A Phase 1/2 Study of Relatlimab (Anti-LAG-3 Monoclonal Antibody) Administered in Combination With Both Nivolumab (Anti-PD-1 Monoclonal Antibody) and BMS-986205 (IDO1 Inhibitor) or in Combination With Both Nivolumab and Ipilimumab (Anti-CTLA-4 Monoclonal Antibody) in Advanced Malignant Tumors
Phase: PHASE1
Conditions: Advanced Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 1/2 Study of Relatlimab (anti-LAG-3 Monoclonal Antibody) Administered in 
Combination with Both Nivolumab (anti-PD-1 Monoclonal Antibody) and BMS-986205 (IDO1 
inhibitor) or in Combination with Both Nivolumab and Ipilimumab (anti-CTLA-4 Monoclonal 
Antibody) in Advanced Malignant Tumors 
 
NCT Number: NCT03459222 
Document Date (Date in which document was last revised): 04 Jan 2023 
 
 
 

Page:
1
Protocol Number:
CA224048
IND Number:
137,483
EUDRACT Number:
2018-000058-22
Date:
05-Jan-2018
Revised Date:
04-Jan-2023
CLINICAL PROTOCOL CA224048
A Phase 1/2 Study of Relatlimab (anti-LAG-3 Monoclonal Antibody) Administered in 
Combination with Both Nivolumab (anti-PD-1 Monoclonal Antibody) and BMS-986205 (IDO1 
inhibitor) or in Combination with Both Nivolumab and Ipilimumab (anti-CTLA-4 Monoclonal 
Antibody) in Advanced Malignant Tumors
Short Title: An Investigational Study of Immunotherapy Combinations in Participants With 
Solid Cancers That Are Advanced or Have Spread
Protocol Amendment Number: 07
Incorporates Administrative Letter 03
Clinical Trial Physician - Medical Monitor
Bristol-Myers Squibb Company
556 Morris Ave
Summit, NJ 07901
Phone: 
email: 
Clinical Scientist
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
Phone:
email:
24-hr Emergency Telephone Number
USA: 1-866-470-2267
International: +1-248-844-7390
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
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confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
© 2022 Bristol-Myers Squibb Company
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Protocol Amendment No.: 07
Date: 04-Jan-2023
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 07
04-Jan-2023
The purpose of this protocol amendment is to: update ipilimumab vial size,
 clarify the 
Response Follow-up period and Survival Follow-up period durations,
 
 
 
The study personnel contact information has been updated.
Appendix 2 was updated.
Administrative 
Letter 03
17-Aug-2022
Updated study personnel.
Protocol 
Amendment 06
13-Dec-2021
Removed erroneous nivolumab myocarditis adverse event management 
algorithms. Updated study personnel information and incorporated 
Administrative Letter 02.
Administrative 
Letter 02
24-Sep-2021
Study personnel information updated and corrected a typographical error in 
Protocol 
Amendment 05
07-Sep-2021
 
Protocol 
Amendment 04
23-Jul-2021
The primary reasons for these changes are to align dose modification criteria 
and immuno-oncology (IO) agent management algorithms (Appendix 5) 
with the current Common Terminology Criteria for Adverse Event 
(CTCAE) version (v5); 
 
 vaccination and washout 
periods; and incorporate additional updates to improve alignment across 
protocol sections and/or clarify expectations for eligibility, assessments, 
tumor tissue collections and treatment administration.
Study personnel information updated. 
Appendices 1, 2, 3, 4, and 5 were updated.
Administrative 
Letter 01
17-Oct-2019
Study personnel information updated.
Revised 
Protocol 03
18-Jan-2019
The primary reasons for these changes include: correction of inconsistencies 
in language for targetable mutations; replacement of Appendix 3 to align 
with latest BMS standards; correction of text concerning survival follow-up 
to ensure uniformity throughout the protocol; 
 
 
 update Appendix 5 Management Algorithms and add 
“Myocarditis Adverse Event Management Algorithm” table to Appendix 5; 
correction of other minor inconsistencies.
Revised 
Protocol 02
26-Jun-2018
To update the starting dose of BMS-986205 to 25 mg once daily in Part 1A 
of the dose-finding phase of the study, clarify details, scenarios, and timing 
for some assessments and follow-up, update contraceptive requirements for 
males, add information for adverse events of special interest, update the 
pharmacokinetics and immunogenicity sampling schedule, and update 
guidance on concomitant therapies.
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Document
Date of Issue
Summary of Change
Revised 
Protocol 01
21-Feb-2018
To address 
comments regarding safety, enrollment, inclusion criteria, 
exclusion criteria, dose modification criteria and assignment of participants 
to the study cohorts. 
Original 
Protocol
05-Jan-2018
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07:
Protocol Amendment No.: 07
Date: 04-Jan-2023
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Revisions apply to future participants enrolled in the study and, where applicable, to all 
participants currently enrolled.
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
•
Updated the name and contact 
information for the clinical scientist.
•
Updated the name and contact 
information for the clinical trial 
physician.
•
Updated due to administrative 
changes and incorporation of 
Administrative Letter 03.
•
Updated due to administrative 
changes in study personnel.
Protocol Summary
•
Updated the protocol summary to 
align with relevant protocol 
revisions.
•
Updated to reflect changes in the 
protocol body as summarized 
below.
Table 2-2: On-treatment 
Procedural Outline Part 1A 
(Relatlimab + Nivolumab + 
BMS-986205) and
Part 1B (Relatlimab + 
Nivolumab + Ipilimumab)
Table 2-3: On-treatment 
Procedural Outline: Part 2A 
(Relatlimab + Nivolumab + 
BMS-986205) and
Part 2B (Relatlimab + 
Nivolumab + Ipilimumab)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2-4: Follow-Up 
Procedural Outline 
CA224048
•
 
 
 
Replaced with “Refer to 
Section 5: Study Design” statement
and footnote c.
•
Updated to ensure consistency 
with Section 5.1.5 and 
Section 5.1.6 changes. 
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.1: Overall Design
Section 5.1.2: Treatment 
Period
Figure 5.1.6-1: Study Visit 
Schematic
•
Clarified Response Follow-up and
Survival Follow-up guidance.
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
Section 5.1.5: Response 
Follow-up Period (Renamed)
Section 5.1.6: Survival 
Follow-up Period
 
 
 
 
 
 
 
•
Provided clarification to the 
Response 
Follow-up 
and 
Survival Follow-up guidance by 
specifying time in Follow-up for 
Part A and Part B participants.
 
 
 
 
 
 
 
 
 
 
 
Table 7.1: Study treatments 
for CA224048
•
.
•
 
 
 
 
 
 
 
 
 
 
 
Table 7.1-2 Part 1A
Table 7.1.-3 Part 1B
•
Removed abbreviation D for dose.
•
Revised for consistency and 
clarity.
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Section 9.1.1: Imaging 
Efficacy Assessments
•
 
 
 
(refer 
to 
Section 5.1.5 and Section 5.1.6).”
•
Updated to ensure consistency 
with Section 5.1.5 and
Section 5.1.6 changes.
Table 9.4.4-1: Laboratory 
Assessments
 
 
 
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 10.3: Statistical 
Analyses
•
 
 
 
 
•
 
 
.
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Appendix 2:
Study Governance 
Considerations
Added new subsections:
•
BMS Commitment to Diversity in 
Clinical Trials.
•
Data Protection, Data Privacy, and 
Data Security.
•
To align with BMS’
commitment to diversity and 
European Union Clinical Trials 
Regulation (EU CTR) 
requirement for data protection
in clinical trials.
All
•
Minor formatting and typographical 
corrections.
•
Minor; therefore, they have not 
been summarized.
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07: ............................ 
 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 07 ......................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 PROTOCOL SUMMARY ......................................................................................... 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 Research Hypothesis ................................................................................ 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Relatlimab Mechanism of Action ............................................................. 
 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
 
3.2.3 BMS-986205 Mechanism of Action ......................................................... 
 
3.2.4 Ipilimumab Mechanism of Action ............................................................ 
 
3.2.5 Nivolumab Combined with Ipilimumab Clinical Activity ........................ 
 
3.2.6 Relatlimab Combined with Nivolumab Clinical Activity ......................... 
 
3.2.7 Nivolumab Combined with BMS-986205 Clinical Activity ..................... 
 
3.2.8 Relatlimab Combined with Nivolumab Clinical Safety ........................... 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Screening Period ...................................................................................... 
 
5.1.2 Treatment Period ..................................................................................... 
 
........................................................ 
 
5.1.4 Clinical Safety Follow-up Period ............................................................ 
 
5.1.5 Response Follow-up Period ..................................................................... 
 
5.1.6 Survival Follow-up Period ....................................................................... 
 
 ................ 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 Justification for Relatlimab Dose ............................................................ 
 
5.5.2 Justification for Nivolumab Dose ............................................................ 
 
5.5.3 Justification for BMS-986205 Dose ......................................................... 
 
5.5.4 Justification for Ipilimumab Dose ........................................................... 
 
5.5.5 Justification for Relatlimab, Nivolumab, and BMS-986205 Combination 
Dose (Part 1A and Part 2A)........................................................................ 
 
5.5.6 Justification for Relatlimab, Nivolumab, and Ipilimumab Combination 
Dose (Part 1B and Part 2B)........................................................................ 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
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6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.3.1 Meals and Dietary Restrictions ............................................................... 
 
6.3.2 Caffeine, Alcohol, and Tobacco ............................................................... 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Relatlimab Combined with Nivolumab Administration ........................... 
 
7.1.2 BMS-986205 Administration ................................................................... 
 
7.1.3 Ipilimumab Administration ...................................................................... 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Relatlimab Dose Modification ................................................................. 
 
7.4.2 Nivolumab Dose Modification ................................................................. 
 
7.4.3 BMS-986205 Dose Modification .............................................................. 
 
7.4.4 Ipilimumab Dose Modification ................................................................ 
 
7.4.5 Dose Modification Criteria for IO Therapies .......................................... 
 
7.4.6 Dose-limiting Toxicities ........................................................................... 
 
 
 
 ........................................................ 
 
7.4.7 Management Algorithms for Immuno-oncology Agents .......................... 
 
7.4.8 Management of Drug-related Infusion Reactions.................................... 
 
 
 
 
 
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 Treatments ............................................................................. 
 
7.7.1.1 Restricted Treatments for Participants Treated with BMS-986205
............................................................................................................... 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
 
7.7.3 Permitted Therapy ................................................................................... 
 
7.7.4 Palliative Local Therapy .......................................................................... 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Relatlimab, Nivolumab, BMS-986205, and Ipilimumab Dose 
Discontinuation ........................................................................................... 
 
8.1.2 Criteria to Resume Treatment .................................................................. 
 
8.1.3 Exceptions to Permanent Discontinuation ............................................... 
 
 
 
 
 
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8.1.5 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 Efficacy Assessments ................................................................. 
 
9.1.2 Imaging Assessment for the Study............................................................ 
 
9.1.3 Imaging Methods of Measurement........................................................... 
 
 
 
 
 
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 ......................................... 
 
............................... 
 
9.2.6 Pregnancy ................................................................................................ 
 
9.2.7 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.8 Potential Drug Induced Liver Injury ....................................................... 
 
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 Electrocardiograms ................................................................................. 
 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.5 Imaging Safety Assessment ...................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.8.3 Additional Research Collection ............................................................... 
 
 
 
 
 
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....................................................................................... 
 
 
 
10.3.4 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 11 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
 
  
 
 
 
APPENDIX 14 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
 
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1
PROTOCOL SUMMARY
Protocol Title: A Phase 1/2 Study of Relatlimab (anti-LAG-3 monoclonal antibody) 
Administered in Combination with Both Nivolumab (anti-PD-1 monoclonal antibody) and 
BMS-986205 (IDO1 inhibitor) or in Combination with Both Nivolumab and Ipilimumab
(anti-CTLA-4 monoclonal antibody) in Advanced Malignant Tumors
Short Title: An Investigational Study of Immunotherapy Combinations in Participants With Solid 
Cancers That Are Advanced or Have Spread
Study Phase: 1/2
Rationale:
Individually targeting immune checkpoint receptors, such as programmed death-1 (PD 1), has 
demonstrated clinical activity across multiple tumor types; several studies to date have 
demonstrated activity of therapeutic compounds aimed at the PD-1 receptor and its ligand, 
programmed death-ligand 1 (PD-L1). This benefit is further extended by dual combination therapy 
of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and PD-1 inhibitors. Despite the 
demonstrated benefit of single or dual combinations of cancer immunotherapies on clinical 
outcome, a large proportion of patients with many tumor types do not respond, or will relapse after 
an initial response to these agents. Substantial efforts are needed to provide therapy to patients 
who do not respond to currently approved single or dual combination immunotherapeutic agents, 
as well as to provide treatment options for relapse patients to increase their survival.
Relatlimab is a human lymphocyte activation gene 3 (LAG-3)-specific antibody expressed as an 
IgG4 isotype antibody including a stabilizing hinge mutation (S228P) isolated after immunization 
of transgenic mice expressing human Ig genes. Relatlimab binds to LAG-3 with high affinity and 
inhibits the negative regulatory function of LAG-3 in vitro. Binding of relatlimab to LAG-3 
prevents binding of this receptor to cells bearing its ligand, major histocompatibility complex 
(MHC) Class II, the peptide antigen presentation molecule recognized by CD4+ T cells. 
 
 
 
 
 
Linrodostat mesylate (BMS-986205) is an optimized indoleamine 2,3-dioxygenase 1 (IDO1) 
inhibitor, characterized by once-daily 
 dose administration and deeper inhibition of IDO1 
activity, as measured by peripheral blood kynurenine suppression, than other inhibitors. 
 
 
The above data support the testing of triple combinations of relatlimab combined with nivolumab 
and BMS-986205 or with nivolumab and ipilimumab to simultaneously engage multiple 
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immuno-oncology (IO) targets. Triple combinations may have the potential to offer superior 
efficacy to single-agent anti PD-1 regimens in the immunotherapy-naive treatment setting as well 
as provide meaningful efficacy to patients that have progressed during anti-PD-1 therapy. In 
therapy naive patients, constitutive LAG-3 expression may limit the antitumor activity of PD-1 
pathway blockade, preventing the maximum magnitude and/or durability of response that a patient 
might otherwise benefit from immunotherapy. Relatlimab triple combinations may increase the 
numbers of responders and/or deepen or increase the durability of responses. In patients previously 
exposed to PD-1 pathway blockade, adaptive upregulation of LAG-3 expression may lead to 
treatment resistance and tumor progression. Relatlimab triple combinations may help to restore 
T cell activation and tumor response.
The current study aims to demonstrate safety and preliminary activity with triple combinations of 
relatlimab in combination with nivolumab and BMS-986205, or in combination with nivolumab 
and ipilimumab in 
 across select tumor types of 
 
 
 
 
 
 
 
Study Population:
Males and Females, ages ≥18 years with select solid tumor histologies as listed below.
Part 1A and Part 1B: 
 
Part 2A and Part 2B:
 
 
 
 
 
 
 
 
 
 
 
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Women of childbearing potential (WOCBP) must not be nursing or pregnant and must be using an 
acceptable method of contraception. WOCBP must have a negative pregnancy test at screening 
and within 24 hours prior to administering study drug.
Objectives and Endpoints:
Information on objectives and endpoints is provided in Table 1, below.
Table 1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
Part 1A and Part 1B: To determine the safety, 
tolerability, DLTs, and MTD of relatlimab administered 
in combination with nivolumab and BMS-986205 or 
nivolumab and ipilimumab in participants with 
advanced malignant tumors.
•
Incidence 
of 
clinical 
laboratory 
test 
abnormalities, AEs, SAEs, AEs meeting 
protocol-defined DLT criteria, AEs leading to 
discontinuation, and deaths.
•
Part 2A and Part 2B: To investigate safety and 
tolerability of relatlimab triple combinations in distinct 
cohorts of participants with advanced malignant tumors.
•
Incidence 
of 
clinical 
laboratory 
test 
abnormalities, AEs, SAEs, AEs leading to 
discontinuation, and deaths.
•
To investigate the antitumor activity of relatlimab triple 
combinations in participants with advanced malignant 
tumors.
•
ORR, DCR, and mDOR in participants with 
advanced malignant tumors.
Secondary
•
To investigate the antitumor activity of relatlimab triple 
combinations in participants with advanced malignant 
tumors.
•
mPFS and PFSR at 6 and 12 months in 
participants with advanced malignant tumors.
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BMS-986016
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Table 1:
Objectives and Endpoints
Abbreviations: AE = adverse event; DCR = disease control rate; DLT = dose-limiting toxicity; 
IgG = immunoglobulin G; 
; mDOR = median duration of response;
; mPFS = median progression-free survival; MTD = maximum tolerated dose; 
 
; PFSR = progression-free survival rate; 
; SAE = serious adverse 
event; 
Overall Design:
This is a Phase 1/2, open-label study of relatlimab in combination with nivolumab and 
BMS-986205 or in combination with nivolumab and ipilimumab in participants with advanced 
solid tumors. Participants will complete up to 5 periods of the study: Screening, Treatment, 
Clinical Safety Follow-up, and Response Follow-up, and Survival Follow-up (see below).
Relatlimab, nivolumab, and ipilimumab will be administered intravenously in the clinical facility 
per the treatment schedule. BMS-986205 will be administered orally at home except for Day 1 of 
Cycle 1, where it will be administered in the clinic.
After establishment of a tolerable and safe dose administration regimen in both Part 1A and 
Part 1B, the Part 2A and Part 2B expansion cohorts will be initiated. The purpose of the cohort 
expansions is to gather preliminary efficacy information in specific patient populations regarding 
relatlimab in combination with nivolumab and BMS-986205, or in combination with nivolumab 
and ipilimumab. Expansion cohorts will only open after data is evaluated from Part 1A and Part 1B
to guide doses selected for Part 2A and Part 2B respectively. Part 2A and Part 2B may be initiated 
independently from each other based on the timing of data evaluation in Part 1.
Part 1A and Part 1B consist of dose finding cohorts of 2 triplet combinations relatlimab, 
nivolumab and BMS-986205, or relatlimab, nivolumab and ipilimumab. 
 
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 If the starting dose is 
not tolerable in the 
 dose-limiting toxicity (DLT) evaluation phase, the dose will be 
de-escalated to D-1 upon safety review from initial dose level D. In Part 1A, if the starting dose is 
tolerable in the 
 DLT evaluation phase, participants will be treated at the next dose levels. 
Part 1A and Part 1B will be initiated in parallel. The evaluation of combination doses of relatlimab 
with nivolumab and BMS-986205 (Part 1A) and relatlimab with nivolumab and ipilimumab 
(Part 1B) will be performed based on safety and tolerability.
Part 2A and Part 2B consist of tumor-specific expansion cohorts of respective triple 
combinations. The dose selected for Part 2A and Part 2B will not exceed the maximum 
administered dose in Part 1;
 
 The 
goal of Part 2 is to estimate the antitumor activity of relatlimab in combination with nivolumab 
and BMS-986205 or relatlimab in combination with nivolumab and ipilimumab.
The study design schematic is presented in Figure 1, below.
Figure 1:
Study Design Schematic
Abbreviations: CNS = central nervous system; CTLA-4 = cytotoxic T lymphocyte antigen-4; D = starting dose level; 
ECOG = Eastern Cooperative Oncology Group; 
; IO = immuno-oncology; 
; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; 
Q4W = every 4 weeks; Q8W = every 8 weeks; QD = once daily; 
 
Screening: The screening period will be up to 28 days and begins by establishing the participant’s 
initial eligibility and signing of the informed consent form. Informed consent will be obtained prior 
to any study-specific procedures. Participants will be evaluated based on the assessments as 
outlined in the Schedule of Activities and Inclusion and Exclusion criteria. If a participant exceeds 
the 28-day screening period due to a study-related procedure 
 the participant must be re consented but will not 
Part 2A 
Relatlimab + Nivolumab + BMS-986205
Part 2B 
Relatlimab + Nivolumab + Ipilimumab
 
 
 
Part 1A: Dose Finding 
Relatlimab + Nivolumab + BMS-986205
•Selected solid tumor types 
except primary CNS tumors
•Subjects naive to IO therapy
•IO pretreated including but not 
limited to anti-PD-1/anti-PD-L1/ 
anti-CTLA-4 therapy allowed 
•ECOG performance status 0-1 
•
 
 
Relatlimab – 160 mg Q4W +
Nivolumab – 480 mg Q4W +
BMS-986205 – 50 mg QD
D+1
D+2
D
RP2D
Part 1B: Dose Finding 
Relatlimab + Nivolumab + Ipilimumab
Relatlimab – 160 mg Q4W +
Nivolumab – 480 mg Q4W +
Ipilimumab – 1 mg/kg Q8W
D
D-1
Relatlimab – 80 mg Q4W +
Nivolumab – 480 mg Q4W +
Ipilimumab – 1 mg/kg Q8W
D-1
RP2D
Relatlimab – 160 mg Q4W +
Nivolumab – 480 mg Q4W +
BMS-986205 – 100 mg QD
Relatlimab – 160 mg Q4W +
Nivolumab – 480 mg Q4W +
BMS-986205 – 25 mg QD
Relatlimab – 80 mg Q4W +
Nivolumab – 480 mg Q4W +
BMS-986205 – 25 mg QD
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require a new participant identification number. In this situation, the fewest number of procedures 
from the initial screening should be repeated to qualify the participant, while maintaining 
participant safety and eligibility.
 
Treatment Period
Dose Finding Part 1A (Relatlimab, Nivolumab, and BMS-986205) 
The DLT evaluation period is 
 in participants with melanoma, NSCLC, SCCHN, RCC,
and GC/GEJ. BMS-986205 will be administered orally once daily (QD) prior to relatlimab and 
nivolumab infusions. Relatlimab will be co-administered with nivolumab in the clinic as an 
intravenous (IV) infusion every 4 weeks (Q4W).
 
Part 1A starting doses will be:
D = Relatlimab 160 mg Q4W + Nivolumab 480 mg Q4W + BMS-986205 25 mg QD.
If during the dose-finding phase, it appears the dose is associated with an acceptable frequency of 
toxicities, then the BMS-986205 dose will be increased as follows:
D+1 = Relatlimab 160 mg Q4W + Nivolumab 480 mg Q4W + BMS-986205 50 mg QD.
D+2 = Relatlimab 160 mg Q4W + Nivolumab 480 mg Q4W + BMS-986205 100 mg QD.
If during the dose-finding phase, it appears the starting dose is associated with an unacceptable 
frequency of toxicities, the relatlimab dose will be decreased as follows:
D-1 = Relatlimab 80 mg Q4W + Nivolumab 480 mg Q4W + BMS-986205 25 mg QD.
Dose Finding Part 1B (Relatlimab, Nivolumab, and Ipilimumab)
The DLT evaluation period is 
 in participants with melanoma, NSCLC, SCCHN, RCC,
and GC/GEJ. Relatlimab will be co-administered with nivolumab in the clinic as an IV infusion 
Q4W. 
 
 
 
Part 1B starting doses will be: 
D = Relatlimab 160 mg Q4W + Nivolumab 480 mg Q4W + Ipilimumab 1 mg/kg Q8W.
If during the dose-finding phase, it appears the dose is associated with an unacceptable frequency 
of toxicities, then the relatlimab dose will be decreased as follows:
D-1 = Relatlimab 80 mg Q4W + Nivolumab 480 mg Q4W + Ipilimumab 1 mg/kg Q8W.
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Expansion: Part 2A (Relatlimab, Nivolumab, and BMS-986205) and Part 2B (Relatlimab, 
Nivolumab, and Ipilimumab)
Part 2 is the safety evaluation, tolerability, and cohort expansion of the triple combinations in 
distinct cohorts advanced malignant tumors to gather preliminary efficacy information. The doses 
to be administered are determined from Part 1A and Part 1B of the study. The recommended Phase 
2 dose (RP2D) selected for Part 2 are as follows:
Part 2A: Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 100 mg QD
Part 2B: Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, Ipilimumab 1 mg/kg Q8W
The tumor cohorts and regimens are:
•
 
 
 
The dose-finding phase of the study (Part 1A and Part 1B) evaluates the safety and tolerability of 
relatlimab in combination with nivolumab and BMS-986205 (Part 1A) or nivolumab and 
ipilimumab (Part 1B) based on DLTs, using 
 and safety evaluation beyond the DLT 
phase. Any toxicities that occur beyond the DLT period will be accounted for in making dose level 
decisions and/or dose level modifications.
After the initial participants (approximately 3) are evaluated at the starting dose levels in Part 1A 
and Part 1B, additional increments of approximately 3 to 6 participants will be treated in the same 
cohort (or at the next dose level)
 At least 6 DLT-evaluable 
participants will be treated and assessed in the selected combination dose level before starting the 
cohort-expansion phase at the same dose.
 
 
 
 
Prior to declaring the maximum tolerated dose, and in consultation with Investigators, the Sponsor 
has the option to expand any dose level previously established to be tolerable, in order to obtain 
additional experience or to investigate dose levels intermediate to those defined in the protocol.
 
 
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECGs), and clinical 
laboratory evaluations will be performed at selected times throughout the dose administration
interval. Participants will be closely monitored for adverse events (AEs) throughout the study. 
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Continuous safety evaluation and tumor assessment 
 will guide the decision to treat a 
participant with additional cycles of study therapy if the participant has confirmed clinical benefit.
 
Participants with unconfirmed progressive disease, stable disease (SD), or partial response (PR) at 
the end of a given cycle will continue to the next treatment cycle.
 
 
 
Continuous evaluation of toxicity events in the cohort expansions will be performed throughout 
enrollment for all expansion cohorts. 
 
 
 Depending on the nature and grade 
of the toxicity, and after assessing the benefit-risk ratio, a new dose for all cohorts may be initiated 
at a previously tested lower dose level or at a dose level intermediate to previously tested lower 
dose levels.
Clinical Safety Follow-up Period
Upon completion of study therapy, or once the decision is made to discontinue the participant from 
treatment (ie, at end of treatment [EOT]), all participants will enter a Clinical Safety Follow-up 
period.
For participants who complete all scheduled cycles of therapy, the 
 
 
 
 
 
 Accordingly, for 
these participants, this visit will be considered the start of the 
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Response Follow-up Period
Participants with SD, PR, or CR at the time of the EOT visit or at the time of study treatment 
discontinuation will continue to have radiologic and clinical tumor assessments every 
 
 Subsequently, they 
will continue to receive tumor assessment scans per standard-of-care guidelines or 
 
 
 Participants who have disease progression after an initial 
course of study therapy will not be evaluated for response beyond the EOT visit and will be 
allowed to receive other tumor-directed therapy as required.
 
 
 
Survival Follow-up Period
In parallel with the Clinical Safety and Response Follow-up periods (as applicable), Part B
participants will start the Survival Follow-up period. Participants will be followed until death, loss 
to Follow-up, withdrawal of consent, or conclusion of the study, whichever comes first (see
Figure 2). 
 
 
 
 
 
 
 
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Treatment Groups and Duration
Information on treatment groups and duration is provided in Table 2, Table 3, and Table 4.
Table 2:
Treatments Administered
Study Treatment
Dose Level
Frequency of Administration and 
Duration of Treatment
Route of 
Administration
Infusion Time,
minutes
Relatlimaba
160 mg, 
80 mg
Q4W
Until progression, unacceptable 
toxicity, withdrawal of consent, or CR
IV
Nivolumaba
480 mg
Q4W
Until progression, unacceptable 
toxicity, withdrawal of consent, or CR
IV
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Table 2:
Treatments Administered
Study Treatment
Dose Level
Frequency of Administration and 
Duration of Treatment
Route of 
Administration
Infusion Time,
minutes
BMS-986205c
100 mg, 
50 mg
25 mg
QD
Until progression, unacceptable 
toxicity, withdrawal of consent, or CR
PO
Ipilimumab
1 mg/kg
Q8W
Until progression, unacceptable 
toxicity, withdrawal of consent, or CR
IV
Abbreviations: 
 IV = intravenous; NA = not applicable; PO = by mouth; Q4W = every 
4 weeks; Q8W = every 8 weeks; QD = once daily.
a Relatlimab and nivolumab are administered as either a co-administration (relatlimab 160 mg and 
nivolumab 480 mg) or a sequential administration (relatlimab 80 mg and nivolumab 480 mg).
Table 3:
Part 1A
Dose
Treatment
Starting Dose
Dose
Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 25 mg QD
Dose Escalation
Dose +1
Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 50 mg QD
Dose +2
Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 100 mg QD
Dose De-escalation
Dose -1
Relatlimab 80 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 25 mg QD
Abbreviations: Q4W = every 4 weeks; QD = once daily.
Note: recommended Phase 2 dose from Part1A will be used in Part 2A.
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Table 4:
Part 1B
Dose
Treatment
Starting Dose
Dose
Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, Ipilimumab 1 mg/kg Q8W
Dose De-escalation
Dose -1
Relatlimab 80 mg Q4W, Nivolumab 480 mg Q4W, Ipilimumab 1 mg/kgQ8W
Abbreviations: Q4W = every 4 weeks; Q8W = every 8 weeks.
Note: recommended Phase 2 dose from Part 1B will be used in Part 2B.
The RP2D selected for Part 2 are as follows:
Part 2A: Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 100 mg QD
Part 2B: Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, Ipilimumab 1 mg/kg Q8W
Dose Limiting Toxicities
For the purpose of guiding dose selection, DLTs will be defined based on the incidence, intensity, 
and duration of AEs that are possibly related to study treatment. The DLT period will be 
 
in Part 1A and Part 1B. Any toxicities that occur beyond the DLT period will be accounted for in 
making final dose level decisions.
Number of Participants: 
Part 1A (relatlimab, nivolumab, and BMS-986205):
Part 1B (relatlimab, nivolumab, and ipilimumab):
The sample size in each of the 2 groups in Part 1 (A and B) will depend on observed toxicity and 
posterior inference from the 
Part 2: 
A Simon 2-stage (optimal) design will be used as a guide for many of the tumor specific cohorts.
STUDY ASSESSMENTS AND ANALYSES:
Safety Analyses:
Safety assessments will be based on reported AEs and the measurement results of vital signs, 
ECGs, physical examinations, and clinical laboratory tests. AEs will be coded using the most 
current version of Medical Dictionary for Regulatory Activities and the incidence of observed AEs 
will be tabulated and reviewed for potential significance and clinical importance. 
 
 
 
 
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 Both AEs and laboratory tests will be graded using the National Cancer 
Institute Common Terminology Criteria for Adverse Events v5.0.
 
 
 
 
 
Efficacy Assessments:
Disease assessment with computed tomography and/or magnetic resonance imaging, as 
appropriate, will be performed at baseline, and the date of the first dose, and then periodically
 
 
 
Disease assessments at other time points may be performed as clinically indicated. 
 
 Sites will be 
trained prior to scanning the first study participant. Image acquisition guidelines and submission 
process will be outlined in the CA224048 Imaging Manual to be provided by 
 
 
 Changes in 
tumor measurements will be assessed by the Investigator and tumor responses will be determined 
using RECIST v1.1 criteria.
Data Monitoring Committee: No
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BMS-986016
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline for All Study Parts (CA224048)
Procedure
Screening Visit 
-28 days
Day -14 to Day -1 Visit
Notesa
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol-
specific informed consent is signed. Obtain participant’s 
number from interactive response technology (IRT).
For Protocol Amendment 05, all current participants will be 
re-consented. New participants will sign the updated informed 
consent for Protocol Amendment 05.
IRT Participant Assignment
X
After the participants meet all eligibility criteria, sites will use 
IRT for participant number assignment. Subsequent visits will 
be registered into the IRT system for drug supply 
(see Section 7.2). If the IRT system is not available, 
participants will be enrolled manually.
Inclusion/Exclusion Criteria
X
See Section 6.1 and Section 6.2.
Medical History
X
Performance Status
X
Eastern Cooperative Oncology Group (ECOG) Performance 
Status (see Appendix 6).
Prior Systemic Therapies
X
Includes prior cancer treatment regimens and medications 
administered within 4 weeks (28 days) of study dose 
administration.
X
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Table 2-1:
Screening Procedural Outline for All Study Parts (CA224048)
Procedure
Screening Visit 
-28 days
Day -14 to Day -1 Visit
Notesa
Concomitant Medications
X
Collected during the 4 weeks (28 days) prior to Cycle 1 Day 1.
Safety Assessments
Physical Examination (PE)
X
If PE screening is performed within 24 hours prior to dose 
administration on Day 1, a single examination may count as 
both the screening and predose evaluation.
Physical Measurements
X
Includes height and weight.
Vital Signs
X
Includes body temperature, seated blood pressure, and heart 
rate. Blood pressure and heart rate should be measured after 
the participant has been seated quietly for at least 5 minutes.
Oxygen Saturation
X
Collected at rest via pulse oximetry to establish baseline. .
Chest Radiograph
X
Posterior-anterior and lateral chest x-ray to establish baseline.
Laboratory Tests
Laboratory Tests
X
 
 
 
 
X
 
 
 
 
X
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Table 2-1:
Screening Procedural Outline for All Study Parts (CA224048)
Procedure
Screening Visit 
-28 days
Day -14 to Day -1 Visit
Notesa
Urinalysis
X
See Section 9.4.4.
Thyroid Function Tests
X
See Section 9.4.4.
Genetic Mutation Status
X
 
 
 
 
Serology
X
See Section 9.4.4. Viral testing to be completed within 28 days 
prior to treatment assignment. For human immunodeficiency 
virus (HIV): testing at sites where locally mandated.
 
 
 
Pregnancy Test (Women of 
Childbearing Potential [WOCBP] 
Only)
X
Women of childbearing potential (WOCBP) only. Sample
tested at screening and within 24 hours prior to dose 
administration. The serum pregnancy test may be completed 
on the first day of treatment, provided the results are available 
before the start of study drug.
Follicle Stimulating Hormone 
(FSH)
X
Women only, as needed to document postmenopausal status. 
Females under the age of 55 years must have a serum FSH 
level > 40 mIU/mL to confirm menopause.
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Table 2-1:
Screening Procedural Outline for All Study Parts (CA224048)
Procedure
Screening Visit 
-28 days
Day -14 to Day -1 Visit
Notesa
Adverse Event Reporting
Monitor for Serious Adverse 
Events (SAEs)
X
All SAEs must be collected from the date of participant’s
written consent until 
 after discontinuation of dose 
administration or participation in the study if the last 
scheduled visit occurs at a later time. 
Electronic SAEs (eSAEs) should be approved in the BMS 
Electronic Data Capture (EDC) tool within 5 business days of 
entry.
Clinical Complaints
X
Collected during the 2 weeks prior to Cycle 1 Day 1.
Tumor Assessments/Baseline Efficacy Assessments
Body Imaging
X
See Section 9.1; must be performed within 28 days prior to 
first dose.
Brain Imaging
X
Magnetic resonance imaging (MRI) of the brain without and 
with contrast is required for participants with known or 
suspected brain metastases who have not had brain imaging 
within 
 of anticipated first study drug administration. 
See imaging assessment details in Section 9.1.
Other Imaging: Bone Scan
X
See Section 9.1; as clinically indicated per local standards.
Abbreviations: AE = adverse events; 
; CRF = case report form; 
 
 ECOG = Eastern Cooperative Oncology Group; EDC = electronic data capture;
;
eSAEs = electronic serios adverse events; FSH = follicle stimulating hormone; G6PD = glucose-6-phosphate dehydrogenase; HIV = human immunodeficiency 
virus; IgG = immunoglobulin; IRT = interactive response technology; 
; MRI = magnetic resonance imaging;
PE = physical examination; 
; SAE = serious adverse events; 
; WOCBP = women of childbearing potential.
a Some of the assessments referred to in this section may not be captured as data in the case report form (CRF). They are intended to be used as safety monitoring 
by the treating physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 
Cycle 2+
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
Safety Assessments
Physical 
Examination
(PE)
X
X
X
Predose.
Symptom-
directed PE
X
X
X
X
Predose.
 
 
Performance
Status
X
X
X
X
X
X
X
Eastern Cooperative Oncology Group (ECOG)
Performance Status for all participants (see 
Appendix 6).
 
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BMS-986016
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Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 
Cycle 2+ 
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
Vital Signs 
X
See 
notes.
X
X
X
X
X
X
Includes temperature, seated blood pressure (BP), 
and heart rate (HR). BP and HR should be 
measured after the participant has been seated 
quietly for at least 5 minutes. 
On Cycle 1 Day 1, vital signs will be obtained 
prior to the infusion 
 
Vital signs on subsequent treatment visits will be 
collected prior to the first infusion
 
 
If any vital sign is abnormal (based upon clinician 
assessment) at the final check, the participants
must be observed further for a period of time, as 
clinically indicated.
 
Oxygen 
Saturation
X
X
X
X
X
X
X
Collected at rest via pulse oximetry. Oxygen 
levels will be used in combination with clinical 
signs and symptoms and radiographic images to 
evaluate pulmonary/respiratory status. Changes in 
O2 levels will not be used in isolation to 
document or diagnose pulmonary toxicity.
 
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Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 
Cycle 2+ 
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
 
X
X
X
X
X
X
 
 
 
 
 
 
 
Chest 
Radiograph
See notes.
As clinically indicated.
Laboratory 
Testsd
X
X
X
X
X
X
X
On-study laboratory tests (including hematology, 
serum chemistry, endocrine panel, troponin, 
 urinalysis, and
pregnancy testing) to be done on site/locally. 
Laboratory tests may be collected within 3 days 
prior to dose administration.
 
 
 
 
 
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1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 
Cycle 2+
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
 
 
 
See Notes
 
 
 
 
 
For C1D1, value taken at screening (pre-
treatment assignment) may be used and need not 
be repeated.
See Section 9.4.4 for laboratory test requirements.
Clinical 
Observationd
See Notes
All participants should be evaluated for any 
immune-mediated adverse events. Evaluations 
should occur every week (± 1 day) up to and 
including Week 8. Participants with any clinical 
symptoms should immediately be evaluated. For 
non-dosing visits, assessments may be performed 
remotely by the Investigator/delegate.
Part 1A Only
(BMS-986205
treated)
Methemoglobin
X
X
X
X
X
X
X
Predose, 
 
, and additional 
assessments as clinically indicated (see 
Section 9.4.4).
 
 
 
 
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Date: 04-Jan-2023
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v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 
Cycle 2+ 
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
Pregnancy Test 
(Women of 
Childbearing 
Potential 
[WOCBP])
X
X
X
X
X
A pregnancy test must be performed within 24 
hours prior to administration of intravenous study 
drug. Serum or urine pregnancy test may be 
performed (for urine pregnancy test, minimum 
sensitivity 25 IU/L or equivalent units of human 
chorionic gonadotropin [hCG] is required). If 
results are positive, hold all study drug and 
perform confirmatory testing. If pregnancy is 
confirmed, permanently discontinue all study 
drug and immediately notify Sponsor per 
Section 9.2.6.
Assess Adequate 
Contraceptive 
Use
X
X
X
X
For WOCBP and male participants who are
sexually active with WOCBP, assess for 
continued use of acceptable methods of 
contraception (see Appendix 4).
Adverse Event Reporting and Concomitant Medication Assessments
Concomitant 
Medication 
Assessments
Continuously
Review prior to dose administration.
Monitor for Non-
serious Adverse 
Events (AEs)
X
Non-serious AEs will be collected starting with 
the first dose of study drug and through 
 
after discontinuation of treatment.
See Section 9.2: Adverse Events.
Protocol Amendment No.: 07
Date: 04-Jan-2023
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10.0
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Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 
Cycle 2+ 
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
Monitor for
Serious Adverse 
Events (SAEs)
X
All SAEs must be collected from the date of 
participant’s written consent until 
 post 
discontinuation of treatment or participation in 
the study if the last scheduled visit occurs at a 
later time. eSAEs should be approved in the BMS 
Electronic Data Capture (EDC) tool within 5 
business days of entry.
See Section 9.2: Adverse Events.
Sample Collection
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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10.0
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Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1
Cycle 2+ 
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
Additional 
Research 
Sampling
X
Residual samples will be used for additional 
research. See Section 9.8.3.
Efficacy Assessments
Body Imaging
See Notes
See Section 9.1; tumor assessments will occur 
 
 
 
 
. 
Brain Imaging
See Notes
See Section 9.1; only for participants with a
history of brain metastasis. Surveillance magnetic 
resonance imaging (MRI) approximately 
 
 or sooner if clinically indicated.
Protocol Amendment No.: 07
Date: 04-Jan-2023
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10.0
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Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 
Cycle 2+ 
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
Other Imaging: 
(Bone Scan)
See Notes
See Section 9.1; as clinically indicated per local 
standards. 
Response 
Assessment
X
X
Assessed by Response Evaluation Criteria in 
Solid Tumors v1.1 (see Appendix 11). 
Assessment must be performed prior to initiating 
the next cycle of treatment and continue on a 
 
Study Treatment
IRT Drug 
Assignment and 
Study Drug 
Dispensation
X
Participant must receive the first dose of study 
medication within 3 calendar days from vial 
allocation. Thereafter, a ± 2-day window is 
permissible.
Study Drug Administration Part 1A (Relatlimab + Nivolumab + BMS-986205)
Details regarding preparation and administration 
of study drugs are provided in the site/pharmacy
training materials.
BMS-986205
Oral Daily Administration
For the first administration of BMS-986205 on 
Day 1 of Cycle 1, BMS-986205 will be 
administered in the clinic. 
 
 
 
 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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10.0
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1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 
Cycle 2+ 
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
Nivolumab and 
Relatlimab 
Administration
X
X
X
X
 
 
 
 
 
BMS-986205
Pill Diary
X
X
X
X
X
X
X
X
X
X
X
Review pill diary during each visit for 
compliance of daily administration of 
BMS-986205. Collect pill diary at completion of 
each cycle, or earlier, and at EOT. 
 
 
 
 
Study Drug Administration Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Details regarding preparation and administration 
of study drugs are provided in the site/pharmacy
training materials.
Nivolumab and 
Relatlimab 
administration
X
X
X
X
 
 
 
 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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930122012
10.0
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Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-2:
On-treatment Procedural Outline Part 1A (Relatlimab + Nivolumab + BMS-986205) and
Part 1B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 
Cycle 2+ 
Notese,f
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
 
(± 2 
days)
End of 
Treatment
(EOT)a,b,c
Ipilimumab 
Administration
X
X
 
 
 
.
Abbreviations: AE = adverse event; BP = blood pressure; C= cycle;
 D = day; 
; ECOG = Eastern 
Cooperative Oncology Group; EDC = electronic data capture; EOT = end of treatment; eSAE = electronic serious adverse event; HCG = of human chorionic 
gonadotropin; HR = heart rate; IRT = interactive response technology; MRI = magnetic resonance imaging; O2 = oxygen; PE = physical examination;
; SAE = serious adverse event;
 
; 
; WOCBP = women of childbearing potential.
a EOT is defined as the visit when a participant discontinues study therapy.
b For participants who complete all scheduled cycles of therapy, the EOT visit will be the same as the last scheduled and completed dosing or non-dosing on-
treatment visit.
c For participants who do not complete all scheduled cycles of therapy, the EOT visit will be the most recent dosing or non-dosing on-treatment visit (with all 
available safety and response data) when treatment is discontinued, does not need to be repeated, and will be considered the start of the Week 1 Clinical/Safety 
Follow-up visit.
 
.
e If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs, 
with the exception of tumor assessments which should occur as scheduled.
f Some of the assessments referred to in this section may not be captured as data in the case report form (CRF). 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.
Protocol Amendment No.: 07
Date: 04-Jan-2023
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10.0
Approved
930122012
10.0
v
Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-3:
On-treatment Procedural Outline: Part 2A (Relatlimab + Nivolumab + BMS-986205) and
Part 2B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 onwards
End of 
Treatment
(EOT)a,b,c
Notese,f
(± 2 days)
(± 2 days)
(± 2 days)
(± 2 days)
 
Safety Assessments
Physical Examination (PE)
X
X
Predose.
Symptom-directed PE
X
X
X
Predose.
 
 
Performance Status
X
X
X
X
X
Eastern Cooperative Oncology Group 
(ECOG) Performance Status for all 
participants (see Appendix 6).
 
 
Vital Signs
X
See notes.
X
X
X
X
Includes temperature, seated blood 
pressure (BP) and heart rate (HR). BP 
and HR should be measured after the 
participant has been seated quietly for 
at least 5 minutes. 
On Cycle 1 Day 1, vital signs will be 
obtained prior to the
 
 
 
Vital signs on subsequent treatment 
visits will be collected prior to the first 
infusion 
 
 
 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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10.0
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Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-3:
On-treatment Procedural Outline: Part 2A (Relatlimab + Nivolumab + BMS-986205) and
Part 2B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 onwards
End of 
Treatment
(EOT)a,b,c
Notese,f
(± 2 days)
(± 2 days)
(± 2 days)
(± 2 days)
 
If any vital sign is abnormal (based 
upon clinician assessment) at the final 
check, the participants must be 
observed further for a period of time, as 
clinically indicated.
 
 
Oxygen Saturation
X
X
X
X
X
Collected at rest via pulse oximetry. 
Oxygen levels will be used in 
combination with clinical signs and 
symptoms and radiographic images to 
evaluate pulmonary/respiratory status. 
Changes in O2 levels will not be used 
in isolation to document or diagnose 
pulmonary toxicity.
 
 
12-lead 
 
X
X
See notes.
X
See notes.
X
See notes.
X
 
 
 
 
 
 
 
Chest Radiograph
See notes.
As clinically indicated.
Laboratory Testsd
X
X
X
X
X
On-study laboratory tests (including 
hematology, serum chemistry, 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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930122012
10.0
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1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-3:
On-treatment Procedural Outline: Part 2A (Relatlimab + Nivolumab + BMS-986205) and
Part 2B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 onwards
End of 
Treatment
(EOT)a,b,c
Notese,f
(± 2 days)
(± 2 days)
(± 2 days)
(± 2 days)
 
endocrine panel, troponin, 
 
, urinalysis, and
pregnancy testing) to be done on 
site/locally. Laboratory tests are 
performed locally and may be collected 
within 3 days prior to dose 
administration. See Section 9.4.4 for 
laboratory test requirements.
 
 
 
 
 
 
 
 
 
See Notes
 
 
 
 
 
 
 
 
 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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10.0
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1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-3:
On-treatment Procedural Outline: Part 2A (Relatlimab + Nivolumab + BMS-986205) and
Part 2B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 onwards
End of 
Treatment
(EOT)a,b,c
Notese,f
(± 2 days)
(± 2 days)
(± 2 days)
(± 2 days)
 
Clinical Observationd
See Notes
All participants should be evaluated for 
any immune-mediated adverse events. 
Evaluations should occur every week 
(± 1 day) up to and including 
 
Participants with any clinical symptoms 
should immediately be evaluated. For 
non-dosing visits, assessments may be 
performed remotely by the 
Investigator/delegate.
Part 2A only
(BMS-986205 treated)
 
X
X
X
X
X
Predose, every 2 weeks for Cycle 1,
then every 
 
 
 
 
 
 
 
 
 
Pregnancy Test
(Women of Childbearing 
Potential [WOCBP])
X
X
X
See notes in Table 2-2: Pregnancy 
Testing.
Assess Adequate 
Contraceptive Use
X
X
For WOCBP and male participants who 
are sexually active with WOCBP, 
assess for continued use of acceptable 
methods of contraception (see 
Appendix 4).
Protocol Amendment No.: 07
Date: 04-Jan-2023
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930122012
10.0
v
Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-3:
On-treatment Procedural Outline: Part 2A (Relatlimab + Nivolumab + BMS-986205) and
Part 2B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 onwards
End of 
Treatment
(EOT)a,b,c
Notese,f
(± 2 days)
(± 2 days)
(± 2 days)
(± 2 days)
 
Adverse Event Reporting and Concomitant Medication Assessments
Concomitant Medication 
Assessments
X
X
X
X
X
X
Review prior to dose administration.
Monitor for Non-serious 
Adverse Events (AEs)
X
Non-serious AEs will be collected 
starting with the first dose of study 
drug and through 
 after 
discontinuation of study treatment.
See Section 9.2: Adverse Events.
Monitor for Serious Adverse 
Events (SAEs)
X
All SAEs must be collected from the 
date of participant’s written consent 
until
 post discontinuation of 
treatment or participation in the study if 
the last scheduled visit occurs at a later 
time. eSAEs should be approved in the 
BMS Electronic Data Capture (EDC)
tool within 5 business days of entry.
See Section 9.2: Adverse Events.
Sample Collection
Protocol Amendment No.: 07
Date: 04-Jan-2023
45
10.0
Approved
930122012
10.0
v
Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-3:
On-treatment Procedural Outline: Part 2A (Relatlimab + Nivolumab + BMS-986205) and
Part 2B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 onwards
End of 
Treatment
(EOT)a,b,c
Notese,f
(± 2 days)
(± 2 days)
(± 2 days)
(± 2 days)
 
 
 
 
 
 
 
 
Additional Research Sampling
X
Residual samples will be used for 
additional research (see Section 9.8.3).
Protocol Amendment No.: 07
Date: 04-Jan-2023
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930122012
10.0
v
Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-3:
On-treatment Procedural Outline: Part 2A (Relatlimab + Nivolumab + BMS-986205) and
Part 2B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 onwards
End of 
Treatment
(EOT)a,b,c
Notese,f
(± 2 days)
(± 2 days)
(± 2 days)
(± 2 days)
 
Efficacy Assessments
Body Imaging
X
Contrast enhanced computed 
tomography (CT) of the chest, 
CT/magnetic resonance imaging (MRI)
of the abdomen, pelvis, and all other 
known and/or suspected sites of disease 
should occur 
 
 
 
 
 
 
 
 
 
Brain Imaging
X
See Section 9.1; only for participants 
with a history of brain metastasis. 
Surveillance magnetic resonance 
imaging (MRI) approximately every 
 or sooner if 
clinically indicated.
Other Imaging: Bone Scan
X
See Section 9.1; as clinically indicated 
per local standards. 
Response Assessment
X
Assessed by Response Evaluation 
Criteria in Solid Tumors v1.1 
(see Appendix 11). Assessment must be 
performed prior to initiating the next 
cycle of treatment and continue on a 
 schedule relative to the 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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930122012
10.0
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Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-3:
On-treatment Procedural Outline: Part 2A (Relatlimab + Nivolumab + BMS-986205) and
Part 2B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 onwards
End of 
Treatment
(EOT)a,b,c
Notese,f
(± 2 days)
(± 2 days)
(± 2 days)
(± 2 days)
 
participant’s first dose, regardless of 
any treatment delay incurred.
Study Drug Administration Part 2A
Details regarding preparation and 
administration of study drugs are 
provided in the site/pharmacy training 
materials.
BMS-986205 Administration
Oral daily administration.
For the first administration of 
BMS-986205 on Day 1 of Cycle 1, 
BMS-986205 will be administered in 
the clinic. 
 
 
 
 
Nivolumab and Relatlimab 
Administration
X
X
 
 
 
 
 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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10.0
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1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-3:
On-treatment Procedural Outline: Part 2A (Relatlimab + Nivolumab + BMS-986205) and
Part 2B (Relatlimab + Nivolumab + Ipilimumab)
Procedure
Cycle 1 onwards
End of 
Treatment
(EOT)a,b,c
Notese,f
(± 2 days)
(± 2 days)
(± 2 days)
(± 2 days)
 
Pill Diary for BMS-986205
X
X
X
X
X
X
Review pill diary during each visit for 
compliance of daily administration of 
BMS-986205. Collect pill diary at the 
completion of each cycle and EOT.
 
 
 
 
 
Study Drug Administration Part 2B
Details regarding preparation and 
administration of study drugs are 
provided in the site/pharmacy training 
materials.
Nivolumab and Relatlimab 
Administration
X
X
 
 
 
 
Ipilimumab Administration
X
 
 
 
 
.
Abbreviations: AE = adverse event; BP = blood pressure; C= cycle; 
 CT = computed tomography; D = day; 
; ECOG = Eastern Cooperative Oncology Group; EDC = electronic data capture; EOT = end of treatment; eSAE = electronic serios 
adverse event; HCG = of human chorionic gonadotropin; HR = heart rate; PE = physical examination; MRI = magnetic resonance imaging; O2 = oxygen; 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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v

Clinical Protocol
CA224048
BMS-986016
relatlimab
; SAE = serious adverse event; 
 
 
WOCBP = women of childbearing potential.
a EOT is defined as the visit when a participant discontinues study therapy.
b For participants who complete all scheduled cycles of therapy, 
c For participants who do not complete all scheduled cycles of therapy, 
 
 
 
e If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs, 
with the exception of tumor assessments which should occur as scheduled.
f Some of the assessments referred to in this section may not be captured as data in the case report form (CRF). 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.
Protocol Amendment No.: 07
Date: 04-Jan-2023
50
10.0
Approved
930122012
10.0
v
Approved
1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-4:
Follow-Up Procedural Outline CA224048
Procedure
Clinical Follow-up (FU)
Response Follow-upa,c
Only for Participants 
with CR, PR, or SD at 
End of Treatment
Survival/Long-term 
Follow-up
All Participantsc
Notes
FU 1 
 
(± 10 days)
FU 2 
 
(± 10 days)
FU 3 
(± 10 days)
Refer to 
Section 5: Study Design
Refer to 
Section 5: Study Design
Safety Assessments
Physical 
Examination 
X
X
X
Vital Signs, and 
Performance Status
X
X
X
Includes body temperature, seated 
blood pressure, and heart rate. Blood 
pressure and heart rate should be 
measured after the participant has 
been seated quietly for at least 
5 minutes.
Electrocardiograms
X
X
X
See note in screening procedures.
Pregnancy Test 
(Women of 
Childbearing 
Potential 
[WOCBP])
X
X
X
See notes in Table 2-2 (Pregnancy 
Testing)
Assess Adequate 
Contraceptive Use
X
X
X
See notes in Table 2-2 (contraceptive 
use)
Laboratory Tests
Laboratory Tests
X
X
X
See Section 9.4.4.
Protocol Amendment No.: 07
Date: 04-Jan-2023
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v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-4:
Follow-Up Procedural Outline CA224048
Procedure
Clinical Follow-up (FU)
Response Follow-upa,c
Only for Participants 
with CR, PR, or SD at 
End of Treatment
Survival/Long-term 
Follow-up
All Participantsc
Notes
FU 1 
 
(± 10 days)
FU 2 
 
(± 10 days)
FU 3 
(± 10 days)
Refer to 
Section 5: Study Design
Refer to 
Section 5: Study Design
Adverse Event Reporting and Concomitant Medication Assessments
Adverse Events
(AEs) Assessment
X
X
X
X
See note in screening procedures. All 
serious adverse events (SAEs) and 
non-serious AEs should be collected 
continuously during the treatment 
period and for a minimum of
 
 following discontinuation of 
study treatment.
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Amendment No.: 07
Date: 04-Jan-2023
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1.0
v

Clinical Protocol
CA224048
BMS-986016
relatlimab
Table 2-4:
Follow-Up Procedural Outline CA224048
Procedure
Clinical Follow-up (FU)
Response Follow-upa,c
Only for Participants 
with CR, PR, or SD at 
End of Treatment
Survival/Long-term 
Follow-up
All Participantsc
Notes
FU 1 
 
(± 10 days)
FU 2 
 
(± 10 days)
FU 3 
(± 10 days)
Refer to 
Section 5: Study Design
Refer to 
Section 5: Study Design
Concomitant 
Medication 
Assessments
X
X
X
Sample Collection
Efficacy Assessments 
Body Imaging
X
Tumor assessments should occur 
 for the 
first year after discontinuation of 
study treatment/end-of-treatment 
visit. Subsequent tumor assessments 
should occur every 
 
 For further details, see 
Section 5.1.5.
Brain Imaging
X
See Section 9.1; only for participants 
with a history of brain metastasis. 
Surveillance magnetic resonance 
imaging (MRI) approximately every 
, or sooner if clinically 
indicated.
Protocol Amendment No.: 07
Date: 04-Jan-2023
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Table 2-4:
Follow-Up Procedural Outline CA224048
Procedure
Clinical Follow-up (FU)
Response Follow-upa,c
Only for Participants 
with CR, PR, or SD at 
End of Treatment
Survival/Long-term 
Follow-up
All Participantsc
Notes
FU 1 
 
(± 10 days)
FU 2 
 
(± 10 days)
FU 3 
(± 10 days)
Refer to 
Section 5: Study Design
Refer to 
Section 5: Study Design
Other Imaging: 
Bone Scan
X
See Section 9.1; as clinically 
indicated per local standards.
Assessment of 
Participant 
Survival Status
X
Participants will be assessed by 
either a clinic visit or telephone 
contact.
New Subsequent 
Anticancer 
Therapies
X
X
X
X
Abbreviations: AE = adverse even; CR = complete response; FU = Follow-up; IgG = immunoglobulin; MRI = magnetic resonance imaging; O2 = oxygen; 
SAE = serious adverse event; 
; SD = stable disease; WOCBP = women of childbearing potential.
a Only for participants with complete response (CR), partial response (PR), or stable disease (SD) at end of treatment.
 
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In the event that multiple procedures are required at a single time point, electrocardiograms (ECGs)
may be obtained up to 15 minutes earlier, vital signs may be obtained up to 10 minutes earlier or 
later, and clinical laboratory samples may be obtained up to 5 minutes earlier than the nominal 
time point to 
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3
INTRODUCTION
CA224048 is a Phase 1/2, open-label, dose-finding and cohort-expansion study of relatlimab 
(BMS-986016) in combination with nivolumab and linrodostat mesylate (BMS-986205) or with 
nivolumab and ipilimumab in participants with advanced solid tumors. Relatlimab is a fully human 
lymphocyte activation gene 3 (LAG-3)-specific antibody that was isolated following 
immunization of transgenic mice expressing human immunoglobulin (Ig) genes. Relatlimab binds 
to LAG-3 expressed on T-cells with high affinity and prevents binding of this checkpoint receptor 
to cells bearing its ligand, major histocompatibility complex (MHC) Class II, the peptide antigen 
presentation molecule recognized by CD4+ T cells. Relatlimab binding inhibits the negative 
regulatory function of LAG-3 in vitro. By blocking the normal down-regulatory pathway, 
relatlimab enhances the antitumor immune response and, thus, has the potential to inhibit the 
growth of multiple malignancies when administered in combination with other therapeutic 
immuno-oncology (IO) agents.
This study will be conducted in 2 parts. Part 1, subdivided into Part 1A and Part 1B, consists of 
dose-finding cohorts of triple combinations of relatlimab, nivolumab, and BMS-986205, or 
relatlimab, nivolumab, and ipilimumab, respectively. Part 1A will and Part 1B will enroll 
participants with 
 
. Part 1A and Part 1B 
will evaluate the safety profile, tolerability,
 
of relatlimab in combination with nivolumab and BMS-986205 or nivolumab and ipilimumab, 
respectively, in order to identify the maximum tolerated dose (MTD)/maximum administered dose 
(MAD) to be used in Part 2. Part 2, subdivided into Part 2A and Part 2B, contains dose-expansion 
cohorts of participants with 
. Part 2A and Part 2B will assess the 
preliminary efficacy of relatlimab in combination with nivolumab and BMS-986205 or nivolumab 
and ipilimumab, respectively, in specific malignant disease populations.
3.1
Study Rationale
Individually targeting immune checkpoint receptors, such as programmed death-1 (PD-1), has 
demonstrated clinical activity across multiple tumor types; several studies to date have 
demonstrated activity of therapeutic compounds aimed at the PD-1 receptor and its ligand, 
programmed death-ligand 1 (PD-L1). This benefit is further extended by dual combination therapy 
of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and PD-1 inhibitors. Despite the 
demonstrated benefit of single or dual combinations of cancer immunotherapies on clinical 
outcome, a large proportion of patients with many tumor types do not respond or will relapse after 
an initial response to these agents. Substantial efforts are needed to provide therapy to patients 
who do not respond to currently approved single or dual combination immunotherapeutic agents, 
as well as to provide treatment options for relapse patients to increase their survival.
Relatlimab is a human LAG-3-specific antibody expressed as an IgG4 isotype antibody including 
a stabilizing hinge mutation (S228P) isolated after immunization of transgenic mice expressing 
human Ig genes. Relatlimab binds to LAG-3 with high affinity and inhibits the negative regulatory 
function of LAG-3 in vitro. Binding of relatlimab to LAG-3 prevents binding of this receptor to 
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cells bearing its ligand, MHC Class II, the peptide antigen presentation molecule recognized by 
CD4+ T cells. 
 
 
 
.
BMS-986205 is an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, characterized by 
once-daily (QD) dose administration and deeper inhibition of IDO1 activity, as measured by 
peripheral blood kynurenine suppression, than other inhibitors.
 
 
 
 
The above data support the testing of triple combinations of relatlimab combined with nivolumab 
and BMS-986205 or with nivolumab and ipilimumab to simultaneously engage multiple IO
targets. Triple combinations may have the potential to offer superior efficacy to single-agent 
anti-PD-1 regimens in the immunotherapy-naive treatment setting as well as provide meaningful 
efficacy to patients that have progressed during anti-PD-1 therapy. In therapy-naive patients, 
constitutive LAG-3 expression may limit the antitumor activity of PD-1 pathway blockade, 
preventing the maximum magnitude and/or durability of response that a patient might otherwise 
benefit from immunotherapy. Relatlimab triple combinations may increase the numbers of 
responders and/or deepen or increase the durability of responses. In patients previously exposed 
to PD-1 pathway blockade, adaptive upregulation of LAG-3 expression may lead to treatment 
resistance and tumor progression. Relatlimab triple combinations may help to restore T-cell 
activation and tumor response.
The current study aims to demonstrate safety and preliminary activity with triple combinations of 
relatlimab in combination with nivolumab and BMS-986205, or in combination with nivolumab 
and ipilimumab in 
 across select tumor types of 
 
 
 
 
 
 
3.1.1
Research Hypothesis
Part 1A and Part 1B: It is anticipated that relatlimab, administered in combination with nivolumab 
and BMS-986205 or with nivolumab and ipilimumab will demonstrate adequate safety and 
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tolerability, as well as a favorable benefit-risk profile, to support further clinical testing. No 
prospective hypotheses are being formally evaluated. 
Part 2A and Part 2B: Treatment with relatlimab in combination with nivolumab and BMS-986205
or with nivolumab and ipilimumab will lead to clinical benefit, as demonstrated by a clinically 
meaningful overall response rate (ORR), including durable responses with substantial magnitude 
of tumor burden reduction in participants who are immunotherapy treatment-naive (IO naive), or 
progressed on IO therapies (including but not limited to PD-1/PD-L1 inhibitors, CTLA-4 
inhibitors, or combinations) in select metastatic solid tumors.
3.2
Background 
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 immuno-surveillance and escape effective innate and adaptive immune responses.2,3,4
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.5 Collectively, these signals govern the 
balance between T-cell activation and tolerance.
Information for nivolumab (OPDIVO,
BMS-936558, anti-PD-1 antibody), relatlimab 
(BMS-986016, anti-LAG-3 antibody), BMS-986205 (optimized IDO1 inhibitor), and ipilimumab
(Yervoy, BMS-734016, anti-CTLA-4 antibody) is provided in the sections below; additional 
details are provided in the respective Investigator Brochures (IBs)/package inserts.6,7,8,9
3.2.1
Relatlimab Mechanism of Action
Relatlimab is a fully human antibody specific for human LAG-3 that was isolated from immunized 
transgenic mice expressing human Ig genes. It is expressed as an IgG4 isotype antibody that 
includes a stabilizing hinge mutation (S228P) for attenuated Fc receptor binding in order to reduce 
or eliminate the possibility of antibody- or complement-mediated target cell killing. Relatlimab 
binds to a defined epitope on LAG-3 with high affinity 
 and specificity and 
potently blocks the interaction of LAG-3 with its ligand, MHC Class II 
 
 The antibody exhibits potent in vitro functional activity in 
reversing LAG-3-mediated inhibition of an antigen-specific murine T-cell hybridoma 
overexpressing human LAG-3 
 
Also refer to Section 4.1 (nonclinical pharmacology studies with relatlimab) and Section 4.2 
(nonclinical pharmacokinetics with relatlimab) of the relatlimab IB.7
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3.2.2
Nivolumab Mechanism of Action
Nivolumab is a fully human, IgG4 (kappa) isotype, monoclonal antibody that binds PD-1. 
Blockade of the PD-1 pathway by nivolumab was studied using the mixed lymphocyte reaction 
(MLR) method. PD-1 blockade resulted in a reproducible enhancement of both proliferation and 
IFN-γ release in the MLR.10 The effect of nivolumab on antigen-specific recall response was 
investigated using a cytomegalovirus (CMV) restimulation assay with human peripheral blood 
mononuclear cells (PBMCs), and was evaluated by enzyme-linked immunosorbent assay (ELISA). 
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (half-maximal effective 
concentration [EC50], 0.39 to 2.62 nM), and inhibits the binding of PD-1 to its ligands PD-L1 and 
programmed death-ligand 2 (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 MLR. Using a CMV restimulation assay with human PBMCs, the effect of 
nivolumab on antigen-specific recall response indicates that nivolumab augments IFN-γ secretion 
from CMV-specific memory T cells in a dose-dependent manner vs isotype-matched controls. 
In vivo blockade of PD-1 by a murine analog of nivolumab enhances the antitumor immune 
response and results in tumor rejection in several immunocompetent mouse tumor models (MC38, 
SA1/N, and PAN02).11
3.2.3
BMS-986205 Mechanism of Action
BMS-986205 is a small molecule inhibitor of IDO1 with 
 
 
 
 
The enzyme IDO1 catalyzes the degradation of tryptophan along the kynurenine pathway, and is 
frequently expressed in human malignancies. In healthy humans, high IDO1 expression is found 
in the placenta, the mucosa of the female genital tract, the lungs, and the lymphoid organs.12 The 
activity of IDO1 induces an immunosuppressive microenvironment in tissues by inhibiting T-cell 
function through local depletion of the essential amino acid tryptophan and through generation of 
active kynurenine pathway metabolites.13 High IDO1 expression in cancers is correlated with more 
aggressive tumor progression and shorter patient survival time in most cancer types.14 Tumor 
IDO1 transcript is elevated in patients with metastatic melanoma and RCC after treatment with the 
anti-PD-1 antibody nivolumab.15,16 In the mouse tumor model, IDO1 is a critical resistance 
mechanism in antitumor T-cell immunotherapy targeting CTLA-4 with a neutralizing antibody.17
Another IDO1 inhibitor in Phase 2 and Phase 3 clinical studies (epacadostat, Incyte corporation) 
has been shown to have a favorable safety profile as monotherapy (ie, well tolerated across all 
dose levels),18 suggesting no intrinsic risk of severe toxicity with IDO1 blockade. These 
observations suggest that IDO1 is a mechanism that contributes to tumor escape from host immune 
surveillance. Therefore, inhibition of IDO1 using pharmaceutical agents may diminish the 
immunosuppressive tumor microenvironment and achieve more durable responses and greater 
patient survival benefits, particularly when used in combination with other cancer immunotherapy 
agents, such as nivolumab and ipilimumab.
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3.2.4
Ipilimumab Mechanism of Action
Ipilimumab is a fully human IgG1 (kappa) monoclonal antibody that has specificity and a high 
affinity for human CTLA-4. The calculated dissociation constant value from an average of several 
studies was 5.25 nM. Binding of ipilimumab to purified, recombinant human CTLA-4 antigen was 
also demonstrated by ELISA with half-maximal binding at 15 ng/mL, whereas saturation was
observed at approximately 0.1 μg/mL. No cross-reactivity was observed against human CD28. 
Ipilimumab completely blocked binding of B7.1 and B7.2 to human CTLA-4 at concentrations
higher than 6 and 1 μg/mL, respectively.
3.2.5
Nivolumab Combined with Ipilimumab Clinical Activity
Multiple clinical studies have evaluated nivolumab combined with ipilimumab at different doses 
and schedules.
Nivolumab 1 mg/kg, in combination with ipilimumab 3 mg/kg for 4 three-week cycles, followed 
by nivolumab 3 mg/kg maintenance every 2 weeks (Q2W) is indicated for the treatment of patients 
with unresectable or metastatic melanoma (BRAF-mutant and BRAF wild-type) based on 
CA209067 (CheckMate 067) in previously untreated participants with advanced melanoma. In the 
United States (US), accelerated approval was granted based on a progression-free survival (PFS) 
advantage compared to either control group. An update of the study had demonstrated 3-year 
overall survival (OS) advantage compared to ipilimumab alone with median survival not yet 
reached in the combination group.19
Subsequent studies have suggested that enhanced anticancer effects may be achieved with the 
combination of nivolumab (N) and ipilimumab (I) compared to either agent alone in historic or 
parallel datasets in other cancers, and that administration of N 3 mg/kg (N3) with I 1 mg/kg (I1) is 
better tolerated than N 1 mg/kg (N1) with I 3 mg/kg (I3) without obvious difference in anticancer 
activity.
In CA209032 (CheckMate 032), a Phase 1/2, open-label study of nivolumab monotherapy or 
nivolumab combined with ipilimumab in participants with advanced or metastatic solid tumors, 
the safety and anticancer efficacy of N3 Q2W, N+I at N1I1, N1I3, and I3N1 every 3 weeks
(Q3W) ×4 followed by N3 Q2W were evaluated in 216 participants with small-cell lung cancer
who had received at least 1 prior platinum-containing regimen. Responses were achieved in 10 
(10%) of 98 participants treated with N3, 1 (33%) of 3 treated with N1I1, 14 (23%) of 61 who 
received N1I3, and 10 (19%) of 54 who received N3I1. Grade 3 or 4 treatment-related adverse 
events (AEs) occurred in 13 (13%) participants in N3 group, 18 (30%) in the N1I3 cohort, and 10 
(19%) in the N3I1 cohort; none of the 3 participants treated with N1I1 experienced treatment-
related Grade 3 or higher AEs.20
CA209016 (CheckMate 016) was a Phase 1 study of nivolumab plus sunitinib, pazopanib, or 
ipilimumab in participants with metastatic RCC. Three different N+I regimens were assessed:
N3I3, N1I3, and N3I1 Q3W for 4 cycles followed by N3 Q2W. The N3I3 group was closed due 
to poor tolerance. The N3I1 and N1I3 groups accrued 47 participants each, and Grade 3 to 4 
treatment-related AEs were reported in 38.3% and 61.7% of the patients in the N3I1 and N1I3 
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groups, respectively. At a median follow-up of 22.3 months, the confirmed ORR was 40.4% in 
both groups, with ongoing responses in 42.1% and 36.8% of patients in the N3I1 and N1I3 arms, 
respectively. The 2-year OS was 67.3% and 69.6% in the N3I1 and N1I3 groups, respectively.21
Based on the CA209016 (CheckMate 016)
study, a randomized study
(CA209214; 
CheckMate 214) of nivolumab combined with ipilimumab (N3I1 Q3W ×4 followed by N3 Q2W) 
vs sunitinib monotherapy was conducted in participants with previously untreated advanced, or 
metastatic RCC. After a minimum follow-up of 17.5 months, improved ORRs (41.6% vs 26.5%, 
p < 0.0001) and median PFS (11.6 vs 8.4 months, p = 0.0331) were seen in intermediate and 
high-risk RCC participants treated with nivolumab and ipilimumab (n = 425) compared to 
sunitinib (n = 422), respectively. Drug-related AEs in the entire study population (including 
low-risk RCC participants) were observed in 509 of 547 participants (93% any Grade, 46% 
Grade 3 to 4) with nivolumab + ipilimumab vs 521 of 535 (97% any Grade, 63% Grade 3 to 5) 
with sunitinib. Death occurred in 159 N+I participants (7 [1%] drug-related) and 202 sunitinib 
participants (4 [1%] drug-related).22
CA209012 (CheckMate 012) was a Phase 1, multiple-cohort study of nivolumab as monotherapy, 
in combination with ipilimumab, or in combination with chemotherapy or targeted therapy, in 
chemotherapy-naive adult (≥18 years) participants with Stage IIIB/IV NSCLC or recurrent disease
that assessed the safety, tolerability, ORR, and progression-free survival (PFS) rate at 24 weeks 
based on Independent Radiologic Review Committee assessment. Cohort P included 38 
participants who received nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg every 12 weeks 
(Q12W), while Cohort Q included 39 participants who received nivolumab 3 mg/kg Q2W 
+ ipilimumab 1 mg/kg every 6 weeks (Q6W). Confirmed objective responses were achieved in 18 
(47% [95% CI: 31, 64]) participants in the ipilimumab Q12W cohort and 15 (38% 
[95% CI: 23, 55]) participants in the ipilimumab Q6W cohort. Median duration of response was 
not reached in either cohort, with median follow-up times of 12.8 months (interquartile range 
[IQR]: 9.3, 15.5) in the ipilimumab Q12W cohort and 11.8 months (IQR: 6.7, 15.9) in the 
ipilimumab Q6W cohort. The safety profiles in Cohorts P and Q were similar; no new types of 
AEs were observed, and AEs were manageable with established algorithms. There were no deaths 
due to study drug toxicity. The rate of treatment-related AEs in the Q12W (82%) and Q6W (72%) 
groups were comparable to monotherapy (69%). In the study, the frequency of Grade 3 to 4 
treatment-related AEs was 37%, 33%, and 19% for the Q12W, Q6W, and nivolumab monotherapy 
groups, respectively. Treatment-related serious adverse events (SAEs) occurred in 32% and 28% 
of participants in the Q12W and Q6W cohorts, respectively, compared to 19% with nivolumab 
monotherapy.23,24
Randomized data on the use of nivolumab in combination with ipilimumab in advanced non-small 
cell lung cancer (NSCLC) as first-line therapy is available from one Phase 3 study, CheckMate 227 
(NCT02477826), an open-label, randomized Phase 3 trial evaluating the use of the following 
regimens versus histology-based chemotherapy (chemo) in biomarker-selected populations with 
chemotherapy-naïve Stage IV or recurrent NSCLC: nivolumab 3 mg/kg every 2 weeks (Q2W) 
+ ipilimumab 1 mg/kg every 6 weeks (Q6W; nivolumab [NIVO] + ipilimumab [IPI]); nivolumab 
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360 mg every 3 weeks (Q3W) plus platinum doublet chemotherapy (NIVO + chemo; in 
participants with tumor PD-L1 < 1%); and nivolumab 3 mg/kg Q2W (NIVO; in participants with 
tumor PD-L1 expression ≥ 1%).25 The study showed that NIVO + IPI provided clinically 
meaningful and durable improvement in efficacy (OS, PFS, ORR, duration of response [DoR]) 
compared with chemotherapy for participants with first-line (1L) advanced NSCLC, in PD-L1 
≥1% and < 1% (exploratory) populations and regardless of histology. The reported 3-year OS 
rates were 33% vs 22% in the PD-L1 ≥ 1% cohort; and 34% vs 15% PD-L1 < 1% cohort.26 With 
3 years’ minimum follow-up, the safety of NIVO + IPI was consistent with previous reports; there 
were no new safety signals were identified with the extended follow-up as participants were off 
treatment for at least 12 months.
Based on Phase 3 data showing improved survival over standard of care therapies, nivolumab 
combined with ipilimumab has been approved in multiple countries for the treatment of 
participants with unresectable or metastatic melanoma, intermediate or poor risk, previously 
untreated advanced RCC, and microsatellite instability-high or mismatch repair deficient 
colorectal cancer (CRC). Details of the clinical activity in these various malignancies are provided 
in the United States Prescribing Information and Summary of Product Characteristics.
3.2.6
Relatlimab Combined with Nivolumab Clinical Activity
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More recently, CA224047, a global, double-blind, randomized, Phase 2/3 study comparing 
relatlimab plus nivolumab in a fixed-dose combination (FDC) formulation (relatlimab [RELA] 
160 mg + nivolumab 480 mg Q4W [RELA + NIVO FDC]) to nivolumab 480 mg Q4W in 
participants with previously untreated advanced melanoma, demonstrated a statistically significant 
and clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways. The study 
achieved its primary endpoint, demonstrating statistically significant improvement in PFS by 
blinded independent clinical review (BICR) with RELA + NIVO FDC compared to nivolumab 
monotherapy in all randomized subjects (N = 714) (PFS hazard ratio = 0.75 [95% CI: 0.62, 0.92], 
P-value = 0.0055). With a median follow-up of 13.2 months, the median PFS in the 
RELA + NIVO FDC group was 10.1 months (95% CI, 6.4–15.7) compared to 4.6 months (95% CI, 
3.4–5.6) in the nivolumab monotherapy arm. PFS rates at 12 months were 47.7% (95% CI, 
41.8-53.2) and 36.0% (95% CI, 30.5–41.6) for RELA + NIVO FDC and NIVO, respectively. The 
PFS benefit of RELA + NIVO FDC were consistent across key prespecified subgroups. Follow up 
for the secondary endpoints of OS and ORR is ongoing.28
3.2.7
Nivolumab Combined with BMS-986205 Clinical Activity
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 The preliminary activity seen with BMS-986205 combined with nivolumab indicates that 
BMS-986205 itself has potential benefit when combined with nivolumab and potentially with 
other IO agents, and further efficacy evaluation is appropriate.
3.2.8
Relatlimab Combined with Nivolumab Clinical Safety
 
 Refer to the IB 
Table 5.5.1-1 for details of the dose levels and DLTs for participants treated in the Part B 
(combination therapy escalation).7
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Source:
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More information can be found in the relatlimab IB.7
The safety profile of the combination of RELA + NIVO FDC (N = 355) was confirmed in the 
pivotal Phase 2/3 global, multicenter study, CA224047, in previously untreated advanced 
melanoma participants. The study findings demonstrated a well-tolerated regimen with a 
manageable safety profile and without unexpected safety signals. The incidence of Grade 3-4 
drug-related AEs was 18.9% in the RELA + NIVO FDC group versus 9.7% in the nivolumab 
monotherapy group. There were 3 treatment-related deaths with RELA + NIVO FDC and 2 with 
nivolumab-treated participants. Drug-related AEs (any grade) led to treatment discontinuation in 
14.6% and 6.7% of participants in the RELA + NIVO FDC and nivolumab monotherapy groups, 
respectively.28
3.3
Benefit/Risk Assessment
All agents to be used in the triple combinations in this study have shown well-defined toxicity 
profiles based on a safety database comprised of participants treated with either monotherapy or 
double combinations across multiple tumor types.
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 
 
 There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level.
As described in Section 3.2.6, clinical activity was seen in multiple indications in the CA224020 
study with the combination of RELA + NIVO.7 Preliminary clinical efficacy has been 
demonstrated in CA224020, where combination dosing of 
 
 
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The clinical efficacy of the combination was further confirmed in the CA224047 study, a 
global, double-blind Phase 2/3 randomized controlled trial, which demonstrated a statistically 
significant and clinically relevant PFS benefit of RELA + NIVO FDC Q4W compared to 
nivolumab 480 mg Q4W.28
Both relatlimab and nivolumab have shown well-defined toxicity profiles based on a safety 
database comprised of participants treated with either monotherapy or combination therapies 
across multiple tumor types. 
 
 
 
 
 
 
 
 
 
 
Safety 
evaluation of the combination dose is ongoing. The safety of relatlimab in combination with 
nivolumab and either ipilimumab or IDO-1 inhibitor (BMS-986205) is manageable and evaluation 
remains ongoing.7
 
 
 
 
 
 
 
 
 
Furthermore, the RELA + NIVO FDC (relatlimab doses of 160 mg + nivolumab 480 mg in a fixed-
dose combination, administered Q4W) was confirmed to be well tolerated with a manageable 
safety profile in 355 participants treated in the CA224047 study. There were no unexpected safety 
signals from this combination.28
Given the safety profile of relatlimab as monotherapy and combination therapy observed to-date 
and the positive benefit-risk of the pivotal Phase 2/3 study of RELA + NIVO FDC (CA224047) 
demonstrated in participants with previously untreated metastatic or unresectable advanced 
melanoma28 and the significant unmet medical need in the studied populations, the continuing 
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evaluation of the combination of relatlimab plus nivolumab is justified for the patient population 
in this protocol.
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The triple combination of relatlimab, nivolumab, and BMS-986205 has not been previously 
evaluated; however, based on well-tolerated safety profiles of respective double combinations, this 
triple combination is expected to be safe and pharmacodynamically active. 
 
 
 
 
Nivolumab and ipilimumab combinations have a well-defined toxicity profile based on a safety 
database of patients treated with the combination across multiple tumor types. Multiple dose 
administration regimens have been evaluated. 
 
 
 
 
 
 
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Investigators and the Sponsor will utilize continuous safety assessments to determine whether 
additional safety measures or termination from the study is required at any time. In addition, AEs 
and SAEs will be reviewed on an ongoing basis by the Sponsor’s Medical Monitor, Clinical 
Scientist and Worldwide Patient Safety (WWPS) representatives to monitor for any safety signals 
or trends. As relatlimab and BMS-986205 are experimental agents and administered in new 
combinations in this protocol, it is possible that unforeseen, unknown, or unanticipated reactions 
may occur; however, data shows that the combination of relatlimab plus nivolumab and 
BMS-986205 plus nivolumab are safe and tolerable at the doses evaluated in this study and at 
higher doses in other studies.
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 5. 
 
 
Additional details on the safety profiles of relatlimab, nivolumab, BMS-986205, and ipilimumab, 
including results from other clinical studies, are also available in IBs.
For dose-finding in Part 1A and Part 1B, the study will utilize a 
 
that will allow evaluation of safety events. This period will be sufficient to cover unanticipated 
acute toxicities associated with all 3 drugs in combination; however, to offset the limited period, 
safety events after subsequent doses will be evaluated very closely throughout the study, focusing
on close monitoring of drug component specific toxicities. At any time, if the triple combination 
is not considered safe for long-term evaluation, the lower dose will be studied and proposed for 
expansion cohorts. In addition, the study will monitor immune-mediated adverse events (IMAEs)
and drug-specific toxicities 
Individually targeting immune checkpoint receptors such as PD-1 and CTLA-4 has proven clinical 
efficacy and is indicated across multiple tumor types. This benefit is further extended by dual 
combination therapy of CTLA-4 and PD-1 inhibitors. Despite the demonstrated benefit of single 
or dual combinations of cancer immunotherapies on clinical outcome, a large proportion of 
patients with many tumor types do not respond or will relapse after an initial response to these 
agents. Substantial efforts are needed to provide therapy to patients who do not respond to currently 
approved single or dual combination immunotherapeutic agents, as well as to provide treatment 
options for relapse patients to increase the survival.
Triple combinations of relatlimab combined with nivolumab and BMS-986205 or with nivolumab 
and ipilimumab to simultaneously engage distinct IO targets may have potential to offer superior 
efficacy to anti-PD-1 monotherapy and in combination with anti-CTLA-4
in the 
immunotherapy-naive treatment setting, as well as provide meaningful efficacy to patients that 
have progressed during anti-PD-1 therapy. In therapy-naive patients, constitutive LAG-3 
expression may limit the antitumor activity of PD-1 pathway blockade, preventing the maximum 
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magnitude and/or durability of response that a patient might otherwise benefit from 
immunotherapy. Relatlimab triple combinations may increase the numbers of responders and/or 
deepen or increase the durability of responses. In patients previously exposed to PD-1 pathway 
blockade, adaptive upregulation of LAG-3 expression may lead to treatment resistance and tumor 
progression.
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4
OBJECTIVES AND ENDPOINTS
The objectives and endpoints for this study are shown in Table 4-1.
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
Part 1A and Part 1B: To determine the safety, tolerability, 
DLTs, and MTD of relatlimab administered in combination 
with nivolumab and BMS-986205
or nivolumab and 
ipilimumab in participants with advanced malignant tumors.
•
Incidence of clinical laboratory test 
abnormalities, AEs, SAEs, AEs meeting 
protocol-defined DLT criteria, AEs 
leading to discontinuation, and deaths.
•
Part 2A and Part 2B: To investigate safety and tolerability of 
relatlimab triple combinations in distinct cohorts of 
participants with advanced malignant tumors.
•
Incidence of clinical laboratory test 
abnormalities, AEs, SAEs, AEs leading 
to discontinuation, and deaths.
•
To investigate the antitumor activity of relatlimab triple 
combinations in participants with advanced malignant tumors.
•
ORR, DCR, and mDOR in participants 
with advanced malignant tumors.
Secondary
•
To investigate the antitumor activity of relatlimab triple 
combinations in participants with advanced malignant tumors.
•
mPFS and PFSR at 6 and 12 months in 
participants with advanced malignant 
tumors.
Exploratory
Abbreviations: AE = adverse event; DCR = disease control rate; DLT = dose-limiting toxicity;
IgG = immunoglobulin G;
; mDOR = median duration of response; 
 mPFS = median progression-free survival; MTD = maximum tolerated dose; ORR = overall response rate; 
 
; PFSR = progression-free survival rate; 
; 
SAE = serious adverse event; 
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5
STUDY DESIGN
5.1
Overall Design
This is a Phase 1/2, open-label study of relatlimab in combination with nivolumab and 
BMS-986205 or in combination with nivolumab and ipilimumab in participants with advanced 
solid tumors. Participants will complete up to 5 periods of the study: 
 
Relatlimab, nivolumab, and ipilimumab will be administered intravenously in the clinical facility 
per the treatment schedule. BMS-986205 will be administered orally at home except for Day 1 of 
Cycle 1, where it will be administered in the clinic. For further details of dose administration, see 
Section 7.1.1.
After establishment of a tolerable and safe dose administration regimen in both Part 1A and 
Part 1B, Part 2A and Part 2B expansion cohorts will be initiated. The purpose of the cohort 
expansions is to gather preliminary efficacy information in specific patient populations regarding 
relatlimab in combination with nivolumab and BMS-986205, or in combination with nivolumab 
and ipilimumab. Expansion cohorts will only open after data is evaluated from Part 1A and Part 1B 
to guide doses selected for Part 2A and Part 2B, respectively. Part 2A and Part 2B may be initiated 
independently from each other based on the timing of data evaluation in Part 1.
Part 1A and Part 1B consist of dose-finding cohorts of 2 triplet combinations: relatlimab, 
nivolumab, and BMS-986205, or relatlimab, nivolumab, and ipilimumab. 
 
. If the starting dose is 
not tolerable in the 
 DLT evaluation phase, the dose will be de-escalated to D-1 upon safety 
review from initial dose level D. In Part 1A, if the starting dose is tolerable in the 
 DLT 
evaluation phase, participants will be treated at the next dose levels. Part 1A and Part 1B will be 
initiated in parallel. The evaluation of combination doses of relatlimab with nivolumab and 
BMS-986205 (Part 1A) and relatlimab with nivolumab and ipilimumab (Part 1B) will be 
performed based on safety and tolerability.
Part 2A and Part 2B consist of tumor-specific expansion cohorts of respective triple 
combinations. The dose selected for Part 2A and Part 2B will not exceed the MAD in Part 1;
however, dose selection will be determined based on assessment of other data including toxicities, 
 The goal of Part 2 is to estimate the antitumor activity of relatlimab in 
combination with nivolumab and BMS-986205 or relatlimab in combination with nivolumab and 
ipilimumab.
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Abbreviations: CNS = central nervous system; CTLA-4 = cytotoxic T lymphocyte antigen-4; D = starting dose level; 
ECOG =-Eastern 
Cooperative 
Oncology 
Group; 
 
 
 
 
IO = immuno-oncology; 
 PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; 
Q4W = every 4 weeks; Q8W = every 8 weeks; QD = once daily; 
 
5.1.1
Screening Period
The screening period will be up to 28 days and begins by establishing the participant’s initial 
eligibility and signing of the informed consent form (ICF). Informed consent will be obtained prior 
to any study-specific procedures. Participants will be evaluated based on the assessments as 
outlined in Table 2-1 and the Inclusion and Exclusion criteria (see Section 6). If a participant 
exceeds the 28-day screening period due to a study-related procedure 
 
, the participant must be reconsented but will 
not require a new participant identification (PID) number. In this situation, the fewest number of 
procedures from the initial screening should be repeated to qualify the participant, while 
maintaining participant safety and eligibility.
 
 
 
 
 
 
 
Part 2A 
Relatlimab + Nivolumab + BMS-986205
Part 2B 
Relatlimab + Nivolumab + Ipilimumab
Part 1A: Dose Finding 
Relatlimab + Nivolumab + BMS-986205
•Selected solid tumor types 
except primary CNS tumors
•Subjects naive to IO therapy
•IO pretreated including but not 
limited to anti-PD-1/anti-PD-L1/ 
anti-CTLA-4 therapy allowed 
•ECOG performance status 0-1 
•
 
 
Relatlimab – 160 mg Q4W +
Nivolumab – 480 mg Q4W +
BMS-986205 – 50 mg QD
D+1
D+2
D
RP2D
Part 1B: Dose Finding 
Relatlimab + Nivolumab + Ipilimumab
Relatlimab – 160 mg Q4W +
Nivolumab – 480 mg Q4W +
Ipilimumab – 1 mg/kg Q8W
D
D-1
Relatlimab – 80 mg Q4W +
Nivolumab – 480 mg Q4W +
Ipilimumab – 1 mg/kg Q8W
D-1
RP2D
Relatlimab – 160 mg Q4W +
Nivolumab – 480 mg Q4W +
BMS-986205 – 100 mg QD
Relatlimab – 160 mg Q4W +
Nivolumab – 480 mg Q4W +
BMS-986205 – 25 mg QD
Relatlimab – 80 mg Q4W +
Nivolumab – 480 mg Q4W +
BMS-986205 – 25 mg QD
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5.1.2
Treatment Period
Dose Finding Part 1A (Relatlimab, Nivolumab, and BMS-986205)
The DLT evaluation period is 
in participants with melanoma, NSCLC, SCCHN, RCC,
and GC/GEJ. BMS986205 will be administered orally QD prior to relatlimab and nivolumab 
infusions. Relatlimab will be co-administered with nivolumab in the clinic as an intravenous (IV)
infusion Q4W. 
 
 
Part 1A starting dose will be: 
D = Relatlimab 160 mg Q4W + Nivolumab 480 mg Q4W + BMS-986205 25 mg QD. 
If during the dose-finding phase, it appears the dose is associated with an acceptable frequency of 
toxicities, then the BMS-986205 dose will be increased as follows:
D+1 = Relatlimab 160 mg Q4W + Nivolumab 480 mg Q4W + BMS-986205 50 mg QD.
D+2 = Relatlimab 160 mg Q4W + Nivolumab 480 mg Q4W + BMS-986205 100 mg QD.
If during the dose-finding phase, it appears the starting dose is associated with an unacceptable 
frequency of toxicities, then the relatlimab dose will be decreased as follows:
D-1 = Relatlimab 80 mg Q4W + Nivolumab 480 mg Q4W + BMS-986205 25 mg QD.
Dose Finding Part 1B (Relatlimab, Nivolumab, and Ipilimumab)
The DLT evaluation period is 
in participants with melanoma, NSCLC, SCCHN, RCC,
and GC/GEJ. Relatlimab will be coadministered with nivolumab in the clinic as an IV infusion 
Q4W. 
 
 
 
Part 1B starting dose will be: 
D = Relatlimab 160 mg Q4W + Nivolumab 480 mg Q4W + Ipilimumab 1 mg/kg Q8W. 
If during the dose-finding phase, it appears the dose is associated with an unacceptable frequency 
of toxicities, then the relatlimab dose will be decreased as follows:
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D-1 = Relatlimab 80 mg Q4W + Nivolumab 480 mg Q4W + Ipilimumab 1 mg/kg Q8W.
Expansion: Part 2A (Relatlimab, Nivolumab, and BMS-986205) and Part 2B (Relatlimab, 
Nivolumab, and Ipilimumab)
Part 2 is the safety evaluation, tolerability, and cohort expansion of the triple combinations in 
distinct cohorts of advanced malignant tumors to gather preliminary efficacy information. The 
doses to be administered will be determined from Part 1A and Part 1B of the study. The 
recommended Phase 2 dose (RP2D) selected for Part 2 are as follows:
Part 2A: Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 100 mg QD.
Part 2B: Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, Ipilimumab 1 mg/kg Q8W.
The tumor cohorts and regimens are:
The dose-finding phase of the study (Part 1A and Part 1B) will evaluate the safety and tolerability 
of relatlimab in combination with nivolumab and BMS-986205 (Part 1A), or nivolumab and 
ipilimumab (Part 1B), based on DLTs, using 
 
 Any toxicities that occur beyond the DLT period will be accounted for in making dose level 
decisions and/or dose level modifications. See Section 7.4.6 for additional information on DLTs. 
After the initial participants (approximately 3) are evaluated at the starting dose levels in Part 1A 
and Part 1B, additional increments of approximately 3 to 6 participants will be treated in the same 
cohort (or at the next dose level)
At least 
DLT-evaluable 
participants will be treated and assessed in the selected combination dose level before starting the 
cohort-expansion phase at the same dose. In Part 1A, approximately 
 are expected 
to be treated.
Planned dose levels may be modified, or additional dose levels added, based upon the 
 for combination and clinical evaluation of all available safety and 
data. Once the tolerability (during DLT evaluation) of a dose level has been established, additional 
participants may be added at that dose level to better characterize the safety, 
Prior to declaring the MTD, and in consultation with Investigators, the Sponsor has the option to 
expand any dose level previously established to be tolerable, in order to obtain additional 
experience or to investigate dose levels intermediate to those defined in the protocol.
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As previously mentioned, 
 are being
explored in the 
dose-expansion phase, Part 2A and Part 2B. Sample size details for Part 2A and Part 2B are 
provided in Section 10.1.2.
Physical examinations, vital sign measurements, 12-lead ECGs, and clinical laboratory evaluations 
will be performed at selected times throughout the dose administration interval. Participants will 
be closely monitored for AEs throughout the study. Samples will be collected after study drug 
administration for 
. 
 
Continuous safety evaluation and tumor assessment 
 will guide the decision to treat a 
participant with additional cycles of study therapy if the participant has confirmed clinical benefit.
Tumor assessments should continue until disease progression or treatment discontinuation, 
whichever occurs later, participant withdrawal of consent, start of subsequent treatment, or death, 
or until completion of the Follow-up periods (see below).
Participants with unconfirmed progressive disease, SD, or PR at the end of a given cycle will 
continue to the next treatment cycle.
Continuous evaluation of toxicity events in the cohort expansions will be performed throughout 
enrollment for all expansion cohorts. If, at any time, the aggregate rate of treatment-related 
toxicities meeting DLT criteria 
 across all participants treated in cohort expansions, 
the findings will be discussed and further enrollment may be interrupted. Depending on the nature 
and grade of the toxicity, and after assessing the benefit-risk ratio, a new dose for all cohorts may 
be initiated at a previously tested lower dose level or at a dose level intermediate to previously 
tested lower dose levels.
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5.1.4
Clinical Safety Follow-up Period 
Upon completion of study therapy or once the decision is made to discontinue the participant from 
treatment, that is, at end of treatment (EOT), all participants will enter a Safety Follow-up period.
For participants who complete all scheduled cycles of therapy, the 
 
 
 
 
 
Accordingly, for 
these participants, this visit will be considered the start of the Safety Follow-up period.
After the EOT visit, all participants will be evaluated for any new AEs for 
 after the last 
dose of study treatment. Follow-up visits should occur at 
 
 after the last dose or at the date of discontinuation (± 10 days; see Figure 5.1.6-1). All 
participants should complete the  Clinical Safety Follow-up visits regardless of whether new 
anticancer therapy is started, except those participants who withdraw consent for study 
participation.
5.1.5
Response Follow-up Period
Participants with SD, PR, or CR at the time of the EOT visit or at the time of study treatment 
discontinuation will continue to have radiologic and clinical tumor assessments
 
 
 
 
 
 
 
 
5.1.6
Survival Follow-up Period
In parallel with the Clinical Safety and Response Follow-up periods (as applicable), Part B
participants will start the Survival Follow-up period. Participants will be followed until death, loss 
to Follow-up, withdrawal of consent, or conclusion of the study, whichever comes first (see Figure 
5.1.6-1).
 
 
 
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Abbreviations: C = cycle; D = day; DLT = dose-limiting toxicity; EOT = end of treatment; FUP = Follow-up; 
IRT = interactive response technology; 
 
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5.2
Number of Participants
See Section 10.1 for details on sample size estimation.
5.3
End of Study Definition
The start of the trial is defined as the date the first participant signs a study-specific ICF. 
A participant is considered enrolled when the study-specific informed consent is signed. End of 
trial is defined as the last visit or scheduled procedure shown in the Schedule of Activities 
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(Section 2) for the last 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
Despite innovations in cancer treatment, alternative therapies are needed for participants with 
advanced cancer. The emerging role of combination immune-modulating therapies in producing 
deep and durable responses in a variety of tumor types, as well as early clinical data from trials 
studying relatlimab in combination with nivolumab, the combination of an IDO1 inhibitor with 
pembrolizumab, and the combination of nivolumab and ipilimumab, suggest that there may be a 
potential benefit with a triple combination that targets multiple mechanisms in action.
Overall, the safety profile of relatlimab in combination with nivolumab has been manageable, and 
there were no additional toxicities with relatlimab in combination with nivolumab. Similarly, the 
safety profile of BMS-986205 has been manageable both as monotherapy and in combination with 
nivolumab. Therefore, it is expected that the addition of relatlimab to nivolumab and BMS-986205
(in doses already shown to be safe in combination with nivolumab) or to nivolumab and 
ipilimumab backbone regimens (with known tolerability in specific tumor types) will be safe. The 
incidence of IMAEs will continue to be monitored across both triple combinations as participants
are treated in the study in order to assess the impact of relatlimab on the known toxicity of 
nivolumab monotherapy and nivolumab combination regimens. The benefit-risk ratio supports
evaluation of these triple combinations in participants with advanced cancer.
5.5
Justification for Dose
5.5.1
Justification for Relatlimab Dose 
The relatlimab dose of 160 mg Q4W was selected in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.5.2
Justification for Nivolumab Dose
The nivolumab dose of 480 mg Q4W was selected for this study based on clinical data and 
modeling and simulation approaches using population 
 
 
 
with body weight-normalized dose administration (mg/kg). A flat dose is expected to reduce the 
potential for medication preparation and administration errors, shorten pharmacy preparation time,
and improve ease of administration. 
 
 
 
 
 
 
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5.5.3
Justification for BMS-986205 Dose
In this study, BMS-986205 25 mg by mouth (PO) QD, as a starting dose, will be administered in 
combination with relatlimab 160 mg Q4W and nivolumab 480 mg Q4W. The selection of the dose 
and schedule for BMS-986205 is primarily based on available data from the ongoing Phase 1/2, 
first-in-human CA017003 study.
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5.5.4
Justification for Ipilimumab Dose 
In this study, ipilimumab 1 mg/kg Q8W will be administered in combination with relatlimab 
160 mg Q4W and nivolumab 480 mg Q4W. Ipilimumab 3 mg/kg Q3W for a total of 4 doses is 
approved as monotherapy and in combination with nivolumab in unresectable and metastatic 
melanoma. In the adjuvant melanoma setting, ipilimumab monotherapy at a dose of 10 mg/kg 
Q3W is approved for total of 4 doses, followed by 10 mg/kg Q12W for 3 years.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.5.5
Justification for Relatlimab, Nivolumab, and BMS-986205 Combination 
Dose (Part 1A and Part 2A)
In this study, relatlimab 160 mg Q4W IV will be administered in combination with nivolumab 
480 mg Q4W IV and BMS-986205 25 mg PO QD as a starting dose level. Nivolumab, relatlimab,
and BMS-986205 administered as monotherapy were found to be tolerable up to the doses of 
 respectively. Additionally, clinical activity was 
demonstrated with relatlimab 
 and nivolumab 
 combination therapy and 
also with BMS-986205
 and nivolumab 
 combination therapy. There is no 
evidence of clinically relevant drug-drug interactions between monoclonal antibodies, and hence 
it is not expected that either nivolumab or relatlimab exposures would be altered. BMS-986205 is 
a small molecule and has a distinct pathway of metabolism and elimination and therefore 
 
 
 
 
 
 
 
 
 
 
5.5.6
Justification for Relatlimab, Nivolumab, and Ipilimumab Combination 
Dose (Part 1B and Part 2B)
In this study, ipilimumab 1 mg/kg Q8W will be administered in combination with relatlimab 
160 mg Q4W and nivolumab 480 mg Q4W as a starting dose level. Nivolumab, relatlimab, and
ipilimumab administered as monotherapy were found to be tolerable up to the doses of 
 
 respectively. 
 
 
 
 
 
 
 
 
 
 
 
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6
STUDY POPULATION
For entry into the study, the following criteria MUST be met prior to dose administration on Day 1. 
No exceptions will be granted. This study permits the re-enrollment of a participant who has 
discontinued the study as a pretreatment failure. If re-enrolled, the participant must be re-consented 
and meet all inclusion/exclusion criteria.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an Institutional Review Board/Independent Ethics 
Committee (IRB/IEC)-approved written ICF in accordance with regulatory and 
institutional guidelines. This must be obtained before the performance of any 
protocol-related procedures that are not part of normal patient care.
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2)
Type of Participant and Target Disease Characteristics
a) Histologic or cytologic confirmation of an incurable solid malignancy that is advanced 
(metastatic and/or unresectable), with measurable disease per RECIST v1.1.
i)
 
 
 
 
 
b) Presence of at least 1 lesion with measurable disease as defined by RECIST v1.1 criteria 
for response assessment. Participants with lesions in a previously irradiated field as the 
sole site of measurable disease will be permitted to enroll provided that the lesion(s) have 
demonstrated clear progression prior to the time of informed consent and can be measured 
accurately.
c) Documentation of IO-containing therapy should include start, stop, and progression dates
of prior IO therapy.
d) Eastern Cooperative Oncology Group Performance Status (ECOG) status of 0 or 1
(see Appendix 6).
e) Life expectancy ≥12 weeks at the time of informed consent per Investigator assessment. 
f)
 
 
 
g) Ability to comply with scheduled visits, treatment schedule, laboratory testing, and other 
requirements of the study (for example, PK, and PD sample collection and required study 
follow-up).
h) Participants receiving BMS-986205: Availability of a suitable formulation and mode of 
administration for the participant’s needs, as detailed in the IB and Pharmacy Manual at 
the time of enrollment Note: at the time of original protocol finalization, BMS-986205 is
available in a tablet formulation only and participants should be able to swallow intact 
tablets to enroll on the study. Ongoing clinical pharmacology studies have expanded the 
options available. Full details can be found in the IB and Pharmacy Manual, which will be 
updated throughout the study. Please contact the Medical Monitor with any queries.
i)
 
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 Participants who 
refuse potentially curative salvage surgery for recurrent disease are ineligible. Participants must 
have tumor progression or recurrence after prior platinum-containing systemic therapy for 
recurrent or metastatic disease. In addition, participants who have progressed within 6 months of 
platinum-based therapy used as part of concurrent chemoradiation (definitive or adjuvant therapy) 
are also eligible. Clinical progression is defined as progression of a lesion at least 10 mm in size 
that is amenable to caliper measurement (eg, superficial skin lesion per RECIST v1.1) or a lesion 
that has been visualized and photographically recorded with measurements and shown to have 
progressed.
(3) Participants cannot have had prior exposure to IO therapies such as, but not limited 
to, anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-KIR, anti-CD137, anti-
LAG-3, or anti-OX40 antibodies.
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3) Age and Reproductive Status
a) Males and females, ages ≥18 years.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin) 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 (see Appendix 4) 
for the duration of treatment with relatlimab, nivolumab, and ipilimumab plus 5 half-lives 
of study treatment for a total of 5 months post-treatment completion and agrees not to 
donate eggs (ova, oocytes) for the purpose of reproduction for the same time period. 
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (see Appendix 4) for the duration of treatment with study 
treatments plus 1 month (approximately 4 weeks) after the last dose of BMS-986205. This 
criterion applies to azoospermic males as well. In addition, male participants must be 
willing to refrain from sperm donation during this time.
f)
WOCBP who are continuously not heterosexually active are exempt from contraceptive 
requirements, and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception (see 
Appendix 4), which have a failure rate of < 1% when used consistently and correctly. Hormonal 
contraceptives are not highly effective methods of contraception for participants in this study 
treated with BMS-986205 who are WOCBP.
6.2
Exclusion Criteria
1) Medical Conditions
a) Participants with known or suspected central nervous system (CNS) metastases or with the 
CNS as the only site of active disease are excluded with the following exceptions:
i)
Participants with controlled brain metastases will be allowed to enroll. Controlled brain 
metastases are defined as those with no radiographic progression for at least 4 weeks 
after radiation and/or surgical treatment at the time of consent. Participants must have 
been off of steroids for at least 2 weeks prior to informed consent, and have no new or 
progressive neurological signs and symptoms.
ii) Participants with signs or symptoms of brain metastases are not eligible unless brain 
metastases are ruled out by computed tomography (CT) or magnetic resonance imaging 
(MRI).
b) Participants with a history of interstitial lung disease/pneumonitis.
c) For participants to be treated with BMS-986205:
 
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d) For participants to be treated with BMS-986205:
 
 
 
 
e) For participants to be treated with BMS-986205:
 
f)
Concurrent malignancy (present during screening) requiring treatment or history of prior 
malignancy active within 2 years prior to treatment assignment (ie, participants with a 
history of prior malignancy are eligible if treatment was completed at least 2 years before 
treatment assignment and the participant has no evidence of disease). Participants with 
history of prior early stage basal/squamous cell skin cancer or non-invasive or in situ 
cancers that have undergone definitive treatment at any time are also eligible.
g) Participants with an active, known, or suspected autoimmune disease; however, 
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.
h) Requirement for daily supplemental oxygen.
i)
Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following:
i)
Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months 
prior to consent.
ii) Uncontrolled angina within the 3 months prior to consent.
iii) Any history of clinically significant arrhythmias (eg, ventricular tachycardia, poorly 
controlled atrial fibrillation ventricular fibrillation, torsades de pointes).
iv) QTc prolongation > 480 ms.
v) History of other clinically significant cardiovascular disease (ie, cardiomyopathy, 
congestive heart failure with New York Heart Association functional classification 
III-IV, pericarditis, significant pericardial effusion, significant coronary stent 
occlusion, poorly controlled venous thrombosis).
vi) Cardiovascular disease-related requirement for daily supplemental oxygen.
vii)History of 2 or more MIs OR 2 or more coronary revascularization procedures.
viii)
Participants with a history of myocarditis, regardless of etiology.
j)
Participants a with history of life-threatening toxicity related to prior immune therapy 
(eg, anti-CTLA-4 or anti-PD-1/PD-L1 treatment, any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways) except those that are 
unlikely to re-occur with standard countermeasures (eg, hormone replacement after 
endocrinopathy).
k) A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior 
to informed consent.
l)
Women who are pregnant or breast feeding.
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m) Any significant acute or chronic medical illness. In the case of prior 
 
infection, acute symptoms must have resolved and based on investigator assessment in 
consultation with the Medical Monitor, and there are no sequelae that would place the 
participant at a higher risk of receiving investigational treatment.
n) For participants to be treated with BMS-986205: current or recent (within 3 months of 
study drug administration) gastrointestinal disease that could impact upon the absorption 
of study drug.
o) For participants to be treated with BMS-986205: any gastrointestinal surgery that could 
impact upon the absorption of study drug for BMS-986205.
p) Blood transfusion within 4 weeks of study drug administration.
q) For participants to be treated with BMS-986205: inability to tolerate oral medication.
See the Pharmacy Manual for updates to this criteria.
r)
Inability to be venipunctured and/or tolerate venous access.
s) Any other sound medical, psychiatric, and/or social reason as determined by the 
Investigator.
t)
 
2) Prior/Concomitant Therapy
a) Any of the following procedures or medications within 2 weeks prior to time of study drug 
administration:
i)
Systemic or topical corticosteroids at immunosuppressive doses (>10 mg/day of 
prednisone or equivalent) are NOT permitted. Inhaled or topical steroids, and adrenal 
replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the 
absence of active autoimmune disease.
ii) Palliative radiation or gamma knife radiosurgery. Participants must have recovered 
(ie, Grade ≤1 or at baseline) from radiation-related toxicities prior to first study 
treatment.
iii) Treatment with complementary medications (eg, herbal supplements or traditional 
Chinese medicines) to treat the disease under study within 2 weeks prior to first study 
treatment. Such medications are permitted if they are used as supportive care. Refer to 
Section 7.7.1 for prohibited/restricted therapies. Note: Prior traditional Chinese 
medicines with anticancer claims are not considered as a prior line of therapy.
b) Any of the following procedures or medications within 4 weeks prior to study drug 
administration:
i)
Any investigational cytotoxic drug. Exposure to any non-cytotoxic drug within 4 weeks 
or 5 half-lives (whichever is shorter) is prohibited. If 5 half-lives are shorter than 
4 weeks, agreement with Sponsor/Medical Monitor is mandatory.
ii) Growth 
factors 
(eg, 
granulocyte-colony 
stimulating 
factor, 
granulocyte 
macrophage-colony stimulating factor, erythropoietin).
iii) Major surgery.
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c) Any of the following procedures or medications within 4 weeks prior to study drug 
administration:
i)
Treatment with any live/attenuated vaccine within
 of first study treatment, 
during treatment, and up to 
 post last dose.
ii) Allergen hyposensitization therapy.
d) Inability to comply with restrictions and prohibited treatments as listed in 
Section 7.7 Concomitant Therapy.
e) Participation in any prior clinical study with nivolumab and/or ipilimumab, including 
participants in comparator arms, in which OS is listed as the primary or coprimary endpoint 
and which has not completed analysis based on the primary endpoint.
f)
Prior treatment with LAG-3 or IDO targeted agents.
g) Participants currently in other interventional trials, including those for COVID-19, may not 
participate in BMS clinical trials until the protocol specific washout period is achieved. If 
a study participant has received an investigational COVID-19 vaccine or other 
investigational product designed to treat or prevent COVID-19 prior to screening, 
enrollment must be delayed until the biologic impact of the vaccine or investigational 
product is stabilized, as determined by discussion between the investigator and the Medical 
Monitor/designee.
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL.
b) Neutrophils < 1500/μL.
c) Platelets < 100K/μL.
d) Hemoglobin < 9.0 g/dL.
e) Serum creatinine > 1.5 × ULN or calculated creatinine clearance (CrCl) < 40 mL/min 
(using the Cockcroft-Gault formula):
Female CrCl = (140 - age in years) × weight in kg × 0.85
72 × serum creatinine in mg/dL
Male CrCl = (140 - age in years) × weight in kg × 1.00
72 × serum creatinine in mg/dL
f)
AST/ALT > 3.0 × ULN.
g) Total bilirubin > 1.5 × ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 × ULN).
h) For participants to be treated with BMS-986205: blood methemoglobin > ULN, assessed 
in an arterial or venous blood sample.
i)
Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Participants with TnT or TnI levels 
between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are ≤ 1 × ULN. 
If TnT or TnI levels are between > 1 to 2 × ULN within 24 hours, the participant may 
undergo a cardiac evaluation and be considered for treatment, based on a favorable 
benefit-risk assessment by the Investigator. When repeat levels within 24 hours are not 
available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels 
beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac evaluation and be 
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considered for treatment, following favorable benefit-risk assessment by the Investigator. 
Notification of the decision to enroll the participant following cardiologist 
recommendation has to be made to the BMS Medical Monitor or designee.
j)
Any positive test result for hepatitis B virus or hepatitis C virus (HCV) indicating presence 
of active viral replication (eg, hepatitis B surface antigen [HBsAg, Australia antigen]
positive, detectable HCV-ribonucleic acid [RNA], hepatitis C antibody [anti-HCV]
positive). NOTE: Participants with positive HCV antibody and an undetectable HCV-RNA 
are eligible to enroll.
k) Known history of positive test for human immunodeficiency virus (HIV) or active infection 
or known acquired immunodeficiency syndrome (AIDS). Note: Testing for HIV must be 
performed at sites where mandated locally or if status is unknown.
l)
Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECGs, or clinical laboratory determinations beyond what 
is consistent with the target population.
m) Any of the following on 12-lead ECGs prior to study drug administration, confirmed by 
repeat:
i)
PR ≥210 ms, except right bundle branch block.
ii) QTcF ≥480 ms, except right bundle branch block.
n) For participants to be treated with BMS-986205: Quantitative or qualitative 
assay 
results suggesting 
4) Allergies and Adverse Drug Reaction
a) History of allergy to monoclonal antibodies or related compounds.
b) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
c) 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 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.3.1
Meals and Dietary Restrictions
See Section 7.7.1.1 for restrictions.
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6.3.2
Caffeine, Alcohol, and Tobacco
No specific restrictions.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any SAEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pretreatment failure (ie, participant has not been randomized/has not 
been treated). If re-enrolled, the participant must be reconsented.
 
 
 
 
 
 
Retesting of laboratory parameters and/or other assessments within any single screening or lead-in 
period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to treatment assignment 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 9.4.4-1 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.
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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 product (IP) and non-investigational product 
(Non-IP) and can consist of the following:
An IP, also known as an 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-IPs.
In this protocol, IPs are the following:
•
Relatlimab
•
Nivolumab
•
BMS-986205 (linrodostat mesylate)
•
Ipilimumab
All 4 drugs used in this open-label study qualify as IPs per previous text, and their descriptions 
and storage information are described in Table 7-1.
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Table 7-1:
Study treatments for CA224048
Product Description/
Class and Dosage 
Form
Potency
IP/Non-IMP
Blinded or Open-label
Packaging/Appearance
Storage Conditions
(per label)
Relatlimaba Injection
IP
Colorless to pale yellow liquid, clear 
to opalescent, light (few) particulates 
(consistent in appearance to protein 
particulates) may be present.
Refer to the label on 
container and/or 
Pharmacy Manual.
Nivolumaba Injection
IP
Clear to opalescent, colorless to pale 
yellow liquid. Light (few) particulates 
may be present.
Refer to the label on 
container and/or 
Pharmacy Manual.
Ipilimumab Injection
IP
Clear to slightly opalescent, colorless 
to pale yellow liquid. Light (few) 
particulates may be present.
Refer to the label on 
container and/or 
Pharmacy Manual.
BMS-986205-04
 Tablet
IP
A beige, oval shaped, plain faced, 
film-coated tablet.
Refer to the label on 
container and/or 
Pharmacy Manual.
BMS-986205-04
 Tablet
IP
A round, concave shaped film-coated 
tablet.
Refer to the label on 
container and/or 
Pharmacy Manual.
BMS-986205-04
 Tablet
IP
A light pink to pink, oval shaped, 
plain faced, film-coated tablet.
Refer to the label on 
container and/or 
Pharmacy Manual.
Abbreviations: IMP = investigational medicinal product; IP = investigational product.
a Relatlimab is sometimes referred to as BMS-986016; Nivolumab is sometimes referred to as BMS-936558.
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7.1
Treatments Administered 
The selection and timing of dose for each participant is as follows:
The dose administration schedule for each IP is detailed below in Table 7.1-1. Refer to the
Pharmacy Manual for updated information.
Table 7.1-1:
Treatments Administered
Study 
Treatment
Dose 
Level
Frequency of Administration and 
Duration of Treatment
Route of 
Administration
Infusion Time,
minutes
Relatlimaba
160 mg, 
80 mg
Q4W
Until progression, unacceptable toxicity, 
withdrawal of consent, or CR
IV
Nivolumaba
480 mg
Q4W
Until progression, unacceptable toxicity, 
withdrawal of consent, or CR
IV
BMS-986205c
100 mg, 
50 mg, 
25 mg
QD
Until progression, unacceptable toxicity, 
withdrawal of consent, or CR
PO
Ipilimumab
1 mg/kg
Q8W
Until progression, unacceptable toxicity, 
withdrawal of consent, or CR
IV
Abbreviations: CR = complete response; IV = intravenous; NA = not applicable; PO = by mouth; 
Q4W = every 4 weeks; Q8W = every 8 weeks; QD = once daily.
a Relatlimab and nivolumab are administered as either a co-administration (relatlimab 160 mg and 
nivolumab 480 mg) or a sequential administration (relatlimab 80 mg and nivolumab 480 mg) See Section 7.1.1.
Treatment information for Dose Finding (Part 1) is provided in Table 7.1-2 and Table 7.1-3.
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Table 7.1-2:
Part 1A
Dose
Treatment
Starting Dose
Dose
Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 25 mg QD
Dose Escalation
Dose +1
Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 50 mg QD
Dose +2
Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 100 mg QD
Dose De-escalation
Dose-1
Relatlimab 80 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 25 mg QD
Abbreviations: Q4W = every 4 weeks; QD: once daily.
Note: recommended Phase 2 dose from Part 1A will be used in Part 2A.
Table 7.1-3:
Part 1B
Dose
Treatment
Starting Dose
Dose
Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, Ipilimumab 1 mg/kg Q8W
Dose De-escalation
Dose-1
Relatlimab 80 mg Q4W, Nivolumab 480 mg Q4W, Ipilimumab 1 mg/kgQ8W
Abbreviations: Q4W = every 4 weeks; Q8W = every 8 weeks.
Note: recommended Phase 2 dose from Part 1B will be used in Part 2B.
The RP2D selected for Part 2 are as follows:
Part 2A: Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, BMS-986205 100 mg QD
Part 2B: Relatlimab 160 mg Q4W, Nivolumab 480 mg Q4W, Ipilimumab 1 mg/kg Q8W
7.1.1
Relatlimab Combined with Nivolumab Administration
Both study drugs will be coadministered at the 160 mg relatlimab and 480 mg nivolumab doses. 
 
After the dose-finding period, intra-participant dose escalation or de-escalation of immunotherapy 
(with the exception of BMS-986205) are not permitted.
 
 
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Further details regarding preparation and administration of relatlimab and nivolumab will be 
provided separately in site/pharmacy training materials.
Premedications are not reommended for the first dose of immunotherapy. Participants should be 
carefully monitored for infusion reactions during administration. If an acute infusion reaction is 
noted, participant should be managed according to Section7.4.8.
Participants should receive relatlimab and nivolumab until progression, unacceptable toxicity, 
withdrawal of consent/assent by the participant, or the study ends, whichever occurs first.
Participants should begin study treatment within 3 calendar days of treatment assignment.
Doses of immunotherapy may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment according to Section 7.4.1.
Dosing visits must not be skipped, only delayed. See Section 7.4and Section 8.1.
If a participant meets criteria for discontinuation and the 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.
The study drug injections can be infused undiluted or diluted. All infusions must be promptly 
followed by a diluent flush to clear the line of IP before starting infusion(s) of any additional 
treatment. Instruction for dilution and infusion of study drug injections will be provided in the 
Pharmacy Manual. Care must be taken to assure sterility of the prepared solution as the product 
does not contain any antimicrobial preservative or bacteriostatic agent. For details on prepared 
drug storage, preparation, and administration, please refer to the IBs and/or Pharmacy Manual. 
The selection and timing of dose for each participant is provided in Table 7.1-1.
Study treatment will be dispensed by interactive response technology (IRT) at the study visits as 
listed in Section 2 (Schedule of Activities). Further details regarding preparation and 
administration will be provided separately in site/pharmacy training materials.
7.1.2
BMS-986205 Administration
BMS-986205 will be dispensed to participants in Part 1A and Part 2A at each Day 1 visit within a 
cycle. Participants will be instructed that BMS-986205 is to be administered once a day in the 
morning (approximately 24 hours apart) following a meal.
On the study days when relatlimab and nivolumab are also administered, participants will take 
BMS-986205 in the morning and then report to the clinic for relatlimab and nivolumab infusions 
(except for Day 1 of Cycle 1, where BMS-986205 is administered in the clinic; see Section 7.1.1). 
Study procedures, and 
 
Further details regarding preparation and administration of BMS-986205 will be provided 
separately in site/pharmacy training materials.
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At the time of original protocol finalization, BMS-986205 will be available in a tablet formulation 
only; therefore, participants must be able to swallow intact tablets to enroll in the study. Ongoing 
clinical pharmacology studies may expand the options available. Full details can be found in the 
IB and Pharmacy Manual, which will be updated throughout the study. Please contact the Medical 
Monitor with any queries.
Participants will be provided with pill diaries and instructed to record intake of BMS-986205 in 
the diary after each daily administration.
 
 
 
 
 
Participants should begin 
study treatment within 3 calendar days of treatment assignment. Doses of BMS-986205 may be 
modified or interrupted, depending on how well the participant tolerates the treatment. 
See Section 7.4.3 for dose modifications. If the dose of BMS-986205 is reduced, re-escalation will 
not be permitted. Skipped doses during interruptions should not be administered within the same 
cycle.
For details on prepared drug storage, preparation, and administration, please refer to the 
BMS-986205 IB and/or Pharmacy Manual. The selection and timing of dose for each participant 
is provided in Section 7.1.
7.1.3
Ipilimumab Administration
 
 
 
 
 
 
 
 
 
 
 
 
 There will be no dose modifications allowed.
Participants should be carefully monitored for infusion reactions during administration. If an acute 
infusion reaction is noted, participants should be managed according to Section 7.4.8.
Doses of immunotherapy may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment according to Section 7.4.1.
Dosing visits must not be skipped, only delayed. See Section 7.4 and Section 8.1.
Participants should receive ipilimumab until progression, unacceptable toxicity, withdrawal of 
consent/assent by the participant, or the study ends, whichever occurs first. Participants should 
begin study treatment within 3 calendar days of treatment assignment.
All infusions must be promptly followed by a diluent flush to clear the line of IP before starting 
infusion(s) of any additional treatment. Instruction for dilution and infusion of study drug 
injections will be provided in the Pharmacy Manual. Care must be taken to assure sterility of the 
prepared solution as the product does not contain any antimicrobial preservative or bacteriostatic 
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agent. For details on prepared drug storage, preparation, and administration, please refer to the IBs 
and/or Pharmacy Manual. The selection and timing of dose for each participant is provided in 
Table 7.1-1.
7.2
Method of Treatment Assignment
All participants will be centrally assigned using an Interactive Response Technology (IRT) system; 
until this system is activated, enrollment may be manually managed by the Sponsor. 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 per the Schedule of Activities (Section 2).
During the screening visit, the investigative site will call into the enrollment option of the IRT 
designated by BMS for assignment of a 5-digit participant number that will be unique across all 
sites. Enrolled participants, including those not dosed, will be assigned sequential participant 
numbers starting with 
 The PID number will ultimately 
be comprised of the site number and participant number. For example, the first participant screened 
(ie, enrolled) at site number 1, will have a PID of 
. Once it is determined that the 
participant meets the eligibility criteria following the screening visit, the investigative site will call 
the IRT to assign the participant into the open dose level.
Treatment assignments for participants eligible for both Part 1A and Part 1B or for melanoma 
participants in Part 2A or Part 2B will alternate among the parts, with consecutively screened
participants assigned to different parts through IRT. If a treatment arm becomes overly enrolled 
because of screen failures in the alternate arm, it can be temporarily closed to allow enrollment in 
the alternate arm only. Once balance is achieved, the temporary hold can be lifted. If there are no 
openings available in the part to which the participant would be assigned by this algorithm, the 
participant will be assigned to the next open part/cohort until respective dose levels or cohorts have 
completed accrual according to principles outlined in Section 5.1.2.
Participants will not be replaced if they are discontinued from the study secondary to an AE unless 
the AE can be determined to be unrelated to treatment.
Participants not evaluable for DLT will be replaced. Participants not evaluable for PD endpoints 
may be replaced at the discretion of the Sponsor.
7.3
Blinding
As this is an open-label study, blinding procedures are not applicable; however, the specific 
treatment to be taken by a participant will be assigned using an IRT. The site will contact the IRT 
prior to the start of study treatment administration for each participant. The site will record the 
treatment assignment on the applicable case report form (CRF), if required. BMS personnel may 
have access to treatment information during the course of the trial to help with internal decision
making and for disclosure of preliminary scientific results.
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7.4
Dosage Modification
7.4.1
Relatlimab Dose Modification
No dose modifications for relatlimab are permitted.
There will be no dose escalations or reductions of relatlimab allowed. Doses of relatlimab may be 
interrupted, delayed, or discontinued according to Section 7.4.5 and Section 8.1. Dosing visits are 
not skipped, only delayed.
7.4.2
Nivolumab Dose Modification
No dose modifications for nivolumab are permitted.
There will be no dose escalations or reductions of nivolumab allowed. Doses of nivolumab may 
be interrupted, delayed, or discontinued according to Section 7.4.5 and Section 8.1. Dosing visits 
are not skipped, only delayed.
7.4.3
BMS-986205 Dose Modification
 
 
 
The dose of BMS-986205 should be reduced for the following AEs attributable to study therapy 
that do not otherwise meet criteria for discontinuation:
•
 
 
 
 
Dose modification and interruption of BMS-986205 may occur in the setting of lower grade AEs 
and/or be more conservative than indicated above based on the clinical judgment of the 
Investigator and in consultation with the BMS Medical Monitor/designee. For an AE requiring 
dose modification, BMS-986205 should be interrupted to allow improvement of the AE, even if 
the AE does not otherwise meet criteria for dose modification (see Section 7.4.5).
Re-escalation of BMS-986205 will not be permitted once the dose of BMS-986205 has been 
reduced for a participant.
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7.4.4
Ipilimumab Dose Modification
No dose modifications for ipilimumab are permitted.
There will be no dose escalations or reductions of ipilimumab allowed. Doses of ipilimumab may 
be interrupted, delayed, or discontinued according to Section 7.4.5 and Section 8.1. Dosing visits 
are not skipped, only delayed.
7.4.5
Dose Modification Criteria for IO Therapies
Dose delay criteria apply only for drug-related AEs. Delay administration of relatlimab,
nivolumab, and ipilimumab (and interrupt dosing of BMS-986205) if any of the delay criteria in 
are met, or if 
 infection is either confirmed or suspected. Delay 
relatlimab, nivolumab, and ipilimumab dosing (and interrupt dosing of BMS-986205) for any AE, 
laboratory abnormality, or intercurrent illness which, in the judgement of the Investigator, warrants 
delaying the dose of study medication.
For participants who require delay of relatlimab, nivolumab, and ipilimumab (or interrupt 
BMS-986205 dosing), re-evaluate weekly, or more frequently, if clinically indicated, and resume 
dosing when criteria to resume treatment are met (refer to Section 8.1.2).
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Participants who experience the following toxicities must have all study treatment(s) withheld:
•
Potential DLTs, until DLT relatedness is defined.
•
 infection either confirmed or suspected.
Criteria for participants who are required to permanently discontinue study treatments are listed in 
Section 8.1. 
 
 
Participants not meeting guidelines for permanent discontinuation will be permitted to resume 
therapy based on the criteria specified in Section 8.1.2 and Section 8.1.3. Participants eligible to 
resume study therapy will resume study therapy at the nominal treatment visit after their last 
received study medication dose.
The end of cycle tumor assessments, such as CT, MRI, or positron emission tomography (PET), 
will continue on a 
schedule relative to the participant’s first dose, regardless of any treatment 
delay incurred.
In extenuating circumstances in which the participant cannot make the dose administration
schedule within the dosing window, the BMS Medical Monitor/designee should be contacted.
Participants who require delay of any study treatment should be re-evaluated weekly or more 
frequently if clinically indicated and resume dose administration when criteria to resume treatment 
are met.
 
 
 
 
If BMS-986205 administration is delayed, dose reduction may be necessary (see Section 7.4.3).
If dose administration is resumed after a delay, BMS-986205 may be resumed as soon as the 
criteria to resume treatment are met (see Section 8.1.2). 
 
 
 Participants who require 
delay of any study treatment should be re-evaluated weekly or more frequently if clinically 
indicated and resume dose administration when retreatment criteria are met.
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7.4.6
Dose-limiting Toxicities
For the purpose of guiding dose selection, DLTs will be defined based on the incidence, intensity, 
and duration of AEs that are possibly related to study treatment. The DLT period will be 
in Part 1A and Part 1B. Any toxicities that occur beyond the DLT period will be accounted for in 
making final dose level decisions.
The DLT evaluation interval begins on the first day of treatment and continues for 
. 
 
 
 
 
 
 
 
 
 
 
 
For the purpose of guiding decisions regarding dose escalation in Part 1A and Part 1B, DLT will 
be determined based on the incidence, intensity, and duration of AEs that are related to study drug 
and that occur within 
 of initiation of study drug (ie, the DLT evaluation interval 
through the completion of Cycle 1). The severity of AEs will be graded according to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
For the purpose of participant management, potential DLTs that occur at any time, will result in 
all study drug(s) being held pending evaluation of the event’s relatedness to study drug, severity, 
and duration, and in accordance with Section 7.4.5. Participants must meet criteria for retreatment 
prior to reinitiation of study treatment (see Section 8.1.2).
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7.4.7
Management Algorithms for Immuno-oncology Agents
IO agents are associated with AEs that can differ in severity and duration than AEs caused by other 
therapeutic classes. Relatlimab, nivolumab, ipilimumab, and BMS-986205 are considered as IO
agents in this protocol. Early recognition and management of AEs associated with IO agents may 
mitigate severe toxicity. Management algorithms have been developed to assess and manage the 
following groups of IMAEs:
•
Gastrointestinal
•
Renal
•
Pulmonary (for participants with dyspnea, complete blood count [CBC] should be measured)
•
Hepatic
•
Endocrinopathy
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•
Skin
•
Neurological
•
Myocarditis
The algorithms recommended for the management of IMAEs in this protocol are in Appendix 5.
7.4.8
Management of Drug-related Infusion Reactions
Since relatlimab, 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, hypotension, hypertension, bronchospasm, or other allergic-like 
reactions. Report all Grade 3 or 4 infusion reactions within 24 hours as an SAE if it meets the 
criteria.
Treatment recommendations are provided below based on CTCAE v5.0 grading definitions and 
may be modified based on local treatment standards and guidelines, as appropriate.
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7.5
Preparation/Handling/Storage/Accountability
For relatlimab, nivolumab, ipilimumab, and BMS-986205, refer to the current version of the IBs 
and/or Pharmacy Manual for complete storage, handling, dispensing, and infusion information.
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 BMS should be contacted immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
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Documentation for IP (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 the Pharmacy Manual.
7.5.1
Retained Samples for Bioavailability/Bioequivalence
Not applicable.
7.6
Treatment Compliance
All IV infusion study treatments will be administered to the participant in the clinical facility. 
Trained medical personnel will dispense study treatments to the participants. Treatment 
compliance for participants administered BMS-986205 orally will be monitored by drug 
accountability, as well as by recording study treatment administration in the participant pill diary, 
medical record, and CRF. Participants should bring all drug containers to each study visit for drug 
reconciliation.
7.7
Concomitant Therapy
7.7.1
Prohibited Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Immunosuppressive agents.
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.2).
•
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive non-palliative radiation therapy, or standard or investigational agents for the 
treatment of cancer).
•
Prior exposure to relatlimab or other LAG-3-targeting agents.
•
For participants to be treated with BMS-986205: prior exposure to IDO1 targeting agents.
•
 
•
Use of any medicinal herbal preparations within 2 weeks of the first dose of study treatment 
and during study treatment unless prescribed by a treating physician.
•
Treatment with any live/attenuated vaccine within 
 of first study treatment, during 
treatment, and up to 
 post last dose.
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7.7.1.1
Restricted Treatments for Participants Treated with BMS-986205
Restricted therapies are not prohibited but are not recommended; consult the BMS Medical 
Monitor/designee if the following are clearly medically indicated:
•
Avoid coadministration of traditional Chinese medicines with any of the study treatments,
unless with Sponsor approval. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.7.2
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.
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7.7.2.1
Imaging Restriction and Precautions 
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, 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 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 
<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 standards set by the local Ethics Committee.
7.7.3
Permitted Therapy
Participants are permitted the use of the following treatments:
•
Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption). 
•
Adrenal replacement steroid doses > 10 mg daily prednisone equivalent.
•
A brief (less-than-3-week) course of corticosteroids for prophylaxis (eg, contrast dye allergy) 
or for treatment of nonautoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by a contact allergen).
7.7.4
Palliative Local Therapy
Palliative and supportive care for disease-related symptoms may be offered to all participants on 
the trial; however, Investigators should consult with the BMS Medical Monitor prior to initiating 
palliative radiation in participants who have not yet completed the DLT evaluation period. Limited 
radiation therapy or surgery to control isolated lesions is permitted for participants who have 
Investigator-assessed clinical benefit following consultation with the BMS Medical Monitor. 
Participants should not receive study drug treatment during radiation, as the potential for 
overlapping toxicities with radiotherapy and the triplet combinations is currently not known. 
Anecdotal data suggest that radiotherapy administered to participants while receiving nivolumab 
therapy is tolerable; however, because concurrent radiotherapy and immunotherapies in cancer 
have not been formally evaluated, in cases where palliative radiotherapy is required for a tumor 
lesion, study treatment 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 related to radiotherapy should resolve to Grade 1 prior to 
resuming study drug.
7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS-supplied study treatment. Study treatment will be provided via an 
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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 relatlimab or BMS-
986205 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
Participants MUST discontinue IP (and non-IP at the discretion of the Investigator) for any of the 
following reasons:
•
If a participant receiving relatlimab, nivolumab, and ipilimumab combination meets criteria 
for discontinuation per 
, they must discontinue all study drugs and be taken off 
the treatment phase of the study.
•
Any drug-related AE occurring at any time that meets DLT criteria as outlined in Section 7.4.6
will require permanent discontinuation. Exceptions to permanent discontinuation are listed in 
Section 8.1.3.
•
Documented disease progression as defined by RECIST v1.1 (Appendix 11), unless 
participants meet criteria for treatment beyond progression 
•
Clinical deterioration while receiving active study therapy that, in the opinion of the 
Investigator, indicates that continued participation in the study is not in the best interest of the
participant.
•
Any clinical 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.
•
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 per 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 the participant
to provide this information.
•
Termination of the study by BMS.
•
Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
•
Inability to comply with the protocol.
•
Discretion of the Investigator.
•
Pregnancy.
•
 
 
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BMS Medical Monitor/designee in settings where benefit-risk justifies discontinuation of 
 
 
 
In the case of pregnancy, the Investigator must notify, within 24 hours of the awareness of the 
pregnancy, the BMS Medical Monitor/designee of this event. In most cases, the study treatment 
will be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
participant safety). Please contact the Sponsor or designee within 24 hours of awareness of the 
pregnancy. Refer to Section 9.2.6 Pregnancy.
Refer to the Schedule of Activities (see Section 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures, including post-treatment study follow-up, or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate CRF page.
8.1.1
Relatlimab, Nivolumab, BMS-986205, and Ipilimumab Dose 
Discontinuation
Relatlimab, nivolumab, BMS-986205, and ipilimumab treatment should be permanently 
discontinued for the following:
•
If a participant receiving relatlimab, nivolumab, and ipilimumab combination meets criteria 
for discontinuation per Table 7.4.5-1, they must discontinue all study drugs and be taken off 
the treatment phase of the study.
•
 
 
•
In most cases of Grade 3 AST or ALT elevation (defined as AST or ALT > 5 x ULN, regardless 
of baseline value), study treatment(s) will be permanently discontinued. If the Investigator 
determines a possible favorable benefit-risk ratio that warrants continuation of study 
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treatment(s), a discussion between the Investigator and the BMS Medical Monitor/designee 
must occur.
•
 
 
 
 
 
 
 
 
 
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued dose 
administration.
•
 
 
 
 
 
 
 
 
8.1.2
Criteria to Resume Treatment
Participants experiencing AEs not meeting criteria for permanent discontinuation as outlined in 
Section 7.4.5 and Section 8.1.1 may resume treatment with study drug under the following criteria:
•
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 7.4.5-1.
•
 
 
 
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved according to 
Management Algorithms (Appendix 5) and meeting the criteria for resumption per Table 7.4.5-
1. Participants with persistent Grade 1 pneumonitis after completion of a steroid taper over at 
least 1 month may be eligible for retreatment if discussed with and approved by the BMS 
Medical Monitor or designee.
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•
 
 
 
 
 
•
If the criteria to resume treatment are met, the participant should restart treatment at the next 
scheduled time point per protocol.
•
 
8.1.3
Exceptions to Permanent Discontinuation
Any drug-related AE occurring at any time that meets DLT criteria as outlined in Section 7.4.6
 
 
 
 
 
 
 
 
 
 
 
 
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•
Any AE, laboratory abnormality, or concurrent illness, which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued dose 
administration.
Even if the criteria to resume treatment are met, the consideration to reinitiate study treatment
under the following exception will be made on a case-by-case basis after considering the overall 
benefit-risk profile and in consultation between the Investigator and the Sponsor. Any AE with 
clinical risk will be assessed on a case-by-case basis with the Investigator and the BMS Medical 
Monitor to determine the risks and benefits of continuing on treatment following resolution vs 
discontinuing treatment permanently.
All participants who discontinue IP should comply with protocol-specified follow-up procedures 
as outlined in the Schedule of Activities (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 (eg, imprisonment, involuntary incarceration 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 CRF page.
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8.1.5
Post Study Treatment Study Follow-up
BMS may request that survival data be collected on all treated participants outside of the protocol-
defined 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 or is lost to follow-
up.
In this study, participants who complete or discontinue study treatment will continue to be 
followed.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the Investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
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.
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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 the 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 use of a third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, 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 (see Section 2).
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before treatment assignment. The Investigator will 
maintain a 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 the signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected 
drug-induced liver enzyme evaluations) will be monitored during the follow-up phase via 
on-site/local laboratories until all study drug-related toxicities resolve, return to baseline, or are 
deemed irreversible.
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If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary AEs, the participant should be immediately evaluated 
to rule out pulmonary toxicity, according to the suspected pulmonary toxicity management 
algorithm in Appendix 5.
The troponin elevations will require the participant to undergo a cardiac evaluation. Following this 
evaluation, determination of further treatment will be based on the discretion of the Investigator.
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
9.1.1
Imaging Efficacy Assessments
Screening images should be acquired as outlined in Table 2-1. On-study images should be acquired 
as outlined in Table 2-2 and Table 2-3 from the date of first dose until participant is off-study as 
defined in Section 8.1. For participants continuing in the Follow-up period, imaging will continue 
as defined in Table 2-4. Any additional imaging that may demonstrate tumor response or 
progression (including scans performed at unscheduled time points and/or at an outside institution) 
 
 
 
9.1.2
Imaging Assessment for the Study
Images will be submitted to 
 on a rolling basis, preferably within 7 days of 
scan acquisition. Sites should be qualified prior to scanning the first study participant. Image 
acquisition guidelines and submission process will be outlined in the CA224048 Imaging Manual 
to be provided by 
 
9.1.3
Imaging Methods of Measurement
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known/suspected sites of 
disease should be performed for tumor assessments. For participants with head and neck cancer, 
the neck is also required. Images should be acquired with a 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 time points. 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 v1.1 criteria.
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the neck (if required), abdomen, pelvis, and other 
known/suspected sites of disease should be obtained.
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Should a participant have contraindication for both MR and CT intravenous contrasts, a 
non-contrast CT of the chest and a non-contrast MRI of the neck (if required), abdomen, pelvis, 
and other known/suspected sites of disease should be obtained. 
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the neck (if required), 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 
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 v1.1 measurements. Note, however, that the PET portion of 
the CT introduces additional data which, may bias an Investigator if it is not routinely or serially 
performed.
Bone scan or PET scan is not adequate for assessment of RECIST v1.1 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 CR is identified in target disease or when progression in 
bone is suspected.
Bone scans may be collected per local standards, as clinically indicated.
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 
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are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study.
Immune-mediated AEs
are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s CRF.
Contacts for SAE reporting are specified in Appendix 3.
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 
) should begin at initiation of study treatment until the time points specified 
in the Schedule of Activities (Section 2). Non-serious AE information should also be collected 
from the start of a placebo lead-in period or other observational period intended to establish a 
baseline status for the participants.
Section 5.6.1 and 5.6.2 in the IBs for relatlimab, nivolumab, BMS-986205, and ipilimumab,
represent the Reference Safety Information, to determine expectedness of SAEs 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 must be collected that occur during the screening period and within 
 of the last 
dose of study treatment. For participants assigned to treatment and never treated with study drug, 
SAEs should be collected for 
 from the date of treatment assignment. If applicable, SAEs 
must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy).
All SAEs, and all AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
 infection must be collected from the date of the participant’s written consent until 
 
following discontinuation of dosing.
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:
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.
•
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 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 
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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
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AEs and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context of known 
AEs, when appropriate for the program or protocol.
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
•
Non-serious 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 non-serious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment, as appropriate.
•
All identified non-serious AEs must be recorded and described on the non-serious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2) and AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
 will be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, the event is deemed irreversible, or until the participant is lost to 
follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification of SAEs by the Investigator to the Sponsor 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 IB and will notify the IRB/IEC, if appropriate according to local requirements.
The Sponsor or designee will be reporting AEs to regulatory authorities and Ethics Committees 
according to local applicable laws, including European Directive 2001/20/EC and FDA Code of 
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Federal Regulations 21 CFR Parts 312 and 320. Suspected, unexpected serious adverse reactions 
(SUSARs) are a subset of SAEs and will be reported to the appropriate regulatory authorities and 
Investigators following local and global guidelines and requirements.
9.2.6
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 or 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 reinitiation 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 
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.
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Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Sponsor or designee. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.7
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE CRF 
page or electronic SAE Report Form, 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 will be used by the 
reporting Investigator (eg, anemia vs low hemoglobin value).
9.2.8
Potential Drug Induced Liver Injury 
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 DILI is defined as: 
1) Aminotransaminase (AT; ALT or AST) elevation >3 × ULN.
AND
2) Total bilirubin >2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase).
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.9
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, x-ray 
filming, or any other potential safety assessment required or not required by protocol, should also 
be recorded as a non-serious AE or SAE, as appropriate, and reported accordingly.
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9.3
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. 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 (see Section 9.2).
For this study, any dose of relatlimab, nivolumab, BMS-986205, or ipilimumab greater than the 
planned dose will be considered an overdose.
In the event of an overdose the Investigator/treating physician should:
1) Contact the Medical Monitor immediately.
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 
3) Document the quantity of the excess dose as well as the duration of the overdose in the CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (see 
Section 2).
9.4.1
Physical Examinations
Refer to Schedule of Activities.
9.4.2
Vital signs
Refer to Schedule of Activities.
9.4.3
Electrocardiograms
Refer to Schedule of Activities.
9.4.4
Clinical Safety Laboratory Assessments 
•
Investigators must document their review of each laboratory safety report.
•
Local laboratory tests may be used to guide clinical decisions and determine eligibility for 
dose administration once eligibility to participate in this study has been confirmed by central 
laboratory results.
A central/local laboratory will perform the analyses and provide reference ranges for these tests.
During screening and treatment, unless otherwise indicated in Table 9.4.4-1, results of clinical 
laboratory tests must be reviewed prior to dose administration.
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Table 9.4.4-1:
Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Methemoglobin; if elevated, draw reticulocyte count, lactate dehydrogenase (LDH), and 
haptoglobin. Methemoglobin is assessed on arterial or venous blood sample
G6PD levels; prior to treatment assignment only, if indicated
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin; reflex if total is abnormal
Alkaline phosphatase
Lactate dehydrogenase
Creatinine
) (see below)
Blood urea nitrogen (BUN)
Uric acid
Glucose
C-reactive protein
Lipase
Gamma glutamyl transferase; reflex when
alkaline phosphatase is Grade ≥ 2
HbA1c; obtain during screening to establish 
baseline in participants with type 2 diabetes, 
then as clinically indicated
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatinine clearance; screening only;
Cockcroft-Gault formula
Cardiac troponin T (cTnT) or I (cTnI); see 
below
Amylase
Thyroid-stimulating hormone (TSH), free T3 
and free T4 - screening; see below
Endocrine Panel
TSH with reflex to free T3 and free T4 as applicable on-treatment
Participants with controlled hyperthyroidism must be negative for thyroglobulin and thyroid 
peroxidase antibodies and thyroid stimulating immunoglobulin; screening only.
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Table 9.4.4-1:
Laboratory Assessments
Urinalysis 
Protein
Glucose
Blood
Leukocyte esterase
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Serology (at screening only)
Hepatitis A antibody
Hepatitis C antibody; if hepatitis C antibody is positive, reflex to hepatitis C RNA
Hepatitis B surface antigen (HBsAg) and/or hepatitis B core antigen
HIV-1, and -2 antibody where mandated by local requirements
Other Analyses
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of human
chorionic gonadotropin [hCG])
Follicle stimulating hormone (FSH) screening - only required to confirm menopause in women 
< age 55) as defined in Appendix 4
Serologic tumor marker for gastric cancer, carcinoembryonic antigen (CEA)
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CEA = carcinoembryonic antigen; 
 
T; FSH = follicle stimulating hormone; GP6D = glucose-6-phosphate dehydrogenase; HbA1c = glycated hemoglobin; 
HBSAg = hepatitis B surface antigen; HCG = human chorionic gonadotropin; HIV-1 = human immunodeficiency 
virus-1; HIV-2 = human immunodeficiency virus-2; LDH = lactate dehydrogenase; RNA = ribonucleic acid; TSH = 
thyroid-stimulating hormone WOCBP = women of child bearing potential.
9.4.5
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the study Investigator per standard 
medical/clinical judgment.
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9.8.3
Additional Research Collection
This protocol will include residual sample storage for additional research.
For All US Sites:
Additional research participation is required for all investigational sites in the U.S.
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 retention for additional research is intended to expand the translational Research and
Development capability at BMS, 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 
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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.
•
 
Samples kept for future research will be stored at the BMS Biorepository in 
 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 the 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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10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
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10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent and are registered into the IRT
Treated
All participants who take at least 1 dose of study treatment
Response-evaluable 
All treated participants with measurable disease at baseline and 1 of the following: 
a) at least 1 post-baseline tumor assessment; b) clinical progression, or c) death
 
Abbreviations: IRT = interactive response technology; 
.
10.3
Statistical Analyses
Final analysis will be performed after all participants are enrolled and have been followed for the 
minimum time to evaluate the primary endpoint. The statistical analysis plan will be developed 
and finalized before the database lock for the final analysis. A description of the participant 
population will be included in the statistical output reported, including subgroup of age, gender, 
and race. Below is a summary of planned statistical analyses of the primary and secondary 
endpoints. In general, summaries will be performed by dose level, cohort, and indication. If 
sufficient data are not available such that adequate interpretation of the result is not warranted, 
some summaries may not be performed and only listings will be presented.
 
 
10.3.1
Efficacy Analyses
The primary efficacy analyses will be performed on the treated population for the final analysis. 
Efficacy analyses based on the response-evaluable population may be performed for interim 
analyses when the minimum follow-up period is less than sufficient to warrant adequate 
interpretation of the result. Efficacy analyses may be performed on selected subgroups, including 
biomarker-selected subgroups. Efficacy analyses will be performed using the RECIST v1.1 
criteria. Additional details on efficacy analyses are provided in Table 10.3.1-1.
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Table 10.3.1-1:
Overview of Efficacy Analysis Methods
Endpoint
Statistical Analysis Methods
ORR is defined as the proportion of participants whose BOR is either 
CR or PR. DCR is defined as the proportion of participants whose 
BOR includes CR, PR, and SD.
Best overall response per RECIST v1.1 is defined as the best response 
designation recorded between the date of first dose and the date of first 
objectively documented progression per RECIST v1.1 or the date of 
subsequent therapy, whichever occurs first. For participants who 
continue treatment beyond progression per RECIST v1.1 or begin 
subsequent therapy, the BOR should be determined based on response 
designations recorded up to the time of the initial progression or 
subsequent therapy, whichever occurs first. For participants without 
documented progression or subsequent therapy, all available response 
designations should contribute to the BOR assessment.
Estimate of ORR and DCR and 
corresponding 2-sided exact 95% CI 
using the Clopper-Pearson method.
mDOR
DOR for a participant with a BOR of CR or PR is defined as the time 
between the date of first response and the date of the first objectively 
documented tumor progression per RECIST v1.1 or death, whichever 
occurs first. For those participants who neither progress nor die, the 
duration of objective response will be censored at the same time they 
will be censored for the primary definition of PFS.
Estimate by the Kaplan-Meier method 
and corresponding 2-sided 95% CI 
using Brookmeyer and Crowley 
methodology (using log-log 
transformation).
mPFS and PFSR at 6 and 12 months
PFS is defined as the time from first dose to the date of first 
objectively documented progression, per RECIST v1.1, or death due to 
any cause, whichever occurs first. Clinical deterioration in the absence 
of objectively documented progression per RECIST v1.1 is not 
considered progression for the purpose of determining PFS. 
Participants who die without a reported progression will be considered 
to have progressed on the date of their death. Participants who did not 
progress or die will be censored on the date of their last evaluable 
tumor assessment. Participants who did not have any on study tumor 
assessments and did not die will be censored on the date of first dose. 
Participants who started any subsequent anticancer therapy, including 
tumor-directed radiotherapy and tumor-directed surgery, without a 
prior reported progression will be censored at the last evaluable tumor 
assessment prior to initiation of the subsequent anticancer therapy. The 
PFSR at time T is defined as the probability that a participant has not 
progressed and is alive at time T following first dose.
Estimate by the Kaplan-Meier method 
and corresponding 2-sided 95% CI 
using Brookmeyer and Crowley 
methodology (using log-log 
transformation) for the median and 
Greenwood formula for the rate.
Abbreviations: BOR = best overall response; CI = confidence interval; CR = complete response; DCR = disease 
control rate; DOR = duration of response; mDOR = median duration of response; mPFS = median progression-free 
survival; 
 ORR = overall response rate; 
 
 PFS = progression-free survival; PFSR = progression-free survival rate; PR = partial response; 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; T= time.
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10.3.2
Safety Analyses
All safety analyses (see Table 10.3.2-1) will be performed on the treated population.
Table 10.3.2-1:
Overview of Safety Analysis Methods
Endpoint
Statistical Analysis Methods
Incidence of AEs, SAEs, AEs meeting 
protocol-defined DLT criteria, AEs leading to 
discontinuation and deaths
AEs will be graded according to CTCAE v5.0
DLT rate by dose level; frequency distribution of treated 
participants with AE using the worst CTC grade. 
Participants will only be counted (1) once at the PT 
level, (2) once at the SOC level, and (3) once in the 
“total participant” row at their worst CTC grade, 
regardless of SOC or PT.
Incidence of clinical laboratory test abnormalities 
Laboratory values will be graded according to 
CTCAE v5.0
Laboratory shift table using the worst CTC grade on 
treatment per participant.
Abbreviations: AE = adverse event; CTC = Common Terminology Criteria; CTCAE = Common Terminology Criteria 
for Adverse Events; DLT = dose-limiting toxicity; PT = preferred term; SAE = serious adverse event; SOC = system 
organ class.
10.3.4
Interim Analyses
The Statistical Analysis Plan will further describe the planned interim analyses.
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11
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1
Luke et al, Society for Immunotherapy of Cancer 2017, Presentation O41
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Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
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Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
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Bristol-Myers Squibb BMS-986205 (IDO1 inhibitor) Investigator Brochure v03,
 
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Bristol-Myers Squibb BMS-734016, MDX-010 (ipilimumab) Investigator Brochure v19, 02-
Mar-2017. Document Control No. 930017531.
10 Alegre ML, Noel PJ, Eisfelder BJ, et al. Regulation of surface and intracellular expression of 
CTLA4 on mouse T cells. J Immunol 1996;157:4762-70.
11 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20.
12 Theate I, van Baren N, Pilotte L, et al. Extensive profiling of the expression of the indoleamine 
2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol Res 
2014;3:161-72.
13 Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor induced tolerance. J Clin 
Invest 2007;117:1147-54.
14 Godin-Ethier J, Hanafi L-A, Piccirillo CA, et al. Indoleamine 2,3 dioxygenase expression in 
human cancers: clinical and immunologic perspectives. Clin Cancer Res 2011;17:6985-91.
15 Urba WJ, Martin-Algarra S, Callahan M, et al. Immunomodulatory activity of nivolumab 
monotherapy in patients with advanced melanoma. American Association for Cancer Research 
2015 Annual Meeting; 2015 Apr 18-22; Philadelphia, PA. Abstract 2855
16 Choueiri TK, Fishman MN, Escudier B, et al. Immunomodulatory activity of nivolumab in 
metastatic renal cell carcinoma. Clin Cancer Res 2016;22(22):5461-71.
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17 Holmgaard RB, Zamarin D, Munn D, et al. Indoleamine 2,3 dioxygenase is a critical resistance 
mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med 2013;210:1389-
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18 Beatty GL, O’Dwyer PJ, Clark J, et al. First-in-human Phase 1 study of the oral inhibitor of 
indoleamine 2,3 dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid 
malignancies. Clin Cancer Res 2017. doi 10.1158/1078-0432.CCR-16-2272. [Accepted article, 
Epub ahead of print]
19 Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined 
Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2017;377:1345-56.
20 Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus 
ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, 
phase 1/2 trial. Lancet Oncol 2016;17:883-95.
21 Hammers HJ, Plimack ER, Infante JR, et al. Safety and Efficacy of Nivolumab in Combination 
With Ipilimumab in Metastatic Renal Cell Carcinoma: The CheckMate 016 Study. J Clin 
Oncol 2017:JCO2016721985.
22 Escudier BJ, Chabaud S, Borchiellini D, et al. Efficacy and safety of nivolumab + ipilimumab 
(N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), 
including IMDC risk and PD-L1 expression subgroups. J Clin Oncol 35, 2017 (suppl; abstr 
4563).
23 Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line 
treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, 
phase 1, multicohort study. Lancet Oncol 2017;18:31-41.
24 Final clinical study report for CA209012. 
 
 
 
 
 
 
 
 
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25 Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced 
non–small cell lung cancer. N Engl J Med 2019;381:2020-31.
26 Ramalingam S, Ciuleanu TE, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-
doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: three-
year update from CheckMate 227 Part 1 [abstract]. J Clin Oncol 2020;38:9500.
27 CA224020 A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety, 
Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered 
Alone and in Combination with Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) 
in Advanced Solid Tumors Bristol-Myers Squibb Company; 2016. Document Control No. 
930071758.
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28 Lipson EJ, Tawbi HA, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) 
versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-
047 (CA224-047). J Clin Oncol 2021;39:9503.
29 Perez RP, Riese MJ, Lewis KD, et al. Epacadostat plus nivolumab in patients with advanced 
solid tumors: preliminary phase 1/2 results of ECHO-204 [abstract]. J Clin Oncol 
2017;35:3003.
30 Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients with 
advanced melanoma and select solid tumors: updated phase 1 results from ECHO-
202/KEYNOTE-037 037. Proceedings of the ASCO Annual Meeting; 2017.
31 Gangadhar TC, Schneider BJ, Bauer TM, et al. Efficacy and safety of epacadostat plus 
pembrolizumab treatment of NSCLC: preliminary phase I/II results of ECHO-
202/KEYNOTE-037 [abstract]. J Clin Oncol 2017;35:9014.
32 Smith DC, Gajewski T, Hamid O, et al Epacadostat plus pembrolizumab in patients with 
advanced urothelial carcinoma: preliminary phase I/II results of ECHO-202/KEYNOTE-037
[abstract]. J Clin Oncol 2017;35:4503.
33 Lara P, Bauer TM, Hamid O, et al. Epacadostat plus pembrolizumab in patients with advanced 
RCC: preliminary phase I/II results from ECHO-202/KEYNOTE-037 [abstract]. J Clin Oncol 
2017;35:4515.
34 Bristol Myers Squibb. Data on File.
35 Zhou H, Tsukamoto Y, Davis HM. Should clinical pharmacokinetic bridging studies between 
Caucasian and Asian populations be required for approval of monoclonal antibodies? J Clin 
Pharmacol 2012;52:1273-6.
36 Terada T, Noda S, Inui K. Management of dose variability and side effects for individualized 
cancer pharmacotherapy with tyrosine kinase inhibitors. Pharmacol Ther 2015;152:125-34.
37
38 Li J, Bluth MH. Pharmacogenomics of drug metabolizing enzymes and transporters: 
implications for cancer therapy. Pharmgenomics Pers Med 2011;4:11-33.
39 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;45:228-47.
40 Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol 2017;18:e143-e52.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
1L
first-line
2L
second-line
ACLS
advanced cardiac life support
ADA
anti-drug antibody
AE
adverse event
AESOI
adverse events of special interest
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
AST
aspartate aminotransferase
AT
aminotransaminase
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
β-hCG
beta-human chorionic gonadotrophin
BICR
blinded independent clinical review
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
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Term
Definition
BMI
body mass index
BMS
Bristol-Myers Squibb Company
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
C
cycle
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
Cavg
average concentration
Cavgss
time-averaged steady-state concentration
CBC
complete blood count
CD
cluster of differentiation
CEA
carcinoembryonic antigen
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CL
clearance
CL/F
apparent clearance
CLss
clearance at steady-state
cm
centimeter
Cmax
maximum observed concentration
Cmaxss
maximum observed steady-state concentration
Cmin
minimum observed concentration
Cminss
minimum observed steady-state concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
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Term
Definition
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
Case Report Form, paper or electronic
CT
computed tomography
CTAg
clinical trial agreement
CTC
common terminology criteria
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated protein-4
cTnI
cardiac troponin I
cTnT
cardiac troponin T
Ctrough
trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D
day
DCR
disease control rate
D/C
discontinue
DIL
Dear Investigator Letter
DILI
drug-induced liver injury
dL
deciliter
DLT
dose limiting toxicity
DMC
data monitoring committee
DoR
duration of response
DRESS
drug reaction with eosinophilia and systemic symptoms
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
EC50
half-maximal effective concentration
ECG
electrocardiogram
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Term
Definition
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EEG
electroencephalogram
eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EOI
end of infusion
EOT
end of treatment
ESR
Expedited Safety Report
F
bioavailability
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FSH
follicle stimulating hormone
FU/FUP
follow-up
g
gram
G6PD
glucose-6-phosphate dehydrogenase
GBS
Guillain-Barre syndrome
GCP
Good Clinical Practice
Geo.
geometric
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
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Term
Definition
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
human immunodeficiency virus
HPV
human papillomavirus
HR
heart rate
HRT
hormone replacement therapy
HuMAb
human monoclonal antibody
hWB
human whole blood
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICD
International Classification of Diseases
ICF
informed consent form
ICH
International Conference on Harmonisation 
IDO1
indoleamine 2,3-dioxygense 1
ie
id est (that is)
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG
immunoglobulin G
IHC
immunohistochemistry
IMAE
immune-mediated adverse event
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IO
immuno-oncology
IP
investigational product
IPI
ipilimumab
IQR
interquartile range
IRB
Institutional Review Board
IRT
Interactive Response Technology
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Term
Definition
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
Kd
dissociation constant
kg
kilogram
L
liter
LAG-3
lymphocyte activation gene 3
LAM
Lactation amenorrhea method
LCMS
liquid chromatography mass spectrometry
LDH
lactate dehydrogenase
ln
natural logarithm
LVEF
left ventricular ejection fraction
MAD
maximum administered dose
mDOR
median duration of response
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
Mg++
magnesium
MG
myasthenia gravis
MHC
major histocompatibility complex
MI
myocardial infarction
min
minute
mL
milliliter
MLR
mixed lymphocyte reaction
mmHg
millimeters of mercury
mPFS
median progression-free survival
MR
medical research
MRI
magnetic resonance imaging
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Term
Definition
MS
mass spectrometry
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition
μg
microgram
n
number of participants or observations
Na+
sodium
NA
not applicable
NCI
National Cancer Institute
ng
nanogram
NIVO
nivolumab
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ORR
overall response rate
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD-1
programmed death 1
PD-L1
programmed death-ligand 1
PD-L2
programmed death-ligand 2
PE
physical examination
PET
positron emission tomography
PFS
progression-free survival
PFSR
progression-free survival rate
PID
participant identification
PO
per os (by mouth route of administration)
PR
partial response
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Term
Definition
PT
preferred term
QD
quaque die, once daily
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q6W
every 6 weeks
Q8W
every 8 weeks
Q12W
every 12 weeks
R2
coefficient of determination
RBC
red blood cell
RCC
renal cell cancer
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
RO
receptor occupancy
RP2D
recommended Phase 2 dose
RT-PCR
reverse transcriptase-polymerase chain reaction
SAE
serious adverse event
SD
stable disease
SJS
Stevens-Johnson syndrome
SNP
single nucleotide polymorphism
SOC
system organ class
SOP
Standard Operating Procedures
sp.
species
SUSAR
suspected, unexpected serious adverse reaction
t
temperature
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Term
Definition
T
time
T.Bili
total bilirubin
TAO
Trial Access Online, the BMS implementation of an EDC capability
TEN
toxic epidermal necrolysis
TID
ter in die, three times a day
Tmax
time to achieve maximum drug concentration
TnI
troponin I
TnT
troponin T
TRAE
treatment-related adverse event
TSH
thyroid-stimulating hormone
TTE
transthoracic echocardiogram
ULN
upper limit of normal
US
United States
UV
ultraviolet
VS
vital signs
Vss
volume of distribution at steady state
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
WWPS
Worldwide Patient Safety
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The terms “participant” and “subject” refer to a person who has consented to participate in the 
clinical research study. Typically, the term “participant” is used in the protocol and the term 
“subject” is used in the Case Report Form (CRF).
REGULATORY AND ETHICAL CONSIDERATIONS
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
•
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines
•
Applicable laws, regulations, and requirements
The study will be conducted in compliance with the protocol. The protocol, any 
revisions/amendments, and the participant informed consent form (ICF) will receive 
approval/favorable opinion by Institutional Review Board/Independent Ethics Committee 
(IRB/IEC), and regulatory authorities according to applicable regulations prior to initiation of the 
study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation) that is likely to affect, 
to a significant degree, one or more of the following: (1) the rights, physical safety or mental 
integrity of one or more participants; (2) the scientific value of the clinical trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP regulation(s) or 
trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment).
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, Investigator’s Brochure, product labeling information, ICF, 
participant recruitment materials (eg, advertisements), and any other written information to be 
provided to participants. 
The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, administrative letters) annually, or more 
frequently, in accordance with regulatory requirements or institution procedures.
The investigator is responsible for providing oversight of the conduct of the study at the site and 
adherence to requirements of the following where applicable:
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•
ICH guidelines, 
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
European Union Directive 2001/20/EC; or
•
European Regulation 536/2014 for clinical studies (if applicable), 
•
European Medical Device Regulation 2017/745 for clinical device research (if applicable),
•
the IRB/IEC
•
and all other applicable local regulations.
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 the local Health Authority), except where necessary to eliminate an immediate 
hazard(s) to study participants. 
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 the local Health Authority, must be sent to Bristol-Myers 
Squibb (BMS).
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the ICF 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 participants 
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 participants prior to enrollment.
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information, in accordance with 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 participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
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The Sponsor or designee will provide the investigator with an appropriate sample ICF, which will 
include all elements required by the ICH GCP, and applicable regulatory requirements. The sample 
ICF will adhere to the ethical principles that have their origin in the Declaration of Helsinki.
The investigator or his/her representative must:
•
Obtain IRB/IEC written approval/favorable opinion of the written ICF and any other 
information to be provided to the participant prior to the beginning of the study and after any 
revisions are completed for new information.
•
Provide a copy of the ICF and written information about the study in the language in which 
the participant is proficient prior to clinical study participation. The language must be 
nontechnical and easily understood. 
•
Explain the nature of the study to the participant or his/her legally acceptable representative
and answer all questions regarding the study.
•
Inform participant that his/her participation is voluntary. Participant or his/her legally 
acceptable representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.
•
Allow time necessary for participant or his/her legally acceptable representative to inquire 
about the details of the study.
Obtain an ICF signed and personally dated by participant or his/her legally acceptable 
representative and by the person who conducted the informed consent discussion. 
•
Include a statement in participant’s medical record that written informed consent was obtained 
before participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
•
Re-consent participant to the most current version of the ICF(s) during his/her participation in 
the study, as applicable.
Revise the ICF 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 his/her legally acceptable representative 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 participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participant’s signed 
ICF, and, in the US, the participant’s signed HIPAA Authorization.
The ICF must also include a statement that BMS and local and foreign regulatory authorities have 
direct access to participant records. 
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In situations where consent cannot be given by participants, their legally acceptable representatives 
(as per country regulation) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
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.
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the ICF approved for the study prior to 
clinical study participation. The explicit wish of a minor, who is capable of forming an opinion 
and assessing this information to refuse participation in, or to be withdrawn from, the clinical study 
at any time, should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written consent. Minors who 
reach the age of majority (legal adulthood) during the clinical trial must give their written consent.
Participant unable to give their written informed consent (eg, stroke or participants with severe 
dementia) may only be enrolled in the study with the consent of a legally acceptable representative. 
The participant must also be informed about the nature of the study to the extent compatible with 
his or her understanding, and should this participant become capable, he or she should personally 
sign and date the ICF as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time, should be 
considered by the investigator.
The rights, safety, and well-being of the study participants are the most important considerations 
and should prevail over interests of science and society.
BMS COMMITMENT TO DIVERSITY IN CLINICAL TRIALS
The mission of BMS is to transform patients’ lives through science by discovering, developing, 
and delivering innovative medicines that help them prevail over serious diseases. 
BMS is committed to doing its part to ensure that patients have a fair and just opportunity to 
achieve optimal health outcomes.
BMS is working to improve the recruitment of a diverse participant population with the goal that 
the clinical trial becomes more reflective of the real-world population and the people impacted by 
the diseases studied.
DATA PROTECTION, DATA PRIVACY, AND DATA SECURITY
BMS collects and processes personal data of study participants, patients, health care providers, 
and researchers for biopharmaceutical research and development to advance innovative, high-
quality medicines that address the medical needs of patients. BMS ensures the privacy, protection, 
and confidentiality of such personal data to comply with applicable laws. To achieve these goals, 
BMS has internal policies that indicate measures and controls for processing personal data. BMS 
adheres to these standards to ensure that collection and processing of personal data are limited and 
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proportionate to the purpose for which BMS collects such personal data. This purpose is clearly 
and unambiguously notified to the individual at the time of collection of personal data. In the true 
spirit of science, BMS is dedicated to sharing clinical trial information and data with participants, 
medical/research communities, the media, policy makers, and the general public. This is done in a 
manner that safeguards participant privacy and informed consent while respecting the integrity of 
national regulatory systems. Clinical trial data, health-related research, and pharmacovigilance 
activities on key-coded health data transferred by BMS across national borders is done in 
compliance with the relevant data protection laws in the country and GCP requirements.
BMS protects Personal Information with adequate and appropriate security controls as indicated 
under the data protection laws. To align with the recommended security standards, BMS has 
adopted internal security standards and policies to protect personal data at every stage of 
its processing.
To supplement these standards, BMS enters into Clinical Trial Agreements (CTAgs) with 
confidentiality obligations to ensure proper handling and protection of personal data by third 
parties accessing and handling personal data.
BMS takes unauthorized access and disclosure of Personal Information very seriously. BMS has 
adopted the security standards that include National Institute of Standards and Technology 
Cybersecurity Framework for studies in the US. BMS aligns with these standards to continuously 
assess and improve its ability to protect, detect, and respond to cyber attacks and other 
unauthorized attempts to access personal data. These standards also aid in mitigating possible 
adverse effects. Furthermore, BMS Information Technology has defined 6 principles to protect our 
digital resources and information: 
1) Responsibilities of IT Personnel
2) Securing the BMS Digital Infrastructure
3) Identity and Access Management
4) External Partner Connections
5) Cyber Threat Detection and Response
6) Internal Cyber Incident Investigation
SOURCE DOCUMENTS
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be explained. 
•
The investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available.
•
Definitions of what constitutes source data can be found in the Site Process and Source 
Documentation (SPSD) form.
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The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are handwritten 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 records/electronic health 
records, adverse event (AE) tracking/reporting, protocol-required assessments, and/or drug 
accountability records.
When paper records from such systems are used in place of an 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 INTERVENTION RECORDS
Records for study intervention (whether supplied by BMS, its vendors, or the site) must 
substantiate study intervention integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
BMS/designee or a Health Authority.
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If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, 
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 
standard 
operating 
procedures/standards of the sourcing pharmacy
BMS or its designee will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents, or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture (EDC) tool, eCRFs will be prepared 
for all data collection fields except for fields specific to SAEs and pregnancy, which will be 
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reported on the electronic SAE form and Pregnancy Surveillance Form, respectively. If the 
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 
the Sponsor or designee.
The confidentiality of records that could identify participants 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 and SAE/pregnancy CRFs must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a sub-investigator and who is delegated this task on 
the Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF 
approval task. For eCRFs, review and approval/signature is completed electronically through the 
BMS EDC tool. The investigator must retain a copy of the CRFs, including records of the changes 
and corrections.
Each individual electronically signing eCRFs must meet Sponsor or designee training 
requirements and must only access the BMS EDC tool using the unique user account provided by 
the 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. 
In addition, the study may be evaluated by the 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 the 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 its designee, whichever is longer. 
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The investigator (or head of the study site in Japan) must contact BMS prior to destroying any 
records associated with the study.
BMS or its designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed-upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or its designee.
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS or 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 interventions supplied by 
BMS can only be destroyed after being 
inspected and reconciled by the responsible 
Study Monitor, unless study treatments 
containers must be immediately destroyed as 
required for safety, or to meet local regulations 
(eg, cytotoxics or biologics).
Partially used study interventions and/or 
empty containers may be destroyed after 
proper reconciliation and documentation. But 
unused IMP must be reconciled by site 
monitor/Clinical Research Associate prior to 
destruction.
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; eg, study treatments 
sourced from the site’s stock or commercial 
supply or a specialty pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal of study interventions, 
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:
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•
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 standard operating procedures 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 (eg, 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 Study 
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.
STUDY AND SITE START AND CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to:
•
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
•
Inadequate recruitment of participants by the investigator
•
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
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DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the Clinical Study Report (CSR). 
For each CSR related to this protocol, the following criteria will be used to select the Signatory 
Investigator:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to the 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 the Sponsor or designee at the earliest practicable time prior to submission or 
presentation and otherwise within the time period set forth in the CTAg.
Scientific publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
Principal Investigator, sub-investigator, or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the 
work (eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
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3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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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 
pre-existing medical condition in a clinical investigation participant administered study 
treatment 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, electrocardiograms, 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/serious adverse event (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).
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.
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SERIOUS ADVERSE EVENTS
A 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 Bristol-Myers Squibb (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 (eg, 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 (eg, 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.
Is an important medical event (defined as a medical event[s] that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm and 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 DILI must follow the same transmission timing and processes to BMS as used for 
SAEs. (See Section 9.2.6 for reporting pregnancies.)
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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 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 the 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 the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
•
Assessment of Intensity or Severity
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 is a 
descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is 
provided for each AE term. The investigator will make an assessment of intensity for each AE 
and SAE reported during the study and assign it to 1 of the following categories: 
•
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
•
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age
appropriate instrumental ADL*.
•
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
ADL**.
•
Grade 4: Life-threatening consequences; urgent intervention indicated.
•
Grade 5: Death related to AE
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
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telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
An AE that is assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event, and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports must include the same investigator term[s] initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study 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 electronic case report 
form (eCRF).
−
The paper SAE Report Form is intended only as a back-up option when the electronic 
data capture 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 
transmission.
♦When paper forms are used, the original paper forms are to remain on site.
•
Pregnancies must be recorded on paper Pregnancy Surveillance Forms and transmitted via 
email or confirmed facsimile transmission.
SAE Email Address: worldwide.safety@BMS.com
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
Appendix 4 provides general information and definitions related to Woman of Childbearing 
Potential and methods of contraception that can be applied to most clinical trials. For information 
specific to this study regarding acceptable contraception requirements for female and male 
participants, refer to Section 6.1 of the protocol. Only the contraception methods as described in 
Section 6.1 are acceptable for this study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 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.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. Suggested 
guidelines for the duration of the washout periods for HRT types are presented below. Investigators 
should use their judgement in checking serum FSH levels. 
•
1-week minimum for vaginal hormonal products (rings, creams, gels)
•
4-week minimum for transdermal products
•
8-week minimum for oral products
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Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the timepoint where the Investigational Medicinal Product 
(IMP) or any active major metabolites have decreased to a concentration that is no longer 
considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in 
context of safety margins from the no-observed-adverse-effect level or the time required for 5 half-
lives of the IMP to pass.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Note: Hormone-based contraceptives are not considered highly effective methods of 
contraception for WOCBP participants treated with BMS-986205.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of < 1% per year when used consistently and correctly.a
•
Not in BMS-986205 treated participants: Combined (estrogen- and progestogen-
containing) hormonal contraception associated with inhibition of ovulation and/or 
implantation. (This method of contraception can only be used by WOCBP participants in 
studies where hormonal contraception is permitted by the study protocol.)b
−
Oral (birth control pills)
−
Intravaginal (rings)
−
Transdermal
•
Not in BMS-986205 treated participants: Combined (estrogen-and progestogen-
containing) hormonal contraception must begin at least 30 days prior to initiation of study 
therapy.
•
Not in BMS-986205 treated participants: Progestogen-only hormonal contraception 
associated with inhibition of ovulation. (This method of contraception can only be used by 
WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol.)b
−
Oral
−
Injectable
•
Not in BMS-986205 treated participants: Progestogen-only hormonal contraception must 
begin at least 30 days prior to initiation of study therapy.
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Highly Effective Methods That Are User Independent
•
Not in BMS-986205 treated participants: Implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation and/or implantation. (This method of 
contraception can only be used by WOCBP participants in studies where hormonal 
contraception is permitted by the study protocol.)b
•
Intrauterine device.
•
Not in BMS-986205 treated participants: Intrauterine hormone-releasing system (IUS). 
(This method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol.)b,c
•
Bilateral tubal occlusion.
•
Vasectomized partner 
Having 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.
For BMS-986205 treated participants: Male participants will be required to always use a latex or other synthetic 
condom during any sexual activity (eg, vaginal, anal, oral) with WOCBP, even if the participants have undergone 
a successful vasectomy or if their partner is already pregnant or breastfeeding.
•
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 treatment. 
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.
•
Continuous abstinence must begin at least 30 days prior to initiation of study therapy.
•
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 participant chooses to forego complete abstinence.
•
Periodic abstinence (including, but not limited to, calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM) are not acceptable methods of contraception for this study.
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NOTES: 
a Typical use failure rates may differ from failure rates when contraceptive methods are used consistently and 
correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, 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. For information specific to this study regarding permissibility of 
hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 7.7.1 PROHIBITED AND/OR 
RESTRICTED TREATMENTS of the protocol.
c IUSs are acceptable methods of contraception in the absence of definitive drug interaction studies when hormone 
exposures from intrauterine devices do not alter contraception effectiveness. For information specific to this 
study regarding permissibility of hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 
7.7.1 PROHIBITED AND/OR RESTRICTED TREATMENTS of the protocol.
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of > 1% per year when used consistently and correctly.
•
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. (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited.)
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, postovulation methods).
•
Withdrawal (coitus interruptus).
•
Spermicide only.
•
LAM.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of pregnancy information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.6 and Appendix 3.
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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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Myocarditis Adverse Event Management Algorithm
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APPENDIX 6
ECOG PERFORMANCE STATUS
PERFORMANCE STATUS CRITERIA: ECOG Score 
ECOG (Zubrod) 
Score 
Description
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 alight or 
sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self care but unable to carry out any work activities; up and about more 
than 50% of waking hours.
3
Capable of only limited self care; confined to bed or chair more than 50% of waking hours.
4
Completely disabled; cannot carry on any self care; totally confined to bed or chair.
5
Dead
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APPENDIX 11
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 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
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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 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
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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.
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 
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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 5 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 
6 is to be used. 
Table 5:
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
Table 6:
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
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Table 6:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
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 7. 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 8 (± 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 
8 weeks (56 days) minus 7 days, for an absolute minimum time on-study of 49 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 7:
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
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
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Table 7:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
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.
REFERENCE FOR APPENDIX 11
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 14
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
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Summary of Key Changes for Protocol Amendment 05
Section Number & Title
Description of Change
Brief Rationale
Section 2 Schedule of 
Activities
Table 2-1: 
• Added language describing consent for current 
and new participants for Protocol Amendment 05.
•
These changes were made 
to:
• Provide expectations for 
participant consent for 
Protocol Amendment 05.
•
 
 
 
.
Table 2-2: 
• Updated Laboratory Tests Notes to: 
o
o
Include text regarding safety laboratory 
collections
To provide clarification; 
Table 2-2: 
•
 
 
 
 
 
Table 2-2: Added Clinical Observation row
Table 2-3: 
• Updated Laboratory Tests Notes to: 
o
 
To provide clarification; 
increase safety monitoring
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Summary of Key Changes for Protocol Amendment 05
Section Number & Title
Description of Change
Brief Rationale
collections
Table 2-3: 
 
 
 
 
 
Section 3.3 Benefit/Risk 
Assessment
 
 
These changes were made to 
align with updated clinical 
experience
Section 6.1 Inclusion 
Criteria
 
 
 
Provide expectations for 
participants consent for 
Protocol Amendment 05
Section 9.4.4 Clinical 
Safety Laboratory 
Assessments
 
 
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Overall Rationale for Protocol Amendment 04, 23-Jul-2021
The primary reasons for the changes are to align dose modification criteria and IO agent 
management algorithms (Appendix 5) with the current Common Terminology Criteria for 
Adverse Event (CTCAE) version 5 (v5); 
 
 vaccination and washout periods; and 
incorporate additional updates to improve alignment across protocol sections and/or clarify 
expectations for eligibility, assessments, tumor tissue collections, and treatment administration. 
Study personnel information updates have been included.
Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
Synopsis, Rationale
Updated to match language in the body of the 
protocol.
For consistency in the 
document.
Synopsis, Study 
Population
 
 
 
 
 
 
 
 
 
 
 
te tissue are 
not excluded.
Clarified that women of childbearing potential 
(WOCBP) must have a negative pregnancy test at 
screening and within 24 hours prior to administering 
study drug.
Pregnancy testing language 
updated for consistency in 
the document.
Synopsis, Objectives and 
Endpoints; Section 4: 
Objectives and Endpoints
 
 
 
 
 
 
 
 
 
 
Synopsis, Overall Design 
(Treatment Period)
 
 
 
 
 
 
 
 
 
 
 
 
Synopsis, Overall Design 
(Clinical Safety Follow-
up Period)
 
 
 
.
For clarity and consistency 
within the protocol.
Synopsis, Overall Design 
(Response Follow-up); 
 
 
Added for clarity and 
consistency with the 
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
Section 5.1: Overall 
Design
 
.
protocol summary and 
Section 2.
Synopsis, Overall Design 
(Treatment Groups and 
Duration [Table 2: 
Treatments 
Administered]); Table 
7.1-1: Treatments 
Administered
 
 
Update made for 
clarification.
Synopsis, Overall Design 
(Treatment Groups and 
Duration); Section 5.1.2: 
Treatment Period; Section 
7.1: Treatments 
Administered
Added the RP2D selected for Part 2.
Update made to clarify the 
RP2D which has been 
selected since the last 
protocol amendment.
Synopsis, Number of 
Participants; Section 5.2: 
Number of Participants
 
 
 
Synopsis, Safety Analyses
 
 
 
 
 
 
 
 
Synopsis, Study 
Assessments and 
Analyses (Efficacy 
Assessments)
 
 
 
 
 
Imaging language clarified 
to ensure adequate data 
collection for efficacy 
assessments.
Section 2, Schedule of 
Activities (Table 2-1: 
Screening Procedural 
Outline for All Study 
Parts [CA224048])
Removed the Day -1 Visit time point and added a 
footnote in the “Notes” column that some of the 
assessments referred to in this section may not be 
captured as data in the CRF.
Removed to avoid 
duplication with the “Notes” 
column.
For clarification and 
consistency across the 
document.
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
 
 
 
 
Removed to reduce 
subjectivity to the 
interpretation of the 
screening criteria.
 
For clarification and 
consistency across the 
document.
 
Added for clarification and 
consistency across the 
document, as cardiac 
troponin is a screening 
criterion for eligibility in 
Section 6.2.
Under “Genetic Mutation Status” added activating 
mutation statuses to be collected.
Added for clarification.
The “Notes” for “Serology” was updated to include 
human immunodeficiency virus (HIV) and 
 
 
 
 
 
 
 HIV status 
positivity is an exclusion 
criterion for study 
participation in Section 6.2.
Added that all AEs (SAEs or non-serious AEs) 
associated with 
 infection are collected 
from time of consent in the row “Monitor for Serious 
Adverse Events”
 
 
 
 
 
 
.
Section 2, Schedule of 
Activities (Table 2-2: On-
treatment Procedural 
Outline Part 1A 
[Relatlimab + Nivolumab 
+ BMS-986205] and Part 
1B [Relatlimab + 
Nivolumab + 
Ipilimumab])
 
 
Added to ensure that cardiac 
troponin is assessed prior to 
first dose administration and 
clarified the required time 
points for assessment.
 
 
 
Added 
 to the table.
 
 
 
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
 
 
 
 
 
 
Imaging language clarified 
to ensure adequate data 
collection for efficacy 
assessments.
 
 
 
 
Response assessment 
language clarified to ensure 
adequate data collection for 
efficacy assessments.
Added a row for IRT Drug Assignment and Study 
Drug Dispensation 
Added for clarity and 
consistency. 
In the notes for the row for 
 
 
 
Added for clarity and 
consistency.
Added the following language in the BMS-986205 
pill diary notes: Collect at completion of each cycle, 
“or earlier” and at EOT.
Added to enable IP 
reconciliation earlier if the 
participant does not 
complete a full cycle of 
therapy, if applicable. 
Footnotes “a” and “c” were updated to clarify the 
end of treatment (EOT) visit.
Added to clarify that the 
EOT visit takes place when 
the participant discontinues 
study therapy to ensure 
safety procedures and data 
collection in the eCRF are 
performed at this time point 
appropriately. 
Footnotes “d” and “e” were added.
Added to clarify trial 
procedure requirements for 
participant safety and 
efficacy assessment, some 
of which may not be 
collected in the eCRF.
Section 2, Schedule of 
Activities (Table 2-3: On-
treatment Procedural 
Outline: Part 2A 
[Relatlimab + Nivolumab 
+ BMS-986205] and Part 
2B [Relatlimab + 
Nivolumab + 
Ipilimumab])
 
Typographical error was 
corrected.
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
Footnotes “d” and “e” were added.
Added to clarify trial 
procedure requirements for 
participant safety and 
efficacy assessment, some 
of which may not be 
collected in the eCRF.
Time points for “Cardiac Troponin” testing were 
clarified.
Added to ensure that cardiac 
troponin is assessed prior to 
first dose administration and 
clarified the required time 
points for assessment.
 
 
 
Added 
 to the table.
 
 
 
 
 
 
The “Notes” for “Body Imaging” was updated.
Imaging language clarified 
to ensure adequate data 
collection for efficacy 
assessments.
In the “Notes” for “Brain Imaging”, a window of ± 7 
days was added.
Added for clarity and 
consistency.
 
 
 
 
To clarify tumor imaging 
and response assessment 
requirements for efficacy 
assessments.
 
 
 
Clarified that the IPs will be 
co-administered because no 
intra-patient dose de-
escalation is permissible in 
Part 2 and sequential 
administration is only 
permissible for de-escalated 
doses.
Footnotes “a”, “b”, and “c” were updated to clarify 
the EOT visit.
Added to clarify that the 
EOT visit takes place when 
the participant discontinues 
study therapy to ensure 
safety procedures and data 
collection in the eCRF are 
performed at this time point 
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
appropriately.
Section 2, Schedule of 
Activities (Table 2-4: 
Follow-Up Procedural 
Outline CA224048)
Clarified when the response follow-up begins for 
participants with complete response (CR), partial 
response (PR), or stable disease (SD) at EOT and the 
duration of this follow-up.
 
 
 
 
 
 
 
 
 
Clarified when the survival/Long-term follow-up 
begins for all participants and the duration of this 
follow-up.
 
 
 
 
 
 
Added rows for “Pregnancy Test” and to “Assess 
Adequate Contraceptive Use”
Added per requirements for 
pregnancy testing after 
study drug discontinuation 
for consistency and 
participant safety.
Added 
 to the table.
 
 
 
 
 
 
Under “Notes” for “Adverse Event Assessment” 
added language for AE/SAE collection including 
those associated with 
 
 
 
 
 
 
 
Section 3: Introduction; 
Section 7: Treatment
Added the generic name for BMS-986205.
Compound generic name 
introduced.
Section 3.1: Study 
Rationale
Clarified that Study CA017003 was a first in human 
dose-finding and cohort expansion study
Clarified type of study.
Section 3.2.5: Nivolumab 
Combined with 
Ipilimumab Clinical 
Activity
Added data from Phase 3 CheckMate 227 study.
Clinical data relevant to the 
expansion cohort (non-small 
cell lung cancer) in Part 2 
added.
Section 3.2.6: Relatlimab 
Combined with 
Added data from the Phase 2/3 CA224047 study.
Clinical data relevant to the 
expansion cohort 
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
Nivolumab Clinical 
Activity
(melanoma) in Part 2 added.
Section 3.2.8: Relatlimab 
Combined with 
Nivolumab Clinical 
Safety
New section added.
Clinical safety data updated.
Section 3.3: Benefit/Risk 
Assessment
Updated the section with the safety profile of 
nivolumab in combination with ipilimumab, 
relatlimab, or BMS-986205.
Benefit-risk assessment 
updated based on emergent 
clinical efficacy and safety 
data of the IO therapy 
combinations.
Section 5.1.1: Screening 
Period; Section 6.4.1: 
Retesting During 
Screening or Lead-In 
Period
Added language for participant eligibility if they 
develop suspected or confirmed 
 
 
 
 
 
Section 5.1.4: Clinical 
Safety Follow-up Period
Clarified EOT visit for participants who complete all 
scheduled cycles of therapy and participants who did 
not complete all scheduled cycles of therapy.
For clarity and consistency 
within the protocol.
Section 5.1.5: Response 
Follow-up 
 
 
Added for clarity and 
consistency with the 
protocol summary and 
Section 2.
Section 5.1.6: Survival 
Follow-up Period
 
 
 
Added for clarity and 
consistency with the 
protocol summary and 
Section 2.
Added abbreviations for Figure 5.1.6-1.
To correct an omission.
Section 6.1: Inclusion 
Criteria
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Existing language 
supplemented to ensure 
participant can comply with 
trial procedures and 
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
treatment.
Added that age is in “years” in criterion “3.a”
Minor editorial change.
Updated the contraceptive language for females and 
males in criteria “3.d” and “3.e”, respectively.
Duration of contraception 
for females, males, and their 
partners changed in 
accordance with the 
Investigator Brochure 
updates for relatlimab, 
nivolumab, ipilimumab and 
BMS-986205.
Section 6.2: Exclusion 
Criteria
Updated criterion “1.d” to say that all participants 
will be screened for methemoglobin levels prior to 
treatment assignment.
Updated as there is no 
randomization in this study.
Criterion “1.f” was updated to define eligibility in 
case of concurrent malignancy.
Updated exclusion criterion 
to permit participants with a 
history of concurrent 
malignancy or prior 
malignancy within 2 years. 
Previous language restricted 
participation of participants 
with a history of active 
malignancy within 3 years. 
Updated criterion “1.m” with eligibility in case of 
 
 
 
Added clarification to criterion “2.a.ii” that 
participants must have recovered from radiation-
related toxicities prior to first study treatment.
Language added for 
participant safety.
Updated criterion “2.a.iii” to add that herbal 
supplements or traditional Chinese medicines are 
permitted if they are used as supportive care.
Language added to clarify 
eligibility based on prior 
therapy with complementary 
medicines, including herbal 
supplements and traditional 
Chinese medicines.
Criterion “2.c.i” was updated to include treatment 
with any live/attenuated vaccine within 
s of 
first study treatment, during treatment, and up to 
 
 post last dose.
Language added to clarify 
eligibility and wash-out 
period for participants 
receiving prior treatment 
with live/attenuated 
vaccine(s). 
Criterion “2.g” was newly added to provide guidance 
related to coronavirus disease 2019 (COVID-19) 
eligibility.
Language added to clarify 
eligibility of participants 
enrolled on other 
interventional studies, 
including COVID-19 trials. 
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
Laboratory hemoglobin levels were updated to 
< 9.0 g/dL in criterion “3.d”. 
Language updated for 
patient safety (eligibility 
criterion is more 
conservative than the 
previous requirement).
Exclusion criteria based on out-of-range troponin 
was revised in criterion “3.i”.
Language updated to 
remove the requirement for 
Medical Monitor discussion 
for out-of-range troponin, 
for eligibility and replaced 
with Investigator judgement. 
The Medical Monitor has to 
be notified of this decision.
Updated criterion “3.j” to state that participants with 
positive HCV antibody and an undetectable HCV-
RNA are eligible to enroll.
Previous language clarified.
Section 7.1.1: Relatlimab 
Combined with 
Nivolumab 
Administration
Revised language for the administration of 
nivolumab combined with relatlimab.
Updated language to 
provide more clarity for the 
administration of relatlimab 
in combination with 
nivolumab to improve 
adherence to trial 
procedures and patient 
safety.
Section 7.1.2: BMS-
986205 Administration
Added that participants should begin study treatment 
within 3 calendar days of treatment assignment.
Updated language for clarity 
and consistency between 
Sections 2 and 7.1.2.
Section 7.1.3: Ipilimumab 
Administration
Revised language for the administration of 
ipilimumab in combination of relatlimab and 
nivolumab.
Updated language to 
provide more clarity for the 
administration of 
ipilimumab plus relatlimab 
in combination with 
nivolumab to improve 
adherence to trial 
procedures and participant 
safety.
Section 7.4.1: Relatlimab 
Dose Modification
Added that there will be no dose escalations or 
reductions of relatlimab allowed, and doses of 
relatlimab may be interrupted, delayed, or 
discontinued.
Updated language to clarify 
dosing of relatlimab.
Section 7.4.2: Nivolumab 
Dose Modification
Added that there will be no dose escalations or 
reductions of nivolumab allowed, and doses of 
nivolumab may be interrupted, delayed, or 
discontinued.
Updated language to clarify 
dosing of nivolumab.
Section 7.4.3: BMS-
986205 Dose 
Modification
Added “Grade 3 AEs (eg, hypoxia, dyspnea, 
confusion) associated to sustained elevations of 
methemoglobin”
Updated to provide further 
clarity to guide dose 
reduction of BMS-986205.
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
Section 7.4.4: Ipilimumab 
Dose Modification
Added that there will be no dose escalations or 
reductions of ipilimumab allowed, and doses of 
ipilimumab may be interrupted, delayed, or 
discontinued.
Updated language to clarify 
dosing of ipilimumab.
Section 7.4.5: Dose 
Modification Criteria for 
IO Therapies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correction of prior 
inconsistent language.
 
 
 
Section 7.4.8: 
Management of Drug-
related Infusion Reactions
Reporting requirements of Grade 3 and 4 infusion 
related reactions updated and other minor 
clarifications for consistency with CTCAE version 
5.0.
Removed requirement for 
reporting of Grade 3 and 4 
infusion-related reactions to 
the Medical Monitor, as 
these only have to be 
reported as an SAE.
Section 7.7.1: Prohibited 
Treatments
Added “treatment with any live/attenuated vaccine 
within 
 of first study treatment, during 
treatment, and up to 
 post last dose” to the 
list of prohibited treatments
Language added based on 
recommendations of 
prohibited treatments for IO 
therapies.
Section 7.7.1.1: Restricted 
Treatments for 
Participants Treated with 
BMS-986205
 
 
 
 
.
Section 8.1: 
Discontinuation from 
Study Treatment; Section 
8.1.1: Relatlimab, 
Nivolumab, BMS-
986205, and Ipilimumab 
Dose Discontinuation
Added a bullet point that participants receiving 
relatlimab, nivolumab, and ipilimumab combination, 
who meet criteria for discontinuation per Table 
7.4.5-1 must discontinue all study drugs and be taken 
off the treatment phase of the study.
Language updated for 
consistency with Section 
7.4.5.
Section 8.1.1: Relatlimab, 
Nivolumab, BMS-
986205, and Ipilimumab 
Dose Discontinuation
Section updated and language for discontinuation 
subsumed in Table 7.4.5-1.
Language updated for 
consistency with Table 
7.4.5-1.
Section 8.1.2: Criteria to 
Resume Treatment
Section updated and criteria to resume treatment 
subsumed into Table 7.4.5-1. Guidance provided on 
Language updated for 
consistency with Table 
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
the criteria to resume treatment after suspected or 
confirmed 
 
 
 
 
 
 
 
Section 8.1.3: Exceptions 
to Permanent 
Discontinuation
Section updated and exceptions for permanent 
discontinuation criteria were subsumed into Table 
7.4.5-1.
Language updated for 
consistency with Table 
7.4.5-1.
Section 9: Study 
Assessments and 
Procedures
Replaced “randomization” with “treatment 
assignment”
Language corrected as there 
is no randomization in this 
Phase 1/2 open-label trial.
 
 
 
 
 
 
Section 9.1.1: Imaging 
Efficacy Assessments
Updated the text to state that imaging should 
continue until disease progression or treatment 
discontinuation, whichever occurs later, participant 
withdrawal of consent, start of subsequent therapy, 
or death.
Imaging language clarified 
to ensure adequate data 
collection for efficacy 
assessments.
Section 9.2.1: Time 
Period and Frequency for 
Collecting AE and SAE 
Information
Clarified that with the exception of non-serious AEs 
related to 
, collection of 
nonserious AEs should begin at initiation of study 
treatment until the time points specified in the 
Schedule of Activities.
 
 
 
 
 
 
Added that all SAEs, and all AEs (SAEs and non-
serious AEs) associated with confirmed or suspected 
 must be collected from the 
date of the participant’s written consent until 
 
 following discontinuation of dosing.
 
 
 
 
 
 
 
Section 9.2.2: Method of 
Detecting AEs and SAEs
Added that every AE must be assessed by the 
investigator with regard to whether it is considered 
immune-mediated and additional information for 
those potentially immune-mediated, will be collected 
on the case report form.
Added to ensure the 
assessment, reporting, and 
data collection of potential 
immune-mediated AEs is 
performed.
Section 9.2.3: Follow-up 
of AEs and SAEs
Added that AEs associated with confirmed or 
suspected 
 will be followed 
until resolution, until the condition stabilizes, until 
 
 
 
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
the event is otherwise explained, the event is deemed 
irreversible, or until the participant is lost to follow-
up.
 
 
 
Table 9.4.4-1: Laboratory 
Assessments
Clarified that thyroid-stimulating hormone (TSH), 
free T3 and free T4 will be assessed at Screening and 
as applicable On Treatment.
Added for clarification.
 
 
 
 
Language for management 
 
 
 
Added pregnancy test having a minimum sensitivity 
of 25 IU/L or equivalent units of hCG in WOCBP 
and follicle stimulating hormone (FSH) at screening 
to confirm menopause in women < age 55. 
Language added for clarity 
of criteria of pregnancy 
tests.
Section 9.4.6: 
Echocardiogram 
(ECHO)/Multiple-gated 
Acquisition (MUGA) 
Testing
Added this new section.
Added as ECHO/MUGA is 
a screening procedure in the 
Schedule of Activities table.
 
 
 
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Summary of Key Changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
Section 10.1.2: Dose 
Expansion (Part 2)
Sample size determination for Part 2 was revised 
based on 
 
 
Section 10.3.3: Other 
Analyses
 
 will be described in the 
Statistical Analysis Plan.
 
 
 
.
Appendix 1: 
Abbreviations and 
Trademarks
Abbreviation list was updated.
For consistency within the 
protocol.
Appendix 2: Study 
Governance 
Considerations
Appendix was updated with standard language.
To align with current 
standards.
Appendix 3: Adverse 
Events and Serious 
Adverse Events: 
Definitions and 
Procedures for Recording, 
Evaluating, Follow-up 
and Reporting
Appendix was updated with standard language.
To align with current 
standards.
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods 
of Contraception
Appendix was updated with standard language.
To align with current 
standards.
Appendix 5: Management 
Algorithms for Studies 
Under CTCAE Version 
5.0
Algorithms were updated.
To align to most current 
version.
Appendix 11: Response 
Evaluation Criteria in 
Solid Tumors Guidelines 
(Version 1.1) with BMS 
Modifications
In Section 2.3.3 (Best Overall Response), the 
timelines for best overall response for stable disease 
was updated.
Clarified that the required 
minimum period for stable 
disease evaluable in this 
protocol is 56 days (minus 7 
days), based on an 8-week 
cycle.
All
Minor formatting and typographical corrections.
Minor, therefore have not 
been summarized.
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Overall Rationale for the Revised Protocol 03, 
 
 
 
 
 
Summary of Key Changes for Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Synopsis
 
 
 
 
 
 
 
 
 
 
 
 
Correction of text concerning survival 
follow-up to ensure uniformity throughout 
the protocol.
Table 2-1 Screening 
Procedural Outline
Section 6.2 Exclusion 
Criteria
Table 9.4.4-1 Laboratory 
Assessments
 
 
 
 
Section 6.1 Inclusion 
Criteria, 2) Type of 
Participant and Target 
Disease Characteristics, j) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correction of irregularities in language for 
targeted mutations.
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Summary of Key Changes for Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 3 Adverse 
Events and Serious 
Adverse Events: 
definitions and 
procedures for recording, 
evaluating, follow up and 
reporting
Previous version of Appendix 3 was 
replaced with most recent version.
Appendix was replaced to align with the 
latest BMS standards.
Appendix 5 Management 
Algorithms;
Section 7.4.7 
Management Algorithms 
for Immuno-oncology 
Agents
 
 
 
 
 
 
 
 
 
 
 
.
All
Minor corrections
Corrections for clarity and consistency 
within the document were minor, and 
therefore have not been summarized.
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Overall Rationale for the Revised Protocol 02, 
The primary reasons for these changes include: updating the starting dose of BMS-986205 to 
25 mg once daily (QD) in Part 1A of the dose-finding phase of the study; clarifying details, 
scenarios, and/or timing for some assessments and follow-up; updating contraceptive 
requirements for males; adding information on adverse events (AEs) of special interest; updating 
the 
; and updating guidance on 
concomitant therapies. Additional amendments, including to sections of the Synopsis, have been 
made to align the protocol with respect to these changes.
Summary of Key Changes for Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Replaced Study Director and Medical Monitor 
contact information with: 
Medical Monitor
Updated contact information.
Title Page; Section 1 
Synopsis
Short Title added.
Short Title added for clarity and 
alignment with Short Title provided 
on ClinicalTrials.gov.
Table 2-1 Screening 
Procedural Outline 
for All Study Parts 
(CA224048); Table 
2-3 On-treatment 
Procedural Outline 
Part 2A and Part 2B; 
Section 6.2 Exclusion 
Criteria; 
 
 
 
 
 
Table 9.4.4-1 
Laboratory 
Assessments
 
 
 
 
Table 2-1 Screening 
Procedural Outline 
for All Study Parts 
(CA224048); 
Table 9.4.4-1 
Laboratory 
Assessments; 
Section 6.2 Exclusion 
Criteria
 
 
 
 
 
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Summary of Key Changes for Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-2 
On-treatment 
Procedural Outline 
Part 1A and Part 1B; 
Table 2-3 
On-treatment 
Procedural Outline 
Part 2A and Part 2B; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2-2 
On-treatment 
Procedural Outline 
Part 1A and Part 1B; 
Table 2-3 
On-treatment 
Procedural Outline 
Part 2A and Part 2B
Removed qualifying text “able to reproduce” 
from notes in Assess Adequate Contraceptive 
Use row.
Clarified that contraceptive use for 
males applies to all male participants 
who are sexually active with 
WOCBP, for consistency with the 
related update made to Section 6.1.
Table 2-4 Follow-up 
Procedural Outline 
CA224048
 
 
 
 
 
 
 
 
 
Section 3.3 
Benefit/Risk 
Assessment
 
 
 
 
Updated information related to the 
safety profile of BMS-986205 to 
align with currently available safety 
and PK/PD data.
Section 5.1 Overall 
Design
Added sentence to second paragraph: 
“Part 2A and Part 2B may be initiated 
independently from each other based on the 
timing of data evaluation in Part 1.” 
Clarified timing of initiating Part 2A 
and Part 2B following evaluation of 
data in Part 1A and Part 2B, 
respectively.
Section 5.1 Overall 
Design; Figure 5.1-1 
Study Design 
Schematic; 
Section 5.1.2 
Treatment Period; 
Table 7.1-2 Part 1A; 
Section 10.1.1 Dose 
Finding (Part 1)
Modified the treatment/dose administration 
scheme and related text for Part 1A: Dose 
Finding.
Information related to the 
treatment/dose administration 
scheme for Part 1A of the study 
updated to reflect a change to the 
starting dose of BMS-986205 to 
25 mg QD.
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Summary of Key Changes for Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.1.2 
Treatment Period; 
Section 10.1.1 Dose 
Finding (Part 1)
Added text to related to the number of study 
participants to clarify that:
•
 
 
 
 
Clarified the planned number of 
participants in Part 1 of the study.
Section 5.1.2 
Treatment Period; 
 
 
 
 
Section 10.1 Sample 
Size Determination
Modified description of Part 1 of the study from 
“safety evaluation” to “dose finding.”
Updated description of Part 1 of the 
study to “dose finding” for 
consistency with the updated 
treatment/dose-administration 
scheme for Part 1A.
Section 5.5.3 
Justification for 
BMS-985205 Dose
Modified the text in this section to:
•
 
 
 
 
 
Updated nonclinical PK and safety 
information to support use of a 
starting BMS-986205 dose of 
25 mg QD.
Section 5.5.5 
Justification for 
Relatlimab, 
Nivolumab, and 
BMS-986205 
Combination Dose 
(Part 1A and Part 2A)
Modified text related to Part 1A to: 
• Update starting dose of BMS-986205 to 
25 mg QD.
•
 
 
Modified dose information for 
BMS-986205 to align with the 
updated starting dose of 25 mg QD.
Section 6.1 Inclusion 
Criteria
Updated criteria 3) e) and 3) f) related to male 
contraceptive requirements to require condom 
use for all males (even azoospermic males).
Male contraceptive requirements 
modified to require condom use for 
all males who are sexually active 
with WOCBP based on recent 
preclinical data.
Section 6.2 Exclusion 
Criteria
Modified text as follows: 
• Updated criterion 1) d) to include prior history 
of 
• Added new exclusion criterion 3) n) for 
 
Updated Exclusion Criteria related to 
 
 
 
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Summary of Key Changes for Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.2 Method 
of Treatment 
Assignment
Added text to provide method for achieving 
balance among treatment groups in Part 1 and 
Part 2 if 1 treatment group becomes overly 
enrolled due to screen failures.
Modified text to clarify method for 
balancing enrollment among 
treatment groups.
Section 7.3 Blinding
Added the following text: “BMS personnel may 
have access to treatment information during the 
course of the trial to help with internal 
decision-making and for disclosure of 
preliminary scientific results.”
Updated blinding information to 
clarify when treatment information 
may be available to BMS.
Section 7.4.3 
BMS-986205 Dose 
Modification
Added text to clarify that for BMS-986205:
•
 
 
 
Clarified dose modification 
information for BMS-986205 to align 
with the updated starting dose of 
25 mg QD.
Section 7.4.6 
Dose-limiting 
Toxicities; 
Section 7.4.8 
Management of
Drug-related Infusion 
Reactions; 
Table 10.3.2-1 
Overview of Safety 
Analysis Methods
Updated Common Terminology Criteria for 
Adverse Events (CTCAE) used for grading AEs 
from v4.0 to v5.0.
Updated method for grading AEs to 
be according to CTCAE v5.0.
Section 7.7.1 
Prohibited 
Treatments; 
 
 
 
Added information related to concomitant use of 
 
Updated information for concomitant 
therapies to include 
Section 7.7.2 Other 
Restrictions and 
Precautions
Added paragraph related to development and 
monitoring of 
Added information related to the 
development and monitoring of 
Section 8.1 
Discontinuation from 
Study Treatment
Modified text related to pregnancy cases to:
• Add that BMS/Medical Monitor must be 
notified within 24 hours of a pregnancy event.
• Remove text related to possible favorable 
benefit-risk ratio discussion.
• Add reference to Section 9.2.6 Pregnancy.
Modified in-the-case-of-pregnancy 
instructions to clarify expectations 
for reporting pregnancy.
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Summary of Key Changes for Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 8.1.1 
Relatlimab, 
Nivolumab, 
BMS-986205, and 
Ipilimumab Dose 
Discontinuation
Added bullet: “For BMS-986205 treated 
participants: any occurrence of 
 
Updated scenarios for discontinuing 
study treatment to include 
 
Section 9.2.6 
Pregnancy
Modified second paragraph related to treatment 
continuation and pregnancy to:
• Remove redundant text related to timing of 
notifying BMS Medical Monitor/designee of 
pregnancy.
• Add text for circumstances in which 
continuation of study treatment may be 
discussed.
Updated text related to treatment 
continuation and pregnancy to clarify 
the circumstances for continuation of 
study treatment in the case of 
pregnancy.
Section 9.3 Overdose
Updated parenthetical text in bullet 2) to 
“(at least 
).”
Updated text to clarify that 
participants should be monitored for 
AEs/serious adverse events for at 
least 
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Summary of Key Changes for Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.3 
Statistical Analyses
Added statement: “A description of the 
participant population will be included in the 
statistical output reported, including subgroup of 
age, gender, and race.”
Statement added to meet compliance 
requirements.
Section 10.3.1 
Efficacy Analyses
Added sentence: “Efficacy analyses may be 
performed on selected subgroups, 
 
”
Clarified that efficacy analysis may 
be performed on selected subgroups.
Appendix 2 Study 
Governance 
Considerations
Modified Good Clinical Practice section in 
Appendix 2 to:
• Add bullet to clarify that the study will also be 
conducted in accordance with ethical 
principles derived from international 
guidelines, including the Declaration of 
Helsinki and Council for International 
Organizations of Medical Sciences 
International Ethical Guidelines Good Clinical 
Practice.
• Align with revised definition of serious breach 
to Regulation No 536/2014 of the European 
Parliament and of the Council.
Modified text to align with statement 
in the informed consent form and 
TransCelerate Common Protocol 
Template.
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Summary of Key Changes for Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Appendix 3 Adverse 
Events and Serious 
Adverse Events 
Definitions and 
Procedures for 
Recording, 
Evaluating, and 
Follow-up and 
Reporting
Added the following new sections:
• Events Meeting the AE Definition.
• Events Not Meeting the AE Definition.
• Definition of Serious Adverse Event (SAE).
Modified the following sections:
• SAEs (text related to pregnancy and 
drug-induced liver injury).
• Evaluating AEs and SAEs (updated and 
rearranged bulleted information).
• Reporting of SAEs to Sponsor or Designee 
(updated and rearranged bulleted information 
related to pregnancy and paper report forms).
Modifications made to information 
related to AEs and SAEs to align 
with the TransCelerate Common 
Protocol Template, regulatory 
definition EMA GVP Module VI 
(EMA/873138/2011) and ICH E2A, 
and clarify the instructions for 
reporting pregnancy.
Appendix 4 Women 
of Childbearing 
Potential Definitions 
and Methods of 
Contraception
Modified Appendix 4 as follows:
• Added several methods to list of Unacceptable 
Methods of Contraception
• Added text to contraception guidance for male 
participates to clarify:
o Condom type.
o That condom use is required for any sexual 
activity with WOCBP.
Further clarified unacceptable 
methods of contraception and 
requirement of condom use for all 
males who are sexually active with 
WOCBP.
Appendix 13 
Statistical 
Methodology
Modified Section 2 of Appendix 13 as follows:
• Updated data tables and descriptive text for 
Section 2.1 Parameters for Dose Finding.
• Added Section 2.2 Dose-Escalation Process in 
Part 1A and Simulations.
Updated statistical methodology 
information related to dose-finding 
parameters and dose-escalation to 
align with most recent study data 
available and updated 
treatment/dose-administration 
scheme for Part 1A.
All
Minor formatting and typographical corrections.
Corrections for clarity and 
consistency within the document 
were minor, and therefore have not 
been summarized.
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Overall Rationale for the Revised Protocol 01, 
The protocol was revised to address questions and clarifications requested by the 
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 2 Schedule of 
Activities On-treatment 
Procedural Outline
Section 6.1 Inclusion 
Criteria 
Section 6.1 Inclusion 
Criteria
Inclusion criteria was 
updated to ensure that 
patients received 
appropriate prior therapy.
Section 6.1 Inclusion 
Criteria
Inclusion criteria was 
updated to ensure that 
patients received 
appropriate prior therapy.
Section 6.1 Inclusion 
Criteria 
Inclusion criteria was 
updated to ensure that 
patients received 
appropriate prior therapy.
Section 6.1 Inclusion 
Criteria
Inclusion criteria was 
updated to ensure that 
patients received 
appropriate prior therapy.
Section 6.2 Exclusion 
Criteria
Revised exclusion criteria 3 l) to include testing 
requirements for active or unknown HIV infection
To provide clarification that 
HIV positive participants 
are excluded
Section 6.2 Exclusion 
Criteria 
Added for participant safety
Section 7.2 Method of 
Treatment Assignment
Added language to clarify the way in which all 
participants in Part 1 will be assigned to either Cohort 
1A or 1B 
 
Further clarify how subjects 
will be allocated to cohorts 
that are open at the same 
time
Section 7.4.3 
BMS-986205 Dose 
Modifications
Added the following additional criteria for 
discontinuation: Grade 3 nausea, vomiting or diarrhea 
related to study treatment that lasts more than 48 hours
Added for participant safety
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Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.4.8 Dose 
Delay Due to Toxicity
Section 7.4.8 was deleted and combined into Section 
7.4.5; redundancies were removed
To reduce redundant 
information in two sections
All
Minor formatting and typographical corrections
Minor, therefore have not 
been summarized
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10.0
Approved
930122012
10.0
v
Approved
1.0
v