A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy With Nivolumab + Relatlimab Fixed-dose Combination Versus Nivolumab Monotherapy After Complete Resection of Stage III-IV Melanoma
Phase: PHASE3
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy with Nivolumab + Relatlimab 
Fixed-dose Combination versus Nivolumab Monotherapy after Complete Resection of Stage III-IV 
Melanoma 
 
NCT Number: NCT05002569 
Document Date (Date in which document was last revised): 27-Jul-2023 
 
 
 

Page:
1
Protocol Number:
CA224098
Date:
25-May-2021
Revised Date:
2 -Jul-2023
CLINICAL PROTOCOL CA224098
A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy with 
Nivolumab + Relatlimab Fixed-dose Combination versus Nivolumab Monotherapy after 
Complete Resection of Stage III-IV Melanoma
Brief Title:
Adjuvant Immunotherapy with Nivolumab + Relatlimab Fixed-dose Combination versus 
Nivolumab 
Monotherapy 
after 
Complete 
Resection 
of 
Stage 
III-IV 
Melanoma 
(RELATIVITY-098)
Protocol Amendment Number: 03
Incorporates Country-Specific Requirements for Countries in the European Union (EU)
Senior Clinical Trial Physician - Medical Monitor
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
Phone: 
email: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Company
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
REGULATORY AGENCY IDENTIFIER NUMBER(S)
IND: 136382
EUDRACT Number: 2021-001641-13
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CA224098
BMS-986213
nivolumab + relatlimab FDC
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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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 
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. References to BMS in this protocol may apply to partners to which BMS 
has transferred obligations (eg, a Contract Research Organization [CRO]).
© 2023 Bristol-Myers Squibb Company
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BMS-986213
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Protocol Amendment No.: 03
Date: 2 -Jul-2023
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol Amendment 
03
2 -Jul-2023
Main changes include:
•
Updated and provided a more detailed endpoint
description for 
•
Corrected typographical errors and included minor
editorial updates
in the Schedule of Activities,
and 
Statistical
Considerations sections.
Protocol Amendment 
02
22-Feb-2023
Main changes include:
•
Changed the trigger for 
 from 
.
•
Population for the distant metastasis-free survival
(DMFS) secondary objective was limited to randomized
participants with Stage III/IVA/IVB no evidence of
disease (NED) melanoma.
•
An additional clarification for neck magnetic resonance
imaging (MRI) was provided for head and neck mucosal
melanomas.
•
To consolidate previously published/implemented
country-specific amendments with the global
amendment in preparation for the European Union
Clinical Trials Regulation (EU CTR) transition, certain
country-specific paragraphs were delineated while
others were consolidated for easier reading without
changing context.
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Protocol Amendment No.: 03
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Document
Date of Issue
Summary of Change
Protocol Amendment 
01 
18-May-2022
Major changes include:
•
Addition of adolescent participants ( 12 years of age
through < 18 years of age).
•
Distant metastasis-free survival was moved from key
secondary endpoint to other secondary endpoint 
•
Participants with a history of myocarditis, regardless of
etiology, are excluded from participation in this study
•
Ultrasonography was updated as a study requirement for
surveillance of participants who have a sentinel lymph
node biopsy but do not undergo complete lymph node
dissection (CLND) and left as optional for those with
CLND.
Administrative Letter 
04
24-Dec-2021
Administrative Letter 
02
12-Aug-2021
The Clinical Trial Physician of the protocol was changed.
Administrative Letter 
01
28-May-2021
During finalization of the original protocol for CA224098, 
the IND and EUDRACT numbers were inadvertently left 
off both the cover page and the protocol signature page.
Additionally, it was noted that the acknowledgement page 
had a typo in the protocol number, which was incorrectly 
noted as CA2224098 with a superfluous “2.”
This administrative letter corrects the IND/EUDRACT 
omission and the signature page typo.
Original Protocol
25-May-2021
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03
The primary reason for this protocol amendment is to clarify and ensure consistencies in the 
objectives and endpoints and statistical considerations sections. Additional minor changes include 
corrections in the schedule of activities, 
 and formatting updates.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Protocol Summary
Text has been updated to align with 
changes 
made 
throughout 
the 
protocol.
Alignment 
between 
Protocol 
Summary and body of the protocol.
Table 2-2: On Study Treatment 
Procedural Outline (CA224098)
Table 2-3: Follow-up Assessments 
(CA224098)
•
To correct typographical errors.
•
To clarify the 
Survival Follow-up
visits.
Table 4-1: Objectives and 
Endpoints
• Rephrased “next-line therapies”
as “next-line systemic therapies”
in the secondary objective to
evaluate 
investigator-assessed
outcomes,
•
.
To clarify and align with the intent 
of analysis.
Section 10.2.1: Recurrence-free 
Survival
• To correct a typographical error of
the 
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 10.3: Analysis Sets
Clarified that the
for the analysis sets for 
 of recurrence-free 
survival (RFS), distant metastasis-
free survival (DMFS), and overall 
survival (OS) will be provided in 
Table 10.4.1-2.
To streamline the definitions for the 
analysis data sets.
Section 10.4.1: General 
Considerations
To be consistent with the definition 
of RFS in Section 4.
Table 10.4.1-2: Definition of 
Estimands for Primary and 
Secondary Endpoints
• Removed 
summary 
statistics
bullet as this will be further
detailed in the statistical analysis
plan.
To clarify and align with the intent 
of analysis and clarify that details 
are presented in the statistical 
analysis plan.
To ensure accuracy and consistency 
of terminology. 
Section 10.4.2: Primary 
Endpoints(s)
 To clarify and align with the intent 
of analysis.
Table 10.4.2-1: Primary Endpoints
Table 10.4.3-1: Secondary Efficacy 
Endpoints
To clarify and align with the intent 
of analysis.
Throughout
Editorial updates.
Minor; therefore, have not been 
summarized.
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TABLE OF CONTENTS
TITLE PAGE................................................................................................................
DOCUMENT HISTORY..............................................................................................
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03.............................
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03................
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 Nivolumab Combined with Relatlimab Preclinical Activity....................
3.2.2 Nivolumab Combined with Relatlimab Clinical Activity.........................
3.2.3 Nivolumab Clinical Activity.....................................................................
3.2.4 Relatlimab Mechanism of Action.............................................................
3.2.5 Nivolumab Mechanism of Action.............................................................
3.2.6 Nivolumab Combined with Relatlimab Clinical Safety ...........................
3.3 Benefit/Risk Assessment ..................................................................................
3.3.1 Risk Assessment .......................................................................................
3.3.2 Benefit Assessment...................................................................................
3.3.3 Overall Benefit/Risk Conclusion..............................................................
4 OBJECTIVES AND ENDPOINTS...........................................................................
5 STUDY DESIGN.......................................................................................................
5.1 Overall Design ..................................................................................................
5.1.1 Data Monitoring Committee and Other Committees...............................
5.2 Number of Participants .....................................................................................
5.3 End of Study Definition....................................................................................
5.4 Scientific Rationale for Study Design...............................................................
5.4.1 Participant Input Into Study Design ........................................................
5.4.2 Rationale for Use of Nivolumab + Relatlimab Fixed Dose Combination
.....................................................................................................................
5.4.3 Rationale for Choice of Comparator.......................................................
5.4.4 Rationale for Choice of Primary Endpoint..............................................
5.4.4.1 Rationale for Choice of Stratification Factors ...............................
5.4.5 Rationale for Blinding..............................................................................
5.4.6 Rationale for Evaluation of 
5.4.7 Rationale for Inclusion of Adolescent Participants.................................
5.4.8 Rationale for Ultrasound in Disease Surveillance ..................................
5.4.9 Rationale for MRI Surveillance of Head and Neck Mucosal Melanomas
.....................................................................................................................
5.5 Justification for Dose........................................................................................
5.5.1 Justification for Fixed Dose Combination Dosing ..................................
5.5.2 Dose Rationale for Adolescent Participants............................................
5.5.3 Justification for Nivolumab Monotherapy Dose......................................
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
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5.6 Clinical Pharmacology Summary .....................................................................
5.6.1 Nivolumab Clinical Pharmacology Summary .........................................
5.6.2 Relatlimab Clinical Pharmacology Summary .........................................
6 STUDY POPULATION............................................................................................
6.1 Inclusion Criteria ..............................................................................................
6.2 Exclusion Criteria .............................................................................................
6.3 Lifestyle Restrictions ........................................................................................
6.4 Screen Failures..................................................................................................
6.4.1 Retesting During Screening or Lead-in Period .......................................
7 STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .......................
7.1 Study Interventions Administered ....................................................................
7.1.1 Study Treatment Details...........................................................................
7.2 Method of Study Intervention Assignment.......................................................
7.3 Blinding.............................................................................................................
7.4 Dosage Modification.........................................................................................
7.4.1 Dose Delay Criteria.................................................................................
7.4.2 Criteria to Resume Treatment..................................................................
7.4.4 Treatment of Infusion-Related Reactions.................................................
7.5 Preparation/Handling/Storage/Accountability..................................................
7.5.1 Retained Samples for Bioavailability/Bioequivalence/Biocomparability
7.6 Treatment Compliance......................................................................................
7.7 Concomitant Therapy........................................................................................
7.7.1 Prohibited and/or Restricted Treatments.................................................
7.7.1.1 Prohibited Treatments ....................................................................
7.7.2 Other Restrictions and Precautions.........................................................
7.7.2.1 SARS-CoV-2 Vaccination Guidelines .............................................
7.7.2.2 Imaging Restriction and Precautions .............................................
7.8 Continued Access to Study Intervention After the End of the Study ...............
8 DISCONTINUATION CRITERIA ...........................................................................
8.1 Discontinuation From Study Treatment............................................................
8.1.1 Dose Discontinuation...............................................................................
8.1.2 Post-study Intervention Study Follow-up.................................................
8.2 Discontinuation From the Study.......................................................................
8.2.1 Individual Discontinuation Criteria ........................................................
8.3 Lost to Follow-up..............................................................................................
9 STUDY ASSESSMENTS AND PROCEDURES.....................................................
9.1 Efficacy Assessments........................................................................................
9.1.1 Efficacy Assessment for the Study............................................................
9.1.2 Imaging Assessment for the Study............................................................
9.1.3 Investigator Assessment of Baseline Disease Status................................
9.1.4 Investigator Assessment of Recurrence ...................................................
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
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9.1.5 Patient-Reported Outcomes.....................................................................
9.2 Adverse Events .................................................................................................
9.2.1 Time Period and Frequency for Collecting AE and SAE Information ....
9.2.2 Method of Detecting AEs and SAEs.........................................................
9.2.3 Follow-up of AEs and SAEs.....................................................................
9.2.4 Regulatory Reporting Requirements for SAEs.........................................
9.2.5 Pregnancy ................................................................................................
9.2.6 Laboratory Test Result Abnormalities.....................................................
9.2.7 Potential Drug-induced Liver Injury .......................................................
9.2.8 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..................................................
9.4.6 Imaging/Other Safety Assessment............................................................
9.8.2.1 Tumor Sample Collection ...............................................................
9.9 Additional Research..........................................................................................
9.10 Other Assessments..........................................................................................
10 STATISTICAL CONSIDERATIONS ....................................................................
10.1 Statistical Hypotheses.....................................................................................
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
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10.2 Sample Size Determination.............................................................................
10.2.1 Recurrence-free Survival .......................................................................
10.3 Analysis Sets...................................................................................................
10.4 Statistical Analyses.........................................................................................
10.4.1 General Considerations.........................................................................
10.4.2 Primary Endpoint(s) ..............................................................................
10.4.3 Secondary Endpoint(s)...........................................................................
10.4.3.1 Safety Analysis ..............................................................................
10.4.5 Other Safety Analysis.............................................................................
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 AND LANSKY/KARNOFSKY PERFORMANCE STATUS
SCALE....................................................................................................................
APPENDIX 7 AJCC MELANOMA STAGING (CANCER STAGING MANUAL 
8TH EDITION).......................................................................................................
APPENDIX 8 MUCOSAL MELANOMA STAGING................................................
APPENDIX 9 COUNTRY-SPECIFIC REQUIREMENTS .........................................
APPENDIX 10 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
.................................................................................................................................
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
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PROTOCOL SUMMARY
Protocol Title: A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy with 
Nivolumab + Relatlimab
Fixed-dose Combination versus Nivolumab Monotherapy after 
Complete Resection of Stage III-IV Melanoma
Brief Title:
Adjuvant Immunotherapy with Nivolumab + Relatlimab
Fixed-dose Combination versus 
Nivolumab
Monotherapy
after 
Complete 
Resection 
of 
Stage 
III-IV 
Melanoma
(RELATIVITY-098)
Rationale:
Surgical resection is currently considered standard of care for Stage III-IV resectable melanoma, 
followed by one year of adjuvant therapy. However, there remains an unmet need to improve 
recurrence-free survival (RFS) while maintaining a favorable safety profile for these patients. 
Targeting lymphocyte activation gene 3 (LAG-3), which is involved in the immune checkpoint 
pathway, is a novel approach that may further overcome immune evasion mechanisms.
Study CA224098 is a Phase 3, randomized, double-blind study of nivolumab and relatlimab
(nivo + rela) fixed-dose combination (FDC) compared with nivolumab monotherapy in 
completely resected Stage III-IV melanoma. This study will generate efficacy and safety data for 
the patient population with Stage IIIA (> 1 mm tumor in lymph node)/B/C/D or Stage IV (no 
evidence of disease [NED]) melanoma following complete resection of their lesion(s).
Objectives and Endpoints:
Objectives
Endpoints
Primary
•
To compare the efficacy, as measured by RFS,
provided by nivo + rela FDC vs nivolumab
monotherapy in participants with completely
resected Stage III/IV NED melanoma.
•
RFS time as assessed by the investigator. RFS is
defined as the time between the date of randomization
and the first date of documented recurrence 
 or death
due to any cause, whichever occurs first.
Key Secondary
•
To compare the OS provided by nivo + rela FDC
vs nivolumab monotherapy in participants with
completely 
resected 
Stage 
III/IV 
NED
melanoma.
•
OS is defined as the time between the date of
randomization and the date of death due to any cause.
Other Secondary
•
To assess the efficacy as measured by DMFS,
provided by nivo + rela FDC vs nivolumab
monotherapy in participants with completely
resected Stage III/IVA/IVB NED melanoma.
•
DMFS, by investigator, is defined as the time between
the date of randomization and the date of first distant
metastasis or date of death due to any cause,
whichever occurs first.
•
To assess safety and toxicity of nivo + rela FDC
and nivolumab monotherapy in participants with
completely 
resected 
Stage 
III/IV 
NED
melanoma.
•
Incidence and severity of AEs, SAEs, IMAEs, drug-
related AE/SAE, other select AEs, AEs leading to
discontinuation, deaths, laboratory abnormalities.
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Objectives
Endpoints
•
To evaluate investigator-assessed outcomes on
next-line systemic therapies.
•
PFS2 defined as time from randomization to second
recurrence/objective disease progression on next-line
systemic therapy per investigator, or death from any
cause, whichever occurs first.
Abbreviations: AE, adverse event; DMFS, distant metastasis-free survival; FDC, fixed dose combination; IMAE, 
immune mediated adverse event; NED, no evidence of disease; nivo, nivolumab; PFS2, progression-free survival 2; 
rela, relatlimab; RFS, recurrence free survival; OS, overall survival; SAE, serious adverse event. 
Overall Design:
This is a Phase 3, randomized, double-blind study of nivo + rela FDC compared with nivolumab 
monotherapy in participants ( 12 years of age) with completely resected Stage IIIA (> 1 mm 
tumor in lymph node)/B/C/D or Stage IV NED melanoma by the American Joint Committee on 
Cancer, version 8 (AJCC v8). Efficacy of nivo + rela FDC, as measured by RFS time (as assessed 
by the investigator), will be compared to nivolumab monotherapy. 
Participants will be randomized 1:1 to receive treatment with one of the following:
•
Nivo + rela FDC dosing:
−
 18 years of age OR  12 years to < 18 years of age and  40 kg: nivolumab 480 mg and
relatlimab 160 mg IV every 4 weeks (Q4W)
−
 12 years to < 18 years of age and < 40 kg: 
•
Nivolumab dosing:
−
 18 years of age OR  12 years to < 18 years of age and  40 kg: nivolumab 480 mg IV
Q4W
−
 12 years to < 18 years of age and < 40 kg: nivolumab 6 mg/kg IV Q4W
Participants will be stratified by AJCC v8 stage (Stage IIIA/IIIB vs IIIC vs IIID/IV [including all 
participants with mucosal melanoma, Stage III, Stage IVA, Stage IVB, and Stage IVC]), and
geographic region (USA/Canada/Australia vs Europe vs rest of the world [ROW]). All participants 
will be treated until: recurrence of disease 
 unacceptable toxicity, 
participant withdrawal of consent, or a maximum of 1 year of treatment from first dose (maximum 
of 13 doses), whichever occurs first.
This study will consist of 3 phases: screening, treatment, and follow-up.
The study design schematic is presented in Figure 1-1.
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Figure 1-1:
Study Design Schema
Abbreviations: AJCC v8, American Joint Committee on Cancer, version 8; ECOG, Eastern Cooperative Oncology Group; FDC, fixed dose combination;
IV, intravenous; LN, lymph node; NED, no evidence of disease; ROW, rest of the world; Q4W, every 4 weeks.
a Stratification:
•
AJCC v8: Stages IIIA/IIIB, Stage IIIC, Stages IIID/IV (including all participants with mucosal melanoma, Stage III, Stage IVA, Stage IVB, and Stage IVC)
•
Geographic Regions: USA/Canada/Australia, Europe, ROW
b Nivo + rela FDC dosing:
•
 18 years of age OR  12 years to < 18 years of age and  40 kg: nivolumab 480 mg and relatlimab 160 mg IV Q4W
•
 12 years to < 18 years of age and < 40 kg: 
c Nivolumab dosing:
•
 18 years of age OR  12 years to < 18 years of age and  40 kg: nivolumab 480 mg IV Q4W
•
 12 years to < 18 years of age and < 40 kg: nivolumab 6 mg/kg IV Q4W
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Clinical Protocol
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Number of Participants:
Approximately 1,050 participants are expected to be randomized (1:1) to the following treatment 
arms: 
•
Nivo + rela FDC (n = 525)
•
Nivolumab monotherapy (n = 525)
The randomization will be stratified by the following stratification factors:
•
Geographic region (USA/Canada/Australia vs Europe vs ROW)
•
AJCC v8 Stage IIIA/IIIB vs Stage IIIC vs Stage IIID/IV (including all participants with
mucosal melanoma, Stage III, Stage IVA, Stage IVB, and Stage IVC)
Study Population:
Male and female participants  12 years of age with completely resected Stage IIIA (> 1 mm tumor 
in lymph node)/B/C/D or Stage IV NED melanoma.
Key Inclusion Criteria:
•
All participants must have been diagnosed with either Stage IIIA (> 1 mm tumor in lymph
node)/B/C/D or Stage IV melanoma by AJCC v8 and have histologically confirmed melanoma
that is completely surgically resected (free of disease) with negative margins in order to be
eligible. All melanomas, except ocular melanoma, regardless of primary site of disease, will
be allowed.
Note: Conjunctival melanoma is not considered to be ocular melanoma and is to be classified
as mucosal melanoma.
•
Participants are eligible if central nervous system (CNS) metastases have been resected and
participants are neurologically stable.
−
Prior resected CNS metastases must be without evidence of recurrence, as determined by
magnetic resonance imaging (MRI) performed at least 4 weeks after resection is complete
and within 35 days prior to randomization.
−
Participants must be off immunosuppressive doses of systemic steroids (>10 mg/day
prednisone or equivalent) for at least 14 days prior to study drug administration and must
have returned to neurologic baseline post-operatively.
−
For CNS lesion(s), pathology report indicating that there has been complete resection of
CNS lesion(s) will suffice as confirmation of negative margins.
•
Complete resection must be performed 
prior to randomization. Management of
residual lymph nodes after positive sentinel lymph node biopsy (SLNB) (ie, completion lymph
node dissection) will be as per local standards and recommendations for the individual
participant.
•
All participants must have disease-free status documented by a complete physical examination
within 14 days prior to randomization and imaging studies within 35 days prior to
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randomization. Imaging studies must include computed tomography (CT) scan of the chest, 
abdomen, pelvis, and all known sites of resected disease, and brain MRI.
•
•
Participants  18 years of age must have an Eastern Cooperative Oncology Group (ECOG)
performance status  1. Adolescent participants between 12 and < 18 years of age must have
a Lansky/Karnofsky performance score  80%.
Key Exclusion Criteria:
•
History of ocular melanoma
Note: Conjunctival melanoma is not considered to be ocular melanoma and is to be classified
as mucosal melanoma
•
Untreated/unresected CNS metastases or leptomeningeal metastases
•
Participants with an active, known, or suspected autoimmune disease. Participants with type I
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such
as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected
to recur in the absence of an external trigger are permitted to enroll.
•
Participants with serious or uncontrolled medical disorder
•
Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection either
suspected or confirmed within 4 weeks prior to screening. Acute symptoms must have resolved
and based on investigator assessment, there are no sequelae that would place the participant at
a higher risk of receiving investigational treatment.
•
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg
daily prednisone equivalent) 
 or other immunosuppressive medications within
30 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune
disease.
•
Participants with a history of myocarditis, regardless of etiology.
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•
•
Treatment with any live/attenuated vaccine within 30 days of first study treatment (inactivated
vaccines are permitted).
•
Pregnant or breastfeeding females.
•
•
Intervention Groups and Duration:
As described in overall design.
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BMS-986213
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Study Intervention:
Study Drug for CA224098
Medication 
Potency 
Investigational Product 
(IP)/Non-IP 
Nivo + rela FDC
(Nivolumab 240 mg/ 
Relatlimab 80 mg)/vial 
16 mg/mL
IP
Nivolumab 100 mg/vial 
10 mg/mL
IP
Abbreviations: FDC, fixed dose combination; IP, investigational product; nivo, nivolumab; rela, relatlimab.
Statistical Methods
•
This is a double-blind, parallel group study in which participants will be randomized 1:1 to
either of the 2 treatment groups: nivo + rela FDC or nivolumab monotherapy. The
randomization will be stratified by AJCC v8 stage at screening and geographic region.
•
The primary objective of the study is to assess the superiority of nivo + rela FDC over
nivolumab monotherapy in improving RFS in participants with completely resected Stage IIIA
(> 1 mm tumor in lymph node), Stage IIIB/C/D, or Stage IV NED melanoma over a treatment
duration of 1 year. RFS distributions will be compared between the 2 treatment groups
(nivo + rela FDC vs nivolumab monotherapy) 
Data Monitoring Committee: Yes
A Data Monitoring Committee will be used in the study.
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Other Committee: Yes
A Study Steering Committee will be used in the study.
Brief Summary:
The purpose of this study is to assess the efficacy, measured as RFS, of nivo + rela FDC compared 
with nivolumab monotherapy, in the setting of adjuvant treatment of Stage III-IV melanoma after 
complete resection. Study details are as follows.
Study drug will be given for a maximum of 1 year from first dose (maximum of 13 doses), 
 
While study drug is being administered, study visits will be every 4 weeks (for a maximum of 
1 year). Once study intervention is completed or discontinued early, the first follow-up visit will 
be 30 days from the date of the last dose. The second follow-up visit is 135 days following last 
dose of study intervention. Long-term follow up visits will be every 12 weeks subsequently (in 
clinic or by telephone) 
The 
trial will end once this follow-up has concluded. 
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CA224098
BMS-986213
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA224098)
Procedure
Screening
Notes: a
All windows are based on calendar days.
Eligibility Assessments
Informed Consent
X
Must be obtained prior to performing any screening procedures. See Section 6.1. 
For adolescent participants ( 12 years to < 18 years), please refer to Informed Consent 
Process in Appendix 2. Where local regulations do not allow for participants < 18 years 
of age (adolescent population) to participate, the eligible participant population is 
 18 years of age (refer to Appendix 9).
Study allows for re-enrollment of a participant that has discontinued the study as a 
pre-treatment failure. If re-enrolled, the participant must be re-consented and assigned a 
new participant number from IRT. 
Enroll in IRT
X
Register in IRT system to obtain participant number.
Inclusion/Exclusion Criteria
X
Assessed at screening and must be confirmed prior to randomization.
Medical History
X
All medical history relevant to the disease under study.
Tumor Sample Submission
X
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Table 2-1:
Screening Procedural Outline (CA224098)
Procedure
Screening
Notes: a
All windows are based on calendar days.
Review of Pathology Report 
X
Diagnosis must be stated in a pathology report confirming negative margins that has 
been finalized prior to randomization. A deidentified copy of the report must be provided 
to the central lab.
Body Imaging 
X
Contrast-enhanced CT of the chest, abdomen, pelvis, and all suspected sites of disease, 
within 35 days prior to randomization. See Section 9.1.2 for further details and 
exceptions. Please refer to Appendix 9 for Germany-specific imaging language.
Brain Imaging
X
MRI of the brain (with and without contrast) is required for ALL participants during 
screening to rule out brain metastases, within 35 days prior to randomization. CT of the 
brain (with and without contrast) can be performed if MRI is contraindicated. See 
Section 9.1.2 for further details.
Ultrasound of Region(s) relevant to the 
Participant’s Tumor Resection
X
Ultrasound of region(s) relevant to the participant’s tumor resection must be performed 
for surveillance of participants who have a positive SNLB who do not undergo 
immediate CLND. Ultrasound is optional for participants who have undergone CLND
relevant to the tumor resection.
All suspicious lesion(s) should undergo proper evaluation. If disease is detected, all 
lesions must be removed and NED must be confirmed within 35 days prior to 
randomization.
Ultrasounds should not be submitted to the imaging vendor.
Safety Assessments
Complete Physical Examination, 
Measurements, Vital signs 
X
Complete physical exam including height, weight, blood pressure, heart rate, and 
temperature. Must be collected within 14 days prior to randomization.
Performance Status
X
Within 14 days prior to randomization. ECOG Performance Status ( 18 years old) OR 
Lansky/Karnofsky Performance Score for adolescents (12 to < 18 years old) (Appendix 
6).
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization.
Concomitant Medications 
X
Within 14 days prior to randomization.
Confirm no live vaccine use within 30 days prior to first study treatment.
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Table 2-1:
Screening Procedural Outline (CA224098)
Procedure
Screening
Notes: a
All windows are based on calendar days.
SAE Assessment
X
SAEs collected from time of consent.
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection collected 
from time of consent.
12-Lead ECG
X
12-lead ECGs should be recorded after the participant has been supine for at least 5
minutes. Must be performed within 14 days prior to randomization. ECG abnormalities
should be reviewed and addressed, if needed, prior to randomization.
Laboratory Tests
Clinical Laboratory Assessments
X
Laboratory tests must be performed within 14 days prior to randomization.
Viral testing to be completed within 35 days prior to randomization. For HIV: testing at 
sites where locally mandated (see Appendix 9).
Refer to Section 9.4.4 for list of laboratory tests to conduct.
Pregnancy Test (WOCBP)
X
Serum or urine pregnancy test (minimum sensitivity equivalent units 25 IU/L or 
equivalent units of HCG) to be done within 35 days prior to randomization.
FSH
X
Females under the age of 55 years must have a serum FSH level > 40 mIU/mL to 
confirm menopause. If not confirmed, protocol pregnancy testing requirements must be 
followed.
 Assessments
Abbreviations: AE, adverse event; 
CLND, complete lymph node dissection;
eCRF, electronic case 
report form; CT, computed tomography; ECG(s), electrocardiogram(s); ECOG, Eastern Cooperative Oncology Group; 
FSH, follicle-stimulating hormone; HCG, human chorionic gonadotropin; HIV, human immunodeficiency virus; IRT, interactive response technology; MRI, 
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magnetic resonance imaging; NED, no evidence of disease;
 SAE(s), serious adverse event(s); SARS-CoV-2, 
severe acute respiratory syndrome coronavirus 2; SNLB, sentinel lymph node biopsy;
 ULN, upper limit of normal; WOCBP, 
women of child-bearing potential.
a Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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CA224098
BMS-986213
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Table 2-2:
On Study Treatment Procedural Outline (CA224098)
Procedure
C1D1a
(Cycle 
Duration = 4 
weeks)
C2D1 and D1 
of Each 
Subsequent 
Cycle (± 3 days)
Notes:b
Study Treatment
Randomize
X
IRT Drug Assignment
X
Participant must receive the first dose of study medication within 3 days from 
randomization.
Dispense Study Treatment
X
X
First drug to be administered within 3 calendar days following randomization, subsequent 
doses can be administered within 3 days before or after scheduled date if necessary (every 
28 days ± 3 days). Treatment will continue until recurrence, unacceptable toxicity, 
withdrawal of consent, or after a maximum duration of 1 year from first-dose (maximum of 
13 doses), whichever occurs first.
See treatment details in Section 7.1.1.
Safety Assessment
Targeted Physical 
Examination, 
Measurements, and Vital 
Signsc
X*
X
Weight, blood pressure, heart rate, and temperature within 3 days prior to dosing.
*Targeted physical exam not required on C1D1 if a full physical exam was completed
within 3 days of first dose.
Performance Statusc
X
X
ECOG Performance Status ( 18 years old) OR Lansky/Karnofsky Performance Score for 
adolescents (12 to < 18 years old). See Appendix 6.
AE and SAE Assessment
Continuously
Record at each visit. All AEs (SAEs or non-serious AEs), including those associated with 
SARS-CoV-2 infection, must be collected continuously during the treatment period.
Concomitant Medications 
Continuously
Record at each visit.
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Table 2-2:
On Study Treatment Procedural Outline (CA224098)
Procedure
C1D1a
(Cycle 
Duration = 4 
weeks)
C2D1 and D1 
of Each 
Subsequent 
Cycle (± 3 days)
Notes:b
Laboratory Tests
Pregnancy Test (WOCBP)
X*
X^
Serum or urine (minimum sensitivity equivalent units 25 IU/L or equivalent units of 
HCG); a negative pregnancy test should be documented within 1 day prior to 
administration of first dose of study treatment.
*Pregnancy test not required to be repeated on C1D1 if completed within 24 hours of first
dose (during screening).
^For subsequent cycles, a negative pregnancy test should be documented within 3 days 
prior to dosing.
Clinical Laboratory 
Assessmentsc
X
X
Laboratory testing should be performed within 3 days prior to each dose.
For the first treatment visit, labs need not be repeated if they were performed within 3 days 
and the results are available and have been reviewed for eligibility.
Refer to Section 9.4.4 for the list of laboratory tests to be conducted.
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Table 2-2:
On Study Treatment Procedural Outline (CA224098)
Procedure
C1D1a
(Cycle 
Duration = 4 
weeks)
C2D1 and D1 
of Each 
Subsequent 
Cycle (± 3 days)
Notes:b
Efficacy Surveillance 
Body Imaging 
See Notes
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other suspected sites of 
disease should occur every 12 weeks (± 7 days) from randomization for the first 2 years
and every 26 weeks (± 14 days) beyond the Week 108 imaging time point thereafter until 
investigator assessed
In case of suspected lesions in the extremities, contrast-enhanced MRI can be substituted 
for contrast-enhanced CT.
For head and neck mucosal melanomas, contrast-enhanced MRI of the head and neck is 
required at every time point for nodal surveillance.
Please refer to Appendix 9 for Germany-specific imaging language.
Brain Imaging 
See Notes
Participants with a history of brain metastasis or symptoms should have a surveillance 
MRI (without and with contrast) approximately every 12 weeks ± 7 days from 
randomization for the first 2 years and every 26 weeks (± 14 days) beyond the Week 108 
imaging time point thereafter until investigator assessed
or sooner if clinically 
indicated. Participants without history of brain metastases should have MRI if clinically 
indicated. See Section 9.1.2 for further details.
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CA224098
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Table 2-2:
On Study Treatment Procedural Outline (CA224098)
Procedure
C1D1a
(Cycle 
Duration = 4 
weeks)
C2D1 and D1 
of Each 
Subsequent 
Cycle (± 3 days)
Notes:b
Ultrasound of Region(s) 
relevant to the 
Participant’s Tumor 
Resection
See Notes
For participants without CLND, active surveillance using ultrasound of region(s) relevant 
to the participant’s tumor resection must occur every 12 weeks (± 7 days) from 
randomization for the first 2 years and every 26 weeks (± 14 days) beyond the Week 108 
imaging time point thereafter until disease recurrence.
Ultrasound is not required for head and neck mucosal participants.
Ultrasound is optional for participants who have undergone CLND relevant to the tumor 
resection.
Ultrasounds should not be submitted to the imaging vendor.
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Table 2-2:
On Study Treatment Procedural Outline (CA224098)
Procedure
C1D1a
(Cycle 
Duration = 4 
weeks)
C2D1 and D1 
of Each 
Subsequent 
Cycle (± 3 days)
Notes:b
Abbreviations: AE, adverse event; C, cycle; CLND, complete lymph node dissection; 
 D, day; eCOA, electronic clinical outcome assessments; ECOG, Eastern Cooperative Oncology Group;  
 HCG, human chorionic gonadotropin; IMAE, immune-mediated adverse event; IRT, interactive response technology; 
MRI, magnetic resonance imaging; 
 SAE, serious adverse event; 
 WOCBP, women of child-bearing potential.
a 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.
b Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
c Screening assessments performed within 3 days of first dose are not required to be repeated at C1D1.
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Table 2-3:
Follow-up Assessments (CA224098)
Procedure
Follow-Up
Visits 1 & 2a
Long-term Follow-upb
Notes:c
Safety Assessment
Targeted Physical 
Examination, Vital Signs, 
and Performance Status
X
Include weight, blood pressure, heart rate, temperature, performance 
status.
AE and SAE Assessment 
X* (see notes)
X* (see notes)
Record at each visit. All SAEs and non-serious AEs should be collected 
continuously during the treatment period and for a minimum of 135 
days following discontinuation of study treatment.
*Beyond 135 days from the last dose of study therapy, participants will
be followed for drug-related AEs/SAEs until resolution, return to
baseline, or event(s) is deemed irreversible, or until the participant is
lost to follow-up, or withdraws study consent.
For all confirmed or suspected SARS-CoV-2 infections, participants 
will be followed for all SAEs, non-serious AEs of special interest (as 
defined in Section 9.2.3), and all AEs (SAEs and non-serious AEs) until 
resolution, the condition stabilizes, the event is otherwise explained, the 
event is deemed irreversible, the participant is lost to follow-up (as 
defined in Section 8.3), or for suspected cases, until SARS-CoV-2 
infection is ruled-out.
Please refer to Section 9.2, and Appendix 3 for further details regarding 
the collection and follow-up of AEs.
Concomitant Medications 
X (see notes)
X (see notes)
All medications with a start date within 135 days of the last dose date of 
study drug are considered concomitant.
Laboratory Tests
Pregnancy Test 
(WOCBP) 
X
Serum or urine (minimum sensitivity equivalent units 25 IU/L or 
equivalent units of HCG).
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Table 2-3:
Follow-up Assessments (CA224098)
Procedure
Follow-Up
Visits 1 & 2a
Long-term Follow-upb
Notes:c
Clinical Laboratory 
Assessments
X (see notes)
To be performed at Follow-up Visit 1, repeat at Follow-up Visit 2 if 
study treatment-related toxicity persists. 
Refer to Section 9.4.4, Clinical Safety Laboratory Assessments for the 
list of laboratory tests.
Laboratory toxicities (eg, suspected drug induced liver enzyme 
elevations) will be monitored during the follow-up phase, based on 
results from on-site/local labs, until all study drug related toxicities 
resolve, return to baseline, or are deemed irreversible.
Efficacy Surveillance
Survival Statusb
X
X (See Notes)
During Long-term Follow-up, participant survival status is assessed 
every 12 weeks (± 14 days) by either a clinic visit or telephone contact, 
and must include documentation of subsequent therapy.
Participants will be followed until death, loss to follow-up, withdrawal 
of consent, conclusion of the study,
Body Imaging
See Notes
Contrast-enhanced CT of the chest, abdomen, pelvis, and suspected sites 
of disease should occur every 12 weeks (± 7 days) for the first 2 years 
from randomization and every 26 weeks (± 14 days) beyond the 
Week 108 imaging time point until investigator assessed 
In cases of suspected lesions of the extremities, contrast-enhanced MRI 
may be substituted for contrast-enhanced CT.
For head and neck mucosal melanomas, contrast-enhanced MRI of head 
and neck is required at every time point for nodal surveillance.
Please refer to Appendix 9 for Germany-specific imaging language.
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CA224098
BMS-986213
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Table 2-3:
Follow-up Assessments (CA224098)
Procedure
Follow-Up
Visits 1 & 2a
Long-term Follow-upb
Notes:c
Brain Imaging 
See Notes
Participants with a history of brain metastasis or symptoms should have
surveillance MRIs (without and with contrast) per standard of care 
(approximately every 12 weeks ± 7 days from randomization for the 
first 2 years and every 26 weeks (± 14 days) beyond the Week 108 
imaging time point thereafter until disease recurrence) 
 
 or sooner if clinically indicated. See Section 9.1.2 for 
further details.
Ultrasound of Region(s) 
Relevant to the 
Participant’s Tumor 
Resection
See Notes
For participants without CLND, active surveillance using ultrasound of 
region(s) relevant to the participant’s tumor resection must occur every 
12 weeks (± 7 days) from randomization for the first 2 years and every 
26 weeks (± 14 days) beyond the Week 108 imaging time point 
thereafter until disease recurrence.
Ultrasound is not required for head and neck mucosal participants.
Ultrasound is optional for participants who have undergone CLND
relevant to the tumor resection.
Ultrasounds should not be submitted to the imaging vendor.
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CA224098
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Table 2-3:
Follow-up Assessments (CA224098)
Procedure
Follow-Up
Visits 1 & 2a
Long-term Follow-upb
Notes:c
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CA224098
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Table 2-3:
Follow-up Assessments (CA224098)
Procedure
Follow-Up
Visits 1 & 2a
Long-term Follow-upb
Notes:c
Abbreviations: AE(s), adverse event(s); BMS, Bristol-Myers Squibb; CLND, complete lymph node dissection; CT, computed tomography; 
U, follow-up; HCG, human chorionic gonadotropin; MRI, magnetic resonance imaging; 
SAE, serious adverse event; 
WOCBP, women of child-bearing potential.
a Participants must be followed for at least 135 days after last dose of study treatment. Follow-Up Visit 1 should occur 30 days from the last dose (± 7 days) or
can be performed on the date of discontinuation if that date is greater than 30 days after last dose. Follow-up Visit 2 occurs approximately 135 days (± 7 days) 
from last dose of study medication if date of discontinuation is < 135 days after last dose. If date of discontinuation is  135 days after the last dose and the 
timing of Follow-up 2 overlaps with Follow-up 1, then only one follow-up visit (Follow-up 1) needs to be completed. Follow-up visits must be conducted in 
person.
b Long-Term Follow-up visits to occur 
 (± 14 days) from the last Follow-up visit completed. If Follow-up visit is not completed, then Survival
visit should be based off the off-treatment date. Visit may be conducted in clinic or by telephone. BMS may request that survival data be collected on all treated 
participants outside of 
. At the time of this request, each participant will be contacted to determine their survival status unless the 
participant has withdrawn consent for all contact.
c Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulation.
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CA224098
BMS-986213
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3
INTRODUCTION
Study CA224098 is a Phase 3, randomized, double-blind study of nivolumab + relatlimab 
(nivo + rela) fixed dose combination (FDC) compared with nivolumab monotherapy in completely 
resected Stage III-IV melanoma. This study will generate efficacy and safety data for the patient 
population with Stage IIIA (> 1 mm tumor in lymph node)/B/C/D or Stage IV (no evidence of 
disease [NED]) melanoma following complete resection of their lesion(s). The study will allow 
for direct comparison of the clinical benefits, as measured by the primary endpoint of recurrence
free survival (RFS), provided by nivo + rela FDC compared with nivolumab monotherapy 
administered over a treatment duration of 12 months.
Melanoma may modulate and evade the host immune response through a number of mechanisms, 
including down regulation of tumor-specific antigen expression and presentation, secretion of anti-
inflammatory cytokines, and upregulation of inhibitory ligands. Immune checkpoint blockade has 
recently demonstrated clinical efficacy in several cancer types, including melanoma, 
hepatocellular carcinoma (HCC), gastric cancer, non-small cell lung cancer (NSCLC), and 
hematologic malignancies.1,2,3
Nivolumab is a fully human, immunoglobulin G4 (IgG4 [kappa]) isotype monoclonal antibody 
that binds the programmed death-ligand 1 (PD-1) receptor on activated immune cells and disrupts 
engagement of the receptor with its ligands PD-L1 (B7-H1/CD274) and programmed death-ligand 
2 (PD-L2) (B7-DC/CD273), thereby abrogating inhibitory signals and augmenting the host anti-
tumor response. In early clinical trials, nivolumab has demonstrated activity in several tumor types, 
including melanoma, renal cell cancer (RCC), and NSCLC.4 Furthermore, adjuvant nivolumab 
after complete resection of Stage III-IV melanoma has become a standard of care.
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 receptors expressed on T-cells with high affinity and prevents 
binding of this receptor to cells bearing its ligands, such as major histocompatibility complex 
(MHC) Class II5 which is the peptide antigen presentation molecule recognized by cluster of 
differentiation 4 (CD4)+ T cells and fibrinogen-like protein 1 (FGL-1)6, which is upregulated in a 
variety of human solid tumors. Relatlimab binding inhibits the negative regulatory function of 
LAG-3 mediated through its interaction with ligands in vitro; and elevated plasma levels of FGL-1 
are correlated with poor prognosis.6 FGL-1 was shown to be capable of delivering an inhibitory 
signal into T cells upon binding to the LAG-3 receptor and has been implicated as having a 
suppressive effect on anti-tumor immunity that is dependent on LAG-3.7 Preclinical evidence 
suggests that the FGL-1-LAG-3 pathway may be a previously unknown immune evasion 
mechanism limiting responses to current cancer immunotherapies, including PD-1 pathway 
blockade.6 By blocking the inhibitory LAG-3 signaling pathway, relatlimab enhances the anti-
tumor 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. Dual 
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CA224098
BMS-986213
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checkpoint inhibition with nivolumab and relatlimab results in enhanced T-cell effector function 
that is greater than the effects of either antibody alone in murine syngeneic tumor models.8
3.1
Study Rationale
Surgical resection followed by 1 year of adjuvant therapy is currently considered standard of care 
for Stage III-IV resectable melanoma. However, there remains an unmet need to improve RFS 
while maintaining favorable safety profile for these patients. The clinical benefit observed with 
nivo + rela FDC in patients with untreated metastatic or unresectable melanoma in the CA224047 
Phase 2/3 study supports the rationale of evaluating nivo + rela FDC in patients with resectable 
melanoma. 
Targeting LAG-3, which is involved in the immune checkpoint pathway, is a novel approach that 
may further overcome immune evasion mechanisms. LAG-3 (CD223) is a checkpoint receptor and 
expressed on several immune cell types including activated CD4+ and CD8+ T cells, memory T 
cells, regulatory lymphocytes, and natural killer cells.5 Activation of the LAG-3 pathway occurs 
when LAG-3 interacts with its ligands, such as MHC Class II or other emerging ligands (eg, 
FGL-1), which triggers inhibitory activity that reduces the function of effector T cells.5,6
LAG-3 is often expressed on chronically exhausted T-cells and is frequently co-expressed with 
PD-1 on tolerized tumor infiltrating lymphocytes (TILs) across many tumor types.9,10,11 Increased 
expression of LAG-3 on TILs, especially in the context of PD-1 expression, further promotes T 
cell exhaustion, leading to an impaired ability to attack tumor cells and an increased potential for 
tumor growth.5,12 Preclinical studies indicate that inhibition of the LAG-3 pathway may restore 
effector function of T cells, promoting proinflammatory cytokine signaling, and ultimately, an 
anti-tumor response. The combination of LAG-3 and PD-1 inhibition demonstrated enhanced anti-
tumor activity by targeting independent pathways with distinct functions.5
Relatlimab is a blocking antibody specific to the LAG-3 receptor. Relatlimab is being investigated 
in different indications and lines of therapies in combination with nivolumab. In the CA224020 
Phase 1/2a study, the combination of nivolumab and relatlimab demonstrated tolerability, and 
preliminary clinical activity in advanced melanoma participants that had been previously treated 
with anti-PD-1/PD-L1 therapy.8,13,14 In the CA224047 Phase 2/3 study, nivo + rela FDC 
demonstrated clinical benefit measured by progression-free survival (PFS) in patients with 
previously untreated metastatic or unresectable melanoma. PFS at 24 months was 38.5% for the 
nivo + rela FDC group versus 29% for the nivolumab monotherapy group.15
3.1.1
Research Hypothesis
Treatment with systemically administered nivo + rela FDC when compared with nivolumab will 
result in improved RFS in participants with completely resected Stage III-IV melanoma.
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3.2
Background
Melanoma accounts for less than 5% of all skin cancers; however, it causes the greatest number of 
skin cancer–related deaths worldwide.16 In 2020, it is estimated that there will be 100,350 new 
cases of melanoma and 6,850 deaths due to melanoma.17
Early melanoma detection followed by surgical excision is usually curative. In contrast, advanced 
melanoma frequently metastasizes to the lung, brain, or liver, and usually has poor prognosis. 
The 5-year melanoma-specific survival (MSS) rate according to Stage III subgroups ranges from 
93% in patients with Stage IIIA disease (1-3 clinically occult, tumor-involved sentinel lymph 
nodes [N1a or N2a] and T1a, T1b, or T2a primaries) to 32% for those with Stage IIID disease 
(patients with a thick and ulcerated primary [T4b] and either  4 tumor-involved regional nodes 
[N3a or N3b] or  2 tumor-involved nodes and evidence of microsatellite, satellite, or in-transit 
metastases [N3c]). Stage IIIB and Stage IIIC had 5-year MSS rates of 83% and 69%, respectively. 
For patients with > 1 mm of tumor burden in the lymph node, the 5-year MSS is 72% as compared 
to those with tumor burden in the lymph node of  1 mm with 5-year MSS of 91%.18,19
Cancer immunotherapies and B-RAF proto-oncogene (BRAF)/mitogen-activated protein kinase 
(MEK) inhibitors have played a role in the Stage III/IV adjuvant setting; however opportunities 
exist to continue enhancing clinical outcomes.
A potential mechanism of resistance to anti-PD-1 therapies is the presence of alternative 
checkpoint receptors that may be upregulated and further impede the function of effector T cells 
within the tumor microenvironment. Thus, targeting such additional checkpoint pathways may 
provide a therapeutic means to delay recurrence in melanoma patients who may rely on such 
checkpoint pathways to suppress the anti-tumor immune response. LAG-3 is one such checkpoint 
and is a potential cancer immunotherapeutic target due to its negative regulatory role on T cells.
The disease course for melanoma has fundamentally changed with the introduction of 
immunotherapies targeting the cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and PD-1 
checkpoints as well as BRAF and MEK inhibitors. Such agents have dramatically improved 
outcome for patients with metastatic melanoma; however, their role in the adjuvant setting 
continues to be evaluated. Studies have demonstrated that these agents enhance survival in the 
adjuvant setting albeit with waning durability in the long term. Therefore, novel immunotherapy 
combinations could address this long-term unmet need.
RFS rates at 1 year for adjuvant checkpoint inhibitor use range from 60.8% with ipilimumab (IPI) 
to 70.5% with nivolumab and 75.4% with pembrolizumab, yet there is a decline to 45% to 58% at 
3 years, irrespective of which checkpoint inhibitor was used.20,21,22 Similarly, adjuvant therapy 
with BRAF and MEK inhibitor combinations yield 3- and 4-year RFS rates of 58% and 54%, 
respectively compared to RFS rates of 88% at 1 year and 67% at 2 years with combination 
Dabrafenib/Trametinib treatment.23,24
Additional data from key studies are provided in Table 3.2-1.
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Table 3.2-1:
Data Comparison of Adjuvant Trials
Patient 
Population
CM238 
Completely 
resected Stage 
IIIB/C or IV 
melanoma20
COMBI-AD
Completely 
resected, BRAF 
v600 E/K-positive 
Stage IIIA/B/C 
Melanoma24
KN054 
Completely resected 
Stage IIIA/B/C 
Melanoma22
CM915 
Completely resected 
Stage IIIB/C/D or IV 
Melanoma25
Treatment
Nivo
Ipi
Dab/ 
Tram
Placebo
Pembro
Placebo
Nivo/Ipi
Nivo
N
453
453
438
432
514
505
920
924
RFS HR
0.65 (97.56% CI 
0.51-0.83), 
P < 0.0001
0.47 (95% CI 0.39-
0.58), P < 0.001
0.57 (98.4% CI 0.43-
0.74), P < 0.001
0.92 (97.295% CI, 0.77–
1.09); P = 0.269
1-year RFS
rate (%)
71
61
88
56
75
61
N/A
N/A
18-months
RFS rate
(%)
66
53
N/A
N/A
71.4
53.2
N/A
N/A
2-years RFS
rate (%)
N/A
N/A
N/A
N/A
N/A
N/A
64.6%
63.2%
3-years OS
rate (%)
N/A
N/A
86
77
N/A
N/A
N/A
N/A
Grade 3-5 
TRAEs (%)
14
46
31
5
15
3
33
13
DC rate due 
to AEs (%)
10
43
26
3
14
2
34
12
Abbreviations: AE, adverse event; BRAF, B-RAF proto-oncogene; CI, confidence interval; Dab, dabrafenib; DC, 
discontinuation; HR, hazard ratio; Ipi, ipilimumab; IV, intravenous; N/A, not applicable; Nivo, nivolumab; OS, overall 
survival; Pembro, pembrolizumab; RFS, recurrence-free survival; TRAE, treatment-related adverse events; Tram, 
trametinib.
The safety profiles of therapies in the adjuvant setting remains an important consideration. For 
instance, in the COMBI-AD trial, 26% of patients had adverse events (AEs) leading to treatment 
discontinuation, 38% had AEs leading to a dose reduction, and 66% had AEs leading to a dose 
interruption.24 It is important to closely monitor for Grade 3 and 4 toxicities, such as colitis, rash, 
pneumonitis, endocrinopathies, and hepatitis with immune checkpoint inhibitors. Additional safety 
information is provided in Table 3.2-1.
Targeting LAG-3 should present a valuable mechanism to improve RFS.
3.2.1
Nivolumab Combined with Relatlimab Preclinical Activity
LAG-3 has been shown to be expressed in TILs of several tumor types, including melanoma, HCC, 
breast, ovarian, and lung cancers, often in connection with increased PD-1+ T cells.26 Preclinical 
data presented in recent years illustrate a clear synergy between the inhibitory receptors LAG-3 
and PD-1 in controlling immune homeostasis, preventing autoimmunity, and enforcing 
tumor-induced tolerance.7,8 Importantly, combined treatment of mice with blocking antibodies 
against both receptors resulted in more robust immune responses than either single-treated group
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in these studies, and analyses of Lag-3/Pdcd1/ double knockout mice revealed a cooperative 
requirement for LAG-3 and PD-1 in maintaining immune homeostasis.
3.2.2
Nivolumab Combined with Relatlimab Clinical Activity
Clinical efficacy of relatlimab as monotherapy and in combination with nivolumab has been 
studied in CA224020 and CA224022 at different doses and schedules. As monotherapy, relatlimab 
demonstrated activity in hematologic malignancies in the Phase 1/2a study CA224022. Objective 
responses were observed in participants with relapsed or refractory marginal zone lymphoma, 
Hodgkin lymphoma, and mantle cell lymphoma.8
The Phase 1/2a study CA224020 is investigating the safety, tolerability, and effectiveness of 
relatlimab, with and without nivolumab, to treat various solid tumors. 
Additionally, in Parts D1, D2, 
 objective responses were achieved in participants with 
IO-refractory melanoma treated with nivolumab + relatlimab. Part D1 included heavily pretreated 
participants with advanced melanoma (with a high proportion of participants treated with 2 or 
more prior lines of therapy including anti-CTLA-4 and/or anti-PD-1) and with a number of 
additional poor prognostic factors such as primary resistance to prior anti-PD-1 Stage IV disease 
with liver metastasis and high lactate dehydrogenase who experienced disease progression. Part 
D1 provided supportive evidence of the anti-tumor activity of nivolumab + relatlimab at doses 
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equivalent to nivolumab 480 mg and relatlimab 160 mg every 4 weeks (Q4W), with long-term 
clinical benefit as demonstrated by blinded independent central review (BICR)-confirmed overall 
response rate (ORR) of 11.8% (22/186 response evaluable) and a meaningful number of complete 
responses (8) and durability of these responses. 
CA224047, a global, double-blind, randomized, Phase 2/3 study comparing a fixed-dose 
combination (FDC) of nivolumab 480 mg + relatlimab 160 mg  Q4W 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 BICR with nivo + rela FDC (3:1) 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 nivo + rela 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 
nivo + rela FDC (3:1) and nivo monotherapy, respectively. The PFS benefit of nivo + rela FDC 
(3:1) was consistent across key prespecified subgroups.30,31 The secondary endpoint of overall 
survival (OS) showed clinically meaningful improvement with nivolumab + relatlimab FDC over 
nivolumab monotherapy (median OS non estimable (34.20, not reached [NR]) versus 34.1 months 
(25.23, NR); HR = 0.80 [0.64-1.01]); p = 0.0593) in all randomized participants but was not 
statistically significant.30,31
Due to the statistical non significance of the secondary endpoint of OS, ORR was not formally 
tested per the statistical testing hierarchy; however, clinically meaningful numerical differences 
were observed with the nivolumab + relatlimab FDC arm over nivolumab monotherapy (43.1% vs 
32.6%).32
3.2.3
Nivolumab Clinical Activity
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including NSCLC, melanoma, RCC, classical Hodgkin’s lymphoma (cHL), SCLC, 
gastric cancer, SCCHN, urothelial cancer, HCC, and colorectal cancer (CRC). In confirmatory 
trials, nivolumab as monotherapy demonstrated a statistically significant improvement in OS as 
compared with the current standard of care in patients with advanced or metastatic NSCLC, 
unresectable or metastatic melanoma, advanced RCC, or recurrent or metastatic SCCHN. Details 
of the clinical activity in these various malignancies are provided in the USPI and SmPC.
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3.2.4
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.8 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 
3.2.5
Nivolumab Mechanism of Action
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal 
antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the PD-1 CD279 cell surface 
membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B 
lymphocytes. Binding of PD-1 to its ligands, PD-L1 and PD-L2, results in the down-regulation of 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as self-
antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration.
Nivolumab (OPDIVOTM) is approved for the treatment of several types of cancer in multiple 
regions including the United States (US, Dec-2014), the European Union (EU, Jun-2015), and 
Japan (Jul-2014).
3.2.6
Nivolumab Combined with Relatlimab Clinical Safety
The Phase 1/2a study CA224020 enrolled the highest number of participants treated with the 
combination therapy of nivolumab + relatlimab in dose-escalation (Part B) and expansion cohorts 
in Parts C, D, 
 tested in every 2 week (Q2W) and Q4W dosing intervals. 
 Part C included expansion cohorts with multiple tumor 
types and Parts D 
 included advanced melanoma participants (1L and progressed on prior-
PD-1 therapy). 
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Troponin is a highly sensitive non-specific indicator of myocardial injury. Troponin is not typically 
monitored during treatment with immune checkpoint inhibitors due to uncertain value in 
preventing immune-related cardiac morbidity.
While myocarditis is a recognized risk with 
immune checkpoint inhibitors, routine troponin monitoring during treatment has not been 
recommended by clinical guidelines due to lack of demonstrated value in preventing morbidity or 
mortality. 
The safety profile of the combination of nivolumab 480 mg + relatlimab 160 mg FDC Q4W was 
confirmed in the pivotal Phase 2/3 global, multicenter study CA224047 (n = 355), in previously 
untreated advanced melanoma participants (clinical data cutoff 09-Mar-2021). 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 nivolumab + 
relatlimab FDC group versus 9.7% in the nivolumab monotherapy group. There were 3 treatment-
related deaths with nivolumab + relatlimab FDC and 2 with nivolumab monotherapy. Drug-related 
AEs (any grade) led to treatment discontinuation in 14.6% and 6.7% of patients in the nivolumab 
+ relatlimab FDC and nivolumab monotherapy groups, respectively.31 Refer to relatlimab +
nivolumab FDC IB Section 5.5.2 for an updated safety analysis based on the clinical data cutoff
date of 30-Jun-2021.30
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3.3
Benefit/Risk Assessment
As described in Section 3.2.2, clinical activity was seen with the combination of nivolumab + 
relatlimab in multiple tumor types, including treatment naive and previously heavily treated tumors
including previous anti-PD-1 therapy, in the CA224020 study.8 The clinical efficacy of the 
combination was further confirmed in study CA224047, a global, double-blind Phase 2/3 
randomized controlled trial that demonstrated a statistically significant and clinically meaningful 
PFS benefit of nivolumab + relatlimab FDC Q4W compared to nivolumab 480 mg Q4W,31 as well 
as clinically meaningful improvement in OS and ORR, although the OS result was not statistically 
significant and ORR could not be formally tested.32
The combination of nivolumab and relatlimab has shown well-defined toxicity profiles based on a 
safety database comprised of participants treated with either relatlimab monotherapy or as a 
combination across multiple tumor types. 
 The most frequent drug-related AEs included 
fatigue, decreased appetite, pruritus, diarrhea, rash, rash maculo-papular, anemia, arthralgia, 
increased lipase, nausea, dry mouth, asthenia, hypothyroidism, hyperthyroidism, cough, pyrexia, 
increased alanine aminotransferase, and increased aspartate aminotransferase.8 Immune-mediated 
AEs (IMAEs) seen with nivolumab in combination with relatlimab appear consistent with those 
seen with other immunotherapy agents, and can potentially include pneumonitis, colitis, hepatitis, 
nephritis, endocrinopathy, neurologic, and skin AEs. In combination with nivolumab, the 
frequency, severity, and reversibility of IMAEs appear consistent with the mechanisms of action 
of either drug. The majority of all drug-related AEs and IMAEs were reversible or manageable by 
withholding study intervention administration, providing standard medical care, and/or following 
IMAE management algorithms (see Appendix 5). Most immune-mediated study intervention-
related endocrinopathies will require life-long management by hormone replacement therapies. 
The overall safety profile of nivolumab + relatlimab across these studies remains unchanged and 
manageable with established management guidelines (including myocarditis cases). 
 
Furthermore, nivolumab 480 mg + relatlimab 160 mg FDC (3:1) administered Q4W was 
confirmed to be well tolerated with a manageable safety profile in 355 1L advanced melanoma 
participants treated in the CA224047 study. There were no unexpected safety signals from this 
combination.31
Safety results to date indicate that sequential, co-administration, and the FDC of nivolumab + 
relatlimab administration have similar manageable safety profiles that are consistent with the 
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mechanisms of action of each agent, nivolumab and relatlimab. No new types of clinically 
important events have been identified.8,30
Given the safety profile of relatlimab as monotherapy and combination therapy observed to-date,8
and the positive benefit-risk of the pivotal Phase 2/3 study of nivo + rela FDC (3:1) demonstrated 
in participants with previously untreated metastatic or unresectable advanced melanoma,31 and the 
significant unmet medical need in adjuvant treatment for Stage III-IV resectable melanoma
population, the continuing evaluation of nivo + rela FDC is justified for the patient population in 
this protocol.
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/designee and 
Worldwide Patient Safety (WS) representatives to monitor for any safety signals or trends. As 
relatlimab is an experimental agent, it is possible that unforeseen, unknown, or unanticipated 
reactions may occur; however, data shows that nivo + rela is safe and tolerable at 480 mg 
nivolumab + 160 mg relatlimab Q4W using FDC product in other studies.
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3.3.1
Risk Assessment
Table 3.3.1-1:
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Interventions
Immune-mediated AEs (eg, colitis 
diarrhea/colitis, pneumonitis, 
hepatitis, nephritis, endocrinopathy, 
rash, neurologic, AEs)
FDC (BMS-986213) IB
Recommended IMAE management 
algorithms are included in
Appendix 5 or as per institutional 
protocol/investigator discretion
Potential Infusion Related Reaction
FDC (BMS-986213) IB
Recommended management 
algorithms are included in 
Appendix 5 or as per institutional 
protocol/ investigator discretion
Dermatologic AEs
Nivolumab IB
Recommended management 
algorithms are included Appendix 5
or as per institutional protocol/ 
investigator discretion
Cardiovascular AEs (ie, 
myocarditis, troponin elevation)
FDC (BMS-986213) IB
Management of Myocarditis per AE 
Management Algorithm in 
Appendix 5 or as per institutional 
protocol/ investigator discretion.
Hemorrhage AE (eg, epistaxis, 
gingival bleeding, GI blood loss)
Relatlimab IB
Monitor clinical signs/symptoms/ 
CBC and coagulation parameters. 
Management as per institutional 
protocol/investigator
Opportunistic Infections due to 
Immunosuppression
FDC (BMS-986213) IB
Monitor signs/symptoms, may
require additional laboratory tests. 
Management as per institutional 
protocol/investigator
Potential developmental toxicity
FDC (BMS-986213) IB
Exclusion criteria, pregnancy 
testing, contraception per protocol, 
as per Section 6.1, 4) and Appendix
4.
Study Procedures
Tumor Biopsy (eg, pain, infection)
Not applicable
Per institutional protocol/ 
investigator discretion.
Phlebotomy (eg, pain, ecchymosis, 
bleeding, syncope)
Not applicable
Per institutional protocol/ 
investigator discretion.
MRI
Not applicable
Management per institutional 
protocol/investigator discretion.
CT
Not applicable
Management per institutional 
protocol/investigator discretion.
Ultrasound
Not applicable
Management per institutional 
protocol/investigator discretion.
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Table 3.3.1-1:
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Other (if applicable)
Allergy to contrast agent (eg, 
reaction to anaphylaxis)
Not applicable
Prophylaxis and/or treatment per 
institutional protocol/ investigator 
discretion
Abbreviations: AE, adverse event; CBC, complete blood count; CT, computed tomography; FDC, fixed dose 
combination; GI, gastrointestinal; IB, investigator brochure; IMAE, immune-mediated adverse events; MRI, magnetic 
resonance imaging.
3.3.2
Benefit Assessment
This study investigates if the adjuvant use of systemic therapy of nivo + rela FDC will improve 
recurrence free survival (RFS) for Stage III-IV completely resected melanoma participants with 
no evidence of disease. Currently, nivolumab monotherapy is an approved treatment for adjuvant 
melanoma patients in many countries. While nivo + rela FDC provided PFS benefit for the 
treatment of untreated metastatic or unresectable melanoma, it is not yet approved for any 
indication.
Despite the availability of effective adjuvant therapies, there is an unmet need to provide safe and 
effective adjuvant systemic therapy that offers additional clinical benefit in RFS in this patient 
population. It is unknown if nivo + rela FDC will improve RFS compared to nivolumab 
monotherapy. Although benefits are hypothesized, actual clinical benefits to patients with Stage 
III or Stage IV resectable melanoma have not been established yet. Participation in this study may 
help offer new therapies for advanced resectable melanoma patients and establish the clinical 
benefits of the combination therapy. 
Participants enrolled in this study will be randomized to either the nivo + rela FDC or nivolumab 
monotherapy. Participants will have an equal chance of being randomized to the nivo + rela FDC 
therapy or the standard of care nivolumab monotherapy.
3.3.3
Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with nivo + rela FDC are justified by the anticipated benefits that 
may be afforded to participants with resectable melanoma.
The Sponsor will evaluate the risk/benefit profile of the study on an ongoing basis. This evaluation 
will be based on all available data – with particular attention to: (i) AEs or other safety trends in 
this or any other clinical study of nivo + rela FDC whose character, severity, and/or frequency 
suggest that participants would be exposed to an unreasonable and significant risk of illness or 
injury; (ii) new nonclinical data suggesting unreasonable and significant risk of illness or injury.
If such evaluation suggests that the risk/benefit profile of the study has become unfavorable to 
participants, the Sponsor will pause enrollment and/or treatment until further evaluation of data, 
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and interaction with the appropriate Health Authority(ies) can take place on potential actions. Such 
actions may include (but are not limited to) study continuation, substantial amendment, or 
termination of the study.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To compare the efficacy, as measured by RFS,
provided by nivo + rela FDC vs nivolumab
monotherapy in participants with completely
resected Stage III/IV NED melanoma.
•
RFS time as assessed by the investigator. RFS is
defined as the time between the date of randomization
and the first date of documented recurrence 
 or death
due to any cause, whichever occurs first.
Key Secondary
•
To compare the OS provided by nivo + rela FDC
vs nivolumab monotherapy in participants with
completely 
resected 
Stage 
III/IV 
NED
melanoma.
•
OS is defined as the time between the date of
randomization and the date of death due to any cause.
Other Secondary 
•
To assess the efficacy, as measured by DMFS,
provided by nivo + rela FDC vs nivolumab
monotherapy in participants with completely
resected Stage III/IVA/IVB NED melanoma.
•
DMFS, by investigator, is defined as the time between
the date of randomization and the date of first distant
metastasis or date of death due to any cause,
whichever occurs first.
•
To assess safety and toxicity of nivo + rela FDC
vs nivolumab monotherapy in participants with
completely 
resected 
Stage 
III/IV 
NED
melanoma.
•
Incidence and severity of AE, SAEs, AEs leading to
DC, IMAEs, drug-related AEs, deaths, laboratory
abnormalities, and other select AEs.
•
To evaluate investigator-assessed outcomes on
next-line systemic therapies.
•
PFS2 defined as time from randomization to second
recurrence/objective disease progression on next-line
systemic therapy per investigator, or death from any 
cause, whichever occurs first.
Exploratory 
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Abbreviations: AE(s), adverse event(s); 
 DC, discontinuation; DMFS, distant metastasis-free survival; 
 FDC, fixed dose combination; 
 NED, no evidence of 
disease; nivo, nivolumab;
 PFS2, 
progression-free survival 2; 
 RFS, recurrence-free survival; OS, overall survival; rela, relatlimab; 
SAE, serious adverse event;
a
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5
STUDY DESIGN
5.1
Overall Design
This is a Phase 3, randomized, double-blind study of nivo + rela FDC compared with nivolumab 
monotherapy in participants ( 12 years of age) with completely resected Stage IIIA (> 1 mm 
tumor in lymph node)/B/C/D or Stage IV NED melanoma by American Joint Committee on 
Cancer version 8 (AJCC v8). Efficacy of nivo + rela FDC, as measured by RFS time (as assessed 
by the investigator), will be compared to nivolumab monotherapy.
Participants will be randomized 1:1 to receive treatment with one of the following:
•
Nivo + rela FDC dosing:
−
 18 years of age OR  12 years to < 18 years of age and  40 kg: nivolumab 480 mg and
relatlimab 160 mg IV every 4 weeks (Q4W)
−
 12 years to < 18 years of age and < 40 kg: 
•
Nivolumab dosing:
−
 18 years of age OR  12 years to < 18 years of age and  40 kg: nivolumab 480 mg IV
Q4W
−
 12 years to < 18 years of age and < 40 kg: nivolumab 6 mg/kg IV Q4W
Participants will be stratified by AJCC v8 stage (Appendix 7) and geographic region. All 
participants will be treated until: recurrence of disease 
, unacceptable toxicity, participant withdrawal of consent, or a maximum of 1 year 
of treatment from first dose (maximum of 13 doses), whichever occurs first.
This study will consist of 3 phases: screening, treatment, and follow-up. For a complete list of 
study required procedures, please refer to Section 2. 
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schema
Abbreviations: AJCC v8, American Joint Committee on Cancer version 8; ECOG, Eastern Cooperative Oncology Group; FDC, fixed dose combination; 
IV, intravenous; LN, lymph node; NED, no evidence of disease; ROW, rest of the world; Q4W, every 4 weeks
a Stratification:
•
AJCC v8: Stages IIIA/IIIB, Stage IIIC, Stages IIID/IV (including all participants with mucosal melanoma, Stage III, Stage IVA, Stage IVB, and Stage IVC)
•
Geographic Regions: USA/Canada/Australia, Europe, ROW
b Nivo + rela FDC dosing:
•
 18 years of age OR  12 years to < 18 years of age and  40 kg: nivolumab 480 mg and relatlimab 160 mg IV Q4W.
•
 12 years to < 18 years of age and < 40 kg: 
c Nivolumab dosing:
•
 18 years of age OR  12 years to < 18 years of age and  40 kg: nivolumab 480 mg IV Q4W.
•
 12 years to < 18 years of age and < 40 kg: nivolumab 6 mg/kg IV Q4W.
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5.1.1
Data Monitoring Committee and Other Committees
When required, adjudicated events will be submitted to the Data Monitoring Committee (DMC) 
and Health Authorities for review on a specified timeframe in accordance with the adjudication 
documentation.
A DMC will be established to provide oversight of safety and efficacy considerations and to 
provide advice to the Sponsor regarding actions the committee deems necessary for the continued 
protection of participants enrolled in the study. The DMC will be charged with assessing such 
actions in light of an acceptable benefit/risk profile for nivo + rela FDC. The DMC will act in an 
advisory capacity to BMS and will monitor participant safety and evaluate the available efficacy 
data for the study. The oncology therapeutic area of BMS has primary responsibility for design 
and conduct of the study.
Details of the DMC responsibilities and procedures will be outlined in the DMC charter.
A Study Steering Committee (SSC), consisting of Investigators and personnel members 
representing the Sponsor of the study, will be established to obtain scientific guidance and advice 
for the protocol and conduct of the study. Details of the SSC responsibilities and procedures will 
be specified in the SSC charter.
5.2
Number of Participants
Approximately 1,050 participants are expected to be randomized to the following treatment arms: 
•
Nivo + rela FDC (n = 525)
•
Nivolumab monotherapy (n = 525)
See Section 10.2 for sample size determination.
The randomization will be stratified by the following stratification factors:
•
Geographic region (USA/Canada/Australia vs Europe vs ROW)
•
American Joint Committee on Cancer (AJCC v8) Stage IIIA/IIIB vs Stage IIIC vs Stage
IIID/IV (including all participants with mucosal melanoma, Stage III, Stage IVA, Stage IVB,
and Stage IVC - see Appendix 8)
5.3
End of Study Definition
The start of the trial is defined as the first participant screened. End of trial is defined as the last 
visit or scheduled procedure shown in the Schedule of Activities for the last participant.
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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.
A participant is considered to have completed the study if he/she has died, is lost to follow-up, has 
withdrawn consent, the study has concluded, the last visit completed, or has been 
5.4
Scientific Rationale for Study Design
5.4.1
Participant Input Into Study Design
BMS may approach advocacy groups and other organizations to discuss key details of the study. 
Those suggestions may be implemented into the study design, at the determination of the sponsor.
5.4.2
Rationale for Use of Nivolumab + Relatlimab Fixed Dose Combination
The rationale for combining a LAG-3 inhibitor and an anti-PD-1/PD-L1 agent is based on the 
potential role of LAG-3 in T-cell exhaustion and anti-PD-1 resistance.10 Relatlimab binds to 
LAG-3 receptors with high affinity and blocks its interaction with ligands such as major 
histocompatibility complex (MHC) Class II on antigen presenting cells. Nivolumab binds to PD-
1 receptors with high affinity and blocks its interaction with its ligands, PD-L1 and PD-L2. LAG-
3 and PD-1 are immune-checkpoint receptors that act synergistically on effector T cells, leading 
to the development of T-cell dysfunction and impaired cytotoxic function. Combined nivolumab 
and relatlimab mediated inhibition enables T-cell activation and restores effector function of T 
cells, that is greater than the effects of either antibody alone, leading to the initiation of an 
improved immune response and promoting tumor cell death. 
The central hypothesis is that dual LAG-3 and PD-1 checkpoint blockade has the potential to offer 
superior efficacy compared with single agent anti-PD-1 therapy in the immunotherapy-naive 
treatment setting, as well as to provide meaningful efficacy to patients who experienced disease 
progression during anti-PD-1 therapy. The mechanism of action for both agents and preclinical 
data support the potential for producing clinical benefit. See Section 3.2 for more details on the 
mechanism of action and preclinical data of relatlimab and nivolumab. Preliminary data from a 
Phase 1/2a study of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) in combination showed 
promising clinical activity in participants with previously treated recurrent or metastatic 
melanoma, with a safety profile similar to nivolumab monotherapy. In the CA224047 Phase 2/3 
study, nivo + rela FDC demonstrated clinical benefit measured by PFS in patients with previously 
untreated metastatic or unresectable melanoma. The FDC was well-tolerated and there were no 
new safety signals reported.
The FDC product contains nivolumab and relatlimab in protein-mass ratio 1:3 in a single vial. The 
FDC will be administered via intravenous (IV) infusion over approximately 30 minutes. Key 
advantages of a FDC are as follows:
•
Patients benefit from reduced infusion time and less time in the clinic and/or doctor’s office
•
Increased ease of administration
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•
Pharmacists require less time in preparation of the intravenous solution to be administered to
the patient
•
Reduces potential error for medication preparation and administration
5.4.3
Rationale for Choice of Comparator
In the adjuvant Stage III/IV resected melanoma setting, nivolumab is an established standard of 
care that is recognized in guidelines globally with positive recommendation ratings. In 
CheckMate-238, nivolumab demonstrated clinical benefit with an acceptable safety profile in the 
patient populations (Stage IIIA with > 1 mm tumor in lymph node was not included) that are being 
evaluated in this study. 
CheckMate-238 randomly assigned patients with resected Stage IIIB, IIIC, or IV disease to receive 
nivolumab vs ipilimumab. Patients’ diseases were categorized by the AJCC v7, and all patients 
underwent resection and lymph node dissection. The 12-month RFS was 70.5% in the nivolumab 
group vs 60.8% in the ipilimumab group. At 24 months, RFS was 62.6% in the nivolumab group 
vs 50.2% in the ipilimumab arm. This benefit was found regardless of stage, PD-L1 status, or 
BRAF status. Treatment was better tolerated in the nivolumab group, with 14.4% of patients 
experiencing Grade 3 or 4 toxicity compared with 45.9% in the ipilimumab group. On the basis of 
the results of CheckMate 238, the use of ipilimumab is no longer recommended in the adjuvant 
setting given the superiority of nivolumab coupled with less toxicity.20
Based on the available data and given the fact that nivolumab is approved for adjuvant treatment 
of patients with melanoma with involvement of lymph nodes or metastatic disease who have 
undergone complete resection, nivolumab is deemed an appropriate clinical comparator. 
5.4.4
Rationale for Choice of Primary Endpoint
Recurrence free survival (RFS) is a validated clinical endpoint and is defined as the time from 
randomization until first recurrence (loco-regional or distant metastasis) or death due to any cause, 
whichever was observed first. Treatment options that are clinically active are increasingly 
available to patients with resected Stage III/IV adjuvant melanoma. These options have 
demonstrated a RFS improvement and have subsequently been granted regulatory approvals.
Overall survival (OS) is often used as the primary endpoint in oncology clinical trials. However, 
OS, although clinically meaningful, has the disadvantages of requiring extended follow-up and of 
being confounded by subsequent lines of treatment. An endpoint that is reached more rapidly could 
potentially expedite decisions on efficacy. 
Based on the available data, a RFS improvement compared with an established standard of care 
would demonstrate a potentially new combination in the resected Stage III/IV adjuvant melanoma 
setting. 
5.4.4.1
Rationale for Choice of Stratification Factors
In order to minimize the potential for imbalances across treatment arms, there will be 
2 stratification factors utilized in this trial: AJCC v8 - Melanoma Stage IIIA/IIIB vs Stage IIIC vs 
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Stage IIID/IV (including all participants with mucosal melanoma, Stage III, Stage IVA, Stage IVB, 
and Stage IVC) and geographic region (USA/Canada/Australia vs Europe vs ROW).
Prognostic implications of AJCC v8 staging are well established. There is a continued need to 
move beyond histopathologic and clinical criteria for risk stratification.
Geographic region (USA/Canada/Australia vs Europe vs ROW): Differences in patient 
populations and clinical practice patterns in the different regions are well known and can impact 
outcomes. Region has been included as a stratification factor to control for potential differences in 
patient populations and different approaches to clinical practice in the different regions. ROW will 
include Central America, Latin America, and China.
5.4.5
Rationale for Blinding
The study will be double-blinded in order to:
•
Minimize bias including bias arising from differences in thresholds for classification of
recurrence between the arms which could subsequently affect treatment duration between the
arms and have an impact on the primary endpoint of RFS
•
Curtail bias in reporting, classification, and management of adverse events
As participants who progress will not require knowledge of which treatment arm they were 
assigned to for selection of subsequent therapies, blinding will be maintained even after disease 
progression. The Sponsor’s central protocol team (including but not limited to clinical, statistics, 
and data management) will remain blinded to treatment assignment throughout the duration of the 
study until the primary endpoint of RFS has been reached or the decision is made to stop the study.
5.4.6
Rationale for Evaluation of 
Immune checkpoint signaling through immune inhibitory pathways such as the PD-1 axis to its 
ligand (PD-L1) and/or LAG-3 interaction with its ligands significantly dampens anti-tumor 
immune responses in different tumor types, including melanoma, NSCLC, and HCC. 
Unfortunately, not all patients respond to immune checkpoint blockade. Therefore, there is a 
continued medical need for a better understanding of factors 
 that predict benefit 
and recurrence free survival (RFS).
Data from CA224020 demonstrated that participants with LAG-3 expression are more likely to 
respond to treatment with nivo + rela FDC in those with advanced melanoma with prior anti-PD-
1/PD-L1 treatment.13,14 In the CA224047 study of patients with previously untreated metastatic or 
unresectable melanoma, longer PFS was observed in participants with LAG-3 expression treated 
with either nivolumab monotherapy or nivo + rela FDC.
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5.4.7
Rationale for Inclusion of Adolescent Participants
Advanced melanoma is generally regarded as a similar disease in adolescents and adults and is 
treated similarly. Metastatic melanoma does not commonly occur in the pediatric population from 
age 0 to less than 12 years.34 The incidence reported in the US population for the age groups of 1 
to 5 years, 5 to 9 years, and 10 to 14 years is 0.10, 0.16, and 0.37 per 100,000, respectively. The 
incidence in the US is higher in adolescents: 1.72/100,000 (15 to 19 years) (The SEER Carcinoma 
Statistics Review).35 In the European Cooperative Study Group for Pediatric Rare Tumors 
(EXPeRT) study of melanoma incidence in Italy, Poland, Germany, and France, incidence of 
cutaneous melanoma was reported as 0.7 to 0.8 per million per year for ages 0 to 10 years and 10 
per million per year for ages 15 to 19 years.36 Overall, the pediatric incidence rates (5.4 per 1 
million children and adolescents in the US)37 are dramatically lower than the adult incidence and 
add to the difficulty of evaluating adolescent melanoma in clinical trials. 
The key primary tumor characteristics, such as the site of the primary tumor, stage at diagnosis, 
tumor thickness, and level of invasion, are comparable between adolescent and adult melanoma 
patients. In an analysis of 1255 children (age younger than 20 years), the 10- to 19-year-old age 
group had similar baseline characteristics compared with the 20- to 24-year-old age group.38  There 
are limited clinical studies evaluating treatment outcomes in pediatric and adolescent participants 
with melanoma. Despite the small number of participants, results of these studies showed that 
safety profiles and treatment effects (such as tumor shrinkage or pharmacodynamic effects of 
immunotherapy) in pediatric participants are comparable with adult participants.
Current treatment options for adolescent melanoma are the same as adults as specific guidelines
for treatment do not exist. In short, biology is similar and treatment options are also similar as 
adults. The FDA approval in Mar-2022 of Opdualag™for the treatment of adult and adolescent 
patients (12 years and older and weighing at least 40 kg) with unresectable or metastatic melanoma 
provides further justification for the inclusion of this population to cover an unmet need in future 
studies.
5.4.8
Rationale for Ultrasound in Disease Surveillance
Ultrasound is one of several imaging modalities (ie, CT scan, chest x-ray) and non-imaging 
modalities (ie, physical exam, blood tests) that have been applied in the follow-up of melanoma 
patients, all of which have had varying levels of effectiveness for detection of recurrence.39 In a 
meta-analyses of 74 studies spanning 10,528 melanoma patients, ultrasonography was noted to 
have the greatest sensitivity, specificity, and diagnostic odds ratio for staging of regional lymph 
nodes as well as for surveillance of lymph node involvement as compared to CT, positron emission 
tomography (PET), and PET-CT.40 National Comprehensive Cancer Network (NCCN) Guidelines 
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(V2.2021) include nodal basin ultrasound surveillance as preferred over complete lymph node 
dissection (CLND) in the management and primary treatment of Stage III melanoma patients.39 In 
the Multicenter Selective Lymphadenectomy Trial (MSLT-II), it was determined that CLND did 
not lead to an increase in melanoma-specific survival in patients with sentinel lymph-node 
metastases compared to observation with ultrasonography.41 In sum, the evidence and 
management guidelines to date suggest a role for ultrasonography in the follow-up melanoma 
patients and supports implementation of ultrasonography in this study for participants with SLND 
only.
5.4.9
Rationale for MRI Surveillance of Head and Neck Mucosal Melanomas
Though mucosal melanomas of the head and neck are rare tumors, they account for 55.4% of cases 
of mucosal melanomas. The majority of these arise in the nasal cavity followed by paranasal 
sinuses, oral cavity, and rarely the pharynx and larynx. The risk of lymph node involvement is 
significantly higher in oral mucosal melanomas, occurring in about 26% of all cases of oral 
mucosal melanomas, as compared to nasal mucosal melanomas. Given the likelihood of lymph 
node spread, metastatic regions of spread may include the brain, lungs, and liver. Imaging plays a 
vital role for the evaluation of these melanomas given the invasion into adjacent soft tissue and 
bone erosion. Enhanced imaging techniques such as MRI are particularly helpful in identifying 
sino-nasal melanomas as iso-attenuating or hyperattenuating mass-like lesions, especially in cases 
of bone involvement due to regional bone remodeling, erosive, or destructive changes.42
5.5
Justification for Dose
5.5.1
Justification for Fixed Dose Combination Dosing
The proposed dose of the FDC product is 480 mg nivolumab + 160 mg relatlimab Q4W. The dose 
and dosing regimen for this study was primarily based on the benefit/risk profile in metastatic 
melanoma participants from Study CA224047 and
CA224020 pharmacokinetics (PK), 
pharmacodynamics, and extensive nivolumab monotherapy clinical experience.8,13 The flat E-R 
relationship for clinical efficacy and safety including data from higher doses supported the 
proposed dose for the adjuvant treatment of melanoma.
While administration of FDC (3:1) using a 30-minute infusion time has not been evaluated in 
participants
with cancer, no clinically meaningful differences in the frequency of 
hypersensitivity/infusion-related reactions are expected when FDC is administered over a 
30-minute infusion compared with the 60-minute infusion.8 Clinical studies of FDC for the
treatment of cancer used a 60-minute infusion duration. Infusion reactions, including high-grade
hypersensitivity reactions, were uncommon across the relatlimab clinical program. The length of
infusion of 30- or 60-minutes is not expected to impact the PK profile of nivolumab and relatlimab.
Overall, an infusion duration of 30 minutes for nivo + rela FDC is likewise not anticipated to
present significant safety concerns (ie, the frequency of hypersensitivity/infusion-related
reactions). The shorter infusion will provide patient convenience by reducing the overall infusion
duration and chair time.
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Based on PPK analysis, relatlimab baseline CL in subjects receiving relatlimab monotherapy and 
nivolumab + relatlimab SAV (sequential or co-administered) was similar to participants receiving 
nivo + rela FDC ( 5% and  18% difference, respectively). Similarly, nivolumab baseline CL in 
subjects receiving nivolumab monotherapy or nivolumab + relatlimab was similar ( 5% 
difference) to participants receiving nivo + rela FDC, thus indicating no clinically relevant effect 
of FDC formulation on relatlimab or nivolumab PK. Nivolumab and relatlimab both exhibit time-
varying clearance (CL) associated with improving disease status over time in metastatic solid 
tumor patient population. However, in the adjuvant setting, participants are expected to have 
improved disease status at baseline and in turn clearance is expected to be time invariant and lower 
than baseline CL observed in metastatic solid tumors patient population. For example, nivolumab 
CL in adjuvant melanoma participants was 40% lower than baseline CL and approximately 20% 
lower than steady-state CL relative to participants with advanced melanoma.43 These changes in 
CL and resulting increase in exposure is not expected to be clinically relevant given the flat E-R 
for safety in the metastatic setting.8
5.5.2
Dose Rationale for Adolescent Participants
The nivo + rela FDC dose in adolescent patients for this indication is supported by evidence from 
RELATIVITY 047, a global Phase 3, double-blinded, randomized controlled study in adults with 
unresectable or metastatic melanoma; additional data analyses that suggest that nivolumab and 
relatlimab exposures in pediatric patients 12 years of age or older are expected to result in similar 
safety and efficacy to that of adults. The pharmacokinetics of monoclonal antibodies and the course 
of unresectable or metastatic melanoma are sufficiently similar in adults and pediatric patients 12 
years of age or older to allow extrapolation of data from adults to pediatric patients 12 years of age 
or older. In addition, overall exposure in adolescent participants in an adjuvant setting is expected 
to be well within established adult safe and tolerable exposure margin. Relatlimab flat doses of 20 
to 800 mg Q2W as monotherapy and up to 1440 mg Q4W in combination with nivolumab 480 mg 
have been studied in adults.44
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Nivo + rela FDC was administered as flat dosing in adults, therefore, a minimum body weight 
threshold in adolescents ( 40 kg) is defined to receive the same adult flat dose to prevent 
exceeding target adult exposures. Adolescents < 40 kg will be administered body weight adjusted 
nivo + rela FDC doses, up to the respective maximum adult flat-doses. Adolescent participants 
 12 years old who weigh  40 kg will be administered a flat-dose of nivo + rela FDC (nivolumab 
480 mg and relatlimab 160 mg Q4W IV infusion [adult dosing]) or nivolumab monotherapy
480 mg Q4W IV infusion (adult dosing). Participants between  12 years and < 18 years of age 
who weigh < 40 kg will be administered body weight adjusted nivolumab 
 of nivo + rela FDC or nivolumab monotherapy 6 mg/kg Q4W IV infusion over 
approximately 30 minutes.
5.5.3
Justification for Nivolumab Monotherapy Dose
The nivolumab dose of 480 mg Q4W was selected based on clinical data and modeling and
simulation approaches using population PK (PPK) and exposure-response (E-R) analyses of data 
from studies in multiple tumor types (melanoma, NSCLC, and RCC) where body weight 
normalized dosing (mg/kg) was used.
Nivolumab PK has been extensively studied in multiple tumor types, including melanoma, 
NSCLC, RCC, cHL, SCCHN, CRC, and urothelial carcinoma and has been safely administered at 
doses up to 10 mg/kg Q2W. Nivolumab monotherapy was originally approved as a body-weight 
based dose of 3 mg/kg Q2W, and was updated to 240 mg Q2W or 480 mg Q4W in multiple 
indications.6,8 Nivolumab 360 mg Q3W is also under evaluation in monotherapy and in 
combination therapy studies. Less frequent 360 mg Q3W and 480 mg Q4W dosing regimens can 
reduce the burden to patients of frequent, lengthy IV treatments and allow combination of 
nivolumab with other agents using alternative dosing regimens.
The benefit-risk profiles of nivolumab 240 mg Q2W, 360 mg Q3W and 480 mg Q4W are predicted 
to be comparable to 3 mg/kg Q2W. This assessment is based on a comprehensive characterization 
of nivolumab PK, safety, efficacy, and exposure-response relationships across indications. PPK 
analyses have shown that the PK of nivolumab is linear with proportional exposures over a dose 
range of 0.1 to 10 mg/kg; no clinically meaningful differences in PK across ethnicities and tumor 
types were observed. Using the PPK model, the exposures following administration of several 
dosing regimens of nivolumab administered as a flat dose were simulated, including 240 mg Q2W, 
360 mg Q3W, and 480 mg Q4W. The simulated average serum concentration at steady state 
[Cavgss] following administration of nivolumab 360 mg Q3W and 480 mg Q4W are predicted to 
be similar to those following administration of nivolumab 240 mg Q2W and nivolumab 3 mg/kg 
Q2W administered to patients over a wide body weight range (34-180 kg) across tumor types. 
Extensive E-R analyses of multiple PK measures (maximum serum concentration at 
Day 1[Cmax1], average serum concentration at Day 28 [Cavg28], and trough serum concentration 
at Day 28 [Cmin28]) and efficacy and safety endpoints indicated that the efficacy of the flat-dose 
480 mg IV regimen are similar to that of 3 mg/kg Q2W IV regimen. In E-R efficacy analyses for 
OS and ORR conducted in melanoma, RCC, and NSCLC using Cavg28 as the exposure measure, 
probabilities of achieving a response and survival probabilities at 1 year and 2 years for IV 
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480 mg Q4W were similar to that of IV 3 mg/kg Q2W. In E-R safety analyses, it was demonstrated 
that the exposure margins for safety are maintained following nivolumab 480 mg Q4W, and the 
predicted risks of discontinuations due to AEs or death, AE Grade 3+, and immune-mediated AEs 
(IMAEs) Grade 2+ are similar following nivolumab 480 mg Q4W relative to nivolumab 3 mg/kg 
Q2W across tumor types. In addition, nivolumab exposures with 240 mg Q2W, 360 mg Q3W, and 
480 mg Q4W flat-dose IV regimens across tumor types are maintained well below the 
corresponding exposures observed with the well-tolerated 10 mg/kg IV nivolumab Q2W dose 
regimen.
Additional details on nivolumab posologies and risk-benefit can be found in the nivolumab IB.
5.6
Clinical Pharmacology Summary
5.6.1
Nivolumab Clinical Pharmacology Summary
Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for single agent 
nivolumab.
Nivolumab as a single agent: The PK of single-agent nivolumab was studied in patients over a 
dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of nivolumab as 
a 60-minute intravenous infusion every 2 or 3 weeks. Nivolumab CL decreases over time, with a 
mean maximal reduction (% coefficient of variation [CV%]) from baseline values of 24.5% 
(47.6%) resulting in a geometric mean steady-state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) 
in patients with metastatic tumors; the decrease in CLss is not considered clinically relevant. 
Nivolumab clearance does not decrease over time in patients with completely resected melanoma, 
as the geometric mean population clearance is 24% lower in this patient population compared with 
patients with metastatic melanoma at steady state. The geometric mean volume of distribution at 
steady state (Vss) (CV%) is 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 
days (77.5%). Steady-state concentrations of nivolumab were reached by 12 weeks when 
administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3.7-fold. The exposure to 
nivolumab increases dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 
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2 weeks. The predicted exposure (Cavg and Cmax) of nivolumab after a 30-minute infusion is 
comparable to that observed with a 60-minute infusion.
Specific Populations: The population PK analysis suggested that the following factors had no 
clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 
kg), gender, race, baseline lactate dehydrogenase (LDH), PD-L1 expression, solid tumor type, 
tumor size, renal impairment, and mild hepatic impairment. 
Renal Impairment: The effect of renal impairment on the clearance of nivolumab was evaluated 
by a population PK analysis in patients with mild (estimated glomerular filtration rate [eGFR] 60 
to 89 mL/min/1.73 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), or severe (eGFR 15 to 29 
mL/min/1.73 m2) renal impairment. No clinically important differences in the clearance of 
nivolumab were found between patients with renal impairment and patients with normal renal 
function.
Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was 
evaluated by population PK analyses in patients with HCC and in patients with other tumors with 
mild hepatic impairment (total bilirubin [TB] less than or equal to the upper limit of normal (ULN) 
and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST) and in HCC 
patients with moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST). 
No clinically important differences in the clearance of nivolumab were found between patients 
with mild/moderate hepatic impairment.
In addition, nivolumab pharmacokinetics (PK) was characterized in adults and pediatric 
participants with solid tumors who received nivolumab alone and in combination with relatlimab. 
Nivolumab exhibits linear and time-varying PK. Nivolumab baseline clearance (CL) in 
participants receiving nivolumab monotherapy or nivolumab + relatlimab was similar ( 5% 
difference) to participants receiving nivolumab + relatlimab FDC.
 Thus, no PK interaction between nivolumab and relatlimab was observed when these 
agents were given in combination.
5.6.2
Relatlimab Clinical Pharmacology Summary
The PK of relatlimab was characterized over a wide range of doses; 20 mg to 800 mg Q2W when 
administered as monotherapy or 20 mg to 240 mg Q2W and 160 mg to 1440 mg Q4W when 
administered in combination with nivolumab.8
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Relatlimab exhibits non-linear and time-varying PK. Nonlinearity in relatlimab CL represents 
~31% of total CL of relatlimab at the relatlimab 160-mg dose Q4W in combination with 
nivolumab. Relatlimab clearance coefficient of variation% (CV%) is 9.7% lower (geometric mean, 
5.48 mL/h [41.3%]) at steady state than after the first dose (6.06 mL/h [38.9%]) 
The geometric mean value (CV%) 
for relatlimab volume of distribution at steady state is 6.65 L (19.8%), consistent with the expected 
distribution of monoclonal antibodies (mAbs) limited to the vascular space. Relatlimab baseline 
CL in participants receiving relatlimab monotherapy and nivolumab + relatlimab single-agent vial 
(SAV) (sequential or coadministered) was similar to participants receiving nivolumab + relatlimab 
FDC ( 5% and  18% difference, respectively), 
6
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1) Signed Written Informed Consent
a) Participants or their legally acceptable representative (LAR; see Appendix 2) must have
signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee
(IEC)-approved written informed consent form (ICF) in accordance with regulatory, local,
and institutional guidelines. This must be obtained before the performance of any
protocol-related procedures that are not part of normal patient care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, tumor biopsies, and other requirements of the study.
c) Participant Re-enrollment: This study permits the re-enrollment of a participant that has
discontinued the study as a pre-treatment failure (ie, participant has not been
randomized/has not been treated). If re-enrolled, the participant must be re-consented.
2) Type of Participant and Target Disease Characteristics
a) All participants must have been diagnosed with either Stage IIIA (> 1 mm tumor in lymph
node)/B/C/D or Stage IV melanoma by AJCC v8 and have histologically confirmed
melanoma that is completely surgically resected (free of disease) with negative margins in
order to be eligible. All melanomas, except ocular melanoma, regardless of primary site of
disease, will be allowed.
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Note: Conjunctival melanoma is not considered to be ocular melanoma and is to be 
classified as mucosal melanoma.
b) Participants are eligible if central nervous system (CNS) metastases have been resected
and participants are neurologically stable.
i)
Prior resected CNS metastases must be without evidence of recurrence, as determined
by magnetic resonance imaging (MRI) performed at least 4 weeks after resection is
complete and within 35 days prior to randomization.
ii) Participants must be off immunosuppressive doses of systemic steroids (>10 mg/day
prednisone or equivalent) for at least 14 days prior to study drug administration and
must have returned to neurologic baseline post-operatively.
iii) For CNS lesion(s), a pathology report indicating that there has been complete resection
of CNS lesion(s) will suffice as confirmation of negative margins.
c) Complete resection must be performed 
prior to randomization. Management
of residual lymph nodes after positive sentinel lymph node biopsy (SLNB) (ie, completion
lymph node dissection) will be as per local standards and recommendations for the
individual participant.
d) All participants must have disease-free status documented by a complete physical
examination within 14 days prior to randomization and imaging studies within 35 days
prior to randomization. Imaging studies must include CT scan of the chest, abdomen,
pelvis, and all known sites of resected disease, and brain MRI. See Section 9.1.2 for details
and exceptions.
e)
f)
Participants  18 years of age must have an ECOG performance status of  1. Adolescent
participants between 12 and < 18 years of age must have a Lansky/Karnofsky performance
score  80% (Appendix 6).
g) Not applicable  - China only.
3) Age of Participant
a) Not applicable per Protocol Amendment 01.
b) Participant must be  12 years of age or local age of majority inclusive, at the time of
signing the informed consent.
Except: Where local regulations do not allow for participants < 18 years of age (adolescent
population) to participate. For those sites, the eligible participant population is  18 years
of age. Refer to Appendix 9.
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4) Reproductive Status
Investigators shall counsel women of child bearing potential (WOCBP) on the importance of
pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal
toxicity occurring due to transmission of study intervention to a developing fetus.
The investigator shall evaluate the effectiveness of the contraceptive method in relationship to
the first dose of study intervention.
Local laws and regulations may require the use of alternative and/or additional contraception
methods.
a) Female Participants:
i)
Female participants must have documented proof that they are not of childbearing
potential.
ii) Women who are not of childbearing potential are exempt from contraceptive
requirements.
iii) WOCBP must have a negative highly sensitive negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the
start of study intervention. An extension up to 72 hours prior to the start of study
treatment is permissible in situations where results cannot be obtained within the
standard 24-hour window.
(1) If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum
pregnancy test is required. In such cases, the participant must be excluded from
participation if the serum pregnancy result is positive.
iv) Additional requirements for pregnancy testing during and after study intervention are
located in Section 2, Schedule of Activities.
v) The investigator is responsible for review of medical history, menstrual history, and
recent sexual activity to decrease the risk for inclusion of a woman with an early
undetected pregnancy.
vi) WOCBP must agree to follow instructions for method(s) of contraception defined in
Appendix 4 and as described below and included in the ICF.
vii)WOCBP are permitted to use hormonal contraception methods (as described in
Appendix 4).
viii)
A female participant is eligible to participate if she is not pregnant or breastfeeding,
and at least 1 of the following conditions applies:
(1) Is not a WOCBP
OR
(2) Is a WOCBP and using a contraceptive method that is highly effective as described
in Appendix 4 during screening and for the duration of treatment for a total of 5
months after the last dose and agrees not to donate eggs (ova, oocytes) for the
purpose of reproduction for the same time period.
b) Male Participants:
i)
No additional contraceptive measures are required to be used.
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6.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1) Medical Conditions
a) History of ocular melanoma.
Note: Conjunctival melanoma is not considered to be ocular melanoma and is to be
classified as mucosal melanoma.
b) Untreated/unresected CNS metastases or leptomeningeal metastases.
c) Participants with an active, known or suspected autoimmune disease. Participants with
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted to enroll.
d) Participants with serious or uncontrolled medical disorder.
e) Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection either
suspected or confirmed within 4 weeks prior to screening. Acute symptoms must have
resolved and based on investigator assessment, there are no sequelae that would place the
participant at a higher risk of receiving investigational treatment.
f)
g) Participants with a condition requiring systemic treatment with either corticosteroids
(> 10 mg daily prednisone equivalent) 
 or other immunosuppressive
medications within 30 days of start of study treatment. Inhaled or topical steroids, and
adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in
the absence of active autoimmune disease.
h) Woman who are breastfeeding.
i)
Participants with a history of myocarditis, regardless of etiology.
2) Prior/Concomitant Therapy
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d) Treatment with complementary medications (eg, herbal supplements or traditional Chinese
medicines) to treat the disease under study within 2 weeks prior to randomization. Such
medications are permitted if they are used as supportive care.
e) Treatment with any live/attenuated vaccine within 30 days of first study treatment
(inactivated vaccines are permitted).
f)
Participants currently in other interventional trials, including those for COVID-19, 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 full dosing
schedule of the vaccine has been completed and the biologic impact of the vaccine or
investigational product is stabilized, unless the delay would compromise the participant’s
health or suitability for enrollment as determined by discussion between the investigator
and the Medical Monitor/designee.
3) Physical and Laboratory Test Findings
a) Positive pregnancy test at enrollment or prior to administration of study medication.
Note: May not transfuse, use growth factors, and/or coagulation factors within 14 days of
randomization to meet criteria 3b to 3e.
k) Known human immunodeficiency virus (HIV) positive with an AIDS defining
opportunistic infection within the last year, or a current CD4 count < 350 cells/uL.
Participants with HIV are eligible if:
i)
they have received antiretroviral therapy (ART dosing) for at least 4 weeks prior to
randomizations as clinically indicated while enrolled on study
ii) they continue on ART as clinically indicated while enrolled on study
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iii) CD4 counts and viral load are monitored per standard of care by a local health care
provider.
NOTE: Testing for HIV must be performed at sites where mandated locally. HIV
positive participants must be excluded where mandated locally (see Appendix 9).
4) Allergies and Adverse Drug Reaction
a) Participants with history of allergy or hypersensitivity to study treatment components.
b) History of life-threatening toxicity related to prior immune therapy (e.g. anti-CTLA4 or
anti-PD-1/PD-L1 treatment or 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, hypothyroidism).
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific
circumstances and only in countries where local regulations permit, a person who has been
imprisoned may be included or permitted to continue as a participant. Strict conditions
apply, and BMS approval is required. [Please refer to Appendix 9 for Greece-specific
differences.])
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical
(eg, infection illness).
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
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participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs.
6.4.1
Retesting During Screening or Lead-in Period
Participant Re-enrollment: This study permits the re-enrollment of a participant who 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 re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization is the value by which study inclusion will be 
assessed, because it represents the participant’s most current clinical state.
Laboratory parameters and/or assessments that are included in Screening Procedural Outline (see 
Table 2-1), may be repeated in an effort to find all possible well-qualified participants. 
Consultation with the Medical Monitor/designee may be needed to identify whether repeat testing 
of any particular parameter is clinically relevant.
7
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
procedure(s), or medical device intended to be administered to a study participant according to the 
study protocol.
Study intervention includes both Investigational [Medicinal] Product (IP/IMP) and 
Non-investigational/Auxiliary [Medicinal] Product (Non-IP/Non-IMP/AxMP) as indicated in
Table 7.1-1.
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An IP, also known as IMP 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 from 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 
IPs/AxMPs.
7.1
Study Interventions Administered
Table 7.1-1:
Study Interventions
ARM Name
Nivo + rela FDC
Nivolumab
Intervention Name
BMS-986213 (Nivolumab 240 mg /
Relatlimab 80 mg) vial
Nivolumab 100 mg/vial
Type 
Drug
Drug
Dose Formulation
Solution for injection
Solution for injection
Unit Dose Strength(s)
16 mg/mL
10 mg/mL
Dosage Level(s) for Adults 
( 18 years of age) and 
Adolescents ( 12 years to 
< 18 years of age)  40 kg
Nivolumab 480 mg
Relatlimab 160 mg
Total: 640 mg
Once every 4 weeks
Nivolumab 480 mg
Once every 4 weeks
Dosage Level(s) for 
Adolescents ( 12 years to 
< 18 years of age) < 40 kg 
(weight-based)
Nivolumab 6 mg/kg
Once every 4 weeks
Route of Administration
IV infusion
IV infusion
Use
Experimental
Active comparator
IMP and Non-IMP/AxMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and Labeling
Study intervention will be provided in a 
kit comprised of 2 vials. Each vial and kit 
will be labeled as required per country 
requirement.
Study intervention will be 
provided in a vial. Each vial will 
be labeled as required per country 
requirement.
Current/Former Name(s) 
or Alias(es)
BMS-986213 (Relatlimab 80
mg/Nivolumab 240 mg/vial)a
Opdualag™
BMS-936558
Opdivo™
Abbreviations: AxMP, auxiliary medical product; FDC, fixed dose combination; IMP, investigational medicinal 
product; IP, investigational product; IV, intravenous; nivo, nivolumab; rela, relatlimab.
a
Study Intervention for Nivo + Rela FDC Arm is currently BMS-986213 (Relatlimab 80 mg/Nivolumab
240 mg/vial) and will be updated to BMS-986213 (Nivolumab 240 mg/Relatlimab 80 mg/vial) approximately 
1Q-2Q 2023.
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For body weight dosing, the dosing calculations should be based on the body weight assessed at 
screening.
7.1.1
Study Treatment Details
Participants will receive nivo + rela FDC or nivolumab monotherapy on Day 1 of every 4-week 
cycle. Blinded study drug will be administered in a single bag IV over approximately 30 minutes. 
Participants should be carefully monitored for infusion reactions during IV administration. If an 
acute infusion reaction is noted, participant should be managed according to Section 7.4.4. 
•
There will be no dose escalations or reductions of immunotherapy allowed.
•
Premedications are not recommended for the first dose of immunotherapy.
•
Participants should be carefully monitored for infusion reactions during immunotherapy
administration.
•
If an acute infusion reaction is noted, participants should be managed according to Section
7.4.4.
•
Participants should receive immunotherapy until recurrence
, unacceptable toxicity, withdrawal of consent, a maximum treatment duration
of 1 year from first dose (maximum of 13 doses), or the study ends, whichever occurs first.
•
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.
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.
7.2
Method of Study Intervention Assignment
All participants will be centrally randomized using Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log-in information and directions on how to 
access the IRT. After the participant’s informed consent has been obtained and initial eligibility is 
established, the participant must be enrolled into the study by using IRT to obtain the participant 
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number. Every participant who signs the ICF must be assigned a participant number in IRT. The 
investigator or designee will register the participant for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:
•
Date that informed consent was obtained
•
Year of birth
•
Gender at birth
After enrollment in the IRT, participants who have met all eligibility criteria will be randomized
through the IRT. The following information is required for participant randomization:
•
Participant number
•
Year of birth
•
Melanoma type (cutaneous or mucosal)
•
AJCC v8 stage at screening (cutaneous melanoma only)
Participants will be randomized in a 1:1 ratio (see Figure 5.1-1) and stratified by geographic region 
(USA/Canada/Australia vs Europe vs ROW) and AJCC v8 stage as described in Section 5.2.
The randomization procedures will be carried out via permuted blocks within each stratum, defined 
by combination of geographic region and AJCC v8 stage. The exact procedures for using the IRT 
will be detailed in the IRT manual.
7.3
Blinding
This is a double-blind study. Access to treatment codes will be restricted from all participants, and 
site and Sponsor personnel prior to primary database lock, with exceptions as specified below.
Blinding of study treatment assignment is critical to the integrity of this clinical study. However, 
in the event of a medical emergency or pregnancy in an individual participant in which knowledge 
of the IP is critical to the participant's management, the blind for that participant may be broken 
by the investigator. The participant’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual participant’s treatment, the investigator should 
determine that the unblinded information is necessary (ie, that it will alter the participant’s 
immediate management). In many cases, particularly when the emergency is clearly not related to 
the IP, the problem may be properly managed by assuming that the participant is receiving the IP. 
It is highly desirable that the decision to unblind treatment assignment be discussed with the 
Medical Monitor/designee, but the investigator always has ultimate authority for the decision to 
unblind. The actual task of unblinding can be delegated by the investigator to a designee assigned 
the task on the Delegation of Authority. The Principal Investigator or appointed designee should 
only call in for emergency unblinding after the decision to unblind the participant has been 
documented.
For information on how to unblind in an emergency, consult the IRT manual.
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In cases of accidental unblinding, contact the Medical Monitor/designee and ensure every attempt 
is made to minimize additional disclosure and the impact of unblinding.
Any request to unblind a participant for nonemergency purposes should be discussed with the 
Medical Monitor/designee. Discussions regarding unblinding with the Medical Monitor/designee 
must be documented.
In case of an emergency, the investigator(s) has unrestricted access to randomization information 
via the IRT and is capable of breaking the blind through the IRT system without prior approval 
from the Sponsor. Following the unblinding, the Investigator shall notify the Medical 
Monitor/designee that the unblinding took place.
A scientist in the NonClinical Disposition and Bioanalysis department of BMS (and/or a designee 
in the external bioanalytical laboratory) will be unblinded to the randomized treatment assignments 
in order to minimize unnecessary bioanalytical analysis of samples. Any results shared by the 
NonClinical Disposition and Bioanalysis group with the Sponsor’s study team will be blinded to 
ensure integrity of the study.
Investigators will remain blinded to each participant’s assigned study intervention throughout the 
course of the study. In order to maintain this blind, an otherwise uninvolved third party will be 
responsible for the reconstitution and dispensation of all study intervention and will endeavor to 
ensure that there are no differences in time taken to dispense following randomization.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded study 
intervention records at the site(s) to verify that randomization/dispensing has been done accurately.
The DMC will assess safety and risk-benefit on an ongoing basis, and will have access to unblinded 
treatment codes for individual subjects. An external analysis team (external to BMS), including a 
reporting statistician and programming support, who are not involved with the conduct of the 
study, will provide analyses to the DMC.
7.4
Dosage Modification
Dose reductions or dose escalations are not permitted. All dose modification rules apply to all 
arms, given the blinded nature of this study.
7.4.1
Dose Delay Criteria
Dose delay criteria apply for all drug-related AE. Delay administration of study treatment if any 
of the delay criteria in Table 7.4.1-1 are met. Delay dosing for any AE, laboratory abnormality, or 
intercurrent illness which, in the judgement of the investigator, warrants delaying the dose of study 
medication.
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Dose must be delayed for SARS-CoV-2 infection either confirmed or suspected.
For participants who require delay of study treatment, re-evaluate weekly, or more frequently, if 
clinically indicated, and resume dosing when criteria to resume treatment are met (see Section 
7.4.2). Continue tumor assessments per protocol even if dosing is delayed. 
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Treatment
Drug-Related Adverse Event (AE) 
per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Gastrointestinal
Colitis or Diarrhea
Grade 2 
Delay dose
Dosing may resume when AE resolves to baseline 
Grade 3 
Delay dose
Dosing may resume when AE resolves to baseline
Grade 4 
Permanently 
discontinue
Renal
Serum Creatinine Increased
Grade 2 or 3 
Delay dose
Dosing may resume when AE resolves to Grade  1 or baseline value
Grade 4 
Permanently 
discontinue
Pulmonary
Pneumonitis
Grade 2 
Delay dose
Dosing may resume after pneumonitis has resolved to  Grade 1.
Grade 3 or 4 
Permanently 
discontinue
Hepatic
Aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), or 
total bilirubin (T.bili) increased
AST or ALT > 3 × and  5 × 
upper limit of normal (ULN) 
or T.bili >1.5 × and  3 × 
ULN, regardless of baseline 
value
Delay dose
Dosing may resume when laboratory values return to baseline.
AST or ALT > 5 × ULN or 
T.bili > 3 × ULN, regardless
of baseline value
Permanently 
discontinue
Concurrent AST or ALT > 3 
× ULN and T.bili > 2 × ULN, 
regardless of baseline value
Permanently 
discontinue 
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Treatment
Drug-Related Adverse Event (AE) 
per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Endocrinopathy
Adrenal Insufficiency
Grade 2 adrenal insufficiency
Delay dose
Dosing may resume after adequately controlled with hormone 
replacement.
Grade 3 or 4 adrenal 
insufficiency or adrenal crisis
Delay dose or 
permanently 
discontinue
Mandatory discussion with and documented approval from the Medical 
Monitor/designee needed prior to resuming therapy. If adrenal 
insufficiency resolves or is adequately controlled with physiologic 
hormone replacement, participant may not require discontinuation of 
study drug.
Hyperglycemia
Hyperglycemia requiring 
initiation or change in daily 
management (Grade 2 or 3)
Delay dose
Dosing may resume if hyperglycemia resolves to Grade  1 or baseline 
value, or is adequately controlled with glucose-controlling agents.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and documented approval from the Medical 
Monitor/designee needed prior to resuming therapy. If hyperglycemia 
resolves, or is adequately controlled with glucose-controlling agents, 
participant may not require discontinuation of study drug.
Hypophysitis/Hypopituitarism 
Symptomatic Grade 1-3 that 
is also associated with 
corresponding abnormal lab 
and/or pituitary scan
Delay dose 
Dosing may resume if endocrinopathy resolves to be asymptomatic, or is 
adequately controlled with only physiologic hormone replacement.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and documented approval from the Medical 
Monitor/designee needed prior to resuming therapy. If endocrinopathy 
resolves or is adequately controlled with physiologic hormone 
replacement, participant may not require discontinuation of study drug.
Hyperthyroidism or Hypothyroidism
Grade 2 or 3
Delay dose
Dosing may resume if endocrinopathy resolves to be asymptomatic, or is 
adequately controlled with only physiologic hormone replacement or 
other medical management.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and documented approval from the Medical 
Monitor/designee needed prior to resuming therapy. If endocrinopathy 
resolves or is adequately controlled with physiologic hormone 
replacement or other medical management, participant may not require 
discontinuation of study drug.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Treatment
Drug-Related Adverse Event (AE) 
per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Skin
Rash
Grade 2 rash covering > 30% 
body surface area or Grade 3 
rash 
Delay dose 
Dosing may resume when rash reduces to  10% body surface area 
Suspected Stevens-Johnson 
syndrome (SJS), toxic 
epidermal necrolysis (TEN) 
or drug reaction with 
eosinophilia and systemic 
symptoms (DRESS)
Delay dose
Dosing may resume if SJS, TEN, or DRESS is ruled out and rash 
reduces to is  10% body surface area
Grade 4 rash or confirmed 
SJS, TEN, or DRESS
Permanently 
discontinue
Neurological
Guillain-Barre Syndrome (GBS)
Any Grade
Permanently 
discontinue
Myasthenia Gravis (MG)
Any Grade
Permanently 
discontinue
Encephalitis
Any Grade encephalitis
Delay dose 
After workup for differential diagnosis, (i.e. infection, tumor-related), if 
encephalitis is not drug related, then dosing may resume when AE 
resolves 
Any Grade drug-related 
encephalitis 
Permanently 
discontinue
Myelitis
Any Grade myelitis
Delay dose
After workup for differential diagnosis, (i.e. infection, tumor-related), if 
myelitis is not drug related, then dosing may resume when AE resolves 
Any Grade drug-related 
myelitis
Permanently 
discontinue
Neurological (other than GBS, MG, 
encephalitis, or myelitis)
Grade 2
Delay dose
Dosing may resume when AE resolves to baseline 
Grade 3 or 4
Permanently 
discontinue
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Treatment
Drug-Related Adverse Event (AE) 
per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Cardiovascular
Myocarditis
Myocarditis
Symptoms induced from mild 
to moderate activity or 
exertion
Delay dose
Dosing may resume after myocarditis has resolved
Severe or life threatening, 
with symptoms at rest or with 
minimal activity or exertion, 
and/or where intervention 
indicated.
Permanently 
discontinue
Other Clinical AE
Pancreatitis:
Amylase or Lipase increased
Grade 3 with symptoms
Delay dose
Note: Grade 3 increased amylase or lipase without signs or symptoms of 
pancreatitis does not require dose delay. 
Dosing may resume when patient becomes asymptomatic.
Grade 4
Permanently 
discontinue
Uveitis 
Grade 2 uveitis
Delay dose
Dosing may resume if uveitis responds to topical therapy (eye drops) 
and after uveitis resolves to Grade  1 or baseline. If patient requires 
oral steroids for uveitis, then permanently discontinue study drug.
Grade 3 or 4 uveitis
Permanently 
discontinue
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of Treatment
Drug-Related Adverse Event (AE) 
per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Other Drug-Related AE (not listed 
above)
Grade 2 non-skin AE, except 
fatigue
Delay dose
Dosing may resume when AE resolves to Grade  1 or baseline value.
Grade 3 AE - First occurrence 
lasting  7 days
Delay dose
Dosing may resume when AE resolves to Grade  1 or baseline value.
Grade 3 AE- First occurrence 
lasting > 7 days
Permanently 
discontinue
Recurrence of Grade 3 AE of 
any duration
Permanently 
discontinue
Grade 4 or Life-threatening 
adverse reaction
Permanently 
discontinue
Other Lab abnormalities 
Other Drug-Related lab abnormality 
(not listed above)
Grade 3
Delay dose
Exceptions:
No delay required for: Grade 3 lymphopenia 
Permanent Discontinuation for: Grade 3 thrombocytopenia > 7 days or 
associated with bleeding. 
Grade 4
Permanently 
discontinue
Exceptions: The following events do not require discontinuation of 
study drug: 
• Grade 4 neutropenia  7 days
• Grade 4 lymphopenia or leukopenia
• Grade 4 isolated electrolyte imbalances/abnormalities that are not
associated with clinical sequelae and are responding to
supplementation/appropriate management within 72 hours of their
onset
Infusion Reactions (manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, hypertension, bronchospasm, or other allergic-like 
reactions.)
Hypersensitivity reaction or infusion 
reaction
Grade 3 or 4
Permanently 
discontinue
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMS, Bristol Myers Squibb; CTCAE, Common Terminology 
Criteria for Adverse Events; DRESS, drug reaction with eosinophilia and systemic symptoms; GBS, Guillain Barre syndrome; MG, myasthenia gravis; 
SJS, Stevens-Johnson syndrome; T.bili, total bilirubin; TEN, toxic epidermal necrolysis; ULN, upper limit of normal.
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7.4.2
Criteria to Resume Treatment
Participants may resume treatment with study intervention if they have completed AE management 
(ie, corticosteroid taper) or are on  10 mg prednisone or equivalent, and meet the requirements 
per Table 7.4.1-1.
7.4.4
Treatment of Infusion-Related Reactions
Since relatlimab and nivolumab contain only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
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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 grading definitions and may 
be modified based on local treatment standards and guidelines, as appropriate:
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated):
•
Remain at bedside and monitor participant until recovery from symptoms. The following
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before
additional study treatment administrations.
For Grade 2 symptoms: (Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment [e.g., antihistamines, NSAIDS, narcotics, IV fluid]; prophylactic 
medications indicated for  24 hours):
•
Stop the study drug infusion, begin an IV infusion of normal saline, and treat the participant
with diphenhydramine 50 mg intravenous (or equivalent) and/or acetaminophen/paracetamol
325 to 1000 mg; remain at bedside and monitor participant until resolution of symptoms.
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms recur,
then no further study medication will be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended:
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg
should be administered at least 30 minutes before study treatment infusions. If necessary,
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae. Grade 4: Life threatening 
consequences; urgent intervention indicated):
•
Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution
injected slowly for intravenous administration, and/or diphenhydramine 50 mg intravenous
with methylprednisolone 100 mg intravenous (or equivalent), as needed. Monitor participant
until the Investigator judges that the symptoms will not recur. Study drug will be permanently
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discontinued. Follow institutional guidelines for the treatment of anaphylaxis. Remain at 
bedside and monitor participant until recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
The IP/AxMP must be stored in a secure area according to local regulations. It is the responsibility 
of the investigator, or designee where permitted, to ensure that IP/AxMP is only dispensed to study 
participants. The IP/AxMP must be dispensed only from official study sites by authorized 
personnel according to local regulations.
The product storage manager should ensure that the study intervention 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 intervention arise, the study intervention 
should not be dispensed, and BMS should be contacted immediately.
Study intervention not supplied by BMS will be stored in accordance with the package insert.
IP/AxMP documentation (whether supplied by BMS or not) must be maintained that includes all 
processes required to ensure the 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).
•
The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study intervention received and any discrepancies are reported
and resolved before use of the study intervention.
•
The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance
(ie, receipt, reconciliation, and final disposition records).
•
Further guidance and information for the final disposition of unused study interventions are
provided in Appendix 2 and the Pharmacy Manual.
7.5.1
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
Not Applicable.
7.6
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and electronic case report form (eCRF). This will be source data reviewed through 
regularly scheduled monitoring visits.
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7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
7.7.1.1
Prohibited Treatments
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring long term systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications. Inhaled or topical 
steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted 
in the absence of active autoimmune disease.
Participants are prohibited from joining another interventional clinical trial if they are still on study
treatment. Participation in observation only studies is allowed at any time.
7.7.2.1
SARS-CoV-2 Vaccination Guidelines
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7.7.2.2
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history, and renal status), the appropriate imaging modality and contrast 
regimen per imaging study. Imaging contraindications and contrast risks are to be considered in 
this assessment. Participants with renal insufficiency are to be assessed as to whether or not they 
should receive contrast and if so, which contrast agent and dose is appropriate based on local 
standard of care.
Specific to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration 
rate (eGFR) < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis, therefore 
MRI contrast is contraindicated. Participants may be excluded from MRI if they have tattoos, 
metallic implants, pacemakers, etc., following local standard of care. 
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant in this study rests with the site radiologist, 
the Investigator, and standards set by the local Ethics Committee. 
7.8
Continued Access to Study Intervention After the End of the Study
At the end of the study, BMS will not continue to provide BMS-supplied study intervention to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
BMS reserves the right to terminate access to BMS-supplied study intervention if any of the 
following occur: a) the study is terminated due to safety concerns; b) the development of 
nivo + rela FDC 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 other 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/AxMP at the discretion of the investigator) for any 
of the following reasons:
•
Participant’s request to stop study intervention. Participants who request to discontinue study
intervention 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 the participant
to provide this information
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•
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
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under
specific circumstances and only in countries where local regulations permit, a participant who
has been imprisoned may be permitted to continue as a participant. Strict conditions apply, and
BMS approval is required.)
•
Disease recurrence 
•
Pregnancy (refer to Section 9.2.5)
•
Significant noncompliance with protocol (eg, procedures, assessments, medications, etc.). The
investigator should discuss such issues with the Medical Monitor/designee and be documented.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
All participants who discontinue study intervention 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 (eg, is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness).
If study intervention 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 per local 
regulatory requirements in each region/country and entered on the appropriate eCRF page.
8.1.1
Dose Discontinuation 
Study treatment must be permanently discontinued per criteria in Table 7.4.1-1 in Section 7.4.
Discontinue study treatment for any AE, laboratory abnormality, or intercurrent illness which in 
the judgment of the Investigator, presents a substantial clinical risk to the participant with 
continued dosing.
Any event that leads to delay in dosing lasting > 10 weeks from the previous dose requires 
discontinuation of study drug, with the following exceptions:
•
Dosing delays to allow for prolonged steroid tapers to manage drug-related AE are allowed.
•
Dosing delays lasting > 10 weeks from the previous dose that occur for non-drug-related
reasons may be allowed if approved by the Medical Monitor/ designee.
Note: dosing delays that are approved by the Medical Monitor/designee must be documented.
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8.1.2
Post-study Intervention Study Follow-up
In this study, RFS is a key endpoint of the study. Post-study follow-up is of critical importance 
and is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study intervention must continue to be followed (in this study or a rollover study) for 
collection of outcome and/or survival follow-up data as required and in line with Section 5.3 until 
death or the conclusion of the study.
BMS may request that survival data be collected on all randomized participants outside of the 
protocol defined window as defined in Section 2. At the time of this request, each participant will 
be contacted to determine their survival status unless the participant has withdrawn consent for all 
contacts or is lost to follow-up.
8.2
Discontinuation From the Study
Participants who request to discontinue study intervention 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.
•
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 intervention
only or also from study procedures and/or post-treatment study follow-up, and entered on the
appropriate eCRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured,
publicly available information should be used to determine vital status only as appropriately
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the Sponsor may
retain and continue to use any data collected before such a withdrawal of consent.
8.2.1
Individual Discontinuation Criteria
•
A participant may withdraw completely from the study at any time at his/her own request, or
may be withdrawn at any time at the discretion of the investigator for safety, behavioral,
compliance, or administrative reasons. This is expected to be uncommon. Stopping study
intervention is not considered withdrawal from the study.
•
Site should document if subject is unwilling to attend future visits, accept phone calls, allow
contact with their personal physician, or allow review of medical records for health status
information.
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•
At the time of discontinuing from the study, an immediate follow-up visit may be needed. See
the Schedule of Activities (Section 2) for data to be collected at the time of study
discontinuation and follow-up and for any further evaluations that need to be completed.
•
The participant will be permanently discontinued both from the study intervention and from
the study at that time.
•
If the participant withdraws consent for disclosure of future information, the Sponsor may
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-up
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
•
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 (3) documented phone calls, faxes, or emails, as well as lack of response by participant
to one (1) 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 the investigator’s use of third-party representative to assist in the follow-up portion of the
study has been included in the participant’s informed consent, then the investigator may use a
Sponsor-retained third-party representative to assist site staff with obtaining the participant’s
contact information or other public vital status data necessary to complete the follow-up
portion of the study.
•
The site staff and representative will consult publicly available sources, such as public health
registries and databases, in order to obtain updated contact information.
•
If, after all attempts, the participant remains lost to follow-up, then the last known alive date
as determined by the investigator should be reported and documented in the participant’s
medical records.
9
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and timing are summarized in the Schedule of Activities.
Protocol waivers or exemptions are not allowed.
All immediate safety concerns must be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue treatment.
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria before randomization. The investigator will maintain a screening log to 
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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 (e.g., blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed within the 
timeframe defined in the Schedule of Activities.
Perform additional measures, including non-study required laboratory tests, should be performed 
as clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected 
drug induced liver enzyme evaluations) will be monitored during the follow-up phase via on 
site/local labs until all study drug related toxicities resolve, return to baseline, or are deemed 
irreversible.
Evaluate participant immediately to rule out cardiac or pulmonary toxicity if participant shows 
cardiac or pulmonary-related signs (hypoxia, abnormal heart rate or changes from baseline) or 
symptoms (eg, dyspnea, cough, chest pain, fatigue, palpitations).
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will be at approximately 775 mL. However, 
the volume of blood drawn for local safety assessments, done before every dose, and in follow-up, 
will depend on local institutional practices and will vary from institution to institution.
9.1
Efficacy Assessments
9.1.1
Efficacy Assessment for the Study
Study evaluations will take place in accordance with Section 2, Schedule of Activities. 
Surveillance for recurrence will be performed until investigator assessed
recurrence
Contrast-enhanced CT of the chest, abdomen, pelvis, and all suspected sites of disease must be 
performed every 12 weeks (± 7 days) from randomization for the first 2 years, and every 26 weeks
(± 14 days) beyond the Week 108 imaging time point thereafter until investigator assessed 
 
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Imaging should be obtained anytime there is suspected disease. In cases of suspected lesions of 
the extremities, contrast-enhanced MRI may be substituted for contrast-enhanced CT. Please refer 
to Appendix 9 for Germany-specific imaging language.
Participants with a history of brain metastasis or symptoms should have a surveillance MRI 
(without and with contrast) approximately every 12 weeks ± 7 days from randomization for the 
first 2 years and subsequently every 26 weeks (± 14 days) beyond the Week 108 imaging time 
point thereafter until investigator assessed 
 recurrence 
or sooner if clinically indicated. Participants without history of brain 
metastases should have MRI if clinically indicated.
9.1.2
Imaging Assessment for the Study 
Images will be submitted to a central imaging vendor and may undergo blinded independent 
central review (BICR) at any time during the study. Prior to scanning the first participant, sites 
should be qualified and understand the image acquisition guidelines and submission process as 
outlined in the Imaging Manual provided by the central imaging vendor.
Screening and on-study images should be acquired as outlined in Section 2, Schedule of Activities 
Tumor assessments at other time points may be performed if clinically indicated and should be 
submitted to the central imaging vendor as soon as possible. All imaging that may demonstrate 
disease recurrence (including scans performed at unscheduled time points and/or at an outside 
institution) should be collected and submitted to the imaging vendor.
Assessments for recurrence should continue on the protocol defined imaging schedule regardless 
if dosing is delayed or discontinued.
The same method of assessment used at Screening should be used for on-study time points. CT 
images should be acquired with slice thickness of 5 mm or less with no intervening gap 
(contiguous). Every attempt should be made to image each participant using an identical 
acquisition protocol on the same scanner for all imaging time points. 
•
If a participant has a contraindication for CT intravenous contrast, then a non-contrast CT of
the chest and a contrast-enhanced MRI of the abdomen, pelvis, and suspected sites of disease
should be obtained.
•
If a participant has a contraindication for both MRI and CT intravenous contrasts, then a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other suspected
sites of disease should be obtained.
•
If a participant has a contraindication for MRI (eg, incompatible pacemaker) in addition to
contraindication to CT intravenous contrast, then a non-contrast CT of the chest, abdomen,
pelvis, and suspected sites of disease is acceptable.
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MRI of brain (without and with contrast) must be acquired as outlined in Section 2 (Schedule of 
Activities). CT of the brain (without and with contrast) can be performed if MRI is contraindicated.
Other imaging may be collected per local standards, as clinically indicated. See Section 7.7.2.2.
Use of CT component of a PET-CT scanner: Combined modality scanning such as with positron 
emission tomography-computed tomography (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 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 
intravenous and oral contrast) then the CT portion of the PET-CT can be used for 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.
9.1.3
Investigator Assessment of Baseline Disease Status
Participant eligibility (disease-free status) must be confirmed by investigator prior to 
randomization. Baseline disease assessments should be performed within 35 days prior to 
randomization, including contrast-enhanced CT of the chest, abdomen, pelvis, and all suspected 
sites of disease. Baseline MRI of the brain (with and without contrast) is required for ALL 
participants during screening to rule out brain metastases, within 35 days prior to randomization. 
CT of the brain (without and with contrast) can be performed if MRI is contraindicated. Please 
refer to Appendix 9 for Germany-specific imaging language.
All participants must have disease-free status defined as no clinical or radiographic evidence of 
recurrence of disease documented by a complete physical examination within 14 days prior to 
randomization and imaging studies within 35 days prior to randomization. 
9.1.4
Investigator Assessment of Recurrence
The same method of assessment used at Screening should be used for on-study time points. 
Post-baseline assessments will be performed at the time points described in Table 2-2 and Table 
2-3 until 
 recurrence
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Tumor assessments for ongoing study treatment decisions will be completed by the investigator. 
Additional imaging of potential disease sites should be performed whenever disease recurrence or 
occurrence of a secondary malignancy is suspected.
Cytology and/or histology are mandatory to confirm recurrence in solitary or in doubtful/suspect
lesions, cutaneous, subcutaneous, or lymph node lesions. Histological or cytological evidence of 
recurrence should be attempted in all cases, except for brain metastases, when safe and clinically 
feasible. Tumor markers or auto-antibodies alone cannot be used to assess recurrence.
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9.1.5
Patient-Reported Outcomes
Health-related quality of life (HRQoL) will be assessed by
in participants
who are  18 years of age at the time of informed consent as outlined in Section 2. Adolescent
participants ( 12 and < 18 years of age) only complete 
Adolescent participants 
will continue to complete only the 
 even if they become  18 years of age during 
treatment or follow-up.
If Health Outcomes Assessments are collected but the dose is subsequently delayed, a data change 
form should be submitted to move the original data entry to an unscheduled visit.
If the participant withdraws from the study prematurely, all attempts should be made to obtain 
prior to withdrawal from the study in participants
who are  18 years of age at the time of informed consent, or 
 for participants who are 
 12 and < 18 years of age at the time of informed consent. Reasons for missing patient-reported 
outcomes questionnaires should also be documented so that the appropriate imputation method 
can be employed to correct for missing data in the analysis.
The questionnaire will be completed by the participants before any clinical assessments are 
performed and treatments administered at any given visit. If participants refuse to complete all or 
any part of a questionnaire, this will be documented. Questionnaires should be completed in the 
language most familiar to each participant (if available), and participants should be given adequate 
time and space to complete the questionnaire. In order to preserve the integrity of trial data, no 
patient-reported data can be changed after the patient initially provides it.
 assessments in Long-term Follow Up (visits beyond Follow Up 2) may be completed 
by other modes of administration (eg, telephone) if deemed necessary by the study team. If 
exceptional circumstances preclude the continued administration of measures using planned 
modalities, then alternate administration methods may be required, after consultation with the 
Sponsor.
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9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, a surrogate, or the 
participant’s LAR).
The investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following up 
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on AEs that are serious, considered related to the study intervention or the study, or that caused 
the participant to discontinue before completing the study. 
Use CTCAE v5 definitions and grading for safety reporting of all AE and SAEs on the case report 
form.
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Refer to Appendix 3 for SAE reporting.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Collect all nonserious adverse events (not only those deemed to be treatment related) continuously 
during the treatment period and for a minimum of 135 days following discontinuation of study 
treatment. All AEs associated with SARS-CoV-2 infection must be collected from time of consent 
and during the treatment period. All SAEs must be collected from the time of signing the consent, 
including those thought to be associated with protocol-specified procedures, and within 135 days 
following discontinuation of dosing, except in cases where a study participant has started a new 
anti-neoplastic therapy. However, any SAE occurring after the start of a new treatment that is 
suspected to be related to study intervention by the investigator will be reported.
For participants randomized to treatment and never treated with study drug, collect SAEs for 30 
days from the date of randomization.
All SAEs, and all AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection must be collected from the date of the participant’s written consent until 
135 days following discontinuation of dosing. Collect all nonserious adverse events, not only those 
deemed to be treatment-related, (with the exception of non-serious AEs related to SARS-CoV-2 
infection) continuously during the treatment period and for a minimum of 135 days following 
discontinuation of study treatment.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study intervention or protocol-specified procedure (eg, a follow-up skin biopsy).
•
Medical occurrences that begin before the start of study intervention but after obtaining
informed consent will be recorded on the appropriate section of the eCRF module.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated
in Appendix 3.
•
The investigator will submit any updated SAE data to the sponsor or designee within 24 hours
of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
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has been discharged from the study, and he/she considers the event reasonably related to the study 
intervention 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.
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 135 days following discontinuation 
of study treatment. 
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they
become serious (see Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of
study intervention and for those present at the end of study intervention as appropriate.
•
All identified nonserious AEs must be recorded and described on the nonserious AE page of
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs
and/or laboratory test result abnormalities that are reported/identified during the study.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal obligations 
and ethical responsibilities toward the safety of participants and the safety of a product under 
clinical investigation are met.
An investigator who receives an investigator safety report describing SAEs or other specific safety 
information (eg, summary or listing of SAEs) from the Sponsor will file it along with the 
Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
The Sponsor or designee must report AEs to regulatory authorities and ethics committees 
according to local applicable laws and regulations. A SUSAR (suspected, unexpected serious 
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adverse reaction) is a subset of SAEs and must be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study intervention, 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 months after study product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to the BMS designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3.
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. Protocol-required procedures for study discontinuation and follow-up must be 
performed on the participant.
For WOCBP who are partners of male participants in the study, pregnancy reporting is not 
required.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE eCRF, 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 intervention
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific
corrective therapy
It is expected that, wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia vs low hemoglobin value).
9.2.7
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (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:
•
Aminotransferase (AT) ALT or AST elevation > 3 times upper limit of normal (ULN)
AND
•
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline
phosphatase)
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AND
•
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia,
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the
administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any significant worsening of conditions noted during interim or final physical examinations, ECG, 
x-ray filming, or any other potential safety assessment required or not required by the protocol
should also be recorded as a nonserious AE or SAE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (see Appendix 3).
In the event of an overdose, the investigator should:
•
Contact the Medical Monitor/designee immediately
•
Closely monitor the participant for AEs/SAEs and laboratory abnormalities
•
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the Medical Monitor/designee based on the clinical evaluation of the participant 
and documented.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Physical Examinations
Refer to Schedule of Activities, Section 2.
9.4.2
Vital signs
Refer to Schedule of Activities, Section 2.
9.4.3
Electrocardiograms
Refer to Schedule of Activities, Section 2.
9.4.4
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
All clinical safety laboratory assessments will be performed locally per Section 2 (Schedule of 
Activities).
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Table 9.4.4-1:
Clinical Laboratory Assessments
Hematology - CBC
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Creatinine
Blood urea nitrogen (BUN) or serum urea level
Glucose
Albumin - screening only
Sodium
Potassium
Chloride
Calcium
Phosphorus
TSH, free (or total) T3 and free (or total) T4 -
screening 
TSH, with reflexive f(or t)T3 and f(or t)T4 if TSH is 
abnormal - on treatment
Serology
Hepatitis B/C 
, (screening only; testing for HIV must be performed at sites 
where mandated by local requirements [see Appendix 9]).
Other Analyses
Pregnancy test (WOCBP only; minimum sensitivity 25 IU/L or equivalent units of HCG; screening, predose, and, 
follow-up. During follow-up,
Follicle stimulating hormone (FSH) screening - only required to confirm menopause in women < age 55. If FSH 
does not confirm postmenopausal status, pregnancy testing is required as per SOA.
Abbreviations: CBC, complete blood count; 
; ft3, free T3; ft4, free T4; HBsAG, hepatitis 
B virus surface antigen; HCG, human chorionic gonadotropin; HCV, hepatitis C virus; HIV, human 
immunodeficiency virus; 
 SOA, Schedule of Activities; T3, triiodothyronine; T4, thyroxine; 
TSH, thyroid stimulating hormone; tT3, total T3; tT4, total T4; WOCBP, women of child bearing potential.
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9.4.6
Imaging/Other Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the study investigator as per standard 
medical/clinical judgment.
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9.8.2.1
Tumor Sample Collection
The Investigator, in consultation with the radiology staff, must determine the degree of risk 
associated with the procedure and find it acceptable. Biopsies may be done with local anesthesia 
or conscious sedation. Institutional guidelines for the safe performance of biopsies should be 
followed. Excisional biopsies may be performed to obtain tumor biopsy samples. Invasive 
procedures that require general anesthesia should not be performed to obtain a biopsy specimen; 
however, if a surgical procedure is performed for a clinical indication, excess tumor tissue may be 
used for research purposes with the consent of the participant. Detailed instructions of the 
obtaining, processing, labeling, handling, storing, and shipping of specimens will be provided in a 
separate Laboratory Manual.
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9.9
Additional Research
This protocol will include residual sample storage for additional research.
For All US Sites
Additional research is required for all study participants, except where prohibited by IRBs/ethics 
committees, 
prohibited 
by 
local 
laws 
or 
regulations, 
or 
academic/institutional 
requirements. Where one or more of these exceptions occurs, participation in the additional 
research should be encouraged but will not be a condition of overall study participation.
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•
If the IRB/ethics committees and site agree to the mandatory additional research retention
and/or collection, then the study participant must agree to the mandatory additional research
as a requirement for inclusion in the study.
•
If optional participation is permitted and approved, then the study participants may opt out of
the additional research retention and/or collection.
For non-US Sites
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
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 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, 
 after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research Sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
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Table 9.9-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Time points for which residual samples will be 
retained
All
All
All
All
All
All
 
All
All
All
Other derived/extracted materials from primary collection 
samples
All
9.10
Other Assessments
Not applicable.
10
STATISTICAL CONSIDERATIONS
10.1
Statistical Hypotheses
The primary hypothesis for the study is that nivo + rela FDC is superior to nivolumab monotherapy 
in achieving RFS as assessed by the investigator. 
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The null hypothesis to be tested in relation to the primary endpoint is as follows:
1) Nivo + rela FDC is not different from nivolumab monotherapy with respect to RFS per
investigator.
The null hypothesis corresponding to the key secondary endpoint is as follows:
1) Nivo + rela FDC is not different from nivolumab monotherapy with respect to overall survival.
10.2
Sample Size Determination 
10.2.1
Recurrence-free Survival
The primary objective of the study is to compare RFS of nivo + rela FDC to nivolumab 
monotherapy in participants with completely resected Stage IIIA (> 1 mm tumor in lymph node), 
Stage IIIB/C/D, or Stage IV NED melanoma. 
The sample size 
calculations were simulated using East® and Statistical Analysis System (SAS®) software (SAS 
Institute, North Carolina, USA).
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10.3
Analysis Sets
For the purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants or their legally acceptable representative who signed an informed consent and 
were registered into IRT.
Randomized
All participants who were randomized to any treatment arm in the study. 
Safety
All participants who take at least 1 dose of double-blind study treatment.
Data in this data set will be analyzed based on randomized treatment, except if a participant 
received the same incorrect treatment throughout the study, then the participant will be 
analyzed based on the treatment received.
Abbreviations: 
 IRT, interactive response technology; 
Defined Analysis Data Sets
Description
Analysis set for 
of RFS
All randomized participants. Refer to Table 10.4.1-2 for details of intercurrent 
strategy.
Analysis set for 
of DMFS
All randomized Stage III/IVA/IVB participants. Refer to Table 10.4.1-2 for 
details of intercurrent strategy.
Analysis set for 
of OS
All randomized participants.
Analysis set for safety 
All safety events reported for all randomized participants who are exposed to 
study drug. For participants who discontinue study intervention, all events post-
discontinuation up to Day 135 post last dose of study intervention will be 
included in the safety summaries. 
Abbreviations: DMFS, distant metastasis-free survival; OS, overall survival; RFS, recurrence-free survival.
10.4
Statistical Analyses
The statistical analysis plan (SAP) will be finalized prior to primary endpoint DBL and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoint.
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender, race, and other study specific populations and demographic 
characteristics. A description of participant disposition will also be included in the clinical study 
report.
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10.4.1
General Considerations
RFS will be programmatically determined based on the disease recurrence date provided by the 
investigator and is defined as the time between the date of randomization and the first date of 
documented recurrence 
, or death (whatever 
the cause), 
Table 10.4.1-1:
Censoring Scheme for Definition of Recurrence-free Survival
The stratification factors for analysis are:
•
AJCC v8 stage: Stage IIIA/IIIB vs Stage IIIC vs Stage IIID/IV (including all participants with
mucosal melanoma, Stage III, Stage IVA, Stage IVB, and Stage IVC)
•
Geographic region (USA/Canada/Australia vs Europe vs ROW)
DMFS, by investigator, is defined as the time between the date of randomization and the date of 
first distant metastasis or date of death (whatever the cause), whichever occurs first. 
 
OS is defined as the time between the date of randomization and the date of death. 
 OS will be followed continuously while participants are on the study drug and every 
12 weeks via in-person or phone contact after participants discontinue the study drug.
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Table 10.4.1-2:
Definition of Estimands for Primary and Secondary Endpoints
Objective
Endpoint
Estimand
Primary
To compare the efficacy, as 
measured by RFS, provided by 
nivo + rela FDC vs nivolumab 
monotherapy in participants 
with completely resected Stage 
III/IV NED melanoma.
Recurrence or 
death per 
investigator
Population: All randomized participants with 
completely resected Stage III/IV NED melanoma.
Treatment: Nivo + rela FDC compared to nivolumab 
monotherapy 
Key Secondary Efficacy
To compare the OS provided by 
nivo + rela FDC vs nivolumab 
monotherapy in participants 
with completely resected Stage 
III/IV NED melanoma.
OS
Population: All randomized participants with 
completely resected Stage III/IV NED melanoma.
Treatment: Nivo + rela FDC compared to nivolumab 
monotherapy
Other Secondary Efficacy
To assess the efficacy as 
measured by distant metastasis-
free survival (DMFS), provided 
by nivo + rela FDC vs 
nivolumab monotherapy in 
participants with completely 
resected Stage III/IVA/IVB
NED melanoma.
Distant recurrence 
or death per 
investigator 
Population: All randomized Stage III/IVA/IVB NED 
participants 
Population level summary:
Treatment: Nivo + rela FDC compared to nivolumab 
monotherapy 
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Table 10.4.1-2:
Definition of Estimands for Primary and Secondary Endpoints
Objective
Endpoint
Estimand
To compare PFS2 between nivo 
+ rela FDC vs nivolumab
monotherapy in randomized
participants.
PFS2
Population: All randomized participants 
Treatment: Nivo + rela FDC compared to nivolumab 
monotherapy
Safety
To assess safety and toxicity of 
nivo + rela FDC vs nivolumab 
monotherapy in participants
with completely resected Stage 
III/IV NED melanoma. 
Incidence and 
severity of AE, 
SAEs, IMAEs, 
drug-related 
AE/SAE, AEs 
leading to 
discontinuation, 
deaths, other select 
AEs and laboratory 
abnormalities.
Population: Safety analysis population (defined in 
Section 10.3)
Treatment: Nivo + rela FDC compared to nivolumab 
monotherapy
Abbreviations: AE, adverse event; 
 CI, confidence interval; DMFS, distant metastasis-free 
survival; FDC, fixed dose combination;
NED, no evidence of disease; OS, overall survival; 
PFS2, progression-free survival 2; RFS, recurrence free survival; SAEs, serious adverse events; 
.
a
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10.4.2
Primary Endpoint(s)
Table 10.4.2-1:
Primary Endpoints
Primary Endpoint
Description
Timeframe
Primary Efficacy 
Recurrence Free Survival (RFS)
Time from randomization to the 
first documentation of recurrence
 or death due to 
any cause, whichever occurs first.
Table 10.4.2-2:
Summary of Primary Endpoint Analysis
Endpoint
Statistical Analysis Methods
RFS as assessed by the investigator. RFS 
is defined as the time between the date of 
randomization and the first date of 
documented recurrence 
or death 
due to any cause, whichever occurs first. 
RFS distributions will be compared between treatment groups 
(nivo + rela FDC vs nivolumab monotherapy) 
in all randomized population.
Abbreviations: 
FDC, fixed dose combination;
 RFS, recurrence-free survival.
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10.4.3
Secondary Endpoint(s)
Table 10.4.3-1:
Secondary Efficacy Endpoints
Secondary Endpoints
Description
Timeframe
Key Secondary Efficacy
Overall Survival
Time from randomization date until 
death (whatever the cause)
Other Secondary Efficacy
Distant metastasis-free survival
Time from date of randomization to 
the date of first distant metastasis or 
date of death (whatever the cause, 
whichever occurs first).
Table 10.4.3-2:
Summary of Secondary Endpoint Analysis
Secondary Endpoints
Statistical Analysis Methods
Key Secondary
OS is defined as the time between the date of 
randomization and the date of death (whatever 
the cause).
Other Secondary
DMFS, by investigator, is defined as the time 
between the date of randomization and the date 
of first distant metastasis or date of death 
(whatever the cause), whichever occurs first.
PFS2 defined as time from randomization to 
second recurrence/objective disease 
progression on next-line systemic therapy per 
investigator, or death from any cause, 
whichever occurs first.
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Abbreviations: 
 DMFS, distant metastasis free 
survival; FDC, fixed dose combination; 
overall survival; PFS2, progression-free survival 2.
10.4.3.1
Safety Analysis
Table 10.4.3.1-1:
Safety Analysis
Safety Endpoint
Description
Timeframe
Safety
Incidence and severity of AEs, 
SAEs, IMAEs, other select AEs,
laboratory abnormalities, drug 
related AEs/SAEs, death
Incidence and severity (i.e. CTC 
grade) of AEs, SAEs, IMAEs, other 
select AEs, laboratory 
abnormalities, drug related 
AEs/SAEs, death
Up to 135 days after the last dose of 
study treatment 
Incidence of AEs leading to 
discontinuation
Incidence and severity of AEs 
leading to discontinuation of study 
treatment
Up to discontinuation of study 
treatment
Abbreviations: AE, adverse event; CTC, Common Terminology Criteria; IMAEs, immune mediated adverse events; 
SAE, serious adverse event.
10.4.5
Other Safety Analysis
All safety analyses will be performed using the Safety analysis population. 
Endpoint
Statistical Analysis Methods
The Safety and tolerability objective will be 
measured by the incidence and severity of adverse 
events (AEs), serious adverse events (SAEs), and 
adverse events leading to discontinuation study drug, 
select AEs, immune-mediated AEs (IMAEs), other 
events of special interest (OESIs), deaths, and 
laboratory abnormalities in each arm.
All safety analyses will be performed using the safety 
analysis population. The frequency of deaths, adverse 
events (AEs), serious adverse events (SAEs), AEs leading 
to discontinuation of study drug, select AEs, immune-
mediated AEs (IMAEs), other events of special interest 
(OESIs), and abnormalities in specific clinical laboratory 
assessments will be presented. The safety summaries will
be presented by severity were applicable. Analyses will be 
conducted using the 30-day and/or 135-day safety window 
from day of last dose received. AEs will be coded using the 
most recent Medical Dictionary for Regulatory Activities 
(MedDRA) version available during the conduct of the 
study. AEs and laboratory values will be graded for severity 
according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 
5.0. 
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11
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14 Ascierto PA, Bono P, Bhatia S, et al. Efficacy of BMS-986016, a monoclonal antibody that 
targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with 
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Madrid, Spain. Abstract 4998.
15 Long GV et al. Journal of Clinical Oncology 2022;40(36_supp): 360385-360385.
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18 Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in 
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19 Madu MF, Franke V, van de Weil BA, et al. External validation of the AJCC 8th edition 
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20 Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected 
Stage III or IV melanoma. N Engl J Med 2017; 377:1824–35.
21 Weber JS, Del Vecchio M, Mandala M, et al. Adjuvant nivolumab (NIVO) versus ipilimumab 
(IPI) in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase 
III CheckMate 238 trial. Ann Oncol 2019;30(Suppl 5): 533-4.
22 Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in 
resected Stage III melanoma. N Engl J Med. 2018;378:1789–1801.
23 Hauschild A, Dummer R, Schadendorf D, et al. Longer follow-up confirms relapse-free 
survival benefit with adjuvant abrafenib plus trametinib in patients with resected BRAF V600-
mutant Stage III melanoma. J Cin Onc. 2018;36:1-9. 
24 Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in Stage III 
BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-23.
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patients with resected stage IIIB–D/IV melanoma. Proceedings of the American Association 
for Cancer Research; 2021 Apr 10 - May 21.
26 He Y, Yu H, Rozeboom L, et al. LAG-3 protein expression in non-small cell lung cancer and 
its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorac Oncol 
2017;12:814–23.
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30 BMS-986213: Relatlimab-nivolumab Investigator Brochure. Bristol-Myers Squibb Company; 
2022. Document Control No. 930119921.
31 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(suppl; abstr9503).
32 Addendum 01 to the Primary Clinical Study Report for CA224047. A randomized, double-
blind Phase 2/3 study of relatlimab combined with nivolumab versus nivolumab in participants 
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Company; 2021. Document Control No. 930168350.
34 Indini A, Brecht I, Del Vecchio M, et al. Cutaneous melanoma in adolescents and young adults.
Pediatr Blood Cancer 2018;65:e27292.
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2005. Available from: https://seer.cancer.gov/explorer/application.html. Accessed 07-Mar-
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European study. Pediatr Blood Cancer 2018;65:e26974.
37 Austin MT, Xing Y, Hayes-Jordan AA, et al. Melanoma incidence rises for children and 
adolescents: an epidemiologic review of pediatric melanoma in the United States. J Pediatr 
Surg 2013;48:2207-13.
38 Strouse JJ, Fears TR, Tucker MA, et al. Pediatric melanoma: risk factor and survival analysis 
of the surveillance, epidemiology and end results database. J Clin Oncol 2005;23:4735-41.
39 NCCN Guidelines Version 4.2020 Cutaneous Melanoma, NCCN.org (2020)
40 Xing Y, Bronstein Y, Ross M, et al. Contemporary diagnostic imaging modalities for the 
staging and surveillance of melanoma patients: a meta-analysis. Journal of the National Cancer 
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41 Faries M, Thompson J, Cochran A, et al. Completion dissection or observation for sentinel-
node metastasis in melanoma. New England Journal of Medicine 2017;376: 2211-22.
42 Saleh M, Javadi S, Elsherif S, et al. Multimodality imaging and genetics of primary mucosal 
melanomas and response to treatment [published correction appears in Radiographics 
2022;42:E81]. Radiographics 2021;41:1954-72.
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43 Hamuro L, Statkevich P, Bello A, et al. Nivolumab clearance is stationary in patients with 
resected melanoma on adjuvant therapy: implications of disease status on time-varying 
clearance. Clin Pharmacol Ther 2019;106:1018-27.
44 Zhao X, Shen J, Ivaturi V, et al. Model-based evaluation of the efficacy and safety of 
nivolumab once every 4 weeks across multiple tumor types. Ann Oncol 2020;31:302-9.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ADA
anti-drug antibodies
AE(s)
adverse event(s)
AIDS
acquired immunodeficiency syndrome
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC(TAU)
area under the plasma concentration-time curve over dosing interval
AxMP
auxiliary medical product
BICR
blinded independent central review
BMS
Bristol Myers Squibb
BRAF
B-RAF proto-oncogene
BUN
blood urea nitrogen
Cavgss
steady state average concentration
CBC
complete blood count
C
cycle 
CD
cluster of differentiation
CFR
Code of Federal Regulations 
cHL
classical Hodgkin’s lymphoma
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL
clearance
CrCl
creatinine clearance
CLNR
nonrenal clearance
CLND
complete lymph node dissection
CLss
steady-state clearance
Cmax 
maximum observed concentration
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Term
Definition
CNS
central nervous system
COVID-19
coronavirus disease 2019
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
case Report Form, paper or electronic (eCRF)
CSR
clinical study report
CT
computed tomography
CTAg
clinical trial agreement
CTCAE
common terminology criteria for adverse events
CTLA
cytotoxic T-lymphocyte-associated protein 4
CV%
coefficient of variation %
D
day
DAB
dabrafenib
dL
deciliter
DILI
drug induced liver injury
DLT
dose limiting toxicity
DMC
data monitoring committee
DMFS
distant metastasis-free survival
DRESS
drug reaction with eosinophilia and systemic symptoms
eCOA
electronic clinical outcome assessments
ECG(s)
electrocardiogram(s)
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EC50
half-maximal effective concentration 
eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
EOI
end of infusion
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Term
Definition
E-R
exposure-response
EUDAMED
European Databank on Medical Devices
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FDG
fluorodeoxyglucose
FFR
Freedom From Relapse
FGL-1
fibrinogen-like protein 1
FSH
follicle stimulating hormone
fT3
free T3
fT4
free T4
FU
follow-up
GBS
Guillain-Barre Syndrome
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GI
gastrointestinal
h
hour
HBsAg
hepatitis B virus surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
H&E
hematoxylin & eosin
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
hazard ratio
HRQoL
health-related quality of life
HRT
hormone replacement therapy
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Term
Definition
IA
interim analysis
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal Editors
IDO
indoleamine 2,3-dioxygenase
ie
id est (that is)
IEC
Independent Ethics Committee
IgG4
immunoglobulin G4
IHC
immunohistochemistry
IMAE
immune-mediated adverse event
IMG
immunogenicity
IP/IMP
investigational [medicinal] products
IND
Investigational New Drug Exemption
IO
immuno-oncology
IPI
ipilimumab
IUS
intrauterine hormone-releasing system
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
kg
kilogram
K-M
Kaplan Meier
LAG-3
lymphocyte activation gene-3
LAM
lactational amenorrhea method
LD
longest diameter
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Term
Definition
LDH
lactate dehydrogenase
LN 
lymph node
MedDRA
Medical Dictionary for Regulatory Activities
MEK
mitogen-activated protein kinase
mg
milligram
MG
Myasthenia Gravis
MHC
major histocompatibility complex
min
minute
mL
milliliter
mmHg
millimeters of mercury
MMR
measles, mumps, rubella 
MRI
magnetic resonance imaging
MSLT-II
Multicenter Selective Lymphadenectomy Trial
MSS
melanoma specific survival rate
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCT
National clinical trial number
NED
no evidence of disease
ng
nanogram
NGS
next generation sequencing
NIMP
non-investigational medicinal products 
Nivo
nivolumab
NK
natural killer
NSAID
nonsteroidal anti-inflammatory drug
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Term
Definition
NSCLC
non-small cell lung cancer
OESI
other events of special interest
ORR
objective response rate
OS
overall survival
PD-1
programmed death-1
PD-L1
programmed death ligand-1
PD-L2
programmed death ligand-2
PEMBRO
pembrolizumab
PET
positron emission tomography
PET-CT
positron emission tomography-computed tomography
PFS
progression-free survival 
PFS2
progression-free survival 2 
PK
pharmacokinetics
PPK
population pharmacokinetics
PRO
patient reported outcome
Q2W
every 2 weeks 
Q3W
every 3 weeks
Q4W
every 4 weeks
R&D
Research and Development
RCC
renal cell carcinoma
Rela
relatlimab
RFS
recurrence free survival
RO
receptor occupancy
ROW
rest of the world
RT-PCR
reverse transcription polymerase chain reaction
SAE(s)
serious adverse event(s)
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
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Term
Definition
SAP 
statistical analysis plan
SAV
single agent vial
SCCHN
squamous cell carcinoma of the head and neck
SJS
Stevens-Johnson syndrome
SLN
sentinel lymph nodes
SLNB
sentinel lymph node biopsy
SOA
Schedule of Activities
SPSD
Site Process and Source Documentation
SUSAR
suspected, unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TB
total bilirubin
T.Bili
total bilirubin
TEN
toxic epidermal necrolysis
TME
tumor microenvironment
TILs
tumor infiltrating lymphocytes
TNM
tumor/node/metastasis
TRAE
treatment-related adverse event
TRAM
trametinib
TSH
thyroid stimulating hormone
TSST
time to second subsequent therapy
tT3
total T3
tT4
total T4
ULN
upper limit of normal
USA
United States of America
USPI
United States Prescribing Information
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Term
Definition
VAS
visual analog scale
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
WES
whole exome sequencing
WOCBP
women of childbearing potential
WS
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 representativeof 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 
(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 study must give their written consent.
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 
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.
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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.
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 
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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.
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.
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CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents, or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture (EDC) tool, eCRFs will be prepared 
for all data collection fields except for fields specific to SAEs and pregnancy, which will be 
reported on the electronic SAE form and Pregnancy Surveillance Form, respectively. If 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.
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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. 
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.
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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:
•
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
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•
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.
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:
•
Participant recruitment (eg, among the top quartile of enrollers)
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator
•
Study Steering Committee chair or their designee
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
•
Other criteria (as determined by the study team)
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.
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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
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.) 
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Pregnancy and DILI must follow the same transmission timing and processes to BMS as used for 
SAEs. (See Section 9.2.5 for reporting pregnancies.)
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk
factors, as well as the temporal relationship of the event to study intervention administration,
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure 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.
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.
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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: 
SAE Facsimile Number: Will be provided by local site monitor.
SAE Telephone Contact (required for SAE and pregnancy reporting): Will be provided by local 
site monitor.
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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.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of < 1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of 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
•
Combined (estrogen-and progestogen-containing) hormonal contraception must begin at
least 30 days prior to initiation of study therapy.
•
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
•
Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of
study therapy.
Highly Effective Methods That Are User Independent
•
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.
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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.A
vasectomy is a highly effective contraception method provided that the participant is the sole
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an
additional highly effective method of contraception should be used.
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study 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.
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.
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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 9.2.5 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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APPENDIX 6
ECOG AND LANSKY/KARNOFSKY PERFORMANCE STATUS 
SCALE
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.
PERFORMANCE STATUS CRITERIA: Karnofsky and Lansky
Score
Karnofsky Description ( 16 years of age)
Lansky Description (12 years to < 16 years age)
100
Normal; no complaints; no evidence of disease.
Fully active, normal.
90
Able to carry on normal activity; minor signs or 
symptoms of disease.
Minor restrictions in physically strenuous activity.
80
Normal activity with effort; some signs or 
symptoms of disease.
Active, but tires more quickly.
70
Cares for self; unable to carry on normal activity 
or to do active work.
Substantial restriction of, and less time spent, in 
play activity.
60
Requires occasional assistance, but is able to care 
for most of their personal needs.
Out of bed, but minimal active play; keeps busy 
with quiet activities.
50
Requires considerable assistance and frequent 
medical care.
Gets dressed, but inactive much of day; no active 
play, able to participate in quiet play.
40
Disabled; requires special care and assistance.
Mostly in bed; participates in some quiet activities.
30
Severely disabled; hospital admission is indicated 
although death not imminent.
In bed; needs assistance even for quiet play.
20
Very sick; hospital admission necessary; active 
supportive treatment necessary.
Often sleeping; play limited to passive activities.
10
Moribund; fatal processes progressing rapidly.
No play; does not get out of bed.
0
Dead
Unresponsive
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APPENDIX 7
AJCC MELANOMA STAGING (CANCER STAGING MANUAL 
8TH EDITION)
Definition of Primary Tumor (T)
T Category
Thickness
Ulceration Status
TX: primary tumor thickness cannot be 
assessed (e.g., diagnosis by curettage)
Not applicable
Not applicable
T0: no evidence of primary tumor (e.g., 
unknown primary or completely 
regressed melanoma)
Not applicable
Not applicable
Not applicable
Not applicable
T1
≤1.0 mm
Unknown or unspecified
T1a
<0.8 mm
Without ulceration
T1b
<0.8 mm
With ulceration
0.8-1.0 mm
With or without ulceration
T2
>1.0-2.0 mm
Unknown or unspecified
T2a
>1.0-2.0 mm
Without ulceration
T2b
>1.0-2.0 mm
With ulceration
T3
>2.0-4.0 mm
Unknown or unspecified
T3a
>2.0-4.0 mm
Without ulceration
T3b
>2.0-4.0 mm
With ulceration
T4
>4.0 mm
Unknown or unspecified
T4a
>4.0 mm
Without ulceration
T4b
>4.0 mm
With ulceration
Definition of Distant Metastasis (M)
M Category
Anatomic site
LDH level
M0
No evidence of distant metastasis
Not applicable
M1
Evidence of distant metastasis
See below
M1a
Distant metastasis to skin, soft tissue 
including muscle, and/or non-regional 
lymph node
Not recorded or unspecified
M1a(0)
Not elevated
M1a(1)
Elevated
M1b
Distant metastasis to lung with or without 
M1a sites of disease
Not recorded or unspecified
M1b(0)
Not elevated
M1b(1)
Elevated
M1c
Distant metastasis to non-CNS visceral 
sites with or without M1a or M1b sites of 
disease
Not recorded or unspecified
M1c(0)
Not elevated
M1c(1)
Elevated
M1d
Distant metastasis to CNS with or without 
M1a, M1b, or M1c sites of disease
Not recorded or unspecified
M1d(0)
Not elevated
M1d(1)
Elevated
Suffixes for M category: (0) LDH not elevated; (1) LDH elevated. No suffix is used if LDH is not recorded or is 
unspecified.
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Definition of Regional Lymph Node (N)
N 
Category
Number of tumor-involved regional 
lymph nodes
Presence of in-transit, 
satellite, or microsatellite 
metastases
NX
Regional nodes not assessed (e.g., SLN biopsy not 
performed, regional nodes previously removed for another 
reason)
Exception: pathological N category is not required for T1 
melanomas, use cN
No
N0
No regional metastases detected
No
N1
One tumor-involved node or in-transit, satellite, and/or 
microsatellite metastases with no tumor-involved nodes
N1a
One clinically occult (i.e., detected by SLN biopsy)
No
N1b
One clinically detected
No
N1c
No regional lymph node disease
Yes
N2
Two or three tumor-involved nodes or in-transit, satellite, 
and/or microsatellite metastases with one tumor-involved 
node
N2a
Two or three clinically occult (i.e., detected by SLN biopsy)
No
N2b
Two or three, at least one of which was clinically detected
No
N2c
One clinically occult or clinically detected
Yes
N3
Four or more tumor-involved nodes or in-transit, satellite, or 
microsatellite metastases with two or more tumor-involved 
nodes, or any number of matted nodes with or without in-
transit, satellite, and/or microsatellite metastases
N3a
Four or more clinically occult (i.e., detected by SLN biopsy)
No
N3b
Four or more, at least one of which was clinically detected, 
or presence any number of matted nodes
No
N3c
Two or more clinically occult or clinically detected, and/or 
presence any number of matted nodes
Yes
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AJCC Prognostic Stage Groups
Clinical (cTNM)
Clinical stage includes microstaging of the primary melanoma and clinical/radiologic/biopsy 
evaluation for metastases. By convention, clinical staging should be used after biopsy of the 
primary melanoma, with clinical assessment for regional and distant metastases. Note that 
pathological assessment of the primary melanoma is used for both clinical and pathological 
classification. Diagnostic biopsies to evaluate possible regional and/or distant metastasis also are 
included. Note there is only one stage group for clinical Stage III melanoma.
When T is....
And N is.....
And M is....
The clinical stage is...
Tis
N0
M0
0
T1a
N0
M0
IA
T1b
N0
M0
IB
T2a
N0
M0
IB
T2b
N0
M0
IIA
T3a
N0
M0
IIA
T3b
N0
M0
IIB
T4a
N0
M0
IIB
T4b
N0
M0
IIC
Any T, Tis
≥N1
M0
III
Any T
Any N
M1
IV
PATHOLOGICAL (pTNM)
Pathological staging includes microstaging of the primary melanoma, including any additional 
staging information from the wide excision (surgical) specimen that constitutes primary tumor 
surgical treatment and pathological information about the regional lymph nodes after SLN biopsy 
or therapeutic lymph node dissection for clinically evident regional lymph node disease.
When T is....
And N is.....
And M is....
The pathological stage 
is...
Tis
N0
M0
0
T1a
N0
M0
IA
T1b
N0
M0
IA
T2a
N0
M0
IB
T2b
N0
M0
IIA
T3a
N0
M0
IIA
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When T is....
And N is.....
And M is....
The pathological stage 
is...
T3b
N0
M0
IIB
T4a
N0
M0
IIB
T4b
N0
M0
IIC
T0
N1b, N1c
M0
IIIB
T0
N2b, N2c, N3b or N3c
M0
IIIC
T1a/b-T2a
N1a or N2a
M0
IIIA
T1a/b-T2a
N1b/c or N2b
M0
IIIB
T2b/T3a
N1a-N2b
M0
IIIB
T1a-T3a
N2c or N3a/b/c
M0
IIIC
T3b/T4a
Any N >N1
M0
IIIC
T4b
N1a-N2c
M0
IIIC
T4b
N3a/b/c
M0
IIID
Ant T, Tis
Any N
M1
IV
Pathological Stage 0 
 and T1 do not require pathological evaluation of lymph nodes 
to complete pathological staging; use cN information to assign their pathological stage.
Adapted from: American Joint Committee on Cancer. Melanoma of the Skin. In: Amin MB, Edge 
SB, Greene FL, et al., editors. AJCC Cancer Staging Manual. 8th ed. Chicago: Springer 
International Publishing AG; 2018 pp 577-8.
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APPENDIX 8
MUCOSAL MELANOMA STAGING
All mucosal melanoma, regardless of anatomical location, should be staged using the following 
classification.
The American Joint Committee on Cancer (AJCC) TNM Staging System for Mucosal 
Melanoma of the Head and Necka,b,c,d
Primary Tumor (T)
Characteristics
T3
Tumors limited to the mucosa and immediately underlying soft tissue, regardless 
of thickness or greatest dimension; for example, polypoid nasal disease, 
pigmented or nonpigmented lesions of the oral cavity, pharynx, or larynx
T4
Moderately advanced or very advanced disease
T4a
Moderately advanced disease -
Tumor involving deep soft tissue, cartilage, bone, or overlying skin
T4b
Very advanced disease -
Tumor involving brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), 
masticator space, carotid artery, prevertebral space, or mediastinal structures
Regional Lymph Nodes (N)
Characteristics
Nx
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis present
Distant Metastasis (M)
Characteristics
M0
No distant metastasis
M1
Distant metastasis
Staging group
Tumor
Node
Metastases
III
T3
N0
M0
IVA
T3-T4a
N1
M0
IVA
T4a
N0
M0
IVB
T4b
Any N
M0
IVC
Any T
Any N
M1
a NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. National Comprehensive Cancer
Network. Version 1.2020 - February 12, 2020. Assessed March 22, 2020.
b Head and Neck. American Joint Committee on Cancer. AJCC Cancer Staging Manual. 8th edition. New York,
NY: Springer, 2016.
c Histologic Grade (G): There is no recommended histologic grading system at this time.
d Prognostic Stage Groups: Currently, there is no clear ability to determine prognosis based on histologic differences.
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APPENDIX 9
COUNTRY-SPECIFIC REQUIREMENTS
Country
Section Number and 
Title
Original Language
Country-specific Language or Differences
Argentina, Czech 
Republic, Germany, 
Romania, and Any 
Other Countries Where 
Exclusion of HIV 
Positive Participants is 
Locally Mandated
Table 2-1, Screening
Procedural Outline -
Clinical Laboratory
Assessments
Add “HIV” to the list of laboratory tests
Argentina, Czech 
Republic, Germany, 
Romania, and Any 
Other Countries Where 
Exclusion of HIV 
Positive Participants is 
Locally Mandated
Section 6.2, 
Exclusion Criteria -
3k
Known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS)
Positive test for HIV.
Table 9.4.4-1, 
Clinical Laboratory 
Assessments
Denmark, Germany, 
Greece, and Sweden
Table 2-1, Screening 
Procedural Outline -
Informed Consent
Adolescents can no longer be enrolled in these 
countries; participants must be  18 years of age.
Section 6.1, Inclusion 
Criteria - 3b
Denmark
Denmark
Table 4-1, Objectives 
and Endpoints -
Exploratory
Objective:
Objective:
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Country
Section Number and 
Title
Original Language
Country-specific Language or Differences
Endpoint:
Endpoint:
Denmark
Table 4-1, Objectives 
and Endpoints -
Exploratory
Objective:
Denmark
Table 4-1, Objectives 
and Endpoints -
Exploratory Endpoint
Denmark 
Section 5.4.6, 
Rationale for
Evaluation of 
Denmark
Denmark
Denmark
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Country
Section Number and 
Title
Original Language
Country-specific Language or Differences
Denmark
Denmark
Germany
Germany
Table 2-1, Screening 
Procedural Outline -
Body Imaging
Contrast-enhanced CT of the chest, abdomen, pelvis, 
and all suspected sites of disease, within 35 days prior 
to randomization. See Section 9.1.2 for further details 
and exceptions. For head and neck mucosal 
melanomas, contrast-enhanced CT of the neck also 
required at screening as reference for on-treatment 
nodal surveillance.
Contrast-enhanced CT of the chest, abdomen, pelvis, 
and all suspected sites of disease, within 35 days prior 
to randomization. See Section 9.1.2 for further details 
and exceptions. For head and neck mucosal 
melanomas, contrast-enhanced CT of the neck also 
required at screening as reference for on-treatment 
nodal surveillance. MRI may be used as an alternative 
imaging modality to CT at screening, during 
treatment, and in follow-up.
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Country
Section Number and 
Title
Original Language
Country-specific Language or Differences
Germany
Table 2-2, On Study 
Treatment Procedural 
Outline - Body 
Imaging
In case of suspected lesions in the extremities, 
contrast-enhanced MRI can be substituted for contrast-
enhanced CT.
For head and neck mucosal melanomas, contrast-
enhanced MRI of the head and neck is required at 
every time point for nodal surveillance.
MRI may be used as an alternative imaging modality 
to CT at screening, during treatment, and in follow-up.
Germany
Table 2-3, Follow-up 
Assessments - Body 
Imaging
In cases of suspected lesions of the extremities, 
contrast-enhanced MRI may be substituted for 
contrast-enhanced CT.
For head and neck mucosal melanoma, contrast-
enhanced MRI of the head and neck is required at 
every time point for nodal surveillance.
MRI may be used as an alternative imaging modality 
to CT at screening, during treatment, and in follow-up.
Germany
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Country
Section Number and 
Title
Original Language
Country-specific Language or Differences
Germany
k 
Germany
Section 9.1.1, 
Efficacy Assessment 
for the Study 
In cases of suspected lesions of the extremities, MRI 
(with and without contrast) may be substituted for 
contrast-enhanced CT.
MRI may be used as an alternative imaging modality 
to CT at screening, during treatment and in follow-up.
Germany
Section 9.1.3, 
Investigator 
Assessment of 
Baseline Disease 
Status
Participant eligibility (disease-free status) must be 
confirmed by investigator prior to randomization. 
Baseline disease assessments should be performed 
within 35 days prior to randomization, including 
contrast-enhanced CT of the chest, abdomen, pelvis, 
and all suspected sites of disease. Baseline MRI of the 
brain (with and without contrast) is required for ALL 
participants during screening to rule out brain 
metastases, within 35 days prior to randomization. CT 
of the brain (without and with contrast) can be 
performed if MRI is contraindicated.
Participant eligibility (disease-free status) must be 
confirmed by investigator prior to randomization. 
Baseline disease assessments should be performed 
within 35 days prior to randomization, including 
contrast-enhanced CT of the chest, abdomen, pelvis, 
and all suspected sites of disease. MRI may be used as 
an alternative imaging modality to CT at screening, 
during treatment, and in follow-up.
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Country
Section Number and 
Title
Original Language
Country-specific Language or Differences
Germany
Greece
Greece
Section 6.2, 
Exclusion Criteria, 5a
Per Administrative Letter effective 13-Jul-2021: Greek sites should follow the stricter local regulations 
according to the Ministerial Decision G5a/59676/21-11-2016 (Government Gazette Issue No 4131/B/22-12-
2016) - Article 11, and not allow participants in prison to participate in the trial.
Prisoners or participants who are involuntarily 
incarcerated. (Note: Under certain specific 
circumstances and only in countries where local 
regulations permit, a person who has been 
imprisoned may be included or permitted to 
continue as a participant. Strict conditions apply, 
and BMS approval is required.)
Prisoners or participants who are involuntarily 
incarcerated.
Norway
Norway
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APPENDIX 10
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 02, 22-Feb-2023
The main reasons for this amendment are the following: 
•
•
•
The population for the distant metastasis-free survival (DMFS) secondary objective was
limited to randomized participants with Stage III/IVA/IVB no evidence of disease (NED)
melanoma.
•
An additional clarification for neck magnetic resonance imaging (MRI) was provided for head
and neck mucosal melanomas, since imaging plays a vital role for the evaluation of these
melanomas given the invasion into adjacent soft tissue.
•
In order to consolidate the previously published and implemented country-specific
amendments for Denmark, Germany, Greece, and Sweden with the global amendment in
preparation for the European Union Clinical Trials Regulation (EU CTR) transition, certain
country-specific paragraphs were delineated while others were consolidated for easier reading
without changing context.
These revisions are specified below and have been incorporated into the Protocol Summary.
Revisions apply to all participants currently enrolled.
Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-1: Screening Procedural 
Outline
Added sentence about local 
regulations that do not allow 
adolescents (< 18 years) to 
participate in the study.
Wording already present in 
country-specific amendments 
modified and/or added to 
consolidate with global amendment 
in preparation for EU CTR.
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Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: On Study Treatment 
Procedural Outline
Section 6.2: Exclusion Criteria
Table 7.4.1-1: AE Criteria for 
Delay, Resume, and Discontinue of 
Treatment
Table 9.4.4-1: Clinical Laboratory 
Assessments
Appendix 9: Country-Specific 
Requirements
Added and revised rows for 
Denmark-, Germany-, Greece-, and 
Sweden-specific requirements and 
differences.
Table 2-1: Screening Procedural 
Outline
Table 2-2: On Study Treatment 
Procedural Outline
Table 2-3: Follow-up Assessments
Added that ultrasounds should not 
be submitted to imaging vendor.
To align with current BMS 
processes.
Table 2-2: On Study Treatment 
Procedural Outline
Table 2-3: Follow-up Assessments
Section 9.1.1: Efficacy Assessment 
for the Study
For body/brain imaging and 
ultrasounds, added that the 
assessments at every 26 weeks 
(± 14 days) should be “beyond the 
Week 108 imaging time point 
thereafter.”
Clarification for the timing when 
sites should switch to imaging 
every 26 weeks.
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Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: On Study Treatment 
Procedural Outline
Table 2-3: Follow-up Assessments
Section 8.1.2 Post-study 
Intervention Study Follow-up
Section 9.1.1: Efficacy Assessment 
for the Study
Section 9.1.2: Imaging Assessment 
for the Study 
Section 9.1.4: Investigator 
Assessment of Recurrence
To align with the tumor/node/ 
metastasis (TNM) staging system 
for Mucosal Melanoma of the Head 
and Neck from the American Joint 
Committee on Cancer (AJCC v8).
Table 2-2: On Study Treatment 
Procedural Outline
Table 2-3: Follow-up Assessments
Added imaging requirements for 
mucosal melanoma of the head and 
neck to require MRI at every time 
point.
To ensure surveillance for mucosal 
head and neck participants is using 
the most clinically appropriate 
modality.
Table 2-2: On Study Treatment 
Procedural Outline
Table 2-3: Follow-up Assessments
Section 9.1.5: Patient-Reported 
Outcomes
Added that Health Outcomes 
assessments 
Added that adolescent participants 
will continue to complete only the 
even if they become 
 18 years of age during treatment 
or follow-up.
Added that if dose is delayed after 
collection of Health Outcomes, 
submit data change form to move 
original data entry to unscheduled 
visit.
To align with current BMS 
processes and for clarity.
Table 2-3: Follow-up Assessments
Table 2-2: On Study Treatment 
Procedural Outline
Table 2-3: Follow-up Assessments
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Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-3: Follow-up Assessments
Removed collection of 
corticosteroids and other immune-
modulating medications beyond 
135 days of last dose for AE/SAEs 
related to study drug.
Section 9.2.1 states that 
investigators are not obligated to 
actively seek AEs/SAEs in former 
study participants, but are required 
to continue to report drug-related 
AEs/SAEs and their management; 
therefore, this sentence was 
removed for consistency.
Revised footnote that defines 
timing of Long-Term Follow-up 
and Survival visits.
In cases where a Follow-up visit is 
unable to be completed, timing of 
Survival Follow-up visit has been 
clarified.
Section 3.3: Benefit/Risk 
Assessment
Added paragraph with data from 
safety memo.
To ensure pertinent study 
information is included to support 
patient safety.
Table 4-1: Objectives and 
Endpoints
Section 10.3: Analysis Sets
Table 10.4.1-2: Definition of 
Estimands for Primary and 
Secondary Endpoints
In the DMFS secondary efficacy 
objective, changed “Stage III/IV” to 
“Stage III/IVA/IVB” in the 
description of participants with 
completely resected NED 
melanoma.
To align with prior adjuvant studies 
CM238 and CM915 as well as 
clinical relevance of occurrence of 
distant metastasis in Stage III 
disease rather than Stage IV.
Table 4-1: Objectives and 
Endpoints
Table 10.4.1-2: Definition of 
Estimands for Primary and 
Secondary Endpoints
Table 10.4.3-2: Summary of 
Secondary Endpoint Analysis
Section 5.4.2: Rationale for Use of 
Nivolumab + Relatlimab Fixed 
Dose Combination
Removed text regarding 
characteristics of effector T cells.
To align with updated BMS 
standards for relatlimab protocols.
Section 5.4.9: Rationale for MRI 
Surveillance of Head and Neck 
Mucosal Melanomas
Added section.
To align with changes in protocol.
Section 7.3: Blinding
Removed paragraph regarding 
randomization schedules.
Included in error in previous 
amendment but not applicable to 
the study.
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Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Section 8.1: Discontinuation From 
Study Treatment
Added “or new primary melanoma” 
to disease recurrence as reason for 
discontinuation.
To clarify existing discontinuation 
reason.
Section 9.1.1: Efficacy Assessment 
for the Study
Revised text regarding the 
discontinuation of follow-up scans 
for Stage III and IV participants.
To ensure comprehensive data 
collection for all Stage III and Stage 
IV participants regardless of 
initiation of subsequent systemic 
therapy or not.
Added “but no later than 12 weeks” 
to timeframe of subsequent scan 
from the time when recurrence is 
suspected.
To define an expected timeframe 
for confirmation of recurrence.
Added that even though ultrasounds 
are not to be submitted to imaging 
vendor, any recurrence identified 
by ultrasound must be recorded as 
recurrence event.
To clarify ultrasound-identified 
recurrence events.
Removal of reference to minimal 
important differences not existing.
New minimal important difference 
estimates were recently released.
Section 9.2.3: Follow-up of AEs 
and SAEs
Updated text to current practice.
To align with updated BMS 
processes.
Section 9.2.5: Pregnancy
Added that pregnancy reporting is 
not required for WOCBP partners 
of male participants. 
For clarity.
For clarity.
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Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Section 10.2.1: Recurrence-free 
Survival
Section 10.3: Analysis Sets
Table 10.4.2-1: Primary Endpoints
Throughout
The copyright holder has updated 
the preferred name.
Added references to Appendix 9 
where appropriate.
For clarity.
All
Minor formatting and typographical 
corrections.
Changes are minor and therefore 
have not been summarized.
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Overall Rationale for Protocol Amendment 01, 18-May-2022
Despite limited clinical studies evaluating immuno-oncologic treatment outcomes in adolescent 
melanoma, with the small number of participants in these studies, results have shown that the 
safety profiles and treatment effects in pediatric participants are generally comparable to adult 
participants.1,2,3,4,5 Surgical and medical management of adolescent melanoma continues to derive 
guidelines from adult melanoma treatment. Hence the addition of adolescent participants 
 12 years through < 18 years of age covers an unmet need within the melanoma population under 
study. The Food and Drug Administration (FDA) approval in Mar-2022 of Opdualag™ for the 
treatment of adult and adolescent patients (12 years and older and weighing at least 40 kg) with 
unresectable or metastatic melanoma provides further justification for the inclusion of this 
population in future studies.
Existing data and National Comprehensive Cancer Network guidelines support ultrasonography 
as a preferred modality compared to other imaging modalities in the management of Stage III 
melanoma patients based on sensitivity, specificity, and surveillance benefit.9 Ultrasonography 
was updated as a study requirement for surveillance of participants who have a sentinel lymph 
node biopsy but do not undergo complete lymph node dissection (CLND) and left as optional for 
those with CLND.
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The benefit/risk section of the protocol was updated to reflect updated data from the publication 
of the combination dosing study in first-line metastatic melanoma, which continues to suggest a 
favorable safety profile of the combination therapy.
Additional minor changes include protocol clarifications, harmonization of collection durations 
(days or weeks versus months), and formatting changes. Revisions to the protocol summary have 
been made to align with changes throughout the protocol. This amendment includes changes from 
approved Administrative Letters 01, 02 and 04 and those changes are not listed in the table below.
References
1
Longo MI, Lázaro P, Bueno C, et al. Fluorodeoxyglucose-positron emission tomography 
imaging versus sentinel node biopsy in the primary staging of melanoma patients. Dermatol 
Surg 2003;29:245-8.
2
Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 
2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 
2001;8:101-8.
3
Harris MN, Shapiro RL, Roses DF. Malignant melanoma. Primary surgical management 
(excision and node dissection) based on pathology and staging. Cancer 1995;75(2 Suppl):715-
25.
4
Jen M, Murphy M, Grant-Kels JM. Childhood melanoma. Clin Dermatol 2009;27:529-36.
5
Saiyed FK, Hamilton EC, Austin MT. Pediatric melanoma: incidence, treatment, and 
prognosis. Pediatric Health Med Ther 2017;8:39-45.
9
Xing Y, Bronstein Y, Ross MI, et al. Contemporary diagnostic imaging modalities for the 
staging and surveillance of melanoma patients: a meta-analysis. J Natl Cancer Inst 2011;103: 
129-42.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Throughout
To align with the naming convention in the 
United States prescribing information 
(USPI), nivolumab will precede relatlimab 
when in reference to any combination 
therapy, and relatlimab and nivolumab 
FDC has been renamed to 
nivolumab + relatlimab (nivo + rela) fixed-
dose combination (FDC) throughout the 
protocol.
To align the naming convention with the 
USPI.
Protocol Summary
Text has been updated to align with 
changes made throughout the protocol.
Alignment between Protocol Summary 
and body of the protocol.
Table 2-1: Screening 
Procedural Outline 
(CA224098)
Specified complete physical examination 
at screening.
Clarification only.
Table 2-1: Screening 
Procedural Outline 
(CA224098)
In regard to the informed consent for 
adolescent participants, a note was added 
referencing Appendix 2 for details 
regarding minor assent.
Hyperlink added to reference to further 
details for minor assent.
Table 2-1: Screening 
Procedural Outline 
(CA224098) 
Section 6.1: Inclusion 
Criteria
For tumor sample submission procedures 
at baseline, the timeline for submission 
was updated from 3 months to 90 days for 
specificity.
Clarification on timing added for 
specificity.
Table 2-1: Screening 
Procedural Outline 
(CA224098)
Table 2-2: On Study 
Treatment Procedural 
Outline (CA224098)
Table 2-3: Follow-up 
Assessments 
(CA224098)
Section 9.1.1: Efficacy 
Assessment for the 
Study
Section 9.1.3: 
Investigator 
Assessment of Baseline 
Disease Status
Under the body imaging assessment, 
clarified that contrast-enhanced computed 
tomography (CT) scans for the listed body 
scans are required. 
Clarified the requirement for contrast-
enhanced CT imaging.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-1: Screening 
Procedural Outline 
(CA224098)
Table 2-2: On Study 
Treatment Procedural 
Outline (CA224098)
Table 2-3: Follow-up 
Assessments 
(CA224098)
Section 5.4.8: Rationale 
for Ultrasound in 
Disease Surveillance
The following changes were made to the 
ultrasound assessments:
•
Ultrasound will now be required of all
participants with positive sentinel
lymph node biopsy and who do not
undergo immediate complete lymph
node dissection (CLND). A note has
also been added to indicate ultrasound
is optional if the participant has
undergone CLND.
•
The ultrasound assessment interval on
study and during follow-up was
updated from 6 months to 26 weeks.
•
A new section that provides the
rationale for requiring ultrasound for
surveillance has been added.
Updated to make ultrasound a study 
requirement for all sentinel lymph node 
dissection (SLND) participants (rather 
than optional) based on the sensitivity 
and specificity of ultrasound as a 
surveillance modality, and to harmonize 
this requirement across the global and 
country-specific protocols.
Clarified timing to align with language 
previously used in the protocol (weeks 
vs months) for imaging duration.
Table 2-1: Screening 
Procedural Outline 
(CA224098
Table 2-2: On Study 
Treatment Procedural 
Outline (CA224098)
Performance status assessment has been 
updated to include both Eastern 
Cooperative Oncology Group (ECOG) and 
Lansky/Karnofsky assessments depending 
on participant age.
Performance scale has been updated to 
be used depending on participant age 
(adults vs adolescent age group).
Table 2-1: Screening 
Procedural Outline 
(CA224098)
Table 9.4.4-1: Clinical 
Laboratory 
Assessments
Table 2-2: On Study 
Treatment Procedural 
Outline (CA224098)
Participants must receive their first dose of 
study intervention within 3 days of 
randomization, changed from IRT drug 
assignment.
Consistency with other assessments that 
are based off randomization. 
Table 2-2: On Study 
Treatment Procedural 
Outline (CA224098)
Table 2-3: Follow-up 
Assessments 
(CA224098)
Appendix 9: Country 
Specific Requirements
Added detailed 
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-2: On Study 
Treatment Procedural 
Outline (CA224098)
Table 2-3: Follow-up 
Assessments 
(CA224098)
Section 9.1.1: Efficacy 
Assessment for the 
Study
The interval of timing between body 
imaging, brain imaging, and ultrasound has 
been updated from 6 months to 26 weeks, 
and 2 years has been clarified as 104 
weeks.
Clarified timing to harmonize with 
language previously used in the protocol 
(weeks vs. months) for imaging 
duration.
Table 2-2: On Study 
Treatment Procedural 
Outline (CA224098)
Table 2-3: Follow-up 
Assessments 
(CA224098)
Section 9.1.1: Efficacy 
Assessment for the 
Study
Follow-up body and brain imaging scans 
has been discontinued during follow-up, 
once systemic therapy starts for a 
melanoma recurrence or for a new non-
melanoma tumor after study drug 
discontinuation.
In Section 9.1.1, clarified when follow-up 
scans may be discontinued (ie, in cases 
when participant has started systemic 
therapy after unequivocal recurrence or for 
a new non-melanoma tumor after study 
drug discontinuation).
Clarification for when discontinuing 
imaging collections is allowed (after 
unequivocal recurrence or new non 
primary melanoma requiring systemic 
therapy).
Table 2-2: On Study 
Treatment Procedural 
Outline (CA224098)
Table 2-3: Follow-up 
Assessments 
(CA224098)
Section 9.1.5: Patient 
Reported Outcomes
Adolescent participants will only be 
required to complete the 
 
assessment for the patient-reported 
outcomes.
Adolescent population is 
Table 2-2: On Study 
Treatment Procedural 
Outline (CA224098)
Table 2-3: Follow-up 
Assessments 
(CA224098)
Tumor tissue collection via biopsy or 
surgical resection at disease recurrence 
must be performed if medically feasible 
and must be submitted to the central 
laboratory within 30 days of collection.
Clarification of protocol requirement 
and incorporation of a timeframe for 
submission of tissue specimen to the 
central laboratory.
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Date: 2 -Jul-2023
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Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-3: Follow-up 
Assessments 
(CA224098)
For concomitant medications, removed 
reference to subsequent therapy and 
specified collection of 
corticosteroid/immune-modulating 
medications only for AE/SAE considered 
study drug related.
Removal of subsequent therapy as it is 
addressed elsewhere and redundant and 
limiting the collection of 
corticosteroid/immune-modulating 
medications for safety.
Table 2-3: Follow-up 
Assessments 
(CA224098)
Figure 5.1-1: Study 
Design Schema
Section 5.3: End of 
Study Definition
Section 10.3: Analysis 
Sets
Section 10.4.1: General 
Considerations
For survival status in long-term follow-up, 
further specified timing of 12 weeks 
instead of 3 months and a window of 14 
days was included for consistency with the 
footnote. 
Harmonize timing of months to weeks 
and addition of window for scheduling 
flexibility.
Table 2-3: Follow-up 
Assessments 
(CA224098)
Table 4.1: Objectives 
and Endpoints
Table 10.4.3-2: 
Summary of Secondary 
Endpoint Analysis
Clarified the wording and intent of 
collecting subsequent therapy and 
associated outcomes for participants who 
recur.
Clarification only.
Table 2-3: Follow-up 
Assessments 
(CA224098)
Section 3: Introduction
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.1: Study 
Rationale
Section 3.2.2: 
Nivolumab Combined 
with Relatlimab 
Clinical Activity
Section 3.2.6: 
Nivolumab Combined 
with Relatlimab 
Clinical Safety
Section 3.3: 
Benefit/Risk 
Assessment
Additional data from the CA224047 study 
has been provided to support the clinical 
efficacy and safety of nivo + rela FDC.
Data from publication of combination 
dosing study in first-line metastatic 
melanoma updated to support rationale 
for combined clinical efficacy and 
safety. 
Section 3.2.2: 
Nivolumab Combined 
with Relatlimab 
Clinical Activity
Section 3.2.6: 
Nivolumab Combined 
with Relatlimab 
Clinical Safety
•
Clinical efficacy and safety sections
have been updated and streamlined.
•
Efficacy numbers for Study
 and
CA224047 overall survival/overall
response rate have been updated.
•
Updated safety information added for
study CA224020.
Updates per nivolumab + relatlimab 
FDC IB.
Section 3.2.6: 
Nivolumab Combined 
with Relatlimab 
Clinical Safety
Safety data information updated and 
clarified for earlier identification of 
cardiac risk based on actual study 
information.
Section 3.3: 
Benefit/Risk 
Assessment
Updated benefit/risk assessment for 
nivolumab and relatlimab combination 
therapy.
Updates per nivolumab + relatlimab 
FDC IB.
Table 3.3.1-1: Risk 
Assessment
Ultrasound added as a study procedure risk 
for comprehensiveness.
For treatment of imaging risks in the 
study, ultrasound was added.
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 4-1: Objectives 
and Endpoints
Section 10.1: Statistical 
Hypotheses
Section 10.4.1: General 
Considerations
Table 10.4.1-2: 
Definition of Estimands 
for Primary and 
Secondary Endpoints
Table 10.4.3-1: 
Secondary Efficacy 
Endpoints
Table 10.4.3-2: 
Summary of Secondary 
Endpoint Analysis
Table 4-1: Objectives 
and Endpoints
Section 10.4.1: General 
Considerations
Table 10.4.1-1: 
Censoring Scheme for 
Primary Definition of 
Recurrence-free 
Survival
Table 10.4.2-1: Primary 
Endpoints
Table 10.4.2-2: 
Summary of Primary 
Endpoint Analysis.
Table 4-1: Objectives 
and Endpoints
Table 4-1: Objectives 
and Endpoints
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.1: Overall 
Design
Section 5.4.7: Rationale 
for Inclusion of 
Adolescent Participants
Section 5.5.2: Dose 
Rationale for 
Adolescent Participants
Table 7.1-1: Study 
Interventions
Adolescent participants  12 years are now 
eligible to participate in the study. The 
protocol has been updated throughout to 
include pediatric dosing information, 
which for a subset of pediatric participants 
will be weight based.
Rationale for the inclusion of adolescent 
participants and dosing rationale for this 
population have been added.
Addition of adolescent participants.
Addition of dosing for adolescent 
participants aged  12 years to 18 years, 
including weight-based differences for 
this group of participants.
Figure 5.1-1: Study 
Design Schema
The study design schema and associated 
footnotes were updated per the changes to 
Protocol Amendment 01.
Addition of dosing for pediatric 
participants for nivo + rela FDC and 
nivolumab only added to study schema 
including footnotes.
Section 5.1.1: Data 
Monitoring Committee 
and Other Committees
Section 5.4.6: Rationale 
for Evaluation of 
Section 5.5.1: 
Justification for Fixed 
Dose Combination 
Dosing
•
Minor rewording throughout the
section and updated infusion safety
data have been provided.
•
Also updated text in regard to
population pharmacokinetic (PPK)
analysis.
•
Updated language for dose
justification for 
infusion.
Clarification of protocol verbiage and 
updates per nivolumab + relatlimab 
FDC IB
Section 5.6.1: 
Nivolumab Clinical 
Pharmacology 
Summary
Section 5.6.2: 
Relatlimab Clinical 
Pharmacology 
Summary
Updated language for clinical 
pharmacology of nivolumab and 
relatlimab.
Updates per nivolumab + relatlimab 
FDC IB.
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 6.1: Inclusion 
Criteria
Section 9.2: Adverse 
Events
Section 10.3: Analysis 
Sets
Appendix 2: Study 
Governance 
Considerations
Multiple changes were made 
throughout the protocol to include 
legally acceptable representatives 
(LAR):
Inclusion criterion 1) a) was 
modified to permit legally 
acceptable representatives (LAR) 
with the inclusion of pediatric 
participants.
Added participant’s LAR as an 
individual who may report AEs if 
applicable.
Redefined enrolled population as 
participant or their LAR who 
signed informed consent and were 
registered into Interactive Response 
Technology.
Inclusion of LAR in the informed 
consent process given inclusion of 
pediatric participants.
Updated the informed consent 
and AE reporting section for 
participants to conform with 
required regulatory and ethics 
guidelines for a legally 
acceptable representative.
Section 6.1: Inclusion 
Criteria
Section 6.2: Exclusion 
Criteria
Inclusion criterion 2) a) and 
exclusion criteria 1) a) were 
modified to exclude participants 
with ocular melanoma. 
Terminology change from uveal 
to ocular.
Section 6.1: Inclusion 
Criteria
Inclusion criterion 2) c) was 
modified regarding timing of 
complete resection prior to 
randomization, from 12 weeks to 90 
days.
Clarified timing to harmonize 
with language used in the 
protocol (days vs weeks).
Section 6.1: Inclusion 
Criteria
Inclusion criterion 2) d) was 
modified to require a brain 
magnetic resonance imaging (MRI) 
scan at screening.
Clarification on procedures 
required at study screening.
Section 6.1: Inclusion 
Criteria
Inclusion criterion 2) f) was 
modified to include both ECOG 
and Lansky/Karnofsky performance 
status scores, depending on 
participant age.
Clarification on performance 
scale for assessment of pediatric 
participants.
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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1.0
v

Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 6.1: Inclusion 
Criteria
Inclusion criterion 2) g) was added 
as a placeholder to align formatting 
with country-specific protocol 
amendments.
Added for formatting alignment 
with country-specific 
amendments.
Section 6.1: Inclusion 
Criteria
Inclusion criterion 3)a) was updated 
to criterion 3)b) to permit pediatric 
participants  12 years of age to 
participate unless local regulations 
do not permit participants 
< 18 years of age.
Clarification provided for 
pediatric participant inclusion to 
conform with local regulatory 
and institutional policies.
Section 6.2: Exclusion 
Criteria
Exclusion criterion 1) f) was 
updated to specify concurrent non-
melanoma malignancy.
Clarification that the criterion is 
referring to non-melanoma 
malignancy.
Section 6.2: Exclusion 
Criteria
Section 6.2: Exclusion 
Criteria
Section 6.2: Exclusion 
Criteria
Section 6.2: Exclusion 
Criteria
Table 7.1-1: Study 
Interventions
Added approved Opdualag™ to the 
current name of BMS-986213.
Naming update.
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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v

Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.1: Study 
Interventions 
Administered
A note regarding the pediatric 
dosing calculations for body weight 
dosing was included.
Clarification on using cumulative 
weight change for dose 
adjustments for newly added 
pediatric population.
Section 7.1.1: Study 
Treatment Details
•
The final bullet point regarding
participant discontinuation was
deleted as it is addressed in the
discontinuation section of the
protocol.
•
The term study treatment has
been replaced with
immunotherapy.
•
As all infusions are diluted, we
have removed an inaccurate
statement.
Minor rewording and corrections 
to the protocol as these items are 
addressed in different sections.
Section 7.3: Blinding
Text added to clarify that 
randomization schedules are 
provided directly to the individual 
dispensing blinded study 
intervention, but who are not 
involved in the study in any other 
aspect. 
To indicate that the blinding is 
maintained throughout the study 
by differentiating blinded versus 
unblinded individuals. 
Section 7.3: Blinding
Details regarding DMC access to 
unblinded treatment codes, and the 
timing of participant, investigator, 
site staff, and sponsor access to 
unblinded treatment assignments 
has been included. 
Clarifying information regarding 
timing of unblinding for DMC, 
sponsor, participants, 
investigator, site staff, and 
sponsor access to unblinded 
treatment assignments is added.
Section 7.4.2: Criteria 
to Resume Treatment
For consistency with Section 8.1.1, 
an exception regarding delays due 
to steroid taper in management of 
drug related-adverse events (AEs) 
was included.
Clarification for consistency.
Section 7.6: Treatment 
Compliance
Clarified that source data will be 
reviewed at routine monitoring 
visits.
Reworded for accuracy.
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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1.0
v

Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.7.1.1: 
Prohibited Treatments
Section 7.7.2: Other 
Restrictions and 
Precautions
Revised wording of text detailing 
restrictions of participation in other 
interventional clinical trials.
Clarification on restrictions for 
participating in interventional 
trials vs observational studies.
Section 7.7.2.1: 
SARS-CoV-2 
Vaccination Guidelines
Section 8.2.1: 
Individual 
Discontinuation Criteria
Clarified that at the time of 
discontinuation from the study, an 
immediate follow-up visit may be 
required.
Removed statement about an 
early termination visit as there is 
no such visit and clarified visit 
requirements at study drug 
discontinuation.
Section 9.1.2: Imaging 
Assessment for the 
Study
Removed a statement that 
assessments should be performed 
by the same investigator or delegate 
at all time points.
To reduce site burden of having 
the same investigator perform the 
assessment at all time points.
Section 9.1.3: 
Investigator 
Assessment of Baseline 
Disease Status
Section 9.1.4: 
Investigator 
Assessment of 
Recurrence
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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1.0
v

Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Minor clarification that 
questionnaires should be obtained 
prior to participant withdrawal from 
the study.
Clarification only.
Section 9.2.1: 
Time Period and 
Frequency for 
Collecting AE and SAE 
Information
For collection of nonserious 
adverse events, a timeframe of all 
study treatment and 135 days 
following discontinuation of study 
intervention was added, and added 
that adverse events associated with 
severe acute respiratory syndrome 
coronavirus-2 must be collected 
from time of consent and during 
treatment period.
The timeframe for the collection 
of non-serious AEs was added.
Table 9.4.4-1: Clinical 
Laboratory 
Assessments 
Updated TSH assessment to add 
total T3 and total T4.
Updated to align with the local 
lab collection parameters.
Protocol Amendment No.: 03
Date: 2 -Jul-2023
192
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Approved
1.0
v

Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 10.4.2-1: Primary 
Endpoints
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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v

Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.3: Analysis 
Sets
Table 10.4.1-1: 
Censoring Scheme for 
Primary Definition of 
Recurrence-free 
Survival
Table 10.4.1-2: 
Definition of Estimands 
for Primary and 
Secondary Endpoints
Clarification of the 
Clarification only.
Appendix 2: Study 
Governance 
Considerations
Added text for legally acceptable 
representatives in the informed 
consent process.
Added text based on inclusion of 
adolescent participants and 
participants who may not be able 
to provide consent.
Appendix 2: Study 
Governance 
Considerations
Added 2 new sections titled:
•
BMS Commitment to Diversity
in Clinical Trials
•
Data Protection, Data Privacy,
and Data Security
Added text for BMS’ 
commitment to diversity in 
clinical trials, and to align BMS 
practice and comply with EU-
CTR requirements.
Appendix 6: ECOG and 
Lansky/ Karnofsky 
Performance Status 
Scale
Lansky/Karnofsky performance 
status scale has been added.
Addition of performance 
assessment scale for pediatric 
participants.
Appendix 9: Country 
Specific Requirements
Germany’s requirements have been 
removed from the global protocol 
and will be included in their 
country-specific protocol.
Removed Germany-specific 
requirements as Germany has a 
country-specific amendment. 
Protocol Amendment No.: 03
Date: 2 -Jul-2023
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930169531
4.0
v
Approved
1.0
v

Clinical Protocol
CA224098
BMS-986213
nivolumab + relatlimab FDC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Appendix 9: Country 
Specific Requirements
All
Minor formatting and typographical 
corrections.
Changes are minor and therefore 
have not been summarized.
Protocol Amendment No.: 03
Date: 2 -Jul-2023
195
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930169531
4.0
v
Approved
1.0
v