fatigue (38%; 0%), pyrexia (21%, 0%), diarrhea (34%; 6%), nausea (21%,
0%), vomiting (11%, 2%), ALT increased (21%; 11%), AST increased (21%; 13%), lipase
increased (19%; 13%), amylase increased (15%, 6%), headache (11%, 0%), and cough (13%, 0%).
The majority of AEs leading to discontinuation (regardless of causality) were Grade 3 or 4 
(reported in 11 of 53 participants, 21%). Grade 3 events included lipase increased, ALT
increased, AST increased, troponin I increased, colitis, diverticular perforation, pancreatitis,
tachycardia, renal failure acute, choroiditis, autoimmune disorder, and pneumonitis. One
participant each discontinued due to Grade 4 events of blood creatinine increased and AST
increased. No drug-related deaths were reported. 21
The combination of nivolumab with ipilimumab has been studied in the Phase 1 study CA209016.
Participants with metastatic RCC (mRCC; Karnofsky performance status (KPS) ≥ 80%; untreated 
or any number of prior therapies) were randomized to receive nivolumab 3 mg/kg + ipilimumab 1 
mg/kg (arm N3 + I1) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg (arm N1 + I3) IV Q3W for 4 
doses followed by nivolumab 3 mg/kg IV Q2W until progression/toxicity. The primary objective 
was to assess safety/tolerability; secondary objective was to assess antitumor activity. 
Participants were randomized to N3 + I1 (n = 47) and N1 + I3 (n = 47). Approximately half (n = 
46; 51%) had prior systemic therapy (N3 + I1: 22; N1 + I3: 26). 
After a median follow-up of 22.3 months, the confirmed ORR per RECIST 1.1 (Response 
Evaluation Criteria in Solid Tumors) was 40.4% (N = 47) in both Arms N3 + I1 and N1 + I3; 
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42.1% (n = 8) and 36.8% (n = 7) had an ongoing response, with a median DOR of 88.7 weeks 
(95% CI: 37.14, NA) and 85.9 weeks (95% CI: 35.14, NA), respectively. Median PFS was 7.7 
months (95% CI: 3.71, 14.29) and 9.4 months (95% CI: 5.62, 18.63) in Arms N3 + I1 and N1 + 
I3, respectively. OS at 12 months was 80.9% and 85.0% in Arms N3 + I1 and N1 + I3, respectively, 
and at 24 months was 67.3% and 69.6%, respectively.
The safety of nivolumab combined with ipilimumab was assessed in study CA209016. Treatment-
related AEs were seen in 88/94 pts (94%), including 43/47 (92%) in N3 + I1 and 45/47 (96%)
in N1 + I3.The most frequently reported drug-related AEs in N3 + I1 included fatigue (66%), 
cough (53.2%), and arthralgia (51.1%); the majority were Grade 1- 2. The most frequently reported
drug-related AEs in N1 + I3 included fatigue (74.5%), nausea (55.3%), and diarrhea (53.2%). The
majority were Grade 1-2.
Treatment-related AEs leading to discontinuation (31.9% versus 10.6%), and treatment-related
serious adverse events (SAEs) (34% versus 23.4%) occurred more commonly in participants
in the N1 + I3 arm than in the N3 + I1 arm, respectively. 22
CA209012 was a multi-arm Phase 1b trial evaluating the safety and tolerability of nivolumab in 
patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC), as either a 
monotherapy or in combination with other agents including ipilimumab, at different doses and 
schedules. The primary endpoint of the study was safety with secondary endpoints of objective 
response rate (ORR) per RECIST 1.1 and 24-week progression-free survival (PFS). Participants 
were assigned to receive nivolumab 3 mg/kg Q2W + ipilimumab 1mg/kg Q12W (n=38), 
nivolumab 3mg/kg Q2W + ipilimumab 1 mg/kg Q6W (n = 39) and nivolumab 3 mg/kg Q2W 
(n=52). The confirmed ORR was 47% (N3 q2w + I1 q12w), 39% (N3 q2w + I1q6w) and 23% (N3 
Q2W). The median duration of response (DOR) was not reached in any of these groups. 
The rate of treatment-related adverse events (AEs) in the Q12W (82%) and Q6W (72%) arms were 
comparable to monotherapy (72%). In the study, Grade 3/4 adverse events were 37%, 33%, and 
19% for the Q12W, Q6W and nivolumab monotherapy arms, respectively. Treatment-related 
Grade 3-4 AEs led to discontinuation in 5% and 8% of participants in the Q12W and Q6W cohorts, 
respectively, and were similar to nivolumab monotherapy. There were no treatment-related deaths. 
The treatment-related select AEs in patients administered the optimized dosing schedule (3 mg/kg 
of nivolumab Q2W plus 1 mg/kg of ipilimumab Q6W) were skin related (36%), gastrointestinal 
(23%), endocrine (20%), and pulmonary (5%) and there were ≤ 5% treatment related Grade 3 and 
Grade 4 AEs per category.23
CA209067 was a phase 3, randomized, double-blind study of nivolumab monotherapy or
nivolumab combined with ipilimumab versus ipilimumab monotherapy in first line melanoma 
patients. In this study, combination of nivolumab 1 mg/kg and ipilimumab 3 mg/kg for 4 doses,
followed by nivolumab 3 mg/kg, Q2W (NIVO+IPI), compared with ipilimumab 3 mg/kg, Q3W x
4 doses (IPI) demonstrated a significant improvement in OS and PFS, with mOS not reached in 
the NIVO+IPI group compared with 19.98 months in the IPI group, and mPFS 11.7 months in the 
NIVO+IPI group compared with 2.9 months in the IPI group. When NIVO+IPI group was 
compared to nivolumab 3 mg/kg group (NIVO), a numeric difference in OS and improved PFS 
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(mPFS of 11.73 vs 6.87 months) were observed in favor of the combination. The ORR in NIVO+IPI 
(58.9%) was significantly higher than the IPI group (19.0%) and numerically higher than NIVO 
group (44.6%). The overall safety profile of
NIVO+IPI combination therapy and NIVO 
monotherapy was consistent with the mechanisms of action of nivolumab and ipilimumab. In
general, the frequency of AEs was lowest across AE categories in the NIVO group and highest
in the NIVO+IPI group. Treatment-related AEs of Grade 3 or 4 occurred in 59% patients of the 
NIVO+IPI group, 21% of the NIVO group and 34% of the IPI group. Analyses of immune-mediated 
AEs (IMAE) showed that most IMAEs were Grade 1-2. The majority of IMAEs in the IMAE 
categories of diarrhea/colitis, and hepatitis were Grade 3-4. The majority of IMAEs resolved
and were manageable using the recommended treatment guidelines for early evaluation and 
intervention.24
CA209214 was a phase 3, randomized, open-label study of nivolumab combined with
ipilimumab
versus sunitinib monotherapy in first line patients with RCC. Among the 
intermediated/poor-risk participants, combination of nivolumab and
ipilimumab
therapy 
(NIVO+IPI, nivolumab 3 mg/kg and ipilimumab 1 mg/kg, Q3W for 4 doses then followed by 
nivolumab 3 mg/kg, Q2W) demonstrated a statistically significant higher ORR (41.6%) than
sunitinib (26.5%). CR was achieved in 9.4% vs 1.2% in NIVO+IPI and sunitinib groups,
respectively. Responses in the NIVO+IPI group occurred early (median TTR of 2.79 months)
and were durable (median DOR not reached). In the sunitinib group, mTTR (3.04 months) was 
similar but responses were less durable (18.17 months). NIVO+IPI combination therapy
demonstrated statistically significant and superior OS (mOS was not reached) compared with 
sunitinib (mOS of 25.95 months). The overall safety profile of NIVO+IPI was acceptable when
compared to sunitinib monotherapy. Treatment-related AEs occurred in 93% of patients receiving 
NIVO+IPI, and 97% receiving sunitinib; Grade 3 or 4 AEs occurred in 46% and 63%, and 
treatment-related AEs leading to discontinuation occurred in 22% and 12%, respectively. Most 
IMAEs were Grade 1-2, and the majority of IMAEs resolved and were manageable using the 
recommended treatment guidelines for early evaluation and intervention.25
3.2.4
Nivolumab Combined with Ipilimumab and Nivolumab Monotherapy 
Clinical Activity in Adolescents
Relatively limited data are available for the use of checkpoint inhibitors in children. A pediatric 
phase 1 trial of ipilimumab monotherapy in 1, 3, 5, and 10 mg/m2 doses concluded that ipilimumab 
may be safely administered to pediatric patients.26 A multi-center phase 2 trial of ipilimumab 3 
mg/kg and 10 mg/kg Q4 weeks x 4 doses in adolescents with metastatic melanoma 
(NCT01696045) has recently closed enrollment, and the study report is being prepared. Another 
phase 1 study with ipilimumab in children and adolescents with treatment-resistant cancer 
(NCT01445379) was reported as completed recently, and study results have not been released.
Nivolumab and nivolumab in combination with ipilimumab are being investigated in pediatric 
participants in an ongoing Children’s Oncology Group (COG) Phase 1/2 study (ADVL 1412; 
CA209070; NCT02304458), including participants with relapsed refractory solid tumors and 
lymphoma. Good tolerability was demonstrated in safety lead-in phase for both treatment arms, 
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with immune-mediated AEs comparable to adult experience, and both have re-opened to expansion 
phase. A total of 110 participants have been studied to date (Spring 2017 COG Meeting; personal 
communication), of which 78 received nivolumab monotherapy and 32 received the combination. 
Of 58 currently evaluable in the monotherapy arm, only 3 DLTs were recorded. Clinical benefit
has not been reported in solid tumors in this trial, and this study is continuing to enroll into multiple
cohorts using treatment with both nivolumab monotherapy and combination therapy of nivolumab
and ipilimumab. Additional BMS-sponsored clinical trials in children/adolescent are ongoing, 
including nivolumab in children with recurrent Hodgkin Lymphoma (CA209744), and nivolumab 
and nivolumab in combination with ipilimumab in pediatric participants with high grade primary
CNS malignancies (CA209908). The Pediatric Brain Tumor Consortium recently opened a safety 
and preliminary efficacy study (PBTC-045, NCT02359565) of anti-PD1 antibody pembrolizumab 
in children with recurrent/refractory high-grade astrocytoma, DIPG, or hypermutated tumors; data 
are not yet available from this trial.
Recently, FDA has approved treatment of adolescent (≥12 yr old) participants with MSI-H CRC 
and MSI-H pan tumor, respectively.
This section is not applicable for sites in Belgium or the Netherlands as adolescents will not be 
included in these countries.
3.2.5
Nivolumab Clinical Pharmacology
Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-
agent OPDIVO and OPDIVO with ipilimumab.
OPDIVO as a single agent: The PK of single-agent nivolumab was studied in patients over a dose 
range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of OPDIVO as a 60-
minute intravenous infusion every 2 or 3 weeks. Nivolumab clearance (CL) decreases over time, 
with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of 24.5% 
(47.6%) resulting in a geometric mean steady-state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) 
in patients with metastatic tumors; the decrease in CLss is not considered clinically relevant. 
Nivolumab clearance does not decrease over time in patients with completely resected melanoma, 
as the geometric mean population clearance is 24% lower in this patient population compared with 
patients with metastatic melanoma at steady state. The geometric mean volume of distribution at 
steady state (Vss) (CV%) is 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 
days (77.5%). Steady-state concentrations of nivolumab were reached by 12 weeks when 
administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3.7-fold. The exposure to 
nivolumab increases dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 
2 weeks. The predicted exposure (Cavg and Cmax) of nivolumab after a 30-minute infusion is 
comparable to that observed with a 60-minute infusion.
OPDIVO with ipilimumab: When OPDIVO 1 mg/kg was administered in combination with 
ipilimumab 3 mg/kg, the CL of nivolumab was increased by 29%, and the CL of ipilimumab was 
unchanged compared to OPDIVO administered alone. When OPDIVO 3 mg/kg was administered 
in combination with ipilimumab 1 mg/kg, the CL of nivolumab and ipilimumab were unchanged.
When OPDIVO was administerd in combination with ipilimumab, the presence of anti-nivolumab 
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antibodies increased the CL of nivolumab by 20% and the CL of ipilimumab was unchanged in 
presence of anti-ipilimumab antibodies.
Specific Populations: The population PK analysis suggested that the following factors had no 
clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 
kg), gender, race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal 
impairment, and mild hepatic impairment. 
Renal Impairment: The effect of renal impairment on the clearance of nivolumab was evaluated 
by a population PK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2), moderate 
(eGFR 30 to 59 mL/min/1.73 m2), or severe (eGFR 15 to 29 mL/min/1.73 m2) renal impairment. 
No clinically important differences in the clearance of nivolumab were found between patients 
with renal impairment and patients with normal renal function.
Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was 
evaluated by population PK analyses in patients with HCC and in patients with other tumors with 
mild hepatic impairment (total bilirubin [TB] less than or equal to the ULN and AST greater than 
ULN or TB greater than 1 to 1.5 times ULN and any AST) and in HCC patients with moderate 
hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST). No clinically important 
differences in the clearance of nivolumab were found between patients with mild/moderate hepatic
impairment.
Full details on the clinical pharmacology aspects of nivolumab can be found in the Investigator 
Brochure (IB).
3.3
Benefit/Risk Assessment
Extensive details on the safety profile of nivolumab are available in the Investigator Brochure and 
will not be repeated herein.
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical trials with no MTD 
reached at any dose tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively 
few related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level.
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 5. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed 
in these algorithms. 
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.
3.3.1
Adult Patients
Emerging data have indicated that tumors of TMB-H are likely to may be more sensitive to IO 
therapies, thus eliciting improved efficacy in patients treated with IO therapies as elaborated 
previously. Of the tumor types included in this trial, despite of available chemotherapies for the 
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treatment of some of these tumors, the incremental benefit of such treatment after progression to 
first line regimen is small and represents an area of unmet medical need.
Overall, the safety profile of nivolumab monotherapy and nivolumab in combination with 
ipilimumab with the selected dose in this study are comparable. Most AEs were low-grade 
(Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs (see Section 3.2.3. 
Nivolumab Combined with Ipilimumab Clinical Activity in Adults). Extensive details on the safety 
profile of nivolumab and the combination of nivolumab and ipilimumab are available in the 
nivolumab and ipilimumab Investigator Brochures and will not be repeated herein. 
3.3.2
Adolescent Patients
The PK characteristics (e.g., steady-state peak and trough concentrations and terminal half-life) of 
many antibody-based therapeutic proteins are essentially comparable between pediatrics and 
adults once the effect of body size on PK is taken into consideration.27,28 Research on
immunotherapy for childhood tumors is still preliminary, but available data suggested similar PK 
profile of nivolumab to adult patients, and did not reveal significant safety concerns that are 
different from adult population (see Section 5.5.3). A
report
of
the
ongoing
COG
trial
ADVL1412 (See Section 3.2.4) indicated good tolerability among the 78 participants treated to
date with nivolumab monotherapy and 32 participants with nivolumab in combination with 
ipilimumab. 
In summary, there is increasing clinical effort with IO therapy, including nivolumab and 
nivolumab in combination with ipilimumab in childhood malignancies, with the aim of delivering 
new effective therapies to children in a more timely fashion. This trial is being conducted to
demonstrate clinical efficacy and safety in adolescent patients with TMB-H tumors. The doses and
schedules of nivolumab and the combination of nivolumab with ipilimumab have been -studied
and found to be well-tolerated. The potential benefit is that some or all of the TMB-H tumor
types in this study will be sensitive to nivolumab alone and/or in combination with ipilimumab, 
thus yielding clinical benefit in these adolescent patients.
The benefit-risk information regarding adolescent participants is not applicable for sites in 
Belgium or the Netherlands as adolescents will not be included in these countries.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To estimate BICR-assessed objective response rate 
(ORR) in participants of tTMB-H treated with 
nivolumab combined with ipilimumab 
•
BICR-assessed ORR using RECIST 1.1, and 
Response 
Assessment 
for 
Neuro-Oncology 
(RANO) criteria in primary CNS tumors 
•
To estimate BICR-assessed ORR in participants of 
bTMB-H treated with nivolumab combined with 
ipilimumab 
•
BICR-assessed ORR using RECIST 1.1, and 
RANO criteria in primary CNS tumors
Secondary
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To estimate the BICR-assessed duration of response 
(DOR) and time to response (TTR) in participants of 
tTMB-H treated with nivolumab combined with 
ipilimumab
•
BICR-assessed DOR
•
BICR-assessed TTR
•
To estimate the BICR-assessed DOR and TTR in 
participants of bTMB-H treated with nivolumab 
combined with ipilimumab
•
BICR-assessed DOR
•
BICR-assessed TTR
•
To evaluate the BICR-assessed ORR, DOR and TTR 
in participants of tTMB-H treated with nivolumab 
monotherapy
•
BICR-assessed ORR
•
BICR-assessed DOR
•
BICR-assessed TTR
•
To evaluate the BICR-assessed ORR, DOR and TTR 
in participants of bTMB-H treated with nivolumab 
monotherapy
•
BICR-assessed ORR
•
BICR-assessed DOR
•
BICR-assessed TTR
•
To evaluate Investigator-assessed ORR, DOR, TTR 
in participants of tTMB-H treated with nivolumab 
combined 
with 
ipilimumab 
and 
nivolumab 
monotherapy
•
Investigator-assessed ORR
•
Investigator-assessed DOR
•
Investigator-assessed TTR
•
To evaluate Investigator-assessed ORR, DOR, TTR 
in participants of bTMB-H treated with nivolumab 
combined 
with 
ipilimumab 
and 
nivolumab 
monotherapy
•
Investigator-assessed ORR
•
Investigator-assessed DOR
•
Investigator-assessed TTR
•
To evaluate BICR-assessed and investigator-
assessed clinical benefit rate (CBR) in participants of 
tTMB-H treated with nivolumab combined with 
ipilimumab and nivolumab monotherapy
•
BICR-assessed CBR
•
Investigator-assessed CBR
•
To evaluate BICR-assessed and investigator-
assessed CBR in participants of bTMB-H treated 
with nivolumab combined with ipilimumab and 
nivolumab monotherapy
•
BICR-assessed CBR
•
Investigator-assessed CBR
•
To evaluate BICR-assessed and investigator-
assessed progression free survival (PFS) in 
participants of tTMB-H treated with nivolumab 
combined 
with 
ipilimumab 
and 
nivolumab 
monotherapy
•
BICR-assessed PFS
•
Investigator-assessed PFS
•
To evaluate BICR-assessed and investigator-
assessed PFS in participants of bTMB-H treated with 
nivolumab 
combined 
with 
ipilimumab 
and 
nivolumab monotherapy
•
BICR-assessed PFS
•
Investigator-assessed PFS
•
To evaluate overall survival (OS) in participants of 
tTMB-H treated with nivolumab combined with 
ipilimumab and nivolumab monotherapy
•
Overall survival
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To evaluate OS in participants of bTMB-H treated 
with nivolumab combined with ipilimumab and 
nivolumab monotherapy
•
Overall survival
•
To assess overall safety and tolerability 
•
AEs, clinical laboratory values, or other safety 
biomarkers
• Exploratory
•
To assess overall health status and health utility 
•
Mean change from baseline in the 3-level version 
of the EQ-5D (EQ-5D-3L) visual analog scale 
(VAS) and utility index, respectively
•
To assess cancer-related symptoms and quality of 
life 
•
Mean change from baseline in domains and 
symptoms in the 30-item European Organization 
for Research and Treatment of Cancer Quality of 
Life Questionnaire (EORTC QLQ-C30).
•
To 
characterize 
the 
pharmacokinetics 
of 
nivolumab/ipilimumab 
and 
explore 
exposure-
response relationships with respect to safety and 
efficacy
•
Population pharmacokinetic parameters 
•
To assess immunogenicity of nivolumab/ipilimumab
•
Incidence 
of 
anti-nivolumab/anti-ipilimumab 
antibodies
•
To characterize tumor and host biomarkers 
•
Analysis 
of 
genomic, 
molecular, 
and 
immunohistochemical profiles
•
To assess OS and BICR-assessed and investigator-
assessed ORR, DOR, PFS in all participants of 
TMB-H treated with nivolumab combined with 
ipilimumab and nivolumab monotherapy
•
OS
•
BICR-assessed ORR
•
BICR-assessed DOR 
•
BICR-assessed PFS 
•
Investigator-assessed ORR
•
Investigator-assessed DOR
•
Investigator-assessed PFS 
5
STUDY DESIGN
5.1
Overall Design
The study will enroll participants diagnosed with select advanced or metastatic solid tumors with 
either tissue (tTMB) or blood TMB (bTMB) ≥ 10 mut/Mb. Both tissue and blood TMB will be 
assessed prior to randomization. 
Participants without a prior known tTMB-H status available via F1CDx assay, or a prior known 
bTMB-validated CLIA result available from Foundation Medicine, will provide consent for pre-
screening and TMB status determination, but consent for further screening procedures and study 
treatment should be deferred until TMB-H status is established. Screening process can continue 
when the participant is TMB-H. 
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Participants with a prior known result of tTMB-H via F1CDx assay or bTMB-H from
Foundation Medicine may proceed immediately with full screening procedures. Both tissue and 
blood TMB will be assessed prior to randomization. Prior results of tTMB or bTMB obtained from 
any other assays except the ones described above are not acceptable, including prior result of tTMB 
obtained via Foundation One assay.
Once the TMB-H status is determined, this study will consist of three phases: screening, treatment, 
and follow-up. 
Efficacy will be evaluated using tumor specific response criteria, ie, RECIST 1.1 for solid tumors29
and RANO criteria30 for primary CNS tumors. 
The primary analysis of BICR-assessed ORR in participants with either bTMB-H or tTMB-H will 
be conducted after a minimum of 12 months following LPFT. This study will end when analysis 
of the primary endpoint is complete. Additional survival analysis may be conducted for up to 5 
years beyond the primary endpoint analysis.
Details regarding the assessments to be performed during these phases are outlined in Section 2
Schedule of Activities.
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
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Note: Mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent participants will 
not be included in these countries.
Physical examinations, vital sign measurements, outcome questionnaires, biomarker collection, 
and clinical laboratory evaluations will be performed at selected times throughout study 
participation. Participants will be closely monitored for AEs throughout the study. Blood samples 
will be collected for safety, pharmacokinetic (PK) and biomarker analysis. 
Participants with progressive disease while on treatment with nivolumab monotherapy may be 
allowed to be treated beyond progression with nivolumab and ipilimumab (see Section 7.4.3).
5.1.1
Data Monitoring Committee and Other External Committees
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
5.1.1.1
Data Monitoring Committee
To provide independent oversight of safety, efficacy, and study conduct, a data monitoring 
committee (DMC) will be instituted. The DMC will meet regularly to ensure that participant safety 
is carefully monitored. The DMC will convene additional ad hoc meetings if necessary. Following 
each meeting, the DMC will recommend continuation, modification, or discontinuation of the 
study based on observed toxicities. The DMC will review the interim analysis results and 
determine whether the cut-off value for bTMB should be adjusted for the first interim analysis and 
whether criteria for superiority are met at that time for the tTMB interim analysis; the DMC will 
also review the bTMB final analysis results. A separate DMC charter will describe the activities 
of this committee in more detail.
5.1.1.2
Blinded Independent Central Review Committee
A Blinded Independent Central Review (BICR) Committee will be formed for standardized 
response assessment. Images will be submitted to an imaging third-party vendor for central review. 
Imaging acquisition guidelines and submission process will be outlined in the CA209848 Study 
Imaging Manual to be provided by the vendors. For tumor types which require clinical indicators 
as part of the standard response assessment, the clinical indicator data will be provided to the BICR
along with imaging data.
5.2
Number of Participants
The number of randomized participants will range from approximately 183 to 342 based on 1) the 
actually observed concordance between tTMB-H and bTMB-H, and 2) the new bTMB cutoff 
determined by the interim analysis should it occur (see Section 10.3.6). The per tumor type cap is
approximately 15% of the total sample size.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of trial is 
defined as the last visit or scheduled procedure shown in the Schedule of Activities for the last 
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participant. Study completion is defined as the final date on which data for the primary endpoint 
was or is expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
The aim of this basket trial is to evaluate the efficacy of nivolumab in combination with ipilimumab 
in TMB-H advanced or metastatic solid tumors excluding melanoma, NSCLC and RCC. The 
clinical benefit of nivolumab and nivolumab in combination with ipilimumab in approved 
indications suggests that studying them in other cancers may identify additional clinical 
applications for which nivolumab in combination with ipilimumab will be safe and effective, 
particularly in tumors with TMB-H which are hypothesized to be more sensitive to immune 
checkpoint targeted therapies. CA209848 study will explore the clinical response and safety in 
participants with TMB-H. 
5.4.1
TMB Cutoff and Stratification
High level of TMB is an emerging predictive biomarker for favorable clinical benefit in response 
to IO therapy, however a universal definition of “TMB high” has not been established. Most 
melanomas have a mutational load greater than 10 mutants/megabase (mut/Mb), and a large body 
of evidence demonstrated higher clinical efficacy in melanoma treated with IO therapy compared 
to many other tumor types which have less than 10 mut/Mb. In melanoma, nivolumab in 
combination with ipilimumab has convincingly demonstrated incremental efficacy than nivolumab 
monotherapy. In CA209568, in response to the treatment of nivolumab combined with ipilimumab 
in first line NSCLC patients, the ORR increased with higher TMB, and peaked at 10 mut/Mb (9% 
at <5 mut/Mb, 15% at ≥5-<10 mut/Mb, 44% at ≥ 10-<15 mut/Mb, and 39% at ≥15 mut/Mb). These 
findings suggest that TMB at 10 mut/Mb is an optimal cutoff for first line NSCLC patients.
Recently, in CA209227, a phase 3 trial with first line NSCLC patients, nivolumab combined with 
ipilimumab demonstrated superior clinical benefit compared to chemotherapy in patients of TMB-
H at a cutoff of ≥10 mut/Mb. Goodman A et al showed that with a TMB cut off of ≥20 mut/Mb, 
diverse tumor types, including melanoma, NSCLC and some rare tumors, responded well to anti-
PD-1/anti-CTLA-4 with higher response rate, disease-free and overall survival31. In this study, we 
have chosen the TMB-H cut off for enrollment as ≥ 10 mut/Mb to maximize the probability of 
inclusion of potential responders. Participants at enrollment will also be stratified by TMB of 16 
mut/Mb to ensure even distribution of participants with relatively low TMB and relatively high 
TMB between the 2 study arms, and allow further analysis based on TMB stratification.
5.4.2
Stratification with Line of Therapy
Patients at enrollment will be stratified by line of therapy to ensure even distribution of patients 
who have failed first line vs second line and beyond between the 2 arms. This is to minimize 
potential imbalance of differential response underlined by the different lines of therapy that the 
patients had received, and allow possible TMB–response analysis based on stratification of prior 
line of therapy.
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5.4.3
Exclusion of Melanoma, NSCLC and RCC
Currently, multiple anti-PD-1/PD-L1 and/or anti-CTLA4 have been approved for Melanoma and 
NSCLC as first or second line treatment. Data from CA209227 highlighted superior clinical 
benefit of nivolumab combined with ipilimumab versus chemotherapy in first line NSCLC 
patients, which may provide additional effective treatment option for this population. The 
probability of identifying IO naïve participants with these two tumor types is considerably low. 
RCCs are characterized by one to two somatically acquired single nucleotide variants or small 
insertions and deletions per megabase pair, and have relatively low overall TMB.32,33 Several 
analyses suggest that clinical response to IO therapy in RCC patients is independent of TMB, thus 
RCC is excluded from this study.34,35
5.4.4
Rationale for Treatment with Nivolumab and Ipilimumab after Disease 
Progression with Nivolumab Monotherapy
The combination of nivolumab with ipilimumab has demonstrated increased clinical benefit in 
comparison with nivolumab monotherapy in patients with melanoma and NSCLC as previously 
described. To maximize the potential clinical benefit for the patient, upon confirmed disease 
progression, patients who are initially randomized to the nivolumab monotherapy (arm B) have 
the option to receive nivolumab in combination ipilimumab, at the discretion of the investigator 
and upon discussion with the BMS Medical Monitor.
5.4.5
Rationale for Two Year Duration of Treatment 
The optimal duration of immunotherapy is an important question and continues to be investigated.
Clinical trials across different tumors types in the nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 
2-4 months, and emerging data suggests that benefit can be maintained in the absence of continued 
treatment. A recent analysis in a melanoma study suggests the majority of patients who discontinue 
nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of further 
treatment.36 Furthermore, a limited duration of ipilimumab, including only 4 induction doses, 
resulted in long term survival in patients with metastatic melanoma, with a sustained plateau in 
survival starting around 2 years after the start of treatment.37
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 participants with NSCLC), specified a maximum treatment duration of 2 years.
Among 16 participants with non-small cell lung cancer (NSCLC) who discontinued nivolumab 
after completing 2 years of treatment, 12 participants were alive >5 years and remained 
progression-free without any subsequent therapy. In the CA209003 NSCLC cohort, the overall 
survival (OS) curve begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 
3 years.38These survival outcomes are similar to phase 3 studies in previously treated NSCLC, in 
which nivolumab treatment was continued until progression or unacceptable toxicity (2 year OS 
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rates of 23% and 29%, and 3 year OS rates of 16%-18% for squamous and non-squamous NSCLC 
respectively).39
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 2 
years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; HR=0.42 (95% CI, 
0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (i.e., 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.40
Collectively, these data suggest that there is minimal if any benefit derived from continuing IO 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, in 
this study, treatment will be given for a maximum of 2 years from the start of study treatment.
5.5
Justification for Dose
5.5.1
Rationale for Nivolumab Monotherapy Dose Selection
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, renal cell carcinoma (RCC), classical Hodgkin’s lymphoma (cHL), head and 
neck (H&N) and urothelial carcinoma (UC), using body weight normalized dosing (mg/kg), and 
has been safely administered at doses up to 10 mg/kg Q2W. Nivolumab is currently approved for 
the treatment of various tumors, including melanoma, NSCLC, RCC, cHL, SCCHN, and UC, 
using a regimen of either nivolumab 240 mg Q2W or nivolumab 480 mg Q4W.
The nivolumab 480 mg Q4W dose was selected for this study based on clinical data and modeling 
and simulation approaches using population pharmacokinetics (PPK) and exposure response (ER) 
analyses examining relationships between nivolumab exposures and efficacy (eg. OS, OR) and 
safety responses, using data from studies in multiple tumor types (melanoma, NSCLC, and RCC) 
with body weight-normalized dosing (mg/kg).41 The PPK analyses have shown that exposure to 
nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered 
Q2W, and no clinically meaningful differences in PK across ethnicities and tumor types were 
observed. Nivolumab clearance and volume of distribution were found to increase as body weight 
increases but less than proportionally with increasing weight, indicating that milligram-per-
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kilogram dosing represents an over-adjustment for the effect of body weight on nivolumab PK. 
Using the PPK and ER models, nivolumab exposures and probabilities of efficacy responses and 
risks of AEs were predicted following nivolumab 480 mg Q4W and compared to those following 
nivolumab 3 mg/kg Q2W, the initially approved dose. The overall distributions of average 
nivolumab steady-state exposures (Cavgss) are comparable following administration with either 
nivolumab 3 mg/kg Q2W or nivolumab 480 mg Q4W. Nivolumab 480 mg Q4W is predicted to 
result in approximately 43% greater steady-state peak concentrations (Cmaxss) compared to 
nivolumab 3 mg/kg Q2W; however, these exposures are predicted to be lower than the exposure 
ranges observed at doses up to nivolumab 10 mg/kg Q2W used in the nivolumab clinical program. 
Although the Cmaxss of nivolumab is expected to be greater following nivolumab 480 mg Q4W 
compared to nivolumab 3 mg/kg Q2W, the predicted Cmaxss following nivolumab 480 mg Q4W 
is well below the median Cmaxss achieved following administration of nivolumab 10 mg/kg Q2W, 
a safe and tolerable dose level (Figure 5.5.1-1).
Figure 5.5.1-1:
Predicted Nivolumab Cmax (with 90% PI) versus Time by Dosing 
Regimen
Exposure-safety analysis demonstrated that the exposure margins for safety are maintained 
following nivolumab 480 mg Q4W, and the predicted risks of AE-DC/D, AE Grade 3+, and AE-
IM Grade 2+, are predicted to be similar following nivolumab 480 mg Q4W relative to nivolumab 
3 mg/kg Q2W across tumor types. Safety analyses using available data following nivolumab 
3 mg/kg Q2W and 10 mg/kg Q2W administration indicated there were no differences in AE 
profiles across body weight groups. Finally, initial evidence demonstrates that following 
administration of nivolumab 480 mg Q4W, nivolumab has been shown to be well tolerated.42
Nivolumab 480 mg Q4W is predicted to be approximately 16% lower steady-state trough 
concentrations (Cminss) compared to nivolumab 3 mg/kg Q2W. While these exposures are 
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predicted to be lower, they are on the flat part of the exposure-response curves and are not predicted 
to affect efficacy, Exposure-efficacy analyses of multiple PK measures and efficacy endpoints (eg, 
OS, OR) indicated that following administration of nivolumab 480 mg Q4W efficacy is predicted 
to be similar to that following administration of nivolumab 3 mg/kg Q2W across multiple tumor 
types. Based on these data, nivolumab 480 mg Q4W is expected to have similar efficacy and safety 
profiles to nivolumab 240 mg Q2W or nivolumab 3 mg/kg Q2W.
5.5.2
Nivolumab/Ipilimumab Combination Therapy Dose Selection and 
Duration
The clinical pharmacology profiling of the combination of nivolumab and ipilimumab together 
with an overview of the results of these analyses are summarized below. In addition, the Clinical 
Pharmacology Section of the product labels for ipilimumab and nivolumab, as well as the 
Investigator Brochures, have additional details.43,44,45,46
5.5.2.1
Population Pharmacokinetics of Nivolumab
The PK, clinical activity, and safety of nivolumab has been assessed in completed and ongoing 
Phase 1, 2, and 3 studies in adult subjects with non-small cell lung cancer (NSCLC), melanoma, 
and renal cell carcinoma (RCC) in addition to other tumor types.47
The PK of nivolumab as monotherapy was characterized by PPK analysis. Nivolumab clearance 
increased with baseline body weight, estimated glomerular filtration (eGFR), and Eastern 
Cooperative Oncology Group (ECOG) performance status > 0. The PPK analysis was performed 
using data from 1908 subjects who received nivolumab from the following studies: nivolumab 
monotherapy data from studies MDX-1106-01, ONO-4538-01, ONO-4538-02, MDX-1106-03, 
CA209010, CA209063, and CA209037. Studies CA209004, CA209069, CA209066, and 
CA209067 provided PK data of nivolumab monotherapy as well as in combination with 
ipilimumab in the target population (advanced melanoma) who received the proposed dosing 
regimens. The data from these studies also allowed for an evaluation of potential drug interactions 
between nivolumab and ipilimumab and of the effect of immunogenicity on clearance. Thus, for 
this analysis, the covariates assessed included ADA status, baseline ECOG status, baseline eGFR, 
baseline body weight (BW), gender and co-administration of ipilimumab.
Co-administration with ipilimumab 3 mg/kg resulted in a modest increase in nivolumab CL of 
35% whereas co-administration with ipilimumab 1 mg/kg did not appear to have an effect on 
nivolumab CL. Presence of anti-nivolumab antibodies increased nivolumab CL by 25%, consistent 
with prior findings. In subjects with an ECOG performance status of > 0, nivolumab CL was 22% 
higher (based on median values). Male subjects had a median of 12% higher volume of distribution 
of central compartment (VC) than females. Baseline body weight was identified as a significant 
covariate for both CL and VC and the magnitude of the effect of baseline eGFR on CL was not 
considered clinically relevant. The geometric mean CL, Vss, and terminal half-life of nivolumab 
were 9.83 mL/h, 7.62 L, and 24.1 days, respectively. When administered in combination, the CL 
of nivolumab was increased by 35%, whereas there was no effect on the clearance of ipilimumab.
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5.5.2.2
Population Pharmacokinetics of Ipilimumab
The PPK of ipilimumab was evaluated using data from 1345 subjects in 4 Phase 2 studies with 
ipilimumab monotherapy (CA184004, CA184007, CA184008, and CA184022), as well as one 
Phase 1 study (CA209004), one Phase 2 study (CA209069) and one Phase 3 study (CA209067) 
with ipilimumab monotherapy and nivolumab in combination with ipilimumab. The ipilimumab 
data from CA209004, CA209069, and CA209067 are included as they provide ipilimumab PK 
samples that were collected in combination with nivolumab in the target population. The data from 
4 ipilimumab monotherapy studies (CA184004, CA184007, CA184008, and CA184022) were 
included in the PPK analysis, to enable the assessment of the potential nivolumab effect on 
ipilimumab PK.
The co-administration of ipilimumab (3 mg/kg) with nivolumab 0.3 mg/kg and nivolumab 
3.0 mg/kg resulted in minimal changes in ipilimumab CL (-7.5% and 11%, respectively); however, 
sample sizes at these doses were small. The CL of ipilimumab co-administered with 1 mg/kg 
nivolumab was estimated to be 1% higher (95% CI: 97.8 - 106) relative to the CL of ipilimumab 
monotherapy, demonstrating that ipilimumab CL is unaffected by co-administration of 1 mg/kg 
nivolumab. Ipilimumab CL was estimated to increase by 6% (95% CI: 96.5 - 115) in the presence 
of ipilimumab ADA, as measured by the drug tolerant (2nd generation) assay. This effect is not 
considered to be statistically significant (95% CI includes 1). Ipilimumab CL and VC increased 
with increasing baseline body weight, and ipilimumab CL increased with increasing baseline LDH.
5.5.2.3
Pharmacokinetics of Nivolumab and Ipilimumab
The PK of nivolumab and ipilimumab, when administered in combination, were characterized by 
summary statistics of observed data from CA209004 and by PPK analyses using serum 
concentration data collected in studies CA209004, CA209069 and CA209067.
A dose-related increase in nivolumab peak and trough concentrations was observed after the first 
dose in Study CA209004. Peak and trough concentrations after the first dose for 1 mg/kg of 
nivolumab in combination with 3 mg/kg of ipilimumab Q3W were in the range of 
18.1 - 21.5 μg/mL and 3.2 - 4.8 μg/mL, respectively. Ipilimumab peak concentrations at 3 mg/kg 
in combination with 1 mg/kg nivolumab after the first dose were in the range of 63.5 - 68.5 μg/mL. 
Ipilimumab trough concentrations at 3 mg/kg in combination with 1 mg/kg nivolumab after the 
first dose were in the range of 9.8 - 11.9 μg/mL.
5.5.3
Dose for Adolescents
The PK of drugs and many therapeutics proteins has been shown to be similar between adolescent 
and adults once the effect of body size on PK is taken into consideration.27,28Therefore, in general, 
adult doses would be expected to achieve similar systemic exposures in adolescents. 
PK data after first dose in pediatric patients are available from CA209-908 and ADVL 1412 / 
CA209-070, where patients were treated with nivolumab 3 mg/kg and ipilimumab 1 mg/kg Q3W 
followed by nivolumab monotherapy. Serum peak and trough concentrations (geometric means 
[CV%]) after the first dose of nivolumab and ipilimumab, in adolescent patients are presented in
Table 5.5.3-1. These values are very similar to geometric mean peak and trough concentrations in 
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adults who received similar dose regimen for nivolumab and ipilimumab, including NSCLC 
(n=501) with nivolumab (peak = 61.8 and trough = 17.5 μg/mL), and RCC (n = 497) with
nivolumab (peak = 62 μg/mL, and trough = 15.3 μg/mL) and ipilimumab (peak = 19.7 μg/mL, and 
trough=3.93 μg/mL) (BMS internal data).
Table 5.5.3-1:
Pharmacokinetics data after first dose in adolescents (12 -
<18 years) patients from CA209-908 and CA209-070 (COG) study 
who received Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Q3W
CA209-908 study
CA209-070 (COG) study
Nivolumab 3 mg/kg
Cmax 1a (μg/mL)
72.4 (34.5)
N=6
55.3 (13)
N=5
Cmin 1b (μg/mL)
18.3 (40.6)
N=3
15.9 (23.8)
N=8
Ipilimumab 1 mg/kg
Cmax 1 (μg/mL)
20.4 (48.2)
N=6
19.1 (24.1)
N=16
Cmin 1 (μg/mL)
3.4 (50.1)
N=3
3.53 (33.6)
N=7
a Cmax1 = Peak concentration after first dose.
b Cmin1 = Trough concentration after first dose.
Population PK model based simulation has shown that exposures produced by nivolumab 480 mg 
Q4W and 240 mg Q2W were well below the simulated exposure range of a 10 mg/kg Q2W 
regimen, a previously established clinically safe dose. The body weight range for adults subjects 
that established the population PK model used for simulation was 34-180 kg. Therefore, a 
minimum body weight threshold in adolescents (≥ 40 kg) is defined to receive the same adult flat 
dose to prevent exceeding target adult exposures.
Adolescent participants < 40 kg body weight will be given weight-based dose that is equivalent to 
the adult dose (typical participant of 80-kg body weight). Adolescents with body weight ≥ 40 kg 
will be administered nivolumab 240 mg Q2W in nivo/ipi arm, and nivolumab 480 mg Q4W in the 
monotherapy arm. Adolescents < 40 kg will be administered body weight adjusted nivolumab dose 
of 3 mg/kg Q2W in the nivolumab in combination with ipilimumab arm, and 6 mg/kg Q4W in the 
monotherapy arm.
This section is not applicable for sites in Belgium or the Netherlands as adolescent participants
will not be included in these countries.
5.5.4
Clinical Pharmacology Summary
Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-
agent nivolumab and nivolumab with ipilimumab.
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Nivolumab as a single agent: The PK of single-agent nivolumab was studied in participants over 
a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of nivolumab 
as a 60-minute intravenous infusion every 2 or 3 weeks. Nivolumab clearance (CL) decreases 
over time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline 
values of 24.5% (47.6%) resulting in a geometric mean steady-state clearance (CLss) (CV%) of 
8.2 mL/h (53.9%) in patients with metastatic tumors; the decrease in CLss is not considered 
clinically relevant. Nivolumab CL does not decrease over time in patients with completely 
resected melanoma, as the geometric mean population clearance is 24% lower in this patient 
population compared with patients with metastatic melanoma at steady state. The geometric 
mean volume of distribution at steady state (Vss) (CV%) is 6.8 L (27.3%), and geometric mean 
elimination half-life (t1/2) is 25 days (77.5%). Steady-state concentrations of nivolumab were 
reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation 
was 3.7-fold. The exposure to nivolumab increases dose proportionally over the dose range of 
0.1 to 10 mg/kg administered every 2 weeks. The predicted exposure (Cavg and Cmax) of 
nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion.
Nivolumab with ipilimumab: When nivolumab 1 mg/kg was administered in combination with 
ipilimumab 3 mg/kg, the CL of nivolumab was increased by 29%, and the CL of ipilimumab was 
unchanged compared to nivolumab administered alone. When nivolumab 3 mg/kg was 
administered in combination with ipilimumab 1 mg/kg, the CL of nivolumab and ipilimumab 
were unchanged. When nivolumab was administered in combination with ipilimumab, the 
presence of anti-nivolumab antibodies increased the CL of nivolumab by 20%, and the CL of 
ipilimumab was unchanged in the presence of anti-ipilimumab antibodies.
Specific Populations: The population PK analysis suggested that the following factors had no 
clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 
kg), gender, race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal
impairment, and mild hepatic impairment. 
Renal Impairment: The effect of renal impairment on the clearance of nivolumab was evaluated 
by a population PK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2), moderate 
(eGFR 30 to 59 mL/min/1.73 m2), or severe (eGFR 15 to 29 mL/min/1.73 m2) renal impairment. 
No clinically important differences in the clearance of nivolumab were found between patients 
with renal impairment and patients with normal renal function.
Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was 
evaluated by population PK analyses in patients with HCC and in patients with other tumors with 
mild hepatic impairment (total bilirubin [TB] less than or equal to the ULN and AST greater than 
ULN or TB greater than 1 to 1.5 times ULN and any AST) and in patients with HCC with 
moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST). No clinically 
important differences in the clearance of nivolumab were found between patients with 
mild/moderate hepatic impairment.
Full details on the clinical pharmacology aspects of nivolumab can be found in the IB and 
product label.
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Rationale for 30-minute Infusion 
Long infusion times place a burden on patients and treatment centers. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of 30 minutes’ duration 
will diminish the burden, provided that there is no change in the safety profile. Previous clinical 
studies of nivolumab and ipilimumab monotherapies and the combination of nivolumab and 
ipilimumab have used a 60-minute infusion duration for nivolumab and a 90-minute infusion 
duration for ipilimumab (1 - 3 mg/kg dosing for both). However, both nivolumab and ipilimumab 
have been administered at up to 10 mg/kg with the same infusion duration (ie, 60 minutes).
Establishing that nivolumab can be safely administered using a shorter infusion time (30 minutes) 
is under investigation. Previous clinical studies of nivolumab monotherapy have used a 60-minute 
infusion duration wherein, nivolumab has been safely administered up to 10 mg/kg over long 
treatment periods. Infusion reactions including high-grade hypersensitivity reactions have been 
uncommon across nivolumab clinical program. In CA209010, a dose association was observed for 
infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 
18.5% at 10 mg/kg). All the events were Grade 1-2 and were manageable. An infusion duration of 
30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not expected to 
present any safety concerns compared to the prior experience at 10 mg/kg nivolumab dose infused 
over a 60-minute duration. The safety of nivolumab 3 mg/kg administered as a 30-min infusion 
was assessed in CA209153 in patients (n = 322) with previously treated advanced NSCLC. 
Overall, 
there 
were 
no 
clinically 
meaningful 
differences 
in 
the 
frequency 
of 
hypersensitivity/infusion-related reactions (of any cause or treatment-related) in patients 
administered nivolumab over a 30-minute infusion compared with that reported for patients with 
the 60-minute infusion. Thus, it was shown that nivolumab can be safely infused over 30 minutes. 
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In participants 
with advanced Stage II or Stage IV melanoma (CA184022 Study), where ipilimumab was 
administered up to a dose of 10 mg/kg, on-study drug related hypersensitivity events (Grade 1/2) 
were reported in 1 participant (1.4%) in the 0.3 mg/kg and in 2 participants (2.8%) in the 10 mg/kg 
group. There were no drug-related hypersensitivity events reported in the 3 mg/kg group. Across 
the 3 treatment groups, no Grade 3/4 drug-related hypersensitivity events were reported and there 
were no reports of infusion reactions. Ipilimumab 10 mg/kg monotherapy has also been safely 
administered as a 90-minute infusion in a large Phase 3 study in prostate cancer (CA184043) and 
as adjuvant therapy for Stage III melanoma (CA184029), with infusion reactions occurring in 
participants. Administering 3 mg/kg of ipilimumab represents approximately one-third of the 
10 mg/kg dose.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across clinical studies of nivolumab, ipilimumab, and nivolumab/ipilimumab combinations. 
Overall, a change in safety profile is not anticipated with 30-minute infusions of nivolumab, 
ipilimumab or combination.
In addition, nivolumab is approved as 30-minute infusion (as monotherapy or combination 
therapy) for the treatment of various tumor types.48 Ipilimumab 1 mg/kg Q6W is approved as a
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30-minute infusion when combined with nivolumab for the treatment of metastatic NSCLC and 
mesothelioma.49
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 tests, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Participants with a refractory, metastatic, or unresectable histologically or cytologically
confirmed solid malignant tumor with TMB-H who are refractory to standard therapies
per local management guidelines,
or for which no standard treatment per local 
management guidelines is available (salvage setting).
i)
Treatment with botanical preparations alone (e.g. herbal supplements or traditional 
Chinese medicines) are not considered a line of therapy. 
b) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue 
sections, obtained within 9 months and no additional intervening therapy (excluding the 
current line of therapy and palliative local therapy) prior to enrollment, with an associated 
pathology report, must be submitted to the core laboratory for inclusion. Palliative local 
therapy includes palliative radiation therapy and palliative surgical resection to 
symptomatic non primary bone lesions, skin lesions, or CNS lesions (only for peripheral 
solid tumors, not applicable for CNS primary tumor). Radiation to the primary lesions and 
systemic chemotherapy are not considered palliative therapy. Biopsy should be excisional, 
incisional or core needle. Fine needle aspiration is unacceptable for submission
i)
If a fresh biopsy is warranted, the participant must have a lesion that can be biopsied at 
an acceptable clinical risk as judged by the investigator in order to be eligible for the 
study
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c) The IRT must be provided with the results of both tissue and blood TMB-H testing for 
eligible participants prior to randomization. Both results are utilized for stratification 
purposes (see Figure 6.1-1).
Figure 6.1-1:
TMB Pre-Screening/Screening
i)
Participants must have either tTMB or bTMB ≥ 10 mut/Mb (tTMB ≥ 10 mut/Mb or the 
new cutoff value of bTMB determined by the 1st interim analysis). Should one of the 
two populations (tTMB-H or bTMB-H) reach the targeted sample size before the other,
then enrollment will continue only with participants for the other TMB-H population
(bTMB-H or tTMB-H, see details in Section 10.1).
ii) Prior results of TMB-H obtained with F1CDx assay (tissue) or bTMB-validated CLIA
assay from Foundation Medicine (blood) are acceptable for eligibility purposes. 
(1) If tTMB result is available, blood sample must be provided for central TMB testing
(2) If bTMB result is available, tissue sample must be provided for central TMB testing 
(3) If neither tTMB nor bTMB result is available, both tissue and blood samples must 
be provided for central TMB testing
iii) TMB results obtained from any other assays are not acceptable for eligibility.
d) Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Status of ≤1 (participants > 16 years old with solid tumors), Karnofsky Performance Score 
(KPS) ≥80 (participants > 16 years old with primary CNS tumors) or Lansky Performance 
Score (LPS) ≥80 (participants 12 to 16 years old ONLY). For details, see Appendix 6 
and 9.
e) Participants must have measurable disease for response assessment as per RECIST 1.1 for 
solid tumors other than CNS, and RANO criteria for primary CNS malignancies.
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3) Age and Reproductive Status
a) Males and Females, ages of 12 years and older
i)
If adolescents are not allowed to participate, then ≥ 18 years applies
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 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 and 5 months after the last dose of study treatment (i.e., 30 days 
[duration of ovulatory cycle] plus the time required for the investigational drug to undergo 
approximately five half-lives). 
e) Not Applicable per Protocol Amendment 04: Males who are sexually active with WOCBP 
must agree to follow instructions for method(s) of contraception for the duration of study 
treatment and 7 months after the last dose of study treatment (i.e., 90 days [duration of 
sperm turnover] plus the time required for the investigational drug to undergo 
approximately five half-lives). In addition, male participants must be willing to refrain 
from sperm donation during this time. 
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. 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.
The inclusion of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent 
participants will not be included in these countries. Participants in these countries must be 18 years 
of age or older.
6.2
Exclusion Criteria
1) Medical Conditions
a) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication.
b) Participants with melanoma, non-small cell lung cancer, renal cell carcinoma or 
hematological malignancy as primary site of disease are not eligible for this study.
c) Active brain metastases (excluding primary CNS malignancies) or leptomeningeal 
metastases. Participants with brain metastases are eligible if these have been treated and 
there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks 
after treatment is complete and within 28 days prior to first dose of study drug 
administration. There must also be no requirement for immunosuppressive doses of 
systemic corticosteroids (> 10 mg/day prednisone equivalents for adults, or > 0.25 mg/kg
daily prednisone equivalent for adolescents) for at least 2 weeks prior to study drug 
administration.
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d) Prior malignancy active within the previous 2 years except for locally curable cancers that 
have been apparently cured or successfully resected, such as basal or squamous cell skin 
cancer, superficial bladder cancer, or GC, or carcinoma in situ of the prostate, cervix, or 
breast.
e) 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.
f)
Excluding participants with serious or uncontrolled medical disorders.
2) Prior/Concomitant Therapy
a) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents for adults, or > 0.25 mg/kg daily prednisone
equivalent for adolescent) or other immunosuppressive medications within 14 days of study 
treatment. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily 
prednisone equivalents for adults, or > 0.25 mg/kg daily prednisone equivalent for 
adolescents are permitted, in the absence of active autoimmune disease.
b) Participants who received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways
c) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 5) or baseline before administration of 
study drug. Participants with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as neuropathy after platinum 
based therapy, are permitted to enroll.
d) Treatment with any chemotherapy, radiation therapy, biologics for cancer, or 
investigational therapy within 28 days (or, for primary CNS tumors, within 12 weeks of 
completion of radiation therapy) of first administration of study treatment (participants 
with prior cytotoxic or investigational products (IP) < 4 weeks prior to randomization might 
be eligible after discussion between investigator and sponsor, if toxicities from the prior 
treatment have been resolved to Grade 1 (NCI CTCAE version 5).
e) Treatment with botanical preparations (e.g. herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 2 
weeks prior to randomization/treatment. Refer to Section 7.7.1 for prohibited therapies.
f)
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.
g) Participants must not have received a live / attenuated vaccine within 30 days of first 
treatment.
3) Physical and Laboratory Test Findings
Participants with any of the following lab criteria will be excluded from the study:
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100x103/μL
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d) Hemoglobin < 9.0 g/dL
e) Serum creatinine:
−
For participants ≥ 18 years old: Serum creatinine > 1.5 x ULN unless creatinine clearance 
≥40 mL/min (measured or calculated using the Cockcroft Gault formula): 
Female CrCl = ([140 - age in years] x weight in kg x 0.85)/
(72 x serum creatinine in mg/dL)
Male CrCl = ([140 - age in years] x weight in kg x 1.00)/
(72 x serum creatinine in mg/dL)
−
For participants ≥ 12 years old and < 18 years old, consider a serum creatinine based the 
table below, unless creatinine clearance ≥70 ml/min/1.73 m2 calculated using the 
Schwartz formula:
Ped CrCl = (k x Ht)/Cr
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
12 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
16 to < 18 years
1.7
1.4
Note: the threshold values in this table were derived from the Schwartz formula for estimating GFR,50 utilizing 
child length and stature data published by the US Centers for Disease Control and Prevention
f)
AST or ALT > 3.0 x ULN 
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).
4) Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal antibodies
b) History of allergy or hypersensitivity to study drug components
5) 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 
(e.g. 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.
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The mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent 
participants will not be included in these countries. Participants in these countries must be 18 years 
of age or older.
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 who 
are not subsequently entered in the study/included in the analysis population. 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, as 
applicable, 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 Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (i.e. participant has not been randomized / has not 
been treated). If re-enrolled, the participant must be re-consented.
The most current result prior to Randomization 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 
randomization or 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:
An IP, 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.
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-
IP.
IPs used in this trial are provided in Table 7-1. There are no non-IPs in this study.
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For body weight-based dosing, the dosing calculations should be based on the body weight 
assessed at baseline. It is not necessary to re-calculate subsequent doses if the participant weight 
is within 10% of the weight used to calculate the previous dose. All doses should be rounded up 
or to the nearest milligram per institutional standard.
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Table 7-1:
Study treatments for CA209848
Product Description / 
Class and Dosage 
Form
Potency
IMP/
Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage Conditions
(per label)
Nivolumab
(BMS-936558-01)
Solution for Injection
100 mg (10 mg/mL) 
and 40 mg (10 mg/mL)
IMP
Open label
Vial or various 
packaging 
configurations
Refer to the label on container and/or pharmacy 
manual
Ipilimumab
(BMS-734016) 
Solution for Injection
200 mg
(5 mg/mL)
IMP
Open label
Vial or various 
packaging 
configurations
Refer to the label on container and/or pharmacy 
manual
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Treatment 
Arm
Study 
Treatment
Participant 
Age/Weight
Unit dose 
strength(s)/
Dosage level(s)
Frequency of 
Administration
Route of 
Administration
Arm A or Arm 
B Rollover: 
nivolumab in 
combination 
with 
ipilimumab
Nivolumab
Adults and 
adolescents 
≥40kg
240 mg
Q2 weeks up to 
24 months
IV
Adolescents 
< 40kg
3 mg/kg
Q2 weeks up to 
24 months
IV
Ipilimumab
All participants
1 mg/kg
Q6 weeks up to 
24 months
IV
Arm B: 
nivolumab 
monotherapy
Nivolumab
Adults and 
adolescents 
≥40kg
480 mg
Q4 weeks up to 
24 months
IV
Adolescents 
< 40kg
6 mg/kg
Q4 weeks up to 
24 months
IV
Note: The mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent participants 
will not be included in these countries.
7.1.1
Arm A or Arm B Rollover – Nivolumab in Combination with Ipilimumab
Nivolumab will be administered every 2 weeks. Adult participants and adolescents ≥ 40kg will 
receive nivolumab at a dose of 240 mg, and adolescents < 40kg will receive nivolumab at a dose 
of 3mg/kg; in both cases, nivolumab will be administered as an approximately 30-minute infusion 
on Day 1 of each treatment cycle. Ipilimumab will be administered every 6 weeks; all participants 
will receive ipilimumab at a dose of 1mg/kg. If needed, flush the intravenous line with an 
appropriate amount of diluent (e.g. 0.9% sodium chloride or 5% dextrose in water) to ensure that 
the complete dose is administered over approximately 30 minutes. Participants should begin study 
treatment within 3 calendar days of randomization.
When study treatments (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 flush 
of diluent to clear the line of nivolumab before starting the ipilimumab infusion. The second 
infusion will always be the ipilimumab study treatment and will start after the infusion line has 
been flushed, filters changed and patient has been observed to ensure no infusion reaction has 
occurred.
Nivolumab and ipilimumab treatment will continue until disease progression, discontinuation due 
to unacceptable toxicity, withdrawal of consent, or study closure. Participants will be treated up to 
24 months in the absence of disease progression or unacceptable toxicity. Maximum 24 months of 
treatment also applies to treatment beyond progression.
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Ipilimumab is not permitted to continue on study after nivolumab is discontinued. The 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 at the same dose and schedule if ipilimumab is discontinued. If a participant meets 
criteria for discontinuation and investigator is unable to determine whether the event is related to 
all or any one study drug, the participant should discontinue all study drugs and be taken off the 
treatment phase of the study. 
For ipilimumab preparation and storage instructions, refer to ipilimumab IB51 and/or pharmacy 
manual.
Separate infusion bags and filters should be used when administering nivolumab and ipilimumab 
on the same day.
Ipilimumab is to be administered as an approximately 30-minute IV infusion and may be infused 
using a volumetric pump with a 0.2 to 1.2 micron low-protein binding in-line filter at the protocol-
specified dose. It is not to be administered as an IV push or bolus injection. 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 diluent.
The mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent 
participants will not be included in these countries.
7.1.2
Arm B – Nivolumab Monotherapy
Adult participants and adolescents ≥ 40kg will receive nivolumab at a dose of 480 mg. Adolescents 
< 40kg will receive nivolumab at a dose of 6mg/kg. In both cases, nivolumab will be administered 
as an approximately 30-minute infusion on Day 1 of each treatment cycle until progression, 
unacceptable toxicity, withdrawal of consent, completion of 24 months of treatment, or the study 
ends, whichever occurs first. If needed, flush the intravenous line with an appropriate amount of 
diluent (e.g. 0.9% sodium chloride or 5% dextrose in water) to ensure that the complete dose is 
administered over approximately 30 minutes. Participants should begin study treatment within 3 
calendar days of randomization.
For nivolumab preparation and storage instructions, please refer to the nivolumab IB and/or 
pharmacy manual.
All participants will be monitored continuously for AEs while on study treatment. Treatment 
modifications (e.g. dose delay, reduction, retreatment, or discontinuation) will be based on specific 
laboratory and adverse event criteria, as described in Sections 7.4.1 and Section 8.
The mention of adolescents is not applicable for sites in Belgium or the Netherlands as adolescent 
participants will not be included in these countries.
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7.2
Method of Treatment Assignment
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.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2).
7.3
Blinding
This is an open-label study, blinding procedures are not applicable.
7.4
Dosage Modification
Dose escalations or reductions of nivolumab or ipilimumab are not allowed. Participants may be 
dosed no less than 12 days from the previous dose during Q2W cycles. For Q4W dosing cycles, 
participants may be dosed within a ±3 day window, and there should be a minimum of 22 days 
between doses. Premedications are not recommended for the first dose of nivolumab or nivolumab 
combined with ipilimumab.
Participants should be carefully monitored for infusion reactions during nivolumab and 
ipilimumab administration. If an acute infusion reaction is noted, participants should be managed 
according to Section 7.
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.
7.4.1
Dose Delay Criteria 
Delay administration of both nivolumab and ipilimumab if any of the delay criteria in Section 7.4.1
are met. Delay nivolumab and ipilimumab dosing for any adverse event, laboratory abnormality, 
or intercurrent illness which, in the judgment of the investigator, warrants delaying the dose of 
study medication.
Delay dosing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, either 
confirmed or suspected.
For participants who require delay of nivolumab and ipilimumab, re-evaluate weekly or more 
frequently if clinically indicated and resume dosing when criteria to resume treatment are met (see 
Section 7.4.2). 
Continue tumor assessments per protocol even if dosing is delayed.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and Ipilimumab
Drug-related Adverse Event 
(AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resumption
Criteria
Gastrointestinal
Colitis or diarrhea
Grade 2 
Delay dose
Dosing may resume when AE resolves to baseline.
Grade 3 
Nivolumab monotherapy: Delay dose
Dosing may resume when AE resolves to baseline.
When administered with ipilimumab: 
Permanently discontinue ipilimumab
Nivolumab monotherapy may be resumed when AE 
resolves to baseline. If Grade 3 diarrhea or colitis 
recurs while on nivolumab monotherapy, 
permanently discontinue.
Grade 4 
Permanently discontinue
Renal
Serum creatinine increased
Grade 2 or 3 
Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 
or baseline value.
Grade 4 
Permanently discontinue
Pulmonary
Pneumonitis
Grade 2 
Delay dose
Dosing may resume after pneumonitis has resolved 
to Grade ≤ 1.
Grade 3 or 4 
Permanently discontinue
Hepatic
Aspartate aminotransferase 
(AST), alanine 
aminotransferase (ALT), or 
total bilirubin (T.bili) increased
AST or ALT > 3× and ≤5×
upper limit of normal (ULN) 
or T.bili  > 1.5× and ≤3×
ULN, regardless of baseline 
value
Delay dose
Dosing may resume when laboratory values return 
to baseline.
AST or ALT > 5 × ULN or 
T. bili > 3 × ULN, regardless 
of baseline value
Delay dose or permanently discontinue 
In most cases of AST or ALT > 5× ULN, study 
treatment will be permanently discontinued. If the 
investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study 
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and Ipilimumab
Drug-related Adverse Event 
(AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resumption
Criteria
treatment, a discussion between the investigator and 
the Medical Monitor/designee must occur and 
approval from the Medical Monitor must be 
obtained prior to resuming therapy.
Concurrent AST or ALT > 3 x 
ULN and T.bili > 2 x ULN, 
regardless of baseline value
Permanently discontinue 
Endocrinopathy
Adrenal insufficiency
Grade 2 adrenal insufficiency
Delay dose
Dosing may resume after adequately controlled 
with hormone replacement.
Grade 3 or 4 adrenal 
insufficiency or adrenal crisis
Delay dose or permanently discontinue
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If adrenal insufficiency resolves or is adequately 
controlled with physiologic hormone replacement, 
participant may not require discontinuation of study 
drug.
Hyperglycemia
Hyperglycemia requiring 
initiation or change in daily 
management (Grade 2 or 3)
Delay dose
Dosing may resume if hyperglycemia resolves to 
Grade ≤1 or baseline value, or is adequately 
controlled with glucose-controlling agents.
Grade 4
Delay dose or permanently discontinue
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If hyperglycemia resolves, or is adequately 
controlled with glucose-controlling agents, 
participant may not require discontinuation of study 
drug.
Hypophysitis/Hypopituitarism 
Symptomatic Grade 1-3 that is 
also associated with 
corresponding abnormal lab 
and/or pituitary scan
Delay dose 
Dosing may resume if endocrinopathy resolves to 
be asymptomatic, or is adequately controlled with 
only physiologic hormone replacement.
Grade 4
Delay dose or permanently discontinue
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If endocrinopathy resolves or is adequately 
controlled with physiologic hormone replacement, 
participant may not require discontinuation of study 
drug.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and Ipilimumab
Drug-related Adverse Event 
(AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resumption
Criteria
Hyperthyroidism or  
Hypothyroidism
Grade 2 or 3
Delay dose
Dosing may resume if endocrinopathy resolves to 
be asymptomatic, or is adequately controlled with 
only physiologic hormone replacement or other 
medical management.
Grade 4
Delay dose or permanently discontinue
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If endocrinopathy resolves or is adequately 
controlled with physiologic hormone replacement
or other medical management, participant may not 
require discontinuation of study drug.
Skin
Rash
Grade 2 rash covering >30% 
body surface area or Grade 3 
rash
Delay dose 
Dosing may resume when rash reduces to ≤10% 
body surface area.
Suspected Stevens-Johnson 
syndrome (SJS), toxic 
epidermal necrolysis (TEN), or 
drug reaction with eosinophilia 
and systemic symptoms 
(DRESS)
Delay dose
Dosing may resume if SJS, TEN, or DRESS is ruled 
out and rash reduces to is ≤10% body surface area.
Grade 4 rash or confirmed 
SJS,TEN, or DRESS
Permanently discontinue
Neurological
Guillain-Barre Syndrome 
(GBS)
Any grade
Permanently discontinue
Myasthenia Gravis (MG)
Any grade
Permanently discontinue
Encephalitis
Any grade encephalitis
Delay dose 
After workup for differential diagnosis, (ie,
infection, tumor-related), if encephalitis is not drug 
related, then dosing may resume when AE resolves.
Any grade drug-related 
encephalitis 
Permanently discontinue
Myelitis
Any grade myelitis
Delay dose
After workup for differential diagnosis, (ie,
infection, tumor-related), if myelitis is not drug 
related, then dosing may resume when AE resolves.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and Ipilimumab
Drug-related Adverse Event 
(AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resumption
Criteria
Any grade drug-related 
myelitis
Permanently discontinue
Neurological (other than GBS, 
MG, encephalitis, or myelitis)
Grade 2
Delay dose
Dosing may resume when AE resolves to baseline.
Grade 3 or 4
Permanently discontinue
Myocarditis
Myocarditis
Symptoms induced from mild 
to moderate activity or 
exertion
Delay dose
Dosing may resume after myocarditis has resolved.
Severe or life threatening, with 
symptoms at rest or with 
minimal activity or exertion, 
and/or where intervention 
indicated
Permanently discontinue
Other Clinical AEs
Pancreatitis: 
Amylase or lipase increased
Grade 3 with symptoms
Delay dose
Note: Grade 3 increased amylase or lipase without 
signs or symptoms of pancreatitis does not require 
dose delay. 
Dosing may resume when patient becomes 
asymptomatic.
Grade 4
Permanently discontinue
Uveitis 
Grade 2 uveitis
Delay dose
Dosing may resume if uveitis responds to topical 
therapy (eye drops) and after uveitis resolves to 
Grade ≤ 1 or baseline. If patient requires oral 
steroids for uveitis, then permanently discontinue 
study drug.
Grade 3 or 4 uveitis
Permanently discontinue
Other drug-related AE (not 
listed above)
Grade 2 non-skin AE, except 
fatigue
Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 
or baseline value.
Grade 3 AE - First occurrence 
lasting ≤ 7 days
Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 
or baseline value.
Grade 3 AE - First occurrence 
lasting > 7 days
Permanently discontinue
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and Ipilimumab
Drug-related Adverse Event 
(AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resumption
Criteria
Recurrence of Grade 3 AE of 
any duration
Permanently discontinue
Grade 4 or life-threatening 
adverse reaction
Permanently discontinue
Other Laboratory Abnormalities 
Other drug-related laboratory
abnormality (not listed above)
Grade 3
Delay dose
Exceptions:
No delay required for: Grade 3 lymphopenia 
Permanent discontinuation for: Grade 3 
thrombocytopenia > 7 days or associated with
bleeding
Grade 4
Permanently discontinue
Exceptions: The following events do not require 
discontinuation of study drug: 
• Grade 4 neutropenia ≤ 7 days
• Grade 4 lymphopenia or leukopenia
• Grade 4 isolated electrolyte 
imbalances/abnormalities that are not associated 
with clinical sequelae and are responding to 
supplementation/appropriate management within 
72 hours of their onset
Infusion Reactions (manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, hypertension, bronchospasm, or other allergic-like 
reactions)
Hypersensitivity reaction or 
infusion reaction
Grade 3 or 4
Permanently discontinue
Refer to Section 7.4.4.
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7.4.2
Criteria to Resume Treatment
Participants may resume treatment with study drug if they have completed AE management (ie,
corticosteroid taper) or are on ≤ 10 mg prednisone or equivalent and meet the requirements per 
Table 7.4.1-1.
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following:
1) At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive test result (e.g. reverse transcription polymerase chain reaction [RT-PCR] or viral 
antigen),
2) Resolution of acute symptoms (including at least 24 hours have passed since last fever without 
fever reducing medications), 
3) Evaluation by the Investigator with confirmation that there are no sequelae that would place 
the participant at a higher risk of receiving investigational treatment, and
4) Consultation by the medical monitor. 
For suspected cases, treatment may also resume if SARS-CoV-2 infection is ruled-out and other 
criteria to resume treatment are met.Prior to re-initiating treatment in a participant with a dosing 
delay lasting > 6 weeks for nivolumab or > 12 weeks for ipilimumab, the Medical Monitor (or 
designee) must be consulted. Continue tumor assessments per protocol even if dosing is delayed. 
Continue periodic study visits to assess safety and laboratory studies every 6 weeks or more 
frequently if clinically indicated during such dosing delays.
When criteria to resume treatment are met, resume both nivolumab and ipilimumab on the same 
day unless the investigator determines that one of the agents must be discontinued due to toxicity 
attributed to that agent alone.
7.4.3
Nivolumab and Ipilimumab or Nivolumab Treatment beyond Disease 
Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of progressive disease (PD).52 Participants treated 
with nivolumab in combination with ipilimumab or nivolumab will be permitted to continue 
treatment beyond initial study criteria defined PD, assessed by the investigator, as long as they 
meet the following criteria:
•
Investigator-assessed clinical benefit.
•
Tolerance of study treatment
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g. CNS metastases)
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•
Participants provides written informed consent prior to receiving additional nivolumab in 
combination with ipilimumab or nivolumab treatment. All other elements of the main consent 
including description of reasonably foreseeable risks or discomforts, or other alternative 
treatment options will still apply.
•
The maximum period allowed of study treatment is 24 months from date of first dose, including 
treatment beyond progression
•
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring 
according to the Schedule of Activities in Section 2.
A radiographic assessment/scan should be performed within 6 weeks of initial investigator-
assessed progression to determine whether there has been a decrease in the tumor size or continued 
PD. The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
participant is clinically deteriorating and unlikely to receive any benefit from continued treatment 
with nivolumab in combination with ipilimumab or nivolumab.
For the participants who continue nivolumab in combination with ipilimumab or nivolumab study 
therapy beyond initial progression, further progression is defined as following: 
1) For solid tumors, an additional 10% increase in tumor burden with a minimum 5 mm absolute 
increase from time of initial PD, this includes an increase in the sum of diameters of all target 
lesions and/or the diameters of new measurable lesions compared to the time of initial PD.  
2) For CNS tumors, an additional approximately 12.5% increase in tumor burden with a minimum 
5 mm absolute increase of either diameter from time of initial PD; this includes an increase in 
the sum of the products of perpendicular diameters (SPD) and the sum of one diameter with 
larger increase of all target lesions and/or new measurable lesions compared to the time of 
initial PD. 
New lesions are considered measureable at the time of initial progression if the longest diameter
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
Nivolumab in combination with ipilimumab or nivolumab treatment should be discontinued 
permanently upon documentation of further progression.
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7.4.3.1
Treatment with nivolumab and ipilimumab after disease progression 
during treatment with nivolumab monotherapy (Arm B rollover) 
Participants who have progressed after treatment with nivolumab monotherapy may be allowed to 
receive treatment with nivolumab in combination with ipilimumab. Besides complying with all 
criteria described above, the following criteria must be met:
•
Investigator-assessed clinical benefit by receiving nivolumab in combination with ipilimumab;
•
Eligibility must be confirmed within 28 days prior to first dose with nivolumab and 
ipilimumab. 
Participants do not need to be retested for TMB-H prior to moving to treatment with nivolumab 
and ipilimumab. Participants are not required to have TMB ≥ 10 at the time of rollover.
The investigator must discuss each case with the BMS Medical Monitor before initiating treatment 
with nivolumab and ipilimumab. Participants who meet study discontinuation criteria and move to 
follow-up are not eligible to re-start treatment.
The first infusion of nivolumab and ipilimumab for these participants should be at least 22 days 
after the last infusion of nivolumab 480mg (or 6mg/kg). Refer to Sections 7.1.1 and 7.1.2 for 
details related to administration of nivolumab and ipilimumab infusions. The PK and 
immunogenicity sampling schedule should resume following the schedule for nivolumab and 
ipilimumab combination as described in Section 9.5 and Table 9.5-1.
The maximum period allowed of study treatment is 24 months from date of first dose of nivolumab 
monotherapy. 
7.4.4
Treatment of Nivolumab- and Ipilimumab-Related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
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, hypo- or hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 
4 infusion reactions should be reported within 24 hours as SAEs if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE (Version 5.0) guidelines.
Treatment recommendations are provided below based on CTCAE v5 grading definitions 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 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
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For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, 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 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1000 mg; 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. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 
participant until resolution of symptoms. The amount of study drug infused must be recorded 
on the electronic case report form (eCRF).
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab or ipilimumab 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; urgent 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 with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab or 
ipilimumab 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).
7.4.5
Management Algorithms for Immuno-oncology Agents
Immuno-oncology (IO) agents are associated with AEs that can differ in severity and duration
from AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered IO 
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agents, and the management algorithms in Appendix 5 provide guidance on assessing and 
managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
•
Myocarditis
Treatment management algorithms are found in the nivolumab IB47 and in Appendix 5. 
7.5
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study Participants. The IP 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.
IP 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).
Further guidance and information for final disposition of unused study treatment are provided in
Appendix 2 and CA209848 Pharmacy Manual. 
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. Sites should discuss discrepancies with the participant at each on-treatment study 
visit.
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7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
adverse event). Medications taken within 2 weeks prior to initial study drug administration and 
medications taken during study must be recorded on the CRF.
•
Immunosuppressive agents 
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.2)
•
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of cancer)
•
Any complementary medications (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care. Use of marijuana and its 
derivatives for treatment of symptoms related to cancer or cancer treatment are permitted if 
obtained by medical prescription or if its use (even without a medical prescription) has been 
legalized locally.
•
Any live / attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella (MMR)) during treatment and until 100 days post last dose.
•
Use of any additional noninvasive medical device treatment of glioblastoma multiforme (eg, 
NovoTTF™, Optune®).
•
Administration of a live (replication competent) coronavirus disease 2019 (COVID-19)
vaccine within 30 days prior to randomization (or screening). Live COVID-19 vaccines should 
not be used during the study, including the treatment period and within 100 days following last 
dose of IP.
7.7.2
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalation 
corticosteroids (with minimal system absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, for contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. Prior palliative 
radiotherapy must have been completed at least 2 weeks prior to first dose of IP.
COVID-19 vaccines that are NOT live (not replication competent) are permitted during the study 
and after the last dose of IP. No data are available on the response to COVID-19 vaccines. The 
efficacy and safety of vaccination in participants who are receiving nivolumab in combination 
with ipilimumab or nivolumab monotherapy are unknown. Please contact the Clinical Trial 
Physician/Medical Monitor (or designee) with any questions related to COVID-19 vaccines.
7.7.3
Palliative Local Therapy
Palliative local therapy, including palliative radiation therapy- and palliative surgical resection, to 
symptomatic non-target bone lesions, skin lesions, or CNS lesions (only for peripheral solid 
tumors, not applicable for CNS primary tumor) is permitted prior to discontinuation of study 
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treatment for participants who do not have evidence of overall clinical or radiographic progression 
per study criteria. Palliative local therapy to lesions causing hemoptysis may also be permitted 
prior to discontinuation of study treatment in participants who do not have evidence of overall 
clinical or radiographic progression per study defined response criteria, provided that the lesions 
undergoing palliative local therapy are not the only sites of measurable disease and the case is 
discussed with and approved by the BMS Medical Monitor.
Participants requiring palliative local therapy should be evaluated for objective evidence of disease 
progression prior to the initiation of such therapy, particularly if the most recent tumor assessment 
was more than 4 weeks prior to the start of local therapy. If progression per study defined response 
criteria is identified on any tumor assessments prior to the initiation of palliative local therapy, 
then participants must either discontinue study drug treatment or they must meet criteria to 
continue treatment beyond progression in order to resume immunotherapy after palliative local 
therapy.
The potential for overlapping toxicities with radiotherapy and nivolumab currently is not known; 
however, anecdotal data suggests that it is tolerable. As concurrent radiotherapy and nivolumab 
have not been formally evaluated, in cases where palliative radiotherapy is required for a tumor 
lesion, then nivolumab should be withheld for at least 1 week before, during, and 1 week after 
radiation. Participants should be closely monitored for any potential toxicity during and after 
receiving radiotherapy, and AEs should resolve to Grade ≤1 prior to resuming nivolumab.
7.7.4
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of treatment 
assignment are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7.7.5
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on 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 renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this participant population. In addition, participants are excluded from MRI if they 
have tattoos, metallic implants, pacemakers, etc. 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.
7.7.6
Surgical Resection Following Initial Response
In some clinical scenarios, investigators may choose to resect solitary lesions in participants with 
metastatic disease and render the patient free of macroscopic disease. Participants enrolled in this 
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study may have lesions surgically resected only if confirmation of response is documented at least 
4 weeks after previous scan and following consultation with the BMS Medical Monitor. If tumor 
shrinkage of the solitary lesion is noted on the re-staging assessment, it is highly encouraged that 
surgical resection be delayed until subsequent scans fail to demonstrate further shrinkage.
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 for the maximum treatment duration specified 
in protocol Section 7.1. 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 nivolumab or 
ipilimumab 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
8.1
Discontinuation from Study Treatment
Nivolumab and/or ipilimumab treatment must be permanently discontinued per criteria in
Section 7.4.1. Discontinue nivolumab and/or ipilimumab for any adverse event, laboratory 
abnormality, or intercurrent illness that, in the judgment of the Investigator, presents a substantial 
clinical risk to the participant with continued nivolumab and/or ipilimumab dosing.
Participants MUST discontinue IP (and non-IP at the discretion of the investigator) for any of the 
following reasons:
•
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 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
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
•
Confirmed disease progression after treatment beyond initial study
criteria defined
progression (see 7.4.3) for Arm A (combination of nivolumab and ipilimumab)
•
Confirmed disease progression after treatment beyond initial study
criteria defined
progression (see 7.4.3) for Arm B unless the participants choose and are eligible for rollover to
receive nivolumab in combination with ipilimumab)
•
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. (Note: Under 
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specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
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.
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (e.g. dose tapering if 
necessary for participant safety). Refer to Section 9.2.5 Pregnancy. 
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 (i.e., 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 entered on the 
appropriate case report form (CRF) page.
The 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.
If a participant in the nivolumab/ipilimumab combination arm 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.
8.1.1
Dose Discontinuation in Nivolumab and Ipilimumab Combination 
Any event that leads to delay in dosing lasting > 6 weeks for nivolumab or > 12 weeks for 
ipilimumab 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 from the previous dose that occur for non-drug-related reasons may be 
allowed if approved by the BMS Medical Monitor (or designee). 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks for nivolumab 
or >12 weeks for ipilimumab, the BMS Medical Monitor (or designee) must be consulted. 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.
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Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab dosing.
The 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.
If a participant in the nivolumab/ipilimumab combination arm meets criteria for discontinuation 
and the 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.
8.1.2
Dose Discontinuation in Nivolumab Monotherapy Arm
Any event that leads to delay in dosing lasting > 10 weeks 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 that occur for non-drug-related reasons may be allowed if approved by the 
BMS Medical Monitor (or designee). 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 10 weeks, the BMS 
Medical Monitor (or designee) must be consulted. 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.
8.1.3
Post Study Treatment Study Follow-up
In this study, overall survival is a key endpoint of the study. Post treatment 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 
outcome and/or survival follow-up data as required and in line with Section 5 until death or the 
conclusion of the study. 
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window (See Table 2-5 in Schedule of Activities). 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. 
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•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
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.
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 randomization. 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 (e.g. 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.
Evaluate participant immediately to rule out cardiac or pulmonary toxicity if participant shows 
cardiac- or pulmonary-related signs (hypoxia, abnormal heart rate, or changes from baseline) or 
symptoms (eg, dyspnea, cough, chest pain, fatigue, palpitations).
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. For solid tumors, response will be assessed 
using RECIST 1.1 for solid tumors (see appendix 7). For CNS tumors, response will be assessed
using RANO 2010 criteria 53supplemented by clinical neurologic examination and performance
status, as well as additional considerations as applicable e.g. adverse events or steroid
requirement. (See Appendix 8).
9.1.1
Imaging Assessment for the Study 
Images will be submitted to an imaging core lab and may undergo blinded independent central 
review (BICR) at any time during the study. Prior to scanning the first participant sites should be 
qualified as well as understand the image acquisition guidelines and submission process as outlined 
in the CA209848 Imaging Manual provided by the imaging core lab. For CNS participants, sites 
need to follow qualification procedures within the imaging manual to demonstrate the ability to 
perform required MRI sequences for this study.
Screening and on study tumor assessment will take place in accordance with the Section 2
Schedule of Activities, according to appropriate response criteria (Appendix 7 and Appendix 8). 
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled timepoints and/or at an outside institution) should be collected for 
RECIST 1.1 tumor assessment and submitted to the BICR.
Scans should be performed until BICR confirmation of progression or treatment discontinuation 
(including treatment beyond progression), whichever occurs later. 
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9.1.2
Methods of Measurement
9.1.2.1
Solid tumors 
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known and/or suspected sites 
of disease should be performed for tumor assessments. Images should be acquired with slice 
thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should be made to 
image each participant using an identical acquisition protocol on the same scanner for all imaging 
timepoints. Tumor measurements should be made by the same investigator or radiologist for each 
assessment whenever possible. Change in tumor measurements and tumor response to guide 
ongoing study treatment decisions will be assessed by the Investigator using the RECIST 1.1 
criteria.
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the, abdomen, pelvis, and other known/suspected sites of 
disease should be obtained.
Should a participant have contraindication for both MRI and CT intravenous contrasts, a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
Should a participant have contraindication for MRI (e.g., incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable.
Use of CT component of a PET-CT scanner: Combined modality scanning such as with PET-CT 
is increasingly used in clinical care, and is a modality/technology that is in rapid evolution; 
therefore, the recommendations outlined here may change rather quickly with time. At present, 
low dose or attenuation correction CT portions of a combined PET-CT are of limited use in 
anatomically-based efficacy assessments and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast-enhanced CT scans for anatomically-based 
RECIST 1.1 measurements. However, if a site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then the 
CT portion of the PET-CT can be used for RECIST 1.1 measurements. Note, however, that the 
PET portion of the CT introduces additional data that may bias an investigator if it is not routinely 
or serially performed.
Bone scan or PET scan is not adequate for assessment of RECIST 1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain 
non-target organs, those non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
Bone scans may be collected per local standards, as clinically indicated.
MRI of brain should be acquired as outlined in Section 2 (Schedule of Activities). CT of the Brain 
(without and with contrast) can be performed if MRI is contraindicated.
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9.1.2.2
Primary CNS Neoplasms
Brain MRI without and with gadolinium contrast should be performed as outlined in Section 2
(Schedule of Activities). 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.
9.1.3
Imaging and Clinical Assessment
Tumor assessments should continue even if dosing is delayed or discontinued. Changes in tumor 
measurements and tumor responses will be assessed by the same investigator. Investigators will 
report the number and size of new lesions that appear while on study. Assessments of PR and CR 
must be confirmed at least 4 weeks (28 days) after initial response. A Best Overall Response of 
SD requires a minimum of 77 days on study from date of first dose to the date of the first imaging 
assessment.
For participants with CNS malignancy, RANO 2010 criteria will be used. 
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 (SPD) 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.
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Table 9.1.3-1:
RANO Criteria for Time-point Response Assessment Incorporating 
MRI and Clinical Factors
Response
Criteria
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.
Table 9.1.3-2:
Assessment of Best Overall Response
Best Overall Response
Criteria54
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
9.1.3.1
BICR Confirmation of Radiographic Progression
Sites should submit all scans to the imaging core lab on a rolling basis, throughout the duration of 
the study. BICR of scans will occur on a rolling basis, blinded to treatment arm, clinical data, and 
investigator assessment of submitted scans. When radiographic progression per RECIST 1.1 or 
RANO criteria is assessed by the investigator, the site will inform the imaging core lab, in order 
for BICR assessment of progression to be performed. The BICR review will be completed and the 
results provided to the site as specified in the imaging vendor documents, provided there are no 
pending imaging queries to the site. All details on the timelines and associated process 
requirements will be outlined in the Imaging Manual. Participants whose RECIST 1.1 or RANO 
radiographic progression is not confirmed by the BICR will be required to continue tumor 
assessments (if clinically feasible) according to the protocol-specified schedule, or sooner if 
clinically indicated. Also, if participants discontinue treatment without radiographic progression, 
tumor assessments will continue according to the protocol specified schedule, as noted in Section 
2 (Schedule of Activities) until progression has been confirmed by BICR. All study treatment 
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decisions will be based on the investigator’s assessment of tumor images and not on the BICR 
assessment.
BICR confirmation of disease progression is mandatory for participants in Arm B (nivolumab 
monotherapy) prior to enrolling in Arm B rollover to receive treatment with nivolumab in 
combination with ipilimumab. The participant will be re-baselined based on the investigator’s 
assessment of the scans with which BICR progression was confirmed. Tumor assessments in 
participants in rollover cohort will be done by BICR and should comply with the requirements 
outlined in this protocol.
9.2
Adverse Events
The definitions of an AE or serious adverse event (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. 
Contacts for SAE reporting specified in Appendix 3.
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (e.g. 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.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE information (with the exception of non-serious AEs related to 
SARS-CoV-2 infection) should begin at initiation of study treatment and for a minimum of 100 
days following discontinuation of study treatment and at the timepoints specified in the Schedule 
of Activities (Section 2).
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent 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 and all AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-
CoV-2 infection must be collected from the time of signing the consent, including those thought 
to be associated with protocol-specified procedures and until 100 days following discontinuation 
of dosing.
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Note: for participants who signed a pre-screening consent with submission of an archived 
tumor sample for eligibility assessment, SAE collection will start at the time of signature of 
the full informed consent. For participants who signed a pre-screening consent to agree to 
collection of a fresh biopsy, SAE collection will start at the time of signature of the pre-
screening informed consent.
For participants randomized and never treated with study drug, SAEs should be collected for 30 
days from the date of randomization.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure, (eg, a follow-up skin biopsy).
•
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 module.
•
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 or designee within 24 hours
of updated information 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 AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known adverse events, when appropriate for the program or protocol.
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment. 
Every adverse event must be assessed by the investigator with regard to whether it is considered
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
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.
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•
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, non-serious AEs of special interest (as defined in Section 
9.2), and AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-CoV-2 
infection will be followed until resolution, until the condition stabilizes, until the participant is lost 
to follow-up (as defined in Section 8.3), or until SARS-CoV-2 infection is ruled out.
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 Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
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.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. If, for whatever reason, the pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
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greater than 6 weeks after the pregnancy has ended), following approvals of participant /sponsor 
/IRB/EC, as applicable.
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.
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
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).
Potential drug induced liver injury is defined as: 
•
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
•
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
•
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
Immune-mediated Adverse Events
Immune-mediated adverse events (IMAEs) 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 
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which were exacerbated by the induction of autoimmunity. Information supporting the assessment 
will be collected on the participant’s case report form.
9.2.9
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.
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. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (see Appendix 3).
In the event of an overdose the investigator should:
•
Contact the BMS Medical Monitor immediately
•
Closely monitor the participant for AEs/SAEs and laboratory abnormalities 
•
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 BMS Medical Monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Physical Examinations
Refer to Schedule of Activities.
9.4.2
Vital signs
Refer to Schedule of Activities.
9.4.3
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Albumin - screening only
Sodium
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Total bilirubin
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN) or serum urea 
Glucose
Potassium
Chloride
Calcium
Phosphorous
TSH, free T3 and free T4 - screening 
TSH, with reflexive fT3 and fT4 if TSH is 
abnormal - on treatment 
Serology
Hepatitis B/C, (HBV sAG, HCV antibody or HCV RNA) - screening only
Serum for HIV testing where locally mandated
Other Analyses
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG). 
Follicle stimulating hormone (FSH) at screening - only required to confirm menopause in 
women < age 55)
9.4.4
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. 
9.5
Pharmacokinetics
Samples for pharmacokinetic and immunogenicity assessment will be collected for participants at 
the timepoints indicated in Table 9.5-1 and Table 9.5-2. All on treatment PK timepoints are 
intended to align with days on which study drug is administered. If it is known that a dose is going 
to be delayed, then the predose sample should be collected just prior to the delayed dose. However, 
if a predose sample is collected but the dose is subsequently delayed, an additional predose sample 
should not be collected. 
Draw blood samples from a site other than the infusion site (ie, contralateral arm) on days of 
infusion for all pre-dose and end of infusion-PK (EOI-PK) samples. Please ensure accurate 
documentation of the time and date of sample collection.
Samples will be evaluated for development of anti-drug antibody (ADA). Samples may also be 
analyzed for neutralizing antibodies, and PK samples may be used for ADA analysis in the event 
of insufficient volume, to complete immunogenicity assessment, or to follow up on suspected 
immunogenicity-related AEs.
Further details of sample collection, processing, and shipment will be provided in the laboratory 
procedures manual.
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Table 9.5-1:
Pharmacokinetic and Immunogenicity Sampling Schedule – Arm A or Arm B Rollover – Nivolumab in 
Combination with Ipilimumab 
Study Day
2 weeks/cycle
Event
Time 
(Relative to Start 
of Infusion)
Hour: Min
Nivolumab 
PK
Blood Sample
Nivolumab 
Immunogenicity 
Sample
Ipilimumab 
PK
Blood Samplec
Ipilimumab 
Immunogenicity 
Samplec
C1 D1 
Ipilimumab Dose 1
predosea
00:00
X
X
X
X
EOIb
X
X
C2D1
predosea
00:00
X
X
X
X
C5D1
predosea
00:00
X
X
X
X
C7 D1
Ipilimumab Dose 3
predosea
00:00
X
X
X
X
EOIb
X
X
C11 D1 
predosea
00:00
X
X
X
X
C17 D1 
predosea
00:00
X
X
X
X
C25 D1 
predosea
00:00
X
X
X
X
After C25 D1, every 8th cycle (16th 
week) until discontinuation or up to 2 
years
predosea
00:00
X
X
X
X
First 2 Follow-up Visits 
(Approximately 30 days and up to ~ 
100 Days from the Discontinuation of 
Study treatment)
NA
X
X
X
X
a Predose samples should be collected just before the start of nivolumab infusion (preferably within 30 minutes). If it is known that a dose is going to be delayed, 
then the predose sample should be collected just prior to the delayed dose. However, if a predose sample is collected but the dose is subsequently delayed, an 
additional predose sample should not be collected.
b
Since the end of infusion-PK (EOI-PK) sample is drawn with the intent of accurately estimating the maximum concentration (Cmax) of the drug, draw 
the EOI-PK when all the study drug has been infused. If the site infuses drug without a flush, then collect the EOI-PK sample within approximately 5 
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minutes after end of infusion. If a flush is administered to clear the IV lines of the drug and to ensure delivery of the entire drug dose, then draw the 
EOI-PK sample within approximately 5 minutes after end of the flush. Do not draw EOI samples from the same IV access from which drug was 
administered.
c If ipilimumab is discontinued, resume ipilimumab PK and ADA (immunogenicity) sample collection for the next scheduled sample collection, then discontinue
ipilimumab sample collection.
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Table 9.5-2:
Pharmacokinetic and Immunogenicity Sampling Schedule Arm B -
Nivolumab Monotherapy
Study Day
4 weeks/cycle
Event
Time 
(Relative to Start of Infusion)
Hour: Min
Nivolumab 
PK
Blood Sample
Nivolumab 
Immunogenicity 
Sample
C1 D1 
predosea
00:00
X
X
EOIb
00:30
X
C2 D1 
predosea
00:00
X
X
C5 D1 
predosea
00:00
X
X
EOIb
00:30
X
C9 D1 
predosea
00:00
X
X
C13 D1 
predosea
00:00
X
X
After C13 D1, every 4th 
cycle (16th week) until 
discontinuation or up to 
2 years
predosea
00:00
X
X
First 2 Follow-up Visits 
(Approximately 30 days 
and up to ~ 100 Days 
from the Discontinuation 
of Study treatment)
NA
X
X
a Predose samples should be collected just before the start of nivolumab infusion (preferably within 30 minutes). If 
it is known that a dose is going to be delayed, then the predose sample should be collected just prior to the delayed 
dose. However, if a predose sample is collected but the dose is subsequently delayed, an additional predose sample 
should not be collected.
b
Since the end of infusion-PK (EOI-PK) sample is drawn with the intent of accurately estimating the maximum 
concentration (Cmax) of the drug, draw the EOI-PK when all the study drug has been infused. If the site infuses 
drug without a flush, then collect the EOI-PK sample within approximately 5 minutes after end of infusion. If a 
flush is administered to clear the IV lines of the drug and to ensure delivery of the entire drug dose, then draw the 
EOI-PK sample within approximately 5 minutes after end of the flush. Do not draw EOI samples from the same IV 
access from which drug was administered.
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9.6
Pharmacodynamics
See Section 9.8.1 and 9.8.2
9.7
Pharmacogenomics
See Section 9.8.5. 
9.8
Biomarkers
The key biomarker goal for this study is to identify factors that could potentially predict clinical 
responses to nivolumab in combination with ipilimumab. Peripheral blood and tumor specimens 
will be taken from all participants’ prior to and on-treatment and as outlined in Table 9.8-1 and 
Table 9.8-2:
Biomarker Tissue and Blood Samples: Arm B Nivolumab Monotherapy. Data will 
be evaluated for associations with clinical response and survival (OS) data. All samples collected 
may also be used for future exploratory analyses (unless restricted by local requirements) to assess 
biomarkers associated with immunotherapy treatment. Complete instructions on the collection, 
processing, handling and shipment of all samples described in this section will be provided in a 
separate procedure manual.
Table 9.8-1:
Biomarker Tissue and Blood Samples: Arm A and Arm B Rollover 
- Nivolumab in Combination with Ipilimumab
Study Day
1 Cycle = 2 weeks
Archival Tumor or 
Fresh Biopsy Tissue
Whole Blood
DNA
Myeloid-
Derived 
Suppressor 
Cells (MDSCs)
Blood TMB
Plasmaa
Pre-screeningb
Xc
Xd
Xd
C1D1
Xb
X
X
C7D1
X
Every 6 Cycles 
(starting at C13D1) 
until end of 
treatment
X
Disease progression
X (optional)e
X
a Plasma samples could be used for evaluation of bTMB or other biomarkers
b For Arm B rollover, pre-screening samples and whole blood DNA are not applicable.
c Fresh biopsies are preferred; however, archival samples are acceptable if obtained within 9 months of signing the 
initial consent form (pre-screening) and no additional intervening therapy (excluding palliative therapy) in between.
d Blood TMB and plasma samples collected during pre-screening should be collected on the same day.
e If a biopsy has been performed and tissue is available, participants are requested to submit fresh tumor tissue at 
disease progression for biomarker research. Tissue submission is optional and biopsy is not required by protocol.
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Table 9.8-2:
Biomarker Tissue and Blood Samples: Arm B Nivolumab 
Monotherapy
Study Day
1 Cycle = 4 weeks
Archival Tumor 
or Fresh Biopsy 
Tissue
Whole Blood 
DNA
Myeloid-
Derived 
Suppressor 
Cells (MDSCs)
Blood TMB
Plasmaa
Pre-screening
Xb
Xc
Xc
C1D1
X
X
X
C4D1
X
Every 3 Cycles 
(starting at C7D1) 
until end of 
treatment
X
Disease progression 
X (optional)d
X
a Plasma samples could be used for evaluation of bTMB or other biomarkers.
b Fresh biopsies are preferred; however, archival samples are acceptable if obtained within 9 months of signing the 
initial consent form (pre-screening and no additional intervening therapy (excluding palliative therapy) in between.
c Blood TMB and plasma samples collected during pre-screening should be collected on the same day.
d If a biopsy has been performed and tissue is available, participants are requested to submit fresh tumor tissue at 
disease progression for biomarker research. Tissue submission is optional and biopsy is not required by protocol.
For biomarker research testing, tumor tissue (formalin-fixed, paraffin embedded archival or recent 
acquisition) must be received during the pre-screening period. Fresh biopsies are preferred; 
however, archival samples (within 9 months of signing the initial study consent form [pre-
screening or screening]) are acceptable. If the required number of slides are not available, the BMS 
Medical Monitor must be consulted, prior to enrollment, to discuss acceptability of the tissue 
available. Please note that fine needle aspiration (FNA) and bone metastases samples are not 
acceptable for submission. Please see the CA209848 Laboratory Manual for more details regarding 
tumor sample collection. 
If a fresh biopsy is warranted, the participant must have a lesion that can be biopsied at an 
acceptable clinical risk as judged by the investigator in order to be eligible for the study.
9.8.1
Additional Research Collection
This protocol will include residual sample storage for additional research (AR).
For All US sites:
Additional research is required for all study participants, except where prohibited by IRBs/ethics 
committees, or academic/institutional requirements. Where one or more of these exceptions 
occurs, participation in the additional research should be encouraged but will not be a condition of 
overall study participation.
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•
If the IRB/ethics committees and site agree to the mandatory additional research retention 
and/or collection, then the study participant must agree to the mandatory additional research 
as a requirement for inclusion in the study.
•
If optional participation is permitted and approved, then the study participants may opt out of 
the additional research retention and/or collection.
For non-US Sites
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc. 
Sample Collection and Storage
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
•
Residual tumor biopsy, residual whole blood and plasma from biomarker collection and PK 
collections (see Table 9.8.1-1) will also be retained for additional research purposes
Samples kept for future research will be stored at the BMS Biorepository in New Jersey, USA or 
an independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
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Table 9.8.1-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Timepoints for which residual samples will be retained
Tumor biopsy 
Screening and at disease progression (if available)
Residual whole blood, plasma and serum
All biomarker collections and all PK collection
9.8.2
Immunogenicity Assessments
Blood samples for immunogenicity analysis will be collected according to the schedule given in
Section 9.5. Samples collected will be evaluated for development of Anti-Drug Antibody (ADA) 
by a validated electrochemiluminescent (ECL) immunoassay.
Samples may also be analyzed for neutralizing antibodies and PK samples may be used for ADA 
analysis in the event of insufficient volume, to complete immunogenicity assessment, or to follow 
up on suspected immunogenicity-related AEs.
Further details of sample collection, processing, and shipment will be provided in the laboratory 
procedures manual.
9.8.3
Blood-based Biomarkers
Blood samples will be collected from all participants. Circulating free tumor DNA (also known as 
cfDNA or ctDNA) will be extracted from blood to assess tumor mutational burden. Genomic DNA 
from whole blood will also be collected and may be used as a comparator for participants with 
tumors examined by whole exome sequencing for tumor mutational burden analyses. Whole blood 
will also be collected to assess myeloid derived suppressor cells (MDSCs) which may be 
associated with response to checkpoint inhibitors. Other biomarkers such as but not limited to 
cytokines, metabolites, etc. may be assessed in plasma. Blood sample collection will follow the 
same time points as mentioned in Table 9.8-1 and Table 9.8-2:
Biomarker Tissue and Blood 
Samples: Arm B Nivolumab Monotherapy. Please see CA209848 Laboratory Manual for 
additional information. 
9.8.4
Tissue-based Biomarkers
Tumor samples may be assessed for gene expression, protein expression, and/or for tumor
mutational burden analyses (TMB) using a variety of methodologies inclusive of, but not limited 
to RNAseq, immunohistochemistry, whole exome sequencing [WES], Next-Generation 
Sequencing [NGS], etc. Immunohistochemistry (IHC) may be used to assess the number and 
composition of immune infiltrates in order to define the immune cell subsets present within 
formalin-fixed, paraffin embedded (FFPE) tumor tissue before and after exposure to therapy. 
These IHC analyses will include, but not necessarily be limited to, PD-L1, PD-L2, immune cell 
profiling to examine T cells, T regs, macrophages, MDSCs, and immune marker expression such 
as PD1, LAG3, IDO, etc. Please see CA209848 Laboratory Manual for additional information. 
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9.8.5
Other Assessments
With available archival tumor tissue and newly obtained biopsy tissue, plasma, and blood, genomic 
and genetic sequencing will be performed (using different sequencing methods, such as whole 
exome sequencing [WES], Next-Generation Sequencing [NGS], etc). Panels of specific genes will 
be performed to determine mutational burden and specific mutations that might affect response to 
nivolumab. Whole blood and plasma collection will follow the same timepoints as biomarker 
collection in Table 9.8-1 and Table 9.8-2:
Biomarker Tissue and Blood Samples: Arm B 
Nivolumab Monotherapy. Please see CA209848 Laboratory Manual for additional information. 
9.9
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters will not be evaluated in this study.
9.10
Patient-Reported Outcomes
Participants, ≥18 years of age at baseline, will be asked to complete the 30-item European
Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-
C30) and 3-level version of the EuroQol Group’s EQ-5D (EQ-5D-3L) after randomization but 
prior to first dose, at on-study clinic visits planned to occur every 4 weeks (nivolumab arm) or 6 
weeks (nivolumab plus ipilimumab arm) while on treatment, and at follow-up visits 1 and 2. In 
addition, the EQ-5D-3L will be completed at designated time points during the survival follow-up 
phase. In cases where a dose of treatment drug is delayed, the PRO assessment should also be 
delayed. 
The EORTC QLQ-C30 will be used to assess the effects of disease symptoms on functioning and 
well-being. The QLQ-C3055 is the most commonly used quality of life instrument in oncology 
trials. The instrument’s 30 items are divided among five functional scales (physical, role, 
cognitive, emotional, and social), nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a global 
health/quality of life scale. With the exception of two items included in the global health/quality 
of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range 
from 1 (Not at all) to 4 (Very much). Raw scores for the QLQ-C30 are transformed to a 0-100 
metric such that higher values indicate better functioning or quality of life or a higher level of 
symptoms. The questionnaire uses a 1-week recall period.
The EQ-5D-3L56 will be used to assess treatment effects on perceived health status and to generate 
utility data for health economic evaluations. The EQ-5D-3L is a generic multi-attribute health-
state classification system by which health is described in 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension is evaluated using 3 levels: no 
problems, some problems, and severe problems. Responses to these 5 dimensions are converted 
into 1 of 243 unique EQ-5D health state descriptions, which range between no problems on all 5 
dimensions (11111) to severe/extreme problems on all 5 dimensions (33333). Using appropriate 
country-specific value weighting algorithms, a respondent’s self-described health state can be 
converted into a utility representing the societal desirability of his/her own health. In addition, the 
EQ-5D includes a visual analogue scale (VAS) allowing a respondent to rate his/her health on a 
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scale ranging from 0–100 with 0 being the worst health state imaginable and 100 being the best 
health state imaginable. The questionnaire uses a recall period of “today.”
The questionnaires will be provided in the participant’s preferred language, if available, and the 
EQ-5D-3L may be administered by telephone during survival follow-up. There exists a 
standardized guide that can be used to facilitate telephone administration of the EQ-5D-3L. If 
exceptional circumstances preclude the continued administration of measures using planned 
modalities, then alternate administration methods may be required after consultation with the 
Sponsor or the Sponsor’s representative. Table 2-2 through Table 2-5 provide information 
regarding the timing of patient-reported outcomes assessments. 
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
Sample size calculation is based on BICR-assessed ORR and DOR.
The two primary objectives are to estimate ORR in tissue TMB (tTMB) high participants in the
salvage setting and blood TMB (bTMB) high participants in the salvage setting enrolled in the
nivolumab + ipilimumab arm. A key secondary objective is DOR in the nivolumab + ipilimumab 
arm.
In CA209227 study, an ORR rate of 45.3% was observed for nivolumab in combination with 
ipilimumab arm in tissue TMB ≥10 mut/Mb population. In CA209032, an ORR of 46% was 
observed for nivolumab + ipilimumab in high TMB SCLC participants and an ORR of 21% was 
observed for nivolumab.57,58 The target ORR chosen in the study is 40% for TMB-high 
participants treated with nivolumab + ipilimumab.
A total of 76 TMB-evaluable subjects in the salvage setting treated with nivolumab + ipilimumab 
are required for each of the tTMB and bTMB populations. The sample size determination was not 
based on power consideration, but to provide precision on the estimation of ORR and DOR for
TMB-high participants treated with nivolumab + ipilimumab. The following table summarizes the 
exact 95% CIs for a sample size of 76 in the nivolumab + ipilimumab arm when observed ORRs 
range from 25% to50%.
Sample size
Number of responses
Response rate
95% Confidence interval
76
19
0.25
(0.16, 0.36)
76
22
0.29
(0.19, 0.40)
76
24
0.32
(0.21, 0.43)
76
26
0.34
(0.24, 0.46)
76
28
0.37
(0.26, 0.49)
76
30
0.39
(0.28, 0.51)
76
32
0.42
(0.31, 0.54)
76
34
0.45
(0.33, 0.57)
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Sample size
Number of responses
Response rate
95% Confidence interval
76
36
0.47
(0.36, 0.59)
76
38
0.50
(0.38, 0.62)
In addition, with ORR of 40% for a sample size of 76 treated participants, the mean percentage of 
responders with DOR ≥ 6 months is 70%, and the corresponding 95% lower bound for the 
responders with DOR ≥ 6 months is 50%, based on 10000 simulations. The calculations assume 
the median DOR for nivolumab + ipilimumab is 11.5 months based on CA20903258 and 
CA20901259 studies. Note for an ORR rate of 10%, typical for standard of care in this refractory 
population, and a median DOR of 5.5 months, the proportion of responders with DOR ≥6 months 
is 47%.
Seventy-six (76) participants in the salvage setting are required for each of tTMB and bTMB for 
nivolumab in combination with ipilimumab arm. Based on the currently observed approximate
40% concordance between tTMB-H and bTMB-H in this study, the total sample size for nivolumab 
in combination with ipilimumab arm will be approximately 122. Nivolumab monotherapy arm is 
a non-comparative arm to evaluate the contribution of components. Approximately 183 to 342
participants will be randomized into nivolumab in combination with ipilimumab (n=122) and 
nivolumab monotherapy (n=61) in a 2:1 randomization ratio. Moreover, if concordance rate 
between tTMB-H and bTMB-H is x%, sample size for nivolumab in combination with ipilimumab 
arm will be approximately 76+76-76*x% and total sample size will be approximately 1.5*(76+76-
76*x%). For example, if x=30% the total sample size will be 194 and if x is close to 0% the total 
sample size will be 228. Note the sample sizes(s) for the primary endpoint of ORR in each of
tTMB-H and bTMB-H in nivolumab + ipilimumab arm remains 76 regardless of the concordance 
but the final sample size required for the study may change depending on the observed 
concordance rate and depending on whether or not the bTMB cut-off is increased after the first 
interim analysis (see Section 10.3.6).
Should the tTMB-H population reach approximately 76 before the bTMB-H population, then 
enrollment will continue only with participants required to meet the eligibility criteria for bTMB 
until approximately 76 participants is reached in the bTMB-H population. Should the bTMB-H 
population reach approximately 76 before the tTMB-H population then enrollment will continue 
only with participants required to meet the eligibility requirement for tTMB-H until approximately 
76 participants is reached in the tTMB-H population.
All tumor types will be pooled in the analysis. In order to ensure that 1 tumor type does not unduly 
impact the overall pooled final efficacy analysis, a cap of approximately 15% of participants per 
tumor type will be enforced.
The final analysis of the primary endpoint ORR based on BICR assessments for tTMB high 
population will be performed at least 12 months after all tTMB ≥ 10 mut/Mb participants in the 
salvage setting have been randomized and study randomization is completed. Final analysis of the 
primary endpoint ORR based on BICR assessments for bTMB high population will be performed 
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at least 12 months after approximately 76 participants with bTMB ≥ 10 mut/Mb (or higher bTMB 
cutoff determined by interim analysis; see Section 10.3.6) in the salvage setting are randomized in 
the nivolumab + ipilimumab arm and study randomization is completed.
Enrollment into the bTMB high population was closed in Dec-2019; enrollment into the tTMB
high population remained ongoing. Given the approximate 40% concordance between tTMB high
and bTMB high, a fraction of the tTMB high participants subsequently randomized into the study
are also bTMB high. These participants will not be included in the primary bTMB efficacy analysis 
population (see Table 10.2-1).
There are two planned interim analyses. The first interim analysis will be used to determine the 
cut-off value for bTMB. The second interim analysis will be used to assess efficacy in the tTMB 
high population. These interim analyses are described in Section 10.3.6. The positive efficacy 
decision is determined when one or both primary endpoints exceed(s) a clinically relevant response 
rate. A search of ORR with salvage therapy yielded a relative wide range of responses ranging from 
no response to more than 30% in various tumor types.60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78
Caution should be taken in referencing these observed ORRs given the limitations on small sample 
size and/or local definition of salvage therapy in some studies. Despite lack of a clearly defined 
clinical response rate across different tumor types, recent approvals by FDA have been granted for 
the treatment of several tumor types in a refractory/rare tumor setting with ORRs ranging from 
12-14%, including small cell lung cancer, cervical cancer and neuroendocrine tumors.12,79,80
There is no formal comparison of ORR between treatment arms (and within tTMB and bTMB 
populations). However, a 95% confidence interval for the difference in ORR between the treatment 
arms will be computed for descriptive purposes for tTMB and bTMB populations separately. 
10.2
Populations for Analyses
The following defined populations will apply to pooled tumor types unless otherwise specified:
Population
Description
Enrolled participants
All participants who signed an informed consent form and were registered 
into the IVRS.
Randomized participants
All participants who were randomized.
Treated participants
All participants who received at least 1 dose of nivolumab or ipilimumab.
Pharmacokinetics participants
All treated participants with available serum time-concentration data.
Immunogenicity participants
All treated participants with baseline and at least 1 post-baseline 
immunogenicity assessment.
The primary endpoint of the trial is BICR-assessed ORR in the tTMB high population and the 
bTMB high population in a salvage setting (Table 10.2-1).
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Table 10.2-1:
Timing of Analysis and Primary Populations for Primary Endpoint
Analysis 
Timing 
Primary Population to be Used for
Primary Endpoint
bTMB interim analysis 
Approximately the first 30 randomized 
participants in the nivolumab + 
ipilimumab arm with bTMB ≥ 10 
mut/Mb at baseline have been 
randomized and followed for at least 6 
months
All bTMB high randomized participants
(followed for at least 6 months)
bTMB final analysis
At least 12 months after approximately 
76 bTMB high participants are treated in 
the nivolumab + ipilimumab arm and 
study randomization is completed
All bTMB high participants randomized 
prior to the closure of the bTMB high 
population in Dec-2019
tTMB interim analysis
Approximately the first 50 randomized 
participants in the nivolumab + 
ipilimumab arm with tTMB ≥ 10 
mut/Mb at baseline have been 
randomized and followed for at least 12 
months and study randomization is 
completed
All tTMB high participants randomized 
at least 12 months prior to the LPLV for 
the analysis
tTMB final analysis 
At least 12 months after all tTMB ≥ 10 
mut/Mb participants have been 
randomized
All tTMB high randomized participants
10.3
Statistical Analyses
Unless otherwise specified, all analyses will be performed for all randomized participants in the 
salvage setting by treatment group as randomized and for tTMB and bTMB populations separately 
within each treatment group.
Demographic and baseline laboratory results will be summarized using descriptive statistics for all 
randomized participants. Baseline characteristics, including demographics (age, gender, 
geographic location, race/ethnicity) and clinical characteristics (date of diagnosis, disease stage, 
liver function status, performance status, co-morbidity/prognostic indicators, location of 
metastases) will be collected at the time of treatment initiation for each arm. General descriptive 
statistics, including mean and standard deviation (SD) for continuous variables, count and 
percentage for categorical variables will be used extensively to examine these variables.
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. A summary of planned statistical analyses of the primary and 
secondary endpoints is in Sections 10.3.2 and 10.3.3.
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10.3.1
Efficacy Analyses
Endpoint Definition
Statistical Analysis Methods
Primary
ORR (based on BICR assessments) is defined as the 
number of participants with a best overall response of 
confirmed CR or PR divided by the number of all 
randomized participants. Best overall response is 
defined as the best response designation, as determined 
by BICR, recorded between the date of randomization
and the date of objectively documented progression (per 
RECIST v1.1 or RANO criteria) or the date of 
subsequent therapy, whichever occurs first. For 
participants without documented progression or 
subsequent therapy, all available response designations 
will contribute to the BOR determination. For 
participants who continue treatment beyond 
progression, the BOR will be determined based on 
response assessments up to the time of initial RECIST 
1.1 progression.
BICR-assessed objective response rate (ORR) using 
disease specific response criteria: Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1), and Response 
Assessment for Neuro-Oncology (RANO) criteria for 
primary CNS neoplasms.
BICR-assessed ORR will be summarized by binomial 
response rates and their corresponding two-sided 95%
exact CIs using Clopper-Pearson method.
Secondary
DOR (based on BICR assessments) is defined as the 
time from first confirmed response (CR or PR) to the 
date of the first documented tumor progression as 
determined using RECIST 1.1 or RANO criteria or 
death due to any cause, whichever occurs first. 
Participants who start subsequent therapy without a 
prior reported progression will be censored at the last 
evaluable tumor assessments prior to initiation of the 
subsequent anticancer therapy. Participants who die 
without a reported prior progression will be considered 
to have progressed on the date of their death. 
Participants who neither progress nor die will be 
censored on the date of their last evaluable tumor 
assessment.
BICR-assessed duration of response (DOR) will be 
estimated for all randomized participants who achieve 
confirmed PR or CR using the Kaplan-Meier (KM) 
product-limit method. Median values of DOR, along 
with two-sided 95% CI using Brookmeyer and 
Crowley method, will also be calculated. Probability 
of achieving DOR≥ 6 months will be calculated using 
KM method with 95% CI.
The investigator-assessed ORR
Investigator-assessed ORR will be summarized by 
binomial response rates and their corresponding two-
sided 95% exact CIs using Clopper-Pearson method.
The investigator-assessed DOR
Investigator- assessed duration of response (DOR) will 
be estimated for all randomized participants who 
achieve confirmed PR or CR using the Kaplan-Meier 
(KM) product-limit method. Median values of DOR, 
along with two-sided 95% CI using Brookmeyer and 
Crowley method, will also be calculated. Probability 
of achieving DOR≥ 6 months will be calculated using 
KM method with 95% CI.
TTR is defined as the time from randomization date to 
the date of the first confirmed response, as assessed by 
the BICR.
Time to response (TTR) will be summarized using 
descriptive summary statistics for the responders.
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Endpoint Definition
Statistical Analysis Methods
CBR is defined as the number of participants with a 
best overall response (BOR) of confirmed complete 
response (CR) or partial response (PR) or stable disease 
(SD) divided by the number of randomized participants.
BICR and Investigator assessed CBR will be 
summarized by binomial response rates and their 
corresponding two-sided 95% exact CIs using 
Clopper-Pearson method.
OS is defined as the time from the randomization date 
to the date of death.
Time to event distribution will be estimated using 
Kaplan Meier techniques. Median OS along with 95% 
CI will be constructed based on a log-log transformed 
CI for the survivor function. Rates at some fixed 
timepoints (6, 12, 18 and 24 months) will be derived 
from the Kaplan Meier estimate and corresponding 
confidence interval will be derived based on 
Greenwood formula for variance derivation and on 
log-log transformation applied on the survivor 
function.
Participants without documentation of death will be 
censored on the last date the participant was known to 
be alive.
PFS is defined as the time from randomization date to 
the date of the first documented tumor progression, 
determined by BICR assessments (per RECIST 1.1 or 
RANO), or death due to any cause, whichever occurs 
first.
BICR and investigator assessments will use Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1), 
and Response Assessment for Neuro-Oncology 
(RANO) criteria for primary CNS neoplasms.
Participants without a reported progression will be 
considered to have progressed on the date of their 
death if no subsequent anti-cancer therapy initiated. 
Participants who did not progress or die will be 
censored on the date of the last tumor assessment. 
Participants who did not have any on study tumor 
assessments and did not die will be censored on the 
first dosing date. Participants who started any 
subsequent anti-cancer therapy and without a prior 
reported progression will be censored at the last tumor 
assessment prior to initiation of the subsequent 
therapy.
Time to event distribution will be estimated using 
Kaplan Meier techniques. Median PFS along with 
95% CI will be constructed based on a log-log 
transformed CI for the survivor function. Rates at 
some fixed time points (6, 12, 18 and 24 months) will 
be derived from the Kaplan Meier estimate and 
corresponding confidence interval will be derived 
based on Greenwood formula for variance derivation 
and on log-log transformation applied on the survivor 
function.
10.3.2
Safety Analyses
Endpoint Definition
Statistical Analysis Methods
Primary
Not applicable
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Endpoint Definition
Statistical Analysis Methods
Secondary
Safety and tolerability
Descriptive statistics of safety will be presented using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 by tumor types. All on-study AEs and SAEs and drug-related AEs and 
SAEs will be tabulated using worst grade per NCI CTCAE version 5.0 criteria by 
system organ class and MedDRA preferred term.
On-study lab parameters including hematology, coagulation, chemistry, liver 
function and renal function will be summarized using worse grade per NCI 
CTCAE version 5.0 criteria.
Exploratory
Will be described in the statistical analysis plan finalized before database lock
10.3.3
Pharmacokinetics Analysis
The nivolumab and ipilimumab concentration data obtained in this study may be combined with 
data from other studies in the clinical development program to develop population PK models. 
These models may be used to evaluate the effects of intrinsic and extrinsic covariates on the PK 
of nivolumab and to determine measures of individual exposure (such as steady state peak, trough 
and time averaged concentration). Model determined exposures may be used for exposure response 
analyses of selected efficacy and safety endpoints. If the analyses are conducted, the results of 
population PK and exposure response analyses will be reported separately.
10.3.4
Outcomes Research Analyses
The analysis of EQ-5D-3L and EORTC QLQ-C30 data will be performed in all treated participants 
who have an assessment at baseline and at least 1 subsequent assessment while on treatment. 
Questionnaire completion rate, defined as the proportion of questionnaires received out of the 
expected number, will be calculated and summarized at each assessment point. Analyses of PROs 
will be replicated for subjects that are treated with nivolumab combined with ipilimumab after 
disease progression under nivolumab monotherapy.
EQ-5D data will be described by treatment group in the following ways:
•
EQ-5D index scores and post-baseline changes in scores will be summarized at each 
assessment time point using descriptive statistics (ie, N, mean with SD and 95% CI, median, 
first and third quartiles, minimum, maximum).
•
EQ-VAS scores and post-baseline changes in scores will be summarized at each assessment 
time point using descriptive statistics (ie, N, mean with SD and 95% CI, median, first and third 
quartiles, minimum, maximum).
•
The proportion (N) of participants reporting no, moderate, or extreme problems will be 
presented for each of the 5 EQ-5D dimensions at each assessment time point. Participants with 
missing data will be excluded from the analysis.
•
A by- participant listing of the level of problems in each dimension, corresponding EQ-5D 
health state (ie, 5-digit vector), EQ-5D index score, and EQ-VAS score will be provided.
EORTC QLQ-C30 data will be described by treatment group in the following ways:
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•
Scale and item scores will be summarized at each assessment time point using descriptive 
statistics (ie, N, mean with SD and 95% CI, median, first and third quartiles, minimum, 
maximum).
•
Changes from baseline in scale and item scores will be summarized at each post-baseline 
assessment time point using descriptive statistics (ie, N, mean with SD and 95% CI, median, 
first and third quartiles, minimum, maximum).
10.3.5
Other Analyses
Immunogenicity: Serum samples collected will be analyzed by a validated immunogenicity assay. 
Selected serum samples may be analyzed by an exploratory orthogonal method that measures 
anti-nivolumab. Potential results generated from any orthogonal method are intended as 
informational for technology exploration purposes and will not be reported.
In addition, ad hoc serum samples designated for pharmacokinetic or biomarker assessments may 
also be used for immunogenicity analysis if required (e.g., insufficient volume for complete 
immunogenicity assessment or to follow up on suspected immunogenicity related AE).
Other exploratory analyses will be described in the statistical analysis plan. 
10.3.6
Interim Analyses
Adjust bTMB cut-off value
An interim analysis will be conducted to evaluate the cut-off value for bTMB using an adaptive 
enrichment procedure.81,82 In order to ensure that 1 tumor type does not unduly impact the overall 
pooled efficacy analysis, a cap of approximately 15% participants per tumor type of the sample 
size for this interim analysis will be enforced. The analysis will be performed after approximately 
the first 30 randomized participants in nivolumab + ipilimumab arm with bTMB ≥ 10 mut/Mb at 
baseline have been randomized and followed for at least 6 months. 
BICR-assessed ORR will be estimated in the following groups 
•
low group (10 ≤bTMB < cut-off )
•
enriched group (bTMB ≥cut-off)
Decision rule: 
If the following 2 criteria are satisfied at the interim analysis,
1) estimated ORR in enriched group minus estimated ORR in low group ≥16.5% 
and 
2) estimated ORR in low group < 30%
then eligibility criteria will be restricted to participants with either tTMB ≥10 mut/Mb or bTMB
≥new cut-off for the remainder of the trial until a total of approximately 114 participants (76 in 
nivolumab + ipilimumab arm and 38 in nivolumab arm) with bTMB ≥ new cut-off are enrolled
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and a total of approximately 114 participants with tTMB ≥10 mut/Mb are enrolled. The maximum 
number of participants for the study may be up to 342 if cut-off value for bTMB is increased and 
all of the previously randomized bTMB participants need to be replaced with new participants who 
have bTMB ≥new cut-off.  
Should the tTMB-H (tTMB ≥10 mut/Mb) population reach the targeted sample size 
(approximately 76 participants in nivolumab + ipilimumab arm and approximately 38 in 
nivolumab arm), participants will continue to provide a tissue sample; however, eligibility will be 
based on a bTMB ≥ new cut-off only.
Simulations have been conducted to evaluate the operating characteristics, including the decision 
rule, and details are provided in Appendix 10. The Statistical Analysis Plan (SAP) will further 
describe the planned interim analyses.
Correlation between bTMB and tTMB will be assessed.
Efficacy for tTMB population
A formal interim analysis for BICR-assessed ORR will be conducted on tTMB high participants
in the salvage setting after approximately the first 50 for nivolumab + ipilimumab arm and 25 for 
nivolumab monotherapy arm randomized participants in the salvage setting with tTMB ≥ 10 
mut/Mb at baseline have been randomized and followed for at least 12 months (approximately 75 
total tTMB high participants), and study-wide randomization has completed. In order to achieve 
the necessary number of study participants in the tTMB high population for the tTMB primary 
endpoint final analysis, enrollment into this population continued after the date on which criteria 
were met for the tTMB interim analysis. The primary analysis population for the interim analysis 
will be the interim tTMB high population (limited to all tTMB high participants randomized at 
least 12 months prior to the LPLV for the analysis). 
BICR-assessed DOR will be analyzed for tTMB high participants who achieve confirmed PR or 
CR using the Kaplan-Meier (KM) product-limit method. Probability of achieving DOR≥6 months 
will also be calculated.
Similar interim analysis may be conducted on bTMB high population.
All of the interim analyses and other unblinded efficacy/safety data will be reviewed by the DMC 
while the Sponsor remains blinded (See DMC charter for more detail).
The Statistical Analysis Plan will further describe the planned interim analyses.
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11
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48 Opdivo 
(nivolumab) 
US 
Prescribing 
Information. 
Bristol-Myers 
Squibb, 
2021. 
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77 BMS protocol CA209141, November 2016, Document Control Number 930075071.
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78 Konda B, Kirschner LS. Novel Targeted Therapies in Adrenocortical Carcinoma. Curr Opin 
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233–241. 
doi:  
[10.1097/MED.0000000000000247].
79 Keytruda [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2014-2018.
80 Lutathera [package insert]. NJ: Advanced Accelerator Applications USA, Inc., 2018.
81 Simon N. et al, Adaptive enrichment designs for clinical trials, Biostatistics (2013), 14, 4, 
p613-625. 
82 Simon N. et al, Using Bayesian modeling in frequentist adaptive enrichment designs,   
Biostatistics (2018), 19, 1, p27-41.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
μ
micro
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
AR
additional research
AST
aspartate aminotransferase
AT
aminotransaminases
BICR
blinded independent central review
BMS
Bristol-Myers Squibb Company
BOR
best overall response
BP
blood pressure
BSA
body surface area
bTMB
blood TMB
bTMB-H
blood TMB high
BUN
blood urea nitrogen
C
cycle
Ca
calcium
Cavg
average concentration
Cavgss
average steady-state exposure
CBC
complete blood count
CBR
clinical benefit rate
CFR
Code of Federal Regulations 
cHL
classical Hodgkin’s lymphoma
CI
confidence interval
C1-
chloride
CL
clearance
CLIA
Clinical Laboratory Improvement Amendments
CLcr
creatinine clearance
Cmax
maximum concentration
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Term
Definition
Cmaxss
steady-state peak concentrations
CNS
central nervous system
COVID-19
coronavirus disease 2019
CR
Complete response
CRC
colorectal cancer
CRF
case report form, paper or electronic
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CV
coefficient of variation
D
day
DC/D
discontinuation/death
dL
deciliter
DLT
Dose Limiting Toxicity
DMC
data monitoring committee
dMMR
deficient mismatch repair deficiency
DNA
deoxynucleic acid
DOR
duration of response
DRESS
drug reaction with eosinophilia and systemic symptoms
EC
endometrial cancer
ECG
electrocardiogram
ECL
electrochemiluminescent
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
EOI
end of infusion
EOI-PK
end of infusion pharmacokinetics
EORTC
European Organization for Research and Treatment of Cancer 
EORTC-QLQ-
C30
European Organization for Research and Treatment of Cancer quality of 
life questionnaire 30
EQ-5D
EuroQol questionnaire comprising 5 dimensions
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Term
Definition
EQ-5D-3L
the 3-level version of the EuroQol questionnaire comprising 5 
dimensions
ER
exposure response
EU
European Union
F1CDx
FoundationOne® Companion Diagnostic
FDG
fluorodeoxyglucose
FFPET
formalin-fixed, paraffin-embedded tumor tissue
FLAIR
fluid-attenuated inversion recovery
FMI
Foundation Medicine Incorporated
FNA
fine needle aspiration
FSH
follicle stimulating hormone
FU
follow-up
g
gram
GBS
Guillain-Barre syndrome
GC
gastric cancer
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
h
hour
H&N
head and neck
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
human immunodeficiency virus
HR
hazard ratio
IA
interim analysis
IB
Investigator Brochure
ICH
International Conference on Harmonisation 
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Term
Definition
IDO
indoleamine 2,3 dioxygenase
ie
id est (that is)
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IO
immuno-oncology
IP
investigational product
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
IVRS
interactive voice response systems
K+
potassium
kg
kilogram
L
liter
LAG-3
Lymphocyte activation gene-3
LDH
lactate dehydrogenase
LPLV
last patient last visit
MDSC
myeloid-derived suppressor cell
mg
milligram
Mg++
magnesium
MG
myasthenia gravis
MHC
major histocompatibility complex
MI
myocardial Infarction
min
minute
mL
milliliter
MMR
mismatch repair
mo
month
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Term
Definition
mPFS
median progression-free survival
MRI
magnetic resonance imaging
MSI
microsatellite instability
MSI-H
microsatellite instability high
MTD
maximum tolerated dose
mut/Mb
mutations per megabase
N
number of subjects or observations
Na
sodium
N/A
not applicable
NCI
National Cancer Institute
NGS
Next-Generation Sequencing
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed death ligand 1
PET 
positron emission tomography
PFS
progression free survival
PK
pharmacokinetics
PPK
population pharmacokinetics
PR
Partial response
PRO
Patient-reported outcome
Q2W
every 2 weeks
Q4W
every 4 weeks
Q6W
every 6 weeks
QOL
quality of life
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Term
Definition
R&D
research and development
RANO
Response Assessment for Neuro-Oncology
RECIST
Response Evaluation Criteria in Solid Tumors
RBC
red blood cell
RCC
renal cell carcinoma
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCCHN
squamous cell carcinoma of the head and neck
SD
standard deviation
SD
stable disease
SJS
Stevens-Johnson syndrome
SOP
Standard Operating Procedures
SPD
Sum of the products of perpendicular diameters
t
temperature
T
time
t1/2
half-life
T2
transverse relaxation time
T3
triiodothyronine
T4
thyroxine
T.bili
total bilirubin
TEN
toxic epidermal necrolysis
TIA
transient ischemic attack
TMB
tumor mutational burden
TMB-H
high tumor mutational burden
Treg
regulatory T cell
tTMB
tissue TMB
TTR
time to response
TSH
thyroid stimulating hormone
UC
urothelial carcinoma
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Term
Definition
ULN
upper limit of normal
USPI
United States Prescribing Information
WBC
white blood cell
VAS
visual analog scale
WHO
World Health Organization
WES
whole exome sequencing
WOCBP
women of childbearing potential
WNOCBP
women not 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:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 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) 
•
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 Good Clinical Practice (GCP) (occurring in 
any country) in connection with that trial or the protocol to the trial which is likely to affect to a 
significant degree, the safety or physical or mental integrity of 1 or more subjects of the trial or 
the scientific value of the trial.
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 (e.g., 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 (e.g., 
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 (e.g., 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 
•
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.
Investigators must:
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•
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. 
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).
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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 (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.
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 treatment integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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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).
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
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
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:
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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 (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
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 (e.g., 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.
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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, i.e., 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.
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:
•
Participant recruitment (e.g., among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (e.g., 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 (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
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Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
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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 treatment
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 treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
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DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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: 
•
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)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
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
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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 [e.g., 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 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
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.) 
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If an ongoing SAE changes in its intensity or relationship to study treatment 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.
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
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 after the end of study 
treatment.*
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 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
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Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
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
Unacceptable Methods of Contraception*
•
Male or female condom with or without spermicide.  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
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Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
NOT APPLICABLE PER PROTOCOL AMENDMENT 04: 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 5
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 6
ECOG PERFORMANCE STATUS
Table 1:
ECOG Performance Status
ECOG PERFORMANCE STATUS
0—Fully active, able to carry on all pre-disease performance without restriction
1—Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work
2—Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 
50% of waking hours
3—Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4—Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5—Dead
References: Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern Cooperative
Oncology Group. Am J Clin Oncol 1982;5:649-655.
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APPENDIX 7
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ൒2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
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small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
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disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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2) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
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Table 2.3.2-2:
Time Point Response: Patients With Non-Target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 8
RADIOGRAPHIC ASSESSMENT FOR NEURO-ONCOLOGY 
(RANO) CRITERIA FOR HIGH-GRADE GLIOMAS
Table 1:
Summary of Proposed Radiographic Assessment for Neuro-
Oncology
Criterion
Complete Response
Partial Response
Stable Disease
Progressive Disease
T1 gadolinium 
enhancing disease
None
≥50% ↓
< 50% ↓ but < 25% ↑
≥25% ↑*
T2/FLAIR
Stable or ↓
Stable or ↓
Stable or ↓
↑*
New lesion
None
None
None
Present*
Corticosteroids
None
Stable or ↓
Stable or ↓
NA†
Clinical status
Stable or ↑
Stable or ↑
Stable or ↑
↓*
Requirement for 
response
All
All
All
Any*
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR, complete response; PR, partial response; SD, 
stable disease; PD, progressive disease; FLAIR, fluid-attenuated inversion recovery; NA, not applicable.
* Progression occurs when this criterion is present.
† Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent 
clinical deterioration.
NOTE. All measurable and nonmeasurable lesions must be assessed using the same techniques as at baseline.
Reference: 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;28-1:3059-3067. 
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APPENDIX 9
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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APPENDIX 10
SIMULATION RESULTS
Simulations have been conducted under the following assumed scenarios:
•
Proportions for enriched group and low group: 0.75 vs. 0.25, 0.7 vs. 0.3, 0.6 vs. 0.4, 0.5 vs. 0.5 
•
True ORRs for enriched group and low group: 40% vs. 25%, 35% vs. 10%, 20% vs. 10%, 10% 
vs. 10%
10,000 replications of trials were simulated with a total of 76 bTMB evaluable participants and 
30 bTMB ≥ 10 mut/MB participants at the time of interim analysis. As shown in Table 1, the 
simulated power for the adaptive procedures (power adapt) and non-adaptive procedures (power 
non-adapt) are calculated for each assumed scenario.
Table 2:
The power for adaptive vs. non-adaptive procedures
Group
Proportion of entire 
population
True ORR
Power non-adapt
Power adapt
Enriched group
0.75
40%
0.723
0.999
Low group
0.25
25%
Enriched group
0.75
35%
0.726
0.987
Low group
0.25
10%
Enriched group
0.75
20%
0.411
0.471
Low group
0.25
10%
Enriched group
0.75
10%
0.019
0.020
Low group
0.25
10%
Enriched group
0.7
40%
0.660
0.999
Low group
0.3
25%
Enriched group
0.7
35%
0.636
0.979
Low group
0.3
10%
Enriched group
0.7
20%
0.346
0.442
Low group
0.3
10%
Enriched group
0.7
10%
0.016
0.017
Low group
0.3
10%
Enriched group
0.6
40%
0.602
0.999
Low group
0.4
25%
Enriched group
0.6
35%
0.467
0.948
Low group
0.4
10%
Enriched group
0.6
20%
0.226
0.383
Low group
0.4
10%
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Table 2:
The power for adaptive vs. non-adaptive procedures
Group
Proportion of entire 
population
True ORR
Power non-adapt
Power adapt
Enriched group
0.6
10%
0.012
0.015
Low group
0.4
10%
Enriched group
0.5
40%
0.570
0.999
Low group
0.5
25%
Enriched group
0.5
35%
0.342
0.896
Low group
0.5
10%
Enriched group
0.5
20%
0.149
0.347
Low group
0.5
10%
Enriched group
0.5
10%
0.013
0.017
Low group
0.5
10%
Note: Enriched group include participants with bTMB>=cut-off and Low group include participants with 
10<=bTMB<cut-off
The simulation result shows that adaptive enrichment procedure appears to increase the power in 
most scenarios. In addition, type I error is well controlled (<0.025).  
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APPENDIX 11
COUNTRY SPECIFIC AMENDMENTS
Argentina, France, Germany, Italy, Spain, and Any Other Countries Where Exclusion of 
HIV Positive Participants Is Locally Mandated
Country-specific language
Section 2 Flow Chart/Time and Events Schedule, Table
2-1: ScreeningAssessments - LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 1.a
“Known history of testing positive for human
immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS)”to be replaced with
“Positive test for HIV”.
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APPENDIX 12
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Revised Protocol 03:
This protocol revision serves to update the protocol per program requirements, company and 
document standards, as well as make changes per the Administrative Letter 02 and 03. The 
following content has also been updated:
•
Updated the range and number of participants and clarified statistical analyses and sample size.
•
Provided clarification on requirements for pre-screening and eligibility.
•
Added language regarding adolescent participants not being included for sites in Belgium and 
the Netherlands per the Country Specific Amendment 03.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Updated Study Director and Medical Monitor 
information
Updated study personnel
Section 2
Schedule of Activities 
Table 2-1
Added the following language-
tTMB and bTMB results should be ≥ 10 mut/Mb 
(tTMB ≥ 10 mut or the new cutoff value of 
bTMB determined by the 1st interim analysis)
Provided clarification on pre-
screening requirements and 
interim analyses
Section 2
Schedule of Activities 
Table 2-1
Table 2-2
Table 2-3
Table 2.4
Section 3.1.3 Rationale for 
Inclusion of Adolescent 
Participants
Section 3.2.4 Nivolumab 
Combined with Ipilimumab 
and Nivolumab 
Monotherapy Clinical 
Activity in Adolescents
Section 3.3.2 Adolescent 
Patients
Section 5.5.3 Dose for 
Adolescents
Section 7.1 Treatments 
Administered 
Table 7.1-1
Section 7.1.1 Arm A or 
Arm B Rollover -
Nivolumab in Combination 
with Ipilimumab
Added content regarding Belgium and the 
Netherlands not enrolling adolescents into study 
sites
At the request of Belgium and 
the Netherlands sites
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.1.2 Arm B –
Nivolumab Monotherapy
Section 2
Schedule of Activities 
Table 2-2
Table 2-3
Table 2-4
Added the following language in the Outcomes 
research row-
If the dose is delayed, then PRO completion 
should also be delayed.
Bring protocol in line with drug 
program standards
Section 3.2.5 Nivolumab 
Clinical Pharmacology
Added updated clinical pharmacology section to 
background
Bring protocol in line with 
document standards
Section 4 Objectives and 
Endpoints Table 4-1
Clarified endpoints for exploratory objectives
Provide further detail on study 
scope
Section 5.1 Overall Design 
Figure 5.1-1
Updated figure to include language regarding 
tTMB ≥ 10 mut or the new cutoff value of 
bTMB determined by the 1st interim analysis
Added content regarding Belgium and the 
Netherlands not enrolling adolescents into study 
sites
Provided clarification on pre-
screening requirements and 
interim analyses
At the request of Belgium and 
the Netherlands sites
Section 5.2 Number of 
Participants
Updated the range of participants and rationale 
of participant range
Provide further detail on study 
scope
Section 5.5.5 Rationale for 
30-Minute infusion
Removed text regarding 30 minute break after 
first infusion for combination cohort
Not applicable to study
Section 6.1 Inclusion 
Criteria
Updated language regarding palliative local 
therapy
Added content regarding Belgium and the 
Netherlands not enrolling adolescents into study 
sites
Bring protocol in line with drug 
program standards
At the request of Belgium and 
the Netherlands sites
Section 6.1 Inclusion 
Criteria Figure 6.1-1
Updated figure to include language regarding 
biomarker testing, prescreening and ≥ 10 mut or 
the new cutoff value of bTMB determined by 
the 1st interim analysis
Provided clarification on pre-
screening requirements and 
interim analyses
Section 6.2 Exclusion 
Criteria
Added content regarding Belgium and the 
Netherlands not enrolling adolescents into study 
sites
Corrected typo in regarding creatinine clearance 
At the request of Belgium and 
the Netherlands sites
Administrative change.
Section 7 Treatment
Added clarification on weight based dosing 
calculations
Bring protocol in line with drug 
program standards
Section 7.4.5 Management 
Algorithms for Immuno-
Oncology Agents
Added Myocarditis to the list of management 
algorithms
Bring protocol in line with drug 
program standards
Section 9.1.2.1 Solid 
tumors
Added language regarding CT component of a 
PET-CT Scanner
Bring protocol in line with 
document standards
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 9.1.3.1 BICR 
Confirmation of 
Radiographic Progression
Added language regarding BICR confirmation 
of disease progression.
Bring protocol in line with drug 
program standards
Section 9.8 Biomarkers
Table 9.8-1 and 
Table 9.8-2
Clarified prescreening procedure and footnotes 
were updated for bTMB and tumor
Provided clarification on pre-
screening requirements
Section 9.10 Patients 
Reported Outcomes
Indicated PRO assessments should be delayed in 
the event dose of treatment drug is also delayed
Bring protocol in line with drug 
program standards
Section 10.1 Sample Size 
Determination
Updated content regarding sample size and 
enrollment based on tTMB and bTMB pre-
screening
Provided clarification on pre-
screening requirements and 
participant population
Section 10.3.6 Interim 
Analyses
Updated content regarding sample size and 
enrollment based on tTMB and bTMB pre-
screening 
Provided clarification on pre-
screening requirements and 
participant population
All
Minor formatting and typographical corrections
Minor, therefore have not been 
summarized
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Overall Rationale for Revised Protocol 02:
This amendment incorporates feedback received from FDA on pursuing a tumor-agnostic 
indication with TMB for the study design of CA209-848.  The key changes include:
1) Revision of the statistical method to be based on precision of the estimation of ORR. The 
efficacy decision is revised to be based on the lower limit of a 95% confidence interval to 
exceed a clinically relevant response rate. Previously, the primary endpoint is to be compared 
with a historical control with a type I error rate set to 0.05. 
2) Clarification on targeted population as in a salvage setting. The inclusion criteria is revised to 
stress participants being “refractory to standard local therapies, or for which no standard 
treatment is available”. Previously, it was “received at least one prior line of therapy including 
standard of care, if available”.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & 
Title
Description of Change
Brief Rationale
Document History
Included Revised Protocol 02; incorporated 
Administrative Letter 01.
Updated summary of 
changes.
Section 2, Schedule of 
Activities, Table 2-1, 
Screening Procedural 
Outline (CA209848)
Revised Notes for Pre-screening for TMB-
H.
Provided more clarity on the 
pre-screening and screening 
procedures.
Section 2, Schedule of 
Activities, Table 2-1, 
Screening Procedural 
Outline (CA209848)
Revised Notes for Tumor tissue collection.
Added section reference 
regarding details for tumor 
tissue collection.
Overall Rationale for Revised Protocol 01:
This protocol is listed a “Revised protocol 1” to remain Title 21 CFR Part 11 compliant (FDA 
regulations on electronic records and electronic signatures). The initial protocol CA209848 was 
never activated as initially written. The study was fully revised and, therefore, there are no 
summary of changes to compare to the initial protocol.
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