A Phase 2 Open-label, Two-cohort Study to Evaluate Patient Preference for Nivolumab + Relatlimab Fixed-dose Combination Subcutaneous Versus Nivolumab + Relatlimab Fixed-dose Combination Intravenous and Nivolumab Subcutaneous Versus Nivolumab Intravenous in Participants With Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 2 Open-label, Two-cohort Study to Evaluate Patient Preference for 
Nivolumab + Relatlimab Fixed-dose Combination Subcutaneous versus Nivolumab + Relatlimab 
Fixed-dose Combination Intravenous and Nivolumab Subcutaneous versus Nivolumab 
Intravenous in Participants with Melanoma 
 
NCT Number: NCT06101134 
Document Date (Date in which document was last revised): 24 May 2024 
 
 
 

Page: 1 
Protocol Number: CA2241044 
Date: 29-Jun-2023
Revised Date: 24-May-2024
CLINICAL PROTOCOL CA2241044 
A Phase 2 Open-label, Two-cohort Study to Evaluate Patient Preference for 
nivolumab + relatlimab Fixed-dose Combination Subcutaneous versus nivolumab + relatlimab 
Fixed-dose Combination Intravenous and nivolumab Subcutaneous versus nivolumab 
Intravenous in Participants with Melanoma 
Compound: BMS-986213, BMS-986298, BMS-936558 
Brief Title: 
Patient Preference for Route of Administration with Intravenous Infusion Switch to Subcutaneous 
I-O Regimens in Melanoma
Protocol Amendment 01 
Medical Monitor Name and Contact Information: 
 
Clinical Trial Physician – Medical Monitor 
Bristol-Myers Squibb Company 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
Phone:
 
 
24-hr Emergency Telephone Number
USA: 1-866-470-2267
International: +1-248-844-7390
Sponsor Name and Legal Registered Address: 
Bristol-Myers Squibb Company 
Route 206 & Province Line Road 
Lawrenceville, NJ 08543 
Bristol-Myers Squibb Services Unlimited Company 
Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland 
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
2 
 
 
REGULATORY AGENCY IDENTIFIER NUMBER(S) 
 
IND Numbers: 150904 and 159987 
EU Trial Number 2023-504515-33  
UTN: U1111-1289-5947 
 
This document is confidential and proprietary information of Bristol-Myers Squibb 
Company (BMS) and its global affiliates. 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]). 
© 2024 Bristol-Myers Squibb Company 
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
3 
DOCUMENT HISTORY 
Document 
Date of Issue 
Summary of Changes 
Protocol 
Amendment 01 
24-May-2024 
This amendment incorporates changes to be consistent with study’s 
Pharmacy Manual, clarifying the methods for study drug 
administration. 
 
 
 
 Additionally, 
administrative changes including clarification regarding AE 
collection have been made including changes 
 
 
Original Protocol 
29-Jun-2023 
Not applicable. 
 
 
 
 
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CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01: 
This amendment includes updates for alignment with the study Pharmacy Manual and minor 
language updates for clarity, including consistency with 01 EU amendment.  
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & 
Title  
Description of Change 
Brief Rationale 
Regulatory Agency 
Identifier Number(s) 
Page 
Added the Investigational New Drug (IND) 
numbers: IND 150904 (nivolumab subcutaneous) 
and IND 159987 (Nivo/Rela FDC SC).  
The EU Trial Number was corrected (removal of 
last 2 digits ‘00’). 
To be consistent with 
BMS standards. 
Corrections were 
made based on EU 
CTR guidance. 
Section 2 Schedule of 
Activities 
Table 2-1: Screening 
Procedural Outline 
(Cohort 1 - Metastatic 
Melanoma) 
Added AE collection to the procedures and in the 
notes clarified the timeframe of AE/SAE 
collection. 
To clarify that both 
AEs and SAEs are to 
be assessed and their 
timeframe of 
collection.  
Section 2 Schedule of 
Activities 
Table 2-2: Screening 
Procedural Outline 
(Cohort 2 - Resected 
Melanoma) 
In the notes column for AE/SAE Assessment: 
clarified that all AEs and SAEs will be collected 
and the timeframe of collection. 
In the notes column for Clinical Laboratory 
Assessment, language was added for local 
laboratory tests and information included on 
 and HIV viral testing, 
 
 to align 
with Cohort 1 Screening Table 2-1. 
To clarify that both 
AEs and SAEs are to 
be assessed and to 
clarify the timeframe 
for collection. 
To align with 
Cohort 1 Screening 
viral Laboratory 
Assessments. 
Section 2 Schedule of 
Activities 
Table 2-3: 
On-treatment 
Procedural Outline 
In the notes column for AE and SAE Assessment: 
clarified that all AEs and SAEs will be collected 
and the timeframe of collection. 
To clarify that both 
AEs and SAEs are to 
be assessed and to 
clarify the timeframe 
for collection. 
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CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
5 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & 
Title  
Description of Change 
Brief Rationale  
(Cohort 1 - Metastatic 
Melanoma) 
Section 2 Schedule of 
Activities 
Table 2-4: 
On-treatment 
Procedural Outline 
(Cohort 2 - Resected 
Melanoma) 
Safety assessment 
 
 
 
In the notes column for AE and SAE Assessment: 
clarified that all AEs and SAEs will be collected 
and the timeframe of collection. 
To align Cohort 2 
Schedule of Activities 
Table 2-4 safety 
assessments with 
Cohort 1 Schedule of 
Activities Table 2-3 
safety assessments.  
To clarify that both 
AEs and SAEs are to 
be assessed and to 
clarify the timeframe 
for collection. 
Section 3.2 
Background 
Section 3.3.1 
Cohort 1 (nivolumab + 
relatlimab) 
Deleted the mention of ‘unmet medical need’ for 
this study population. 
To avoid 
misinterpretation with 
the other BMS 127 
study.  
Section 3.3.1: Cohort 1 
(nivolumab + 
relatlimab)  
Add the following text “regardless of PD-L1 
expression” to the first paragraph in this section.  
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CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & 
Title  
Description of Change 
Brief Rationale  
 
 
 
 
Section 7.1.3 
Subcutaneous 
Administration of 
nivolumab Combined 
with relatlimab 
Administration 
 
 
 
 
 
 
 
 
 
Instructions regarding 
administration are 
provided in the 
Pharmacy Manual. 
Section 9.2.1 
Period and Frequency 
for Collecting AE and 
SAE Information 
This section was revised to clarify that the 
timeframe of AE and SAE collection (including if 
associated with confirmed or suspected 
SARS-CoV-2 infection) begins at the time of 
signing the informed consent. 
To provide 
clarification of the 
timeframe for the start 
of AE/SAE collection. 
Section 11 
References 
Latest versions of the Investigators Brochure’s 
(IB) were added and/or updated, and a new 
reference for nivolumab (subcutaneous) IB was 
added. 
To reflect latest 
versions and to align 
with EU submissions. 
Appendix 8 
Country Specific 
Requirements/ 
Differences 
Deleted the mention of “Argentina”. 
Argentina is no longer 
a participating 
country. 
Synopsis and 
throughout the 
document  
Where applicable, the synopsis was updated for 
consistency in line with the above changes to the 
main body. In addition, minor formatting and 
typographical corrections were made to the 
document. 
To improve overall 
readability, 
consistency. 
 
 
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CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
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TABLE OF CONTENTS 
TITLE PAGE....................................................................................................................................1 
CLINICAL PROTOCOL CA2241044 ............................................................................................1 
DOCUMENT HISTORY.................................................................................................................3 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01: ...............................................4 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01 ............................................4 
TABLE OF CONTENTS .................................................................................................................7 
1 
PROTOCOL SUMMARY ..........................................................................................11 
2 
SCHEDULE OF ACTIVITIES ..................................................................................26 
3 
INTRODUCTION ......................................................................................................42 
3.1 
Study Rationale ...........................................................................................................43 
3.2 
Background .................................................................................................................43 
3.2.1 
Relatlimab Mechanism of Action ................................................................................44 
3.2.2 
Nivolumab Combined with relatlimab Pre-clinical Activity ......................................45 
3.2.3 
Nivolumab Combined with relatlimab Clinical Activity .............................................45 
3.2.4 
Nivolumab Combined with relatlimab Clinical Safety ...............................................47 
3.2.5 
Nivolumab Mechanism of Action ................................................................................48 
3.2.6 
Nivolumab Clinical Activity ........................................................................................48 
3.2.7 
Nivolumab Clinical Safety ..........................................................................................48 
3.2.8 
Recombinant Human Hyaluronidase PH20 Enzyme ..................................................49 
3.2.9 
Nonclinical Toxicity of Recombinant Human Hyaluronidase PH20 ..........................49 
3.3 
Benefit/Risk Assessment ............................................................................................50 
3.3.1 
Cohort 1 (nivolumab + relatlimab) ............................................................................50 
3.3.2 
Cohort 2 (nivolumab) .................................................................................................51 
3.3.3 
General Considerations ..............................................................................................51 
4 
OBJECTIVES AND ENDPOINTS ............................................................................53 
5 
STUDY DESIGN .......................................................................................................55 
5.1 
Overall Design ............................................................................................................55 
5.1.1 
Screening Phase ..........................................................................................................56 
5.1.2 
Treatment Period ........................................................................................................56 
5.1.3 
Follow-Up Period .......................................................................................................56 
5.1.4 
Data Monitoring Committee and Other Committees ..................................................57 
5.2 
Number of Participants ...............................................................................................57 
5.3 
End of Study Definition ..............................................................................................57 
5.4 
Scientific Rationale for Study Design ........................................................................58 
...58 
...58 
...58 
...59 
5.4.2 
Cohort 2: Resected Melanoma: ..................................................................................59 
5.4.2.1 
Rationale for Use of nivolumab ..................................................................................59 
 
 ...............................................................................60 
5.4.3 
Rationale for Patient Preference Endpoints ...............................................................60 
 
 
 .................................................................................................................60 
5.5 
Justification of Dose ...................................................................................................61 
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5.5.1 
Nivolumab Clinical Pharmacology Summary ............................................................61 
 
 ............................................................61 
5.5.3 
Justification of nivolumab + relatlimab FDC IV Dose ..............................................62 
 
 .............................................62 
5.5.5 
Justification of nivolumab IV Dose .............................................................................63 
5.5.6 
Justification of nivolumab SC Dose ............................................................................63 
6 
STUDY POPULATION .............................................................................................65 
6.1 
Inclusion Criteria ........................................................................................................65 
6.1.1 
Inclusion Criteria for Cohort 1...................................................................................65 
6.1.2 
Inclusion Criteria for Cohort 2...................................................................................67 
6.2 
Exclusion Criteria .......................................................................................................69 
6.2.1 
Exclusion Criteria for Cohort 1 ..................................................................................69 
6.2.2 
Exclusion Criteria for Cohort 2 ..................................................................................72 
6.3 
Lifestyle Restrictions ..................................................................................................75 
6.4 
Screen Failures ............................................................................................................75 
6.4.1 
Re-testing During Screening .......................................................................................75 
7 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................76 
7.1 
Study Interventions Administered ..............................................................................77 
7.1.1 
General Considerations ..............................................................................................78 
7.1.2 
Intravenous Administration of nivolumab Combined with relatlimab 
Administration 
 ...............................................................79 
7.1.3 
Subcutaneous Administration of nivolumab Combined with relatlimab 
Administration 
 .........................................79 
7.1.4 
Intravenous Administration of nivolumab 
.....................80 
7.1.5 
Subcutaneous Administration of nivolumab with rHuPH20 
 
 ......................................................................................80 
7.2 
Assignment to Study Intervention ..............................................................................81 
7.3 
Blinding ......................................................................................................................81 
7.4 
Dosage Modification ..................................................................................................82 
7.4.1 
Dose Delay Criteria for nivolumab and nivolumab + relatlimab FDC .....................82 
...95 
...95 
7.4.4 
Treatment of Related Infusion- and Injection-reactions .............................................96 
 
 .....................................................................96 
7.4.4.2 
Management of Local Infusion or Injection Site Reactions........................................97 
7.4.4.3 
Management of Needle Stick Injuries .........................................................................97 
7.5 
Preparation/Handling/Storage/Accountability ............................................................97 
7.6 
Study Intervention Compliance ..................................................................................98 
7.7 
Concomitant Therapy .................................................................................................98 
 
 ...................................................................98 
7.7.2 
Other Restrictions and Precautions ............................................................................99 
7.7.2.1 
Imaging Restrictions and Precautions ........................................................................99 
...............................................................................................100 
...............................................................................................100 
7.7.4 
Antiviral Therapy ......................................................................................................100 
7.8 
Continued Access to Study Intervention After the End of the Study .......................101 
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
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8 
DISCONTINUATION CRITERIA ..........................................................................101 
8.1 
Discontinuation of Study Intervention......................................................................101 
 
 ........103 
8.3 
Discontinuation From the Study ...............................................................................103 
8.3.1 
Individual Discontinuation Criteria .........................................................................104 
8.4 
Lost to Follow-up .....................................................................................................104 
9 
STUDY ASSESSMENTS AND PROCEDURES ....................................................105 
9.1 
Efficacy Surveillance ................................................................................................106 
9.1.1 
Imaging Assessment for the Study ............................................................................106 
9.1.2 
Investigator Assessment of Recurrence/Progression ................................................106 
9.1.3 
Clinical Outcome Assessments .................................................................................106 
9.1.3.1 
Patient Experience Questionnaire (PEQ) and Patient Experience and 
Preference Questionnaire (PEPQ) ...........................................................................107 
 
 .....................................107 
9.2 
Adverse Events .........................................................................................................108 
9.2.1 
Period and Frequency for Collecting AE and SAE Information ..............................108 
9.2.2 
Method of Detecting AEs and SAEs ..........................................................................109 
9.2.3 
Follow-up of AEs and SAEs ......................................................................................109 
9.2.4 
Regulatory Reporting Requirements for SAEs .........................................................110 
9.2.5 
Pregnancy .................................................................................................................110 
9.2.6 
Laboratory Test Result Abnormalities ......................................................................111 
9.2.7 
Potential Drug-induced Liver Injury ........................................................................111 
9.2.8 
Other Safety Considerations .....................................................................................111 
9.3 
Overdose ...................................................................................................................111 
9.4 
Safety ........................................................................................................................112 
9.4.1 
Physical Examinations ..............................................................................................112 
9.4.2 
Vital Signs .................................................................................................................112 
 
 ..................................................................................................112 
9.4.4 
Clinical Safety Laboratory Assessments ...................................................................112 
9.4.5 
Imaging/Other Safety Assessment.............................................................................113 
9.5 
Pharmacokinetics ......................................................................................................113 
9.6 
Immunogenicity Assessments ..................................................................................113 
9.7 
Biomarkers ................................................................................................................113 
9.7.1 
Germline Genetics ....................................................................................................113 
9.7.2 
Other Biomarkers .....................................................................................................113 
9.8 
Optional Future Research .........................................................................................114 
10 
STATISTICAL CONSIDERATIONS .....................................................................114 
10.1 
Statistical Hypotheses ...............................................................................................114 
10.2 
Sample Size Determination ......................................................................................114 
10.3 
Analysis Sets .............................................................................................................115 
10.4 
Statistical Analyses ...................................................................................................115 
10.4.1 
General Considerations ............................................................................................116 
10.4.2 
Primary Endpoint(s) .................................................................................................116 
10.4.3 
Secondary Endpoint(s) ..............................................................................................116 
 
...........................................................................................117 
10.4.5 
Other Safety Analyses ...............................................................................................117 
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CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
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10.4.6 
Other Analyses ..........................................................................................................117 
 
 .......................................................................................................117 
11 
REFERENCES .........................................................................................................118 
12 
APPENDICES ..........................................................................................................121 
APPENDIX 1 
ABBREVIATIONS ......................................................................................122 
APPENDIX 2 
STUDY GOVERNANCE CONSIDERATIONS ........................................124 
APPENDIX 3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING .................................135 
APPENDIX 4 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..........................................................139 
.143 
APPENDIX 6 
ECOG PERFORMANCE STATUS SCALE AND CONVERSION 
FORM ...........................................................................................................153 
APPENDIX 7 
AJCC MELANOMA STAGING (CANCER STAGING MANUAL 
8TH EDITION) ..............................................................................................154 
APPENDIX 8 
COUNTRY SPECIFIC REQUIREMENTS/DIFFERENCES .....................155 
APPENDIX 9 
PRODUCT QUALITY ISSUES ..................................................................156 
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CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
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1 
PROTOCOL SUMMARY 
Protocol Title: 
A Phase 2, Open-label, Two-cohort Study to Evaluate Patient Preference for 
nivolumab + relatlimab Fixed-dose Combination Subcutaneous versus nivolumab + relatlimab 
Fixed-dose Combination Intravenous and nivolumab Subcutaneous versus nivolumab 
Intravenous in Participants with Melanoma 
Brief Title:  
Patient Preference for Route of Administration with Intravenous Infusion Switch to Subcutaneous 
I-O Regimens in Melanoma   
Rationale: 
With the growing cancer patient population and increasing burden on healthcare resources, there 
is a need for more efficient treatment options, such as alternative routes of administration. 
 
 
 
 
 
 
 
 CA2241044 will address this important data question by 
assessing the patient’s preference for nivolumab SC or nivolumab + relatlimab FDC SC and 
provide patient experience data by route of administration. The study will also generate data to 
further characterize the safety profile of immuno-oncology (IO) therapy in patients switching the 
route of administration from IV to SC. 
 
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
Cohort 1: Metastatic melanoma  
Primary 
Cohort 1: Metastatic melanoma  
• 
To evaluate participants’ preference for route 
of 
administration 
upon 
switching 
from 
nivolumab + relatlimab FDC IV to nivolumab 
+ relatlimab FDC SC  
Cohort 2: Resected melanoma  
• 
To evaluate participants’ preference for route 
of 
administration 
upon 
switching 
from 
nivolumab IV to nivolumab SC  
• 
Proportion of evaluable participants that prefer SC route 
of administration using the Patient Experience and 
Preference Questionnaire (Question 7) after Cycle 4 
Day 1 dose 
Cohort 2: Resected melanoma  
• 
Proportion of evaluable participants that prefer SC route 
of administration using the Patient Experience and 
Preference Questionnaire (Question 7) after Cycle 4 
Day 1 dose 
Secondary 
Cohort 1: Metastatic melanoma  
Secondary 
Cohort 1: Metastatic melanoma  
• 
To assess the safety and tolerability of 
nivolumab + relatlimab FDC IV and nivolumab 
+ relatlimab FDC SC  
Cohort 2: Resected melanoma  
• 
To assess the safety and tolerability of 
nivolumab IV and nivolumab SC 
• 
AEs, SAEs, treatment-related AEs, AEs leading to 
discontinuation, IMAEs, OESIs, injection/infusion 
related AEs, deaths and laboratory abnormalities  
Cohort 2: Resected melanoma  
• 
AEs, SAEs, treatment-related AEs, AEs leading to 
discontinuation, IMAEs, OESIs, injection/infusion 
related AEs, deaths and laboratory abnormalities  
Abbreviations: AE, adverse event; FDC, fixed-dose combination; 
; IMAEs, 
immune-mediated adverse events; IV, intravenous; OESIs, other events of special interest; SAE, serious adverse 
event; SC, subcutaneous. 
Overall Design: 
CA2241044 is a Phase 2, open-label, two-cohort study to evaluate patient preference for 
nivolumab SC or nivolumab + relatlimab FDC SC versus the IV formulations in participants with 
previously untreated Stage III (unresectable) or Stage IV (metastatic) melanoma (Cohort 1) and 
those with completely resected Stage IIB/C, III, or IV (Cohort 2).  
In Cohort 1, 
 adult participants with previously untreated unresectable (Stage III) or metastatic 
(Stage IV) melanoma will be treated with nivolumab + relatlimab FDC IV for 2 treatment cycles 
followed by nivolumab + relatlimab FDC SC until disease progression, unacceptable toxicity, 
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Clinical Protocol 
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Protocol Amendment No. 01 
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death, end of study, withdrawal of consent, or a maximum treatment duration of 2 years, whichever 
comes first.  
In Cohort 2, 
 adult participants with completely resected Stage IIB/C, III, or IV melanoma will 
be treated with nivolumab IV for 2 treatment cycles followed by nivolumab SC until disease 
recurrence, unacceptable toxicity, death, end of study, withdrawal of consent, or a maximum 
treatment duration of 1 year, whichever comes first.   
Number of Participants: 
Approximately 
 participants will be enrolled in two cohorts of 
 treated participants each. 
• Cohort 1: 
 treated participants with previously untreated Stage III (unresectable) or Stage IV 
(metastatic) melanoma 
 
 
• Cohort 2: 
 treated participants with completely resected Stage IIB/C, III, or Stage IV 
(≤ 12 weeks post resection) 
 
 
 
Study Population: 
Inclusion Criteria for Cohort 1 
Participants are eligible to be included in the study only if all the following criteria apply: 
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CA2241044 
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Protocol Amendment No. 01 
Date: 24-May-2024 
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1) Signed Written Informed Consent 
a) Participants must have signed and dated an Institutional Review Board /Independent Ethics 
Committee 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 testing, and other requirements of the study. 
2) Type of Participant and Target Disease Characteristics 
a) Participants must have an Eastern Cooperative Oncology Group performance status 
(ECOG PS) score of ≤ 1. 
b) Participants must have histologically confirmed Stage III (unresectable) or Stage IV 
(metastatic) melanoma, per the American Joint Committee on Cancer (AJCC) staging 
system (8th edition). 
c) Participants must be treatment-naïve (ie, no prior systemic anticancer therapy) for 
unresectable or metastatic melanoma. 
d) Participants are eligible regardless of BRAF status. Participants with known BRAF V600 
mutation status, or who consent to BRAF V600 mutation testing per local institutional 
standards during the Screening Period with the sample collected within 3 months prior to 
treatment assignment must report BRAF status. 
3) Age of Participant  
Participants must be ≥ 18 years of age at the time of consent.  
4) Reproductive Status 
a) Female Participants: 
i) Female participants must have documented proof that they are not of childbearing 
potential. 
Note: Women who are not of childbearing potential (as defined in Appendix 4) are 
exempt from contraceptive requirements.  
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Clinical Protocol 
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BMS-986213 
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Protocol Amendment No. 01 
Date: 24-May-2024 
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ii) WOCBP must have a negative highly sensitive serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) 
within 24 hours prior to the start of study intervention. An extension up to 72 hours 
prior to start of study treatment is permissible in situations where results cannot be 
obtained within the standard 24-hour window. 
i) WOCBP must agree to follow instructions for method(s) of contraception as described 
below and included in the ICF. 
• WOCBP are permitted to use hormonal contraception methods (as described in Appendix 4). 
ii) 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 (with a 
failure rate of < 1% per year), with low user dependency, during the intervention 
period and for the duration of treatment with nivolumab and relatlimab plus 5 half-
lives of study treatment for 
 post-treatment completion and 
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the 
same time period. 
 
Inclusion Criteria for Cohort 2 
Participants are eligible to be included in the study only if all the following criteria apply: 
1) Signed Written Informed Consent 
a) Participants must have signed and dated an Institutional Review Board /Independent Ethics 
Committee 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 testing, and other requirements of the study. 
2) Type of Participant and Target Disease Characteristics 
a) Participants must have an (ECOG-PS) score of ≤ 1. 
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
16 
b) Participants must be eligible for adjuvant therapy for melanoma.  
i) All participants must have completed surgical resection of Stage IIB/C, IIIA (> 1 mm 
tumor in lymph node)/B/C/D or stage IV (AJCC Cancer Staging, 8th edition) 
melanoma. All melanomas, except ocular and mucosal melanomas, are allowed 
regardless of primary site of disease.  
ii) Participants with complete melanoma resection within 12 weeks of treatment 
assignment. Participants must be surgically rendered free of disease with negative 
margins on resected specimens. Complete resection must be documented on surgical 
and pathology report. For central nervous system (CNS) lesion(s), documentation 
indicating that there has been complete resection of CNS lesion(s) will suffice as 
confirmation of negative margins. 
c) All participants must have disease-free status documented by a complete physical 
examination and imaging studies within 4 weeks prior to treatment assignment. Imaging 
studies must include computed tomography (CT) or magnetic resonance imaging (MRI) 
scans of the chest, abdomen, pelvis, and all known sites of resected disease, and brain MRI 
or CT with contrast (brain CT allowable if MRI is contraindicated or if there is no known 
history of resected brain lesions). 
3) Age of Participant  
Participants must be ≥ 18 years of age at the time of consent.  
4) Reproductive Status 
a) Female Participants: 
i) Female participants must have documented proof that they are not of childbearing 
potential. 
Note: Women who are not of childbearing potential (as defined in Appendix 4) are 
exempt from contraceptive requirements.  
ii) WOCBP must have a negative highly sensitive serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) 
within 24 hours prior to the start of study intervention. An extension up to 72 hours 
prior to start of study treatment is permissible in situations where results cannot be 
obtained within the standard 24-hour window. 
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
17 
i) WOCBP must agree to follow instructions for method(s) of contraception as described 
below and included in the ICF. 
• WOCBP are permitted to use hormonal contraception methods (as described in Appendix 4). 
i) 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 (with a 
failure rate of < 1% per year), with low user dependency, during the intervention 
period and for the duration of treatment with nivolumab and relatlimab plus 5 half-
lives of study treatment for 
 post-treatment completion and 
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the 
same time period. 
 
Exclusion Criteria for Cohort 1 
Participants are excluded from the study if any of the following criteria apply: 
1) Medical Conditions 
a) Participants must not have active brain metastases or leptomeningeal metastases. 
b) Participants with brain disease treated with whole brain radiation are not eligible. 
c) Participants must not have ocular or mucosal melanoma. 
d) Participants must not have an active, known, or suspected autoimmune disease. 
e) Participants may enroll with the following conditions: 
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
18 
i) Type 1 diabetes mellitus. 
ii) Hypothyroidism only requiring hormone replacement therapy. 
iii) Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment. 
iv) Conditions not expected to recur in the absence of an external trigger. 
f) Participants must not have a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 
 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. 
g) Participants must not have a concurrent malignancy (present during screening) requiring 
treatment or history of prior malignancy active within 2 years prior to treatment assignment 
(ie, participants with a history of prior malignancy are eligible if treatment was completed 
at least 2 years before treatment assignment and the participant has no evidence of disease). 
Participants with history of prior early stage basal/squamous cell skin cancer or 
non-invasive or in situ cancers that have undergone definitive treatment at any time are 
also eligible. 
h) Participants must not have known human immunodeficiency virus (HIV) positive with an 
acquired immunodeficiency syndrome 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) for at least 4 weeks prior to treatment 
assignment as clinically indicated.  
ii) they continue on ART as clinically indicated while enrolled on study. 
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. (Refer to Appendix 8.) 
i) Participants must not have any serious or uncontrolled medical disorder that, in the opinion 
of the investigator in consultation with the BMS Medical Monitor, may increase the risk 
associated with study participation or study treatment administration, impair the ability of 
the participant to receive protocol therapy, or interfere with the interpretation of study 
results. 
j) Participants must not have previous SARS-CoV-2 infection either suspected or confirmed 
within 4 weeks prior to screening. Acute symptoms must have resolved and based on 
investigator assessment in consultation with the Medical Monitor, there are no sequelae 
that would place the participant at a higher risk of receiving investigational treatment. 
k) Participant has not recovered adequately from toxicity and/or complications from surgery 
prior to starting study treatment 
l) Participants must not have a history of myocarditis, regardless of etiology.  
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
19 
2) Reproductive Status 
a) Women who are breastfeeding. 
b) Women who are pregnant. 
3) Prior/Concomitant Therapy 
a) Participant must not have had prior treatment with an anti-PD-1 (except if given as adjuvant 
or neoadjuvant therapy for melanoma), anti- programmed death-ligand 1 (PD-L1), 
anti-programmed death-ligand 2 (PD-L2), anti-CTLA-4 antibody (except if given as 
adjuvant or neoadjuvant therapy for melanoma), or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways (except for interferon 
given as adjuvant or neoadjuvant therapy for melanoma) within 6 months prior to start of 
study treatment 
b) Participant must not have had prior treatment with relatlimab or any other lymphocyte 
activation gene-3 targeted agents. 
c) Inability to comply with restrictions and prohibited treatments. 
d) Treatment with complementary medications (eg, herbal supplements or traditional Chinese 
medicines) to treat the disease under study within 2 weeks prior to first study treatment. 
Such medications are permitted if they are used as supportive care. 
e) 
. Participants must have 
recovered (ie, Grade ≤ 1 or at baseline) from radiation-related toxicities prior to first study 
treatment. 
f) Treatment with any live / attenuated vaccine within 30 days of first study treatment. 
g) Participants currently in other interventional trials, including those for coronavirus disease 
2019 (COVID-19), may not participate in BMS clinical trials until the protocol specific 
washout period is achieved. If a study participant has received an investigational 
COVID-19 vaccine or other investigational product designed to treat or prevent COVID-19 
prior to screening, treatment assignment must be delayed until the biologic impact of the 
vaccine or investigational product is stabilized, as determined by discussion between the 
investigator and the Medical Monitor. 
2.0
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Approved
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v

Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
20 
5) Allergies and Adverse Drug Reactions 
a) Participants must not have a history of allergy or hypersensitivity to study intervention 
components. 
6) Other Exclusion Criteria 
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 Sponsor approval is required.) 
 
Exclusion Criteria for Cohort 2 
Participants are excluded from the study if any of the following criteria apply: 
1) Medical Conditions 
a) Participants must not have active brain metastases or leptomeningeal metastases. 
b) Participants with brain disease treated with whole brain radiation are not eligible. 
c) Participants must not have ocular or mucosal melanoma. 
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
21 
d) Participants must not have an active, known, or suspected autoimmune disease. 
e) Participants may enroll with the following conditions: 
i) Type 1 diabetes mellitus. 
ii) Hypothyroidism only requiring hormone replacement therapy. 
iii) Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment. 
iv) Conditions not expected to recur in the absence of an external trigger. 
f) Participants must not have a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 
 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. 
g) Participants must not have a concurrent malignancy (present during screening) requiring 
treatment or history of prior malignancy active within 2 years prior to treatment assignment 
(ie, participants with a history of prior malignancy are eligible if treatment was completed 
at least 2 years before treatment assignment and the participant has no evidence of disease). 
Participants with history of prior early stage basal/squamous cell skin cancer or 
non-invasive or in situ cancers that have undergone definitive treatment at any time are 
also eligible. 
h) Participants must not have known human immunodeficiency virus (HIV) positive with an 
acquired immunodeficiency syndrome 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) for at least 4 weeks prior to treatment 
assignment as clinically indicated.  
ii) they continue on ART as clinically indicated while enrolled on study. 
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. (Refer to Appendix 8.) 
i) Participants must not have any serious or uncontrolled medical disorder that, in the opinion 
of the investigator in consultation with the BMS Medical Monitor, may increase the risk 
associated with study participation or study treatment administration, impair the ability of 
the participant to receive protocol therapy, or interfere with the interpretation of study 
results. 
j) Participants must not have previous SARS-CoV-2 infection either suspected or confirmed 
within 4 weeks prior to screening. Acute symptoms must have resolved and based on 
2.0
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
22 
investigator assessment in consultation with the Medical Monitor, there are no sequelae 
that would place the participant at a higher risk of receiving investigational treatment. 
2) Reproductive Status 
a) Women who are breastfeeding. 
b) Women who are pregnant. 
3) Prior/Concomitant Therapy 
a) Participant must not have had prior treatment with an anti-PD-1 (except if given as adjuvant 
or neoadjuvant therapy for melanoma), anti-programmed death-ligand 1 (PD-L1), 
anti-programmed death-ligand 2 (PD-L2), anti-CTLA-4 antibody (except if given as 
adjuvant or neoadjuvant therapy for melanoma), or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways (except for interferon 
given as adjuvant or neoadjuvant therapy for melanoma)  
b) Participant must not have had prior treatment with relatlimab or any other lymphocyte 
activation gene-3 targeted agents. 
c) Inability to comply with restriction and prohibited treatments. 
d) Treatment with complementary medications (eg, herbal supplements or traditional Chinese 
medicines) to treat the disease under study within 2 weeks prior to first study treatment. 
Such medications are permitted if they are used as supportive care. 
e) 
. Participants must have 
recovered (ie, Grade ≤ 1 or at baseline) from radiation-related toxicities prior to first study 
treatment. 
f) Treatment with any live / attenuated vaccine within 30 days of first study treatment. 
g) Participants currently in other interventional trials, including those for coronavirus disease 
2019 (COVID-19), may not participate in BMS clinical trials until the protocol specific 
washout period is achieved. If a study participant has received an investigational 
COVID-19 vaccine or other investigational product designed to treat or prevent COVID-19 
prior to screening, treatment assignment must be delayed until the biologic impact of the 
vaccine or investigational product is stabilized, as determined by discussion between the 
investigator and the Medical Monitor. 
2.0
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930207750
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Approved
1.0
v

Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
23 
5) Allergies and Adverse Drug Reactions 
Participants must not have a history of allergy or hypersensitivity to study intervention 
components. 
6) Participants must not have active brain metastases or leptomeningeal metastases. 
7) Prior immunotherapy treatments for any prior malignancies are not permitted (such as, but not 
limited to anti-PD-1, anti-PD-L1, PD-L2, or any other antibody or drug specifically targeting 
T-cell co-stimulation or immune checkpoint pathways). 
8) Other Exclusion Criteria 
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 
Sponsor approval is required.) 
 
Intervention Groups and Duration: 
Approximately 
 participants will be enrolled in two cohorts of 
 treated participants each.  
Cohort 1: 
 treated participants in Cohort 1 (metastatic melanoma) 
 
;  
Participants will receive two cycles of treatment with nivolumab (480 mg) and relatlimab (160mg) 
FDC (nivolumab + relatlimab FDC IV). Starting with Cycle 3, participants will receive nivolumab 
(960 mg) and relatlimab (320 mg) FDC and rHuPH20 SC (nivolumab + relatlimab FDC SC). 
Participants will continue to receive study treatment until investigator-determined disease 
progression, unacceptable toxicity, withdrawal of consent, lost to follow-up, completion of up to 
2 years (104 weeks) of treatment, death, or the end of study, whichever occurs first.   
Participants will be permitted to continue study treatment beyond disease progression, as 
determined by investigator, provided that the treating investigator considers that the participant 
may experience clinical benefit with continued treatment, and the participant is tolerating study 
treatment with a stable or improved performance and clinical status 
 
  
 
Cohort 2: 
 treated participants in Cohort 2 (resected melanoma) 
 
 
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
24 
Participants will receive two cycles of treatment with nivolumab (480 mg) (nivolumab IV). 
Starting with Cycle 3, participants will receive nivolumab (1200 mg) and rHuPH20 SC (nivolumab 
SC). Participants will continue to receive study treatment until investigator-determined disease 
recurrence, unacceptable toxicity, withdrawal of consent, lost to follow-up, completion of up to 
1 year (52 weeks) of treatment, death, or the end of study, whichever occurs first.   
 
Study Intervention: 
Study Intervention for CA2241044 
Intervention Name 
Unit Dose Strength(s) 
IP/IMP/Non IP/ 
Non IMP/AxMP 
nivolumab + relatlimab FDC IV 
IMP 
nivolumab + relatlimab FDC SC 
IMP 
nivolumab IV 
nivolumab (10 mg/mL) 
IMP 
nivolumab SC 
IMP 
Abbreviations: AxMP, Auxiliary Medicinal Product; FDC, Fixed-dose combination; IMP, Investigational Medicinal 
Product; IP, Investigational Product; IV, Intravenous; Non-IMP, Non-investigational Medicinal Product; 
Non-IP, Non-investigational Product; SC, Subcutaneous.  
 
Statistical Methods: 
All analyses will be descriptive in nature. Descriptive statistics including n (the corresponding 
sample size), means, medians, standard deviations, minimum, and maximum will be calculated for 
continuous variables, and categorical data will be summarized using frequency counts and 
percentages. 
 
 
Data Monitoring Committee: No 
A Data Monitoring Committee will not be used in the study.  
Brief Summary: 
With the advancement in I-O therapies, cancer patients are surviving longer while receiving 
long-term maintenance therapy. Currently, immunotherapies are administered by IV infusion. The 
option of treatment administered by subcutaneous injection presents multiple potential benefits, 
including shorter administration times (less than 5 minutes) as compared with IV infusion (30 to 
60 minutes), improved patient quality of life as well as efficiencies in healthcare resource 
utilization.  
Immunotherapy has become the standard of care for the treatment of melanoma.  
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
25 
The pivotal Phase 2/3 CA224047 study demonstrated clinical benefit with nivolumab 480 mg + 
relatlimab 160 mg IV FDC Q4W in participants with previously untreated metastatic or 
unresectable melanoma and has received FDA approval for the treatment of these patients.  
Similarly, in Stage III/IV completely resected melanoma, adjuvant nivolumab is an established 
standard of care that is recognized in guidelines globally. In CA209238, adjuvant nivolumab 
demonstrated clinical benefit with an acceptable safety profile in patients with resected 
Stage IIIB/C or Stage IV melanoma (AJCC 7th edition). Recently, the Phase 3 CA20976K study 
demonstrated statistically significant and clinically meaningful RFS benefit with adjuvant 
nivolumab versus placebo in patients with completely resected Stage IIB or IIC melanoma.  
The current study, CA2241044, is a Phase 2, open-label study, to evaluate patient preference of 
IV vs SC immunotherapy in adult participants with previously untreated metastatic or unresectable 
melanoma (Cohort 1) or resectable melanoma (Cohort 2).  
Participants in Cohort 1 will receive nivolumab + relatlimab FDC IV for 2 treatment cycles 
followed by nivolumab + relatlimab FDC SC until investigator-assessed disease progression per 
RECIST v1.1, unacceptable toxicity, withdrawal of consent for study treatment, lost to follow-up, 
death, study termination by the Sponsor, or up to a maximum of 26 cycles or 2 years, whichever 
comes first. For this cohort, consideration may be given to optional retreatment post progression 
after discussion between the Investigator and Sponsor. 
Participants in Cohort 2 will receive nivolumab IV for 2 treatment cycles followed by nivolumab 
SC until investigator-assessed disease recurrence per RECIST v1.1, unacceptable toxicity, 
withdrawal of consent for study treatment, lost to follow-up, death, study termination by the 
Sponsor, or up to a maximum of 13 cycles or 1 year, whichever comes first.  
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
26 
2 
SCHEDULE OF ACTIVITIES 
Table 2-1: 
Screening Procedural Outline (Cohort 1 – Metastatic Melanoma) 
Procedure 
Screening 
(Day -28 to Day -1) 
Notesa
All windows are based on calendar days 
Eligibility Assessments 
See Section 6 
Informed Consent 
X 
A participant is considered enrolled only when a protocol-specific informed 
consent is signed; IRB/IEC-approved informed consent must be obtained prior to 
performing any screening procedures.   
The 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 Interactive Response Technology (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 treatment assignment 
Demography and Participant Characteristics 
X 
For US only. See Appendix 8 for further information. 
Medical History 
X 
All medical history relevant to disease under study. Include findings from 
physical examination. 
Baseline Tumor Assessments 
Body Imaging 
X 
Brain Imaging 
X 
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v

Clinical Protocol  
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC  
Protocol Amendment No. 01 
Date: 24-May-2024 
27 
Table 2-1: 
Screening Procedural Outline (Cohort 1 – Metastatic Melanoma) 
Procedure 
Screening 
(Day -28 to Day -1) 
Notesa 
All windows are based on calendar days 
Safety Assessments 
 
See Section 9.4 
Physical Examination, Measurements, Vital 
signs, and ECOG PS 
X 
Complete physical exam including height, weight, body mass index, ECOG PS, 
respiratory rate, seated blood pressure and heart rate, and body temperature. 
Must be collected within 
 days prior to treatment assignment. 
If the screening physical examination is within 
 hours prior to Cycle 1 Day 1, 
then a single exam may count as both the screening and predose evaluation. 
Any findings during the Physical Examination will be recorded as medical history 
in the participant’s medical records and on the appropriate CRF. 
Assessment of Signs and Symptoms 
X 
Within 
 days prior to treatment assignment. 
Prior Medications 
X 
Prior medications will include medications taken within 
 days prior to 
treatment assignment. 
Document live/attenuated vaccine use if within 30 days prior to first study 
treatment. (Use of live/attenuated vaccine within 30 days prior to first study visit 
is prohibited.)  
See Section 7.7. 
AE/SAE Assessment 
X 
AEs/SAEs will be graded according to the NCI-CTCAE version 5.0. 
All AEs and SAEs must be collected from the time of signing the informed 
consent. Record at each visit. Collect continuously throughout the treatment 
period and for a minimum of 
 days following discontinuation of study 
treatment. 
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection must 
be collected from the time of signing the informed consent. 
For AE/SAE monitoring on-study during the treatment period, please refer to 
Table 2-3. 
For participants assigned to treatment and never treated with study drug, collect 
SAEs for 30 days from the date of treatment assignment. 
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Clinical Protocol  
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC  
Protocol Amendment No. 01 
Date: 24-May-2024 
28 
Table 2-1: 
Screening Procedural Outline (Cohort 1 – Metastatic Melanoma) 
Procedure 
Screening 
(Day -28 to Day -1) 
Notesa 
All windows are based on calendar days 
Laboratory Tests 
 
See Section 9.4.4. 
Clinical Laboratory Assessments 
X 
On-site/local laboratory tests must be performed within 
 days prior to treatment 
assignment.   
See Section 9.4.4 for list of laboratory tests to conduct. 
Pregnancy Test (WOCBP Only) 
X 
Negative highly sensitive serum or urine pregnancy test (minimum sensitivity 
equivalent units 25 IU/L or equivalent units of human chorionic gonadotropin 
[hCG]) to be done at screening visit and repeated within 24 hours prior to first 
dose of study treatment. 
Results of the test should be reported by the study site to the sponsor in a timely 
manner. 
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Clinical Protocol  
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC  
Protocol Amendment No. 01 
Date: 24-May-2024 
29 
Table 2-1: 
Screening Procedural Outline (Cohort 1 – Metastatic Melanoma) 
Procedure 
Screening 
(Day -28 to Day -1) 
Notesa 
All windows are based on calendar days 
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. See Appendix 4. 
Abbreviations: AE, adverse event; 
; ECOG, Eastern Cooperative Oncology 
Group; eCRF, electronic case report form; FSH, follicle-stimulating hormone; HIV, human immunodeficiency virus; IEC, Independent Ethics Committee; IRB, 
Institutional Review Board; 
 
; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; SAE, serious adverse event; 
 
; WOCBP, women of childbearing 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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Clinical Protocol  
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC  
Protocol Amendment No. 01 
Date: 24-May-2024 
30 
 Table 2-2: 
Screening Procedural Outline (Cohort 2 – Resected Melanoma) 
Procedure 
Screening 
Notesa 
All windows are based on calendar days. 
Eligibility Assessments 
See Section 6 
Informed Consent 
X 
A participant is considered enrolled only when a protocol-specific informed consent is 
signed; IRB/IEC-approved informed consent must be obtained prior to performing any 
screening procedures. 
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 treatment assignment 
Demography and Participant 
Characteristics 
X 
For US only. See Appendix 8 for further information. 
Medical History 
X 
All medical history relevant to the disease under study. Include findings from physical 
examination. 
Baseline Tumor Assessments  
 
 
Review of Pathology Report  
X 
Confirm negative margins prior to treatment assignment and file as source document by 
site. 
Body Imaging  
X 
Brain Imaging 
X 
Safety Assessments 
 
See Section 9.4 
Complete Physical Examination, 
Measurements, Vital signs, Performance 
Status,  
X 
Complete physical exam including height, weight, body mass index, ECOG PS, 
respiratory rate, seated blood pressure and heart rate, and body temperature.   
Must be collected within 
 days prior to treatment assignment. 
2.0
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930207750
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v

Clinical Protocol  
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC  
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31 
 Table 2-2: 
Screening Procedural Outline (Cohort 2 – Resected Melanoma) 
Procedure 
Screening 
Notesa 
All windows are based on calendar days. 
If the screening physical examination is within 
 hours prior to Cycle 1 Day 1, then a 
single exam may count as both the screening and predose evaluation. 
Any findings during the Physical Examination will be recorded as medical history in the 
participant’s medical records and on the appropriate CRF. 
Assessment of Signs and Symptoms  
 
Within 
days prior to treatment assignment 
Prior Medications  
X 
Prior medications will include medication taken within 
 days prior to treatment 
assignment. 
Document live/attenuated vaccine use if within 30 days prior to first study treatment. 
(Use of live/attenuated vaccine within 30 days prior to the first study treatment is 
prohibited)  
See Section 7.7 
AE/SAE Assessment 
X 
AEs/SAEs will be graded according to the NCI-CTCAE version 5.0. 
All AEs and SAEs must be collected from the time of signing the informed consent. 
Record at each visit. Collect continuously throughout the treatment period and for a 
minimum of 
 days following discontinuation of study treatment. 
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection must be 
collected from the time of signing the informed consent. 
For AE/SAE monitoring on-study during the treatment period, please refer to Table 2-4. 
For participants assigned to treatment and never treated with study drug, collect SAEs for 
30 days from the date of treatment assignment. 
Laboratory Tests 
Clinical Laboratory Assessments 
X 
On-site/local laboratory tests must be performed within 
 days prior to treatment 
assignment. 
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BMS-986213 
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Protocol Amendment No. 01 
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 Table 2-2: 
Screening Procedural Outline (Cohort 2 – Resected Melanoma) 
Procedure 
Screening 
Notesa 
All windows are based on calendar days. 
- 
.  
For HIV: testing at sites where locally mandated. 
See Section 9.4.4 for list of laboratory tests to conduct. 
Pregnancy Test (WOCBP) 
X 
Negative highly sensitive serum or urine pregnancy test (minimum sensitivity equivalent 
units 25 IU/L or equivalent units of hCG) to be done at screening visit and repeated 
within 24 hours prior to first dose of study treatment. 
Results of the test should be reported by the study site to the sponsor in a timely manner.  
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. See Appendix 4. 
Abbreviations: AE, adverse event; 
; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case 
report form; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; HIV, human immunodeficiency virus; IEC, Independent Ethics 
Committee; IRB, Institutional Review Board; 
; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer Institute 
Common Terminology Criteria for Adverse Events; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; 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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BMS-986213 
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Table 2-3: On-treatment Procedural Outline (Cohort 1 – Metastatic Melanoma) 
Procedure 
Intravenous 
Treatment 
Subcutaneous 
Treatment 
Notes ,b 
Cycle Duration = 4 weeks/28 days 
All windows based on calendar day 
Study Treatment 
 
 
See Section 7.1 
Dispense Study 
Treatment 
X 
X 
First drug to be administered within 3 calendar days following treatment 
assignment, subsequent doses can be administered within 3 days before or after 
scheduled date if necessary (every 28 days ± 3 days).  
Route of administration will switch from IV to SC starting at Cycle 3, Day 1.  
Treatment will continue until progression, unacceptable toxicity, withdrawal of 
consent, lost to follow-up, death, study termination by the Sponsor, or after a 
maximum treatment duration of up to 2 years (26 cycles) from first dose. 
See treatment details in Section 7 
Safety Assessments  
See Section 9.4 
Targeted Physical 
Examination, 
Measurements, and Vital 
Signsc 
X* 
X 
Weight, seated blood pressure, respiratory rate, heart rate, and body temperature 
within 3 days prior to each dosing 
*Targeted physical exam not required on Cycle 1 Day 1 if a full physical exam was 
completed within 3 days of first dose. 
Performance Statusc 
X 
X 
ECOG PS, See Appendix 6. 
AE and SAE Assessment 
Continuous 
AEs/SAEs will be graded according to the NCI-CTCAE version 5.0. 
AEs/SAEs will be graded according to the NCI-CTCAE version 5.0. 
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BMS-986213 
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Protocol Amendment No. 01 
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Table 2-3: On-treatment Procedural Outline (Cohort 1 – Metastatic Melanoma) 
Procedure 
Intravenous 
Treatment 
Subcutaneous 
Treatment 
Notes ,b 
Cycle Duration = 4 weeks/28 days 
All windows based on calendar day 
All AEs and SAEs must be collected from the time of signing the informed consent. 
Record at each visit. Collect continuously throughout the treatment period and for a 
minimum of 
 days following discontinuation of study treatment. 
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection must be 
collected from the time of signing the informed consent. 
For AE/SAE monitoring on-study during the treatment period, please refer to 
Table 2-3. 
For participants assigned to treatment and never treated with study drug, collect 
SAEs for 30 days from the date of treatment assignment. 
Concomitant Medications  
Continuous 
Concomitant medications will include medications taken from treatment assignment 
and throughout treatment phase. Record at each visit. See Section 7.7. 
Report of Product 
Complaints  
Continuously 
By site  
Laboratory Tests 
 
 
See Section 9.4.4 
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. For Norway, see Appendix 8 for 
specific requirements.  
*Pregnancy test not required to be repeated on Cycle 1 Day 1 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 2-3: On-treatment Procedural Outline (Cohort 1 – Metastatic Melanoma) 
Procedure 
Intravenous 
Treatment 
Subcutaneous 
Treatment 
Notes ,b 
Cycle Duration = 4 weeks/28 days 
All windows based on calendar day 
Efficacy Surveillance 
 
 
See Section 9.1 
Imaging Assessments 
X  
X 
Assessment of 
Progression 
X 
X 
 assess and report disease progression per local guidelines. The 
timepoint of disease progression should be reported on the eCRF based on the 
investigator’s assessment using RECIST v1.1 criteria to document any disease 
progression. Documentation of progression should be provided for source 
verification 
Clinical Outcomes 
Assessments 
 
 
 
PEQ 
X 
 
PEPQ 
 
X 
To be completed immediately after treatment administration on Cycle 4 Day 1 (no 
greater than 24 hours post dose). See Section 9.1.3.1 
Abbreviations: AE, adverse event; 
; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case report form; hCG, human 
chorionic gonadotropin; 
; IMAE, immune-mediated adverse event; IV, intravenous; 
; NCI-
CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PEPQ, Patient Experience and Preference Questionnaire; PEQ, Patient 
Experience Questionnaire; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SC, subcutaneous; WOCBP, women of 
child-bearing potential. 
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 Cycle 1 Day 1. 
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Clinical Protocol  
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BMS-986213 
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Protocol Amendment No. 01 
Date: 24-May-2024 
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Table 2-4: 
On-treatment Procedural Outline (Cohort 2 – Resected Melanoma) 
Procedure 
Intravenous 
Treatment 
Subcutaneous 
Treatment 
Notes ,b 
Cycle duration = 4 weeks 
Study Treatment 
See Section 7.1 
Dispense Study Treatment 
X 
X 
First drug to be administered within 3 calendar days following 
treatment assignment, subsequent doses can be administered 
within 3 days before or after scheduled date if necessary (every 
28 days ± 3 days).  
Route of administration will switch from IV to SC starting at 
Cycle 3, Day 1. 
Treatment will continue until recurrence, unacceptable toxicity, 
withdrawal of consent, lost to follow-up, death, study 
termination by the Sponsor, or after a maximum duration of 
1 year from first dose (maximum of 13 doses), whichever occurs 
first. 
See treatment details in Section 7 
Safety Assessment 
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BMS-986213 
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Protocol Amendment No. 01 
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Table 2-4: 
On-treatment Procedural Outline (Cohort 2 – Resected Melanoma) 
Procedure 
Intravenous 
Treatment 
Subcutaneous 
Treatment 
Notes ,b 
 
Targeted Physical Examination, 
Measurements, and Vital Signsc 
X* 
X 
Weight, seated blood pressure, respiratory rate, heart rate, and 
body temperature within 3 days prior to each dosing. 
*Targeted physical exam not required on Cycle 1 Day 1 if a full 
physical exam was completed within 3 days of first dose. 
Performance Statusc 
X 
X 
ECOG PS (≥ 18 years old) See Appendix 6. 
AE and SAE Assessment 
Continuously 
All AEs and SAEs must be collected from the time of signing 
the informed consent. Record at each visit. Collect continuously 
throughout the treatment period and for a minimum of 
 days 
following discontinuation of study treatment. 
All AEs (SAEs or non-serious AEs) associated with SARS-
CoV-2 infection must be collected from the time of signing the 
informed consent. 
For AE/SAE monitoring on-study during the treatment period, 
please refer to Table 2-4. 
For participants assigned to treatment and never treated with 
study drug, collect SAEs for 30 days from the date of treatment 
assignment. 
Concomitant Medications  
Continuously 
Concomitant medications will include medications taken from 
treatment assignment and throughout treatment phase. Record at 
each visit. See Section 7.7.  
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Clinical Protocol  
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC  
Protocol Amendment No. 01 
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Table 2-4: 
On-treatment Procedural Outline (Cohort 2 – Resected Melanoma) 
Procedure 
Intravenous 
Treatment 
Subcutaneous 
Treatment 
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 Cycle 1 Day 1 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. 
Efficacy Surveillance  
Imaging Assessment 
See Notes 
Assessment of Recurrence  
See Notes 
 assess and report disease recurrence per local 
guidelines. Documentation of recurrence should be provided for 
source verification. 
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC  
Protocol Amendment No. 01 
Date: 24-May-2024 
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Table 2-4: 
On-treatment Procedural Outline (Cohort 2 – Resected Melanoma) 
Procedure 
Intravenous 
Treatment 
Subcutaneous 
Treatment 
Notes ,b 
 
Health Outcomes Assessments 
PEQ 
X 
 
PEPQ 
 
X 
To be completed immediately after Cycle 4 Day 1 (no greater 
than 24 hours post dose). See Section 9.1.3.1 
Abbreviations: AE, adverse event; 
; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case report form; hCG, human 
chorionic gonadotropin; 
; IMAE, immune-mediated adverse event; IV, intravenous; 
; NCI-CTCAE, 
National Cancer Institute Common Terminology Criteria for Adverse Events; PEPQ, Patient Experience and Preference Questionnaire; PEQ, Patient Experience 
Questionnaire; SAE, serious adverse event; SARSCoV-2, severe acute respiratory syndrome coronavirus 2; SC, subcutaneous; WOCBP, women of child-bearing 
potential. 
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 Cycle 1 Day 1 . 
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CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC  
Protocol Amendment No. 01 
Date: 24-May-2024 
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Table 2-5: 
Long-term Follow-up Procedural Outline (Cohort 1a and Cohort 2b) 
Procedure 
Follow-up 
Visits 1 & 2   
Notesc 
All windows are based on calendar days 
Safety Assessments 
 
See Section 9.4 
Targeted Physical Examination, 
Measurements, Vital signs, and ECOG 
PS 
X 
Include weight, seated blood pressure, respiratory rate, heart rate, body temperature, 
and ECOG PS  
AE and SAE Assessment 
See Notes 
AEs/SAEs will be graded according to the NCI-CTCAE version 5.0. 
Record at each visit. 
Collect continuously from date of signed informed consent and for a minimum of 
 following discontinuation of study 
treatment. 
Beyond 
 from the last dose of study 
treatment, participants will be followed for drug-related AEs/SAEs until resolution, 
returns to baseline, or is deemed irreversible, or until the participant is lost to 
follow-up or withdraws study consent. 
All AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-
CoV-2 infection must be collected from the time of the participant’s signing the 
informed consent until 
 days for Cohort 1 and 
 days for Cohort 2 following 
discontinuation of study treatment. 
Concomitant Medications 
X 
Record at each visit. 
All medications with a start date occurring between 14 days prior to treatment 
administration and within 
 of the last 
dose date of study intervention are considered concomitant. 
See Section 7.7. 
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BMS-986213 
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Protocol Amendment No. 01 
Date: 24-May-2024 
41 
Table 2-5: 
Long-term Follow-up Procedural Outline (Cohort 1a and Cohort 2b) 
Procedure 
Follow-up 
Visits 1 & 2   
Notesc 
All windows are based on calendar days 
Laboratory Tests 
 
 
See Section 9.4.4. 
Clinical Laboratory Assessments 
X 
To be performed at Follow-up Visit 1, repeat at Follow-up Visit 2 if study treatment-
related toxicity persists. 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 intervention related toxicities resolve, return to 
baseline, or are deemed irreversible. 
Pregnancy Test (WOCBP Only) 
X 
Serum or urine. 
Results of the test should be reported to the study site as well as the sponsor in a timely 
manner. 
Efficacy Surveillance Assessments 
 
 
Imaging Assessment 
X 
Abbreviations: AE, adverse event; 
; ECOG, Eastern Cooperative Oncology Group; 
; NCI-CTCAE, 
National Cancer Institute Common Terminology Criteria for Adverse Events; SAE, serious adverse event; WOCBP, women of childbearing potential. 
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 
In the event that multiple procedures are required at a single time point, the following is the order in which the procedures should be performed, from highest to 
lowest priority: 
•  
Safety 
 
•  
Safety (clinical laboratory tests) 
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3 
INTRODUCTION 
For many patients with cancer, intravenous (IV) administration of anticancer therapies can be 
associated with significant burdens including more time spent in clinic (treatment preparation and 
IV administration time), challenges with implantable venous access ports, and complex scheduling 
placing a strain on medical centers. Some patients also describe negative psychological impact 
factors due to stress and anxiety associated with IV administration. As the cancer patient 
population continues to grow, the impact of these burdens is poised to increase accordingly. 
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Throughout the protocol, the co-formulation of nivolumab 960 mg + relatlimab 320 mg FDC 
(BMS-986213; 
 nivolumab and relatlimab) and rHuPH20 
 administered SC 
will be referred to as nivolumab + relatlimab FDC SC, and the IV formulation of nivolumab 
480 mg + relatlimab 160 mg FDC (BMS-986213; 
 of nivolumab and relatlimab) will be 
referred to as nivolumab + relatlimab FDC IV. 
The coformulation of nivolumab 1200 mg (BMS-986298) and rHuPH20 
 administered 
SC will be referred to as nivolumab SC, and the IV formulation of nivolumab 480 mg 
(BMS-936558) will be referred to as nivolumab IV. 
3.1 
Study Rationale 
Repeated IV infusion appointments require considerable time and resources from both patients 
and the healthcare system. With the growing cancer patient population and increasing burden on 
healthcare resources, there is a need for more efficient treatment options, such as alternative routes 
of administration. 
 
 
 
 
CA2241044 will address this important data question by assessing the patient’s preference for 
nivolumab SC or nivolumab + relatlimab FDC SC and provide patient experience data by route of 
administration. Two cohorts of patients will be enrolled in this study. In addition to addressing 
patient preferences, this study will also generate safety data which will further characterize the 
safety profile of patients switching the route of administration from IV to SC. 
• Cohort 1 will include participants with previously untreated Stage III (unresectable) or 
Stage IV (metastatic) melanoma. 
• Cohort 2 will include participants with completely resected melanoma Stage IIB/C, III, or 
Stage IV. 
 
3.2 
Background 
Melanoma, the most serious form of skin cancer, is the 5th most common cause of cancer in the 
United States (US)1 and accounts for approximately 1% to 2% of all cancer deaths and 
approximately 5% of all new cases of cancer in the US with a historical 5-year survival rate of 
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Protocol Amendment No. 01 
Date: 24-May-2024 
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18% for late-stage disease.2 While rare in the pediatric population, melanoma is the second leading 
cause of cancer in adolescents and young adults over the age of 15, with an incidence of over 10 
per million in 15- to 19-year-olds.3 In the era of immuno-oncology (IO) therapy, the expected 
5-year survival rate for metastatic melanoma has a lower bound of approximately 35% and could 
be as high as 50% for the nivolumab+ ipilimumab combination among patients who would meet 
criteria for clinical trials.4 
Prior to 2011, approved therapies for the treatment of metastatic melanoma were limited and 
included chemotherapy (dacarbazine) and immunotherapy (interleukin 2). Since then, 3 new 
therapeutic classes have been added to the treatment armamentarium and include 7 new drugs 
administered as monotherapy or in combination. These drugs include 1) ipilimumab, an anti-
cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4)-blocking antibody, 2) drugs targeting 
the tyrosine kinase pathways including BRAF and MEK, which include vemurafenib, dabrafenib, 
trametinib, and cobimetinib, and 3) mAbs that bind to the programmed death-1 (PD-1) receptor, 
which include nivolumab and pembrolizumab. Though many of these therapies have demonstrated 
an overall survival (OS) benefit in Phase 3 studies, there are still areas of high unmet medical need 
for this population. Many patients relapse within months of initiating treatment5,6,7 or are not 
eligible for treatment due to tumor mutation status requirements (eg, BRAF V600 mutation is 
present in approximately 50% of melanoma tumors).6,7 
 
 
 
 
 
 
 Disease course for 
melanoma has fundamentally changed with the introduction of immunotherapies targeting the 
cytotoxic T-lymphocyte-associated antigen 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. 
3.2.1 
Relatlimab Mechanism of Action 
Relatlimab is a fully human antibody specific for human lymphocyte activation gene-3 (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 
 for attenuated Fc 
receptor binding 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 (dissociation 
constant, 0.25 to 0.5 nM) and specificity and potently blocks the interaction of LAG-3 with its 
known ligands, major histocompatibility complex (MHC) Class II (half maximal inhibitory 
concentration [IC50], 0.7 nM) and fibrinogen-like protein 1 (FGL1). 
 
 
 
 
 
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Protocol Amendment No. 01 
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3.2.2 
Nivolumab Combined with relatlimab Pre-clinical Activity 
LAG-3 is expressed on tumor-infiltrating lymphocytes (TILs) of several tumor types, including 
melanoma; hepatocellular carcinoma (HCC); and breast, ovarian, and lung cancers, often in 
connection with increased PD-1+ T cells.9 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.6,8,9 Importantly, 
combined treatment of mice with blocking antibodies against both receptors resulted in more 
robust immune responses than either single-treated group in these studies and analyses of 
Lag3−/−Pdcd1−/− double knockout mice revealed a cooperative requirement for LAG-3 and PD-1 
in maintaining immune homeostasis. 
The single-agent anti-tumor activity of anti-LAG-3 antibody (19C7) was evaluated in the 
immunogenic Sa1N fibrosarcoma tumor model.10 Compared with the isotype control group, all 
doses between 1 mg/kg and 30 mg/kg of anti-LAG-3 clone 19C7 demonstrated anti-tumor efficacy 
leading to between 30% and 60% of the mice being rendered tumor-free at the end of study. 
Combined anti-PD-1 and anti-LAG-3 activity were also assessed in the Sa1N model. In 2 different 
studies, an anti-LAG-3 antibody, C9B7W, inhibited the growth of Sa1N tumors in mice when 
administered as monotherapy and when combined with anti-PD-1 antibody, 4H2.11,12 The 
combination of these 2 antibodies resulted in 80% to 90% tumor-free mice and reductions in 
median tumor volumes superior to that of anti-PD-1 or anti-LAG-3 antibody monotherapy alone.8  
Similarly, a greater anti-tumor effect was also demonstrated for combined anti-PD-1 and anti-
LAG-3 in the MC38 colon adenocarcinoma models than with either agent alone.8 
3.2.3 
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. 
 
 
 
 
 
 
 As of the cutoff date of 25-Feb-2021 for Part C of study CA224020, objective 
responses in the range of 5.3% to 47% were achieved with nivolumab + relatlimab combination 
therapy in participants with IO-refractory and 1L advanced melanoma, IO-naive bladder cancer, 
IO-refractory/relapsed and 1L NSCLC, IO-naive RCC, IO-naive gastric cancer (GC), IO-naive 
HCC, and IO-naive squamous cell carcinoma of the head and neck.8  
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Protocol Amendment No. 01 
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As of the cutoff date of 25-Feb-2021, 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 many 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. In part D1, 
189 patients received nivolumab and 
 
 
 
 
 
 The overall response rate 
(ORR) by blinded independent central review (BICR) was 12.0% (95% confidence interval [CI], 
8.8 to 15.8) in D1 pooled and 9.2% (95% CI, 5.2 to 14.7) in D2.13 
As of the same cutoff date (25-Feb-2021), the advanced melanoma participants with progression 
on prior I-O therapies in Part E treated with nivolumab 
 
 the ORR by BICR was 11.7%. With a minimum follow-up of 11.3 months, the median 
duration of response was not reached (NR; 95% CI: 3.06, nonestimable).8 Refer to the 
 
 for further information. 
CA224047, a global, double-blind, randomized, Phase 2/3 study comparing an FDC formulation 
of nivolumab 480 mg + relatlimab 160 mg FDC 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 progression-
free survival (PFS) by BICR with nivolumab + relatlimab FDC 
 compared to nivolumab 
monotherapy in all randomized participants (N = 714) (PFS hazard ratio [HR] = 0.75 [95% CI: 
0.62, 0.92], P-value = 0.0055). With a median follow-up of 19.3 months, the median PFS according 
to BICR in the nivolumab + relatlimab FDC 
 group was 10.2 months (95% CI, 6.5–14.8) 
compared to 4.6 months (95% CI, 3.5–6.4) in the nivolumab monotherapy arm. PFS rates at 12 
months were 48.0% (95% CI, 42.5–53.4) and 36.9% (95% CI, 31.7–42.1) for nivolumab 
+ relatlimab FDC 
 and nivolumab monotherapy, respectively. The PFS benefit of nivolumab
+ relatlimab FDC 
 was consistent across key prespecified subgroups.12,15 The secondary 
endpoint of OS showed clinically meaningful improvement with nivolumab + relatlimab FDC over 
nivolumab monotherapy (median OS nonestimable (95% CI 34.20, NR) versus 34.1 months (95%
CI 25.23, NR); HR = 0.80 [0.64-1.01]); p = 0.0593) in all randomized participants but was not 
statistically significant.12,15
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% 
versus 32.6%).24 
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3.2.4 
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, and E tested in Q2W 
 dosing intervals. Refer to 
 for details 
of the dose levels tested across a range of solid tumor cohorts in Part B and dose-limiting 
toxicities observed.8 The safety profile was acceptable at all dose levels tested up to 
 
relatlimab in combination with nivolumab 
, with the MTD not reached at this 
dose level. Part C included expansion cohorts with multiple tumor types and Parts D and E 
included advanced melanoma participants (1L and progressed on prior-PD-1 therapy). Refer to 
 for the details of the number of participants tested with the dose 
combinations.8 
, 1457 participants in study CA224020 have been treated with nivolumab + 
relatlimab across Parts B, C, D, and E demonstrating that the combination was well tolerated across 
multiple tumor types.8 Based on an analysis of adverse events (AEs) in the all-combination group, 
1422 (97.6%) participants experienced at least 1 event and 1422 (97.6%) participants experienced 
at least 1 event occurring in ≥ 5% of participants (refer to 
 for details). 
Across Parts B, C, D, and E, drug-related AEs were reported in 1003 (68.8%) participants, with 
the most commonly reported (≥ 5% of participants) being fatigue (17.4%), pruritus (13.0%), rash 
(10.0%), diarrhea (9.1%), hypothyroidism (8.6%), arthralgia (7.9%), increased lipase and nausea 
(7.3% each), asthenia (7.1%), and dry mouth (5.9%). Most drug-related AEs were Grades 1 to 2. 
Grade 3- 4 drug-related AEs were reported in 251 (17.2%) participants and the most frequently 
reported included lipase increased (3.7%), and 3 (0.2%) participants reported Grade 5 events 
(dyspnea, pulmonary fibrosis, and pneumopathy). 
Refer to the 
 for details of 
drug-related AEs analyzed separately for Part D1, which included 82 heavily pretreated 
participants with advanced melanoma, with poor prognostic factors treated with 
 
 
Drug-related serious AEs (SAEs) were reported in 196 of the 1457 (13.5%) participants with 
Grade 3-4 drug-related SAEs occurring in 145 (10.0%) participants and Grade 5 events occurring 
in 3 (0.2%) participants (dyspnea, pulmonary fibrosis, and immune-mediated lung disease). More 
information can be found in
 
The safety profile of the combination of nivolumab 
 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 to 4 drug-related AEs was 24.5% in the nivolumab + 
relatlimab FDC group. There were 4 treatment-related deaths with nivolumab + relatlimab FDC. 
Drug-related AEs (any grade) led to treatment discontinuation in 20.6% of participants in the 
nivolumab + relatlimab FDC group.25 
 for 
safety analysis based on the clinical data cutoff date of 12-Sep-2022.15  
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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]-
) that targets the PD-1 cluster of 
differentiation 279 (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 
programmed death ligands 1 (PD-L1) and 2 (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 cells and is produced using standard 
mammalian cell cultivation and chromatographic purification technologies. The clinical study 
product is a sterile solution for parenteral administration. 
3.2.6 
Nivolumab Clinical Activity 
Nivolumab has been approved for the treatment of unresectable or metastatic melanoma, adjuvant 
treatment of melanoma, neoadjuvant treatment of resectable NSCLC, metastatic NSCLC, 
malignant pleural mesothelioma, advanced renal cell carcinoma, classical Hodgkin lymphoma, 
squamous cell carcinoma of the head and neck, urothelial carcinoma, microsatellite instability-
high or mismatch repair deficient metastatic colorectal cancer, hepatocellular carcinoma, 
esophageal cancer, gastric cancer, gastroesophageal junction cancer, and esophageal 
adenocarcinoma. 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types. 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 squamous cell carcinoma of head and neck (SCCHN). Details of the clinical activity 
in these various malignancies are provided in the US Package Insert and Summary of Product 
Characteristics (SmPC).  
For resected melanoma, nivolumab is an established standard of care that is recognized in 
guidelines globally with positive recommendation ratings. In CA209238, 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. For resected 
stage IIB or IIC melanoma, the CA20976K study demonstrated statistically significant and 
clinically meaningful RFS benefits with adjuvant nivolumab versus placebo in patients with 
completely resected stage IIB or IIC melanoma. At the interim analysis with a minimum follow-
up of 8 months, the endpoint was met, demonstrating improved RFS with nivolumab versus 
placebo (stratified HR 0.42 [95% CI: 0.30, 0.59] p<0.0001. The landmark 12-month RFS rate for 
nivolumab was 89% and 79% for the placebo arm. 
3.2.7 
Nivolumab Clinical Safety  
The overall safety experience with IV nivolumab (BMS-936558), as a monotherapy or in 
combination with other therapeutics, is based on experience in approximately 29,349 subjects 
treated to date. For monotherapy, the IV nivolumab safety profile is similar across tumor types. In 
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Phase 3 controlled studies, the safety profile of nivolumab monotherapy is acceptable in the 
context of the observed clinical efficacy, and manageable using established safety guidelines. 
Clinically relevant AEs typical of stimulation of the immune system were infrequent and 
manageable by delaying or stopping nivolumab treatment and timely immunosuppressive therapy 
or other supportive care. Based on data from a completed Phase 1b study and a Phase 1/2 study, 
single doses of either 
 mg nivolumab did not result in unexpected safety findings for 
participants with sepsis or septic shock. In several ongoing clinical trials, the safety of nivolumab 
in combination with other therapeutics such as ipilimumab, cytotoxic chemotherapy, 
anti-angiogenics, and targeted therapies is being explored. Most studies are ongoing and, as such, 
the safety profile of nivolumab combinations continues to evolve. Nivolumab as monotherapy and 
nivolumab in combination with other agents are approved in subjects with melanoma, RCC, 
microsatellite instability-high or mismatch repair deficient colorectal cancer (CRC), HCC, 
non-small cell lung cancer (NSCLC), cHL, SCCHN, UC, esophageal cancer (EC) gastric cancer 
(GC), and malignant pleural mesothelioma MPM.  
Study CA2098KX is ongoing and clinical safety regarding the use of SC nivolumab 
(BMS-986298)16 is collected on ongoing basis. Overall, the safety profile of SC nivolumab 
monotherapy in subjects with advanced/metastatic cancer is manageable and consistent with the 
AE profile observed with nivolumab when administered via IV route. There was no pattern in the 
incidence, severity, or causality of AEs across all doses studied of nivolumab (600, 720, 960 and 
1,200 mg) with or without rHuPH20. Most AEs were low-grade (Grade 1-2) with relatively few 
drug-related (Grade 3-4) AEs. The majority of treatment-related AEs regardless of grade were 
manageable based on established management guidelines. 
3.2.8 
Recombinant Human Hyaluronidase PH20 Enzyme 
rHuPH20 is a glycosylated 447-amino acid single-chain recombinant human polypeptide that 
depolymerizes hyaluronan in the SC space locally at the site of injection. Hyaluronan is an anionic, 
nonsulfated glycosaminoglycan that consists of a polymer of N-acetyl-glucosamine and glucuronic 
acid subunits. It contributes to the soluble gel-like component of the extracellular matrix of the 
skin. Depolymerization of hyaluronan by rHuPH20 results in a transient reduction in the viscosity 
of the gel-like phase of the extracellular matrix and increased hydraulic conductance that facilitates 
the dispersion and absorption of injected drugs (see rHuPH20 IB). Use of rHuPH20 enables the 
delivery of large volumes of liquid into the SC space (approximately 2 to 20 mL), decreasing dose 
administration times. 
3.2.9 
Nonclinical Toxicity of Recombinant Human Hyaluronidase PH20 
General toxicity studies were performed in cynomolgus monkeys, and a developmental and 
reproductive toxicity program was performed in mice (see rHuPH20 IB17). 
 
 
 
 In mice, at very high doses (≥ 9 mg/kg/day SC) of rHuPH20, 
embryo-fetal toxicity consisted of reduced fetal weights and a trend for late resorption; however, 
these high dose levels did not result in prenatal or postnatal developmental effects. Rabbit studies 
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were also conducted to evaluate the potential effects of anti-rHuPH20 antibody exposure on 
reproduction and development. These studies showed no adverse effects on general toxicity 
endpoints, male or female fertility, or embryo-fetal development. In a pivotal Good Laboratory 
Practice compliant lifetime repeat-dose toxicity study conducted in juvenile mice, there were no 
rHuPH20-related effects on any of the parameters tested, except for minimal-to-moderate, 
nonadverse microscopic findings at the injection site noted in male and female mice in the subset 
treated through postnatal Day 241. There were no adverse effects of rHuPH20 at 1 mg/kg/dose or 
anti-rHuPH20 antibodies on neurobehavioral assessments, reproductive capacity, fetal 
evaluations, or any other toxicity endpoints evaluated in juvenile mice through adulthood. 
Genotoxicity and carcinogenicity studies have not been conducted. 
See the rHuPH20 IB for detailed descriptions of the nonclinical pharmacology, clinical safety, PK, 
and toxicity studies of rHuPH20 and results.17 
3.3 
Benefit/Risk Assessment 
BMS is evaluating novel ways of administering nivolumab, as well as nivolumab + relatlimab 
FDC as a SC injection to provide patients with an alternate route of administration as compared 
with IV infusion. Study CA2241044 has been designed to assess patient preferences for the SC 
route of administration versus IV infusions. An SC injection is less invasive and has a substantially 
shorter administration period as compared with a conventional IV infusion, which for other SC 
biologics has translated to improved patient quality of life, as well as efficiencies in medical 
resource utilization.18,19,20 Both patients and prescribers have reported a preference for SC to IV 
administration for other drug products.21,22  
3.3.1 
Cohort 1 (nivolumab + relatlimab) 
CA224047, a pivotal Phase 2/3 study in participants with unresectable or metastatic melanoma, 
demonstrated that nivolumab 480 mg + relatlimab 160 mg FDC IV Q4W has clinical benefit, 
regardless of PD-L1 expression, with a statistically significant and clinically relevant PFS benefit 
 compared to nivolumab 
.23,24 The 
combination was confirmed to be well tolerated with a manageable safety profile in the 355 
participants treated and there were no unexpected safety signals from this combination.24  
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3.3.2 
Cohort 2 (nivolumab) 
Despite the availability of nivolumab IV, there is a need to improve patient quality of life in cancer 
care. In addition to the benefits of nivolumab to potentially improve RFS and overall OS in 
resected melanoma patients, participants would also benefit from the use of the SC route of 
administration of nivolumab co-formulated with rHuPH20. 
3.3.3 
General Considerations 
Preliminary safety data for relatlimab SC from the Phase 1 CA224087 study have been consistent 
with safety data seen across studies for nivolumab + relatlimab FDC IV. Further details can be 
found in the relatlimab IB. 
Overall, the safety profile of SC nivolumab monotherapy in subjects with advanced/metastatic 
cancer is manageable and consistent with the AE profile observed with IV nivolumab. Further 
details can be found in the 
. 
The risks anticipated for CA2241044 and proposed mitigations are summarized in Table 3.3-1. 
Key to mitigating these risks, investigators and the Sponsor will utilize continuous safety 
assessments to determine whether additional safety measures or termination from the study are 
required at any time. In addition, AEs and SAEs will be reviewed on an ongoing basis by the 
Sponsor’s Medical Monitor and Worldwide Patient Safety representatives to monitor for any 
safety signals or trends. 
Table 3.3-1: 
Potential Risk Assessment and Mitigation Strategy 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk8,16, 26
Mitigation Strategy 
Study Intervention: nivolumab + relatlimab 
IMAEs (eg, colitis diarrhea/colitis, 
pneumonitis, 
, nephritis, 
endocrinopathy, rash, neurologic) 
Relatlimab IV and SC IBs 
nivolumab IV and SC IBs 
BMS-986213 IB  
Recommended IMAE management 
algorithms are included in 
 or as per institutional 
protocol/investigator discretion. 
Potential infusion-related reaction, 
Potential injection-site reaction, 
and cytokine release syndrome 
Relatlimab IV and SC IBs 
nivolumab IV and SC IBs  
BMS-986213 IB  
Please refer to Section 7.4.4 
of protocol. 
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Table 3.3-1: 
Potential Risk Assessment and Mitigation Strategy 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk8, 16, 26
Mitigation Strategy 
Cardiovascular AEs (ie, 
myocarditis, 
) 
Relatlimab IV and SC IBs 
nivolumab IV and SC IBs  
BMS-986213 IB 
relatlimab management of 
myocarditis per AE Management 
Algorithm in 
 or as per 
institutional protocol/investigator 
discretion. 
Study Intervention: nivolumab 
IMAEs (eg, colitis diarrhea/colitis, 
pneumonitis, 
 nephritis, 
endocrinopathy, rash, neurologic) 
nivolumab SC and IV IBs 
Recommended IMAE management 
algorithms are included in 
 or as per institutional 
protocol/investigator discretion. 
Potential infusion-related reaction, 
potential injection site reaction   
nivolumab IV IB  
nivolumab SC IB 
Please refer to Section 7.4.4 of 
protocol. 
Cardiovascular AEs (ie, myocarditis, 
) 
Nivolumab IV and SC IBs 
Management of myocarditis per AE 
Management Algorithm in 
 or as per institutional 
protocol/investigator discretion. 
Study Procedures (Both Cohorts) 
SC Injection 
Please refer to Section 3.3 
(Benefit/Risk Assessment). 
Per IFU. 
MRI 
Not applicable 
Per institutional 
protocol/investigator discretion. 
CT 
Not applicable 
Per institutional 
protocol/investigator discretion. 
Allergy to Contrast Agent (eg, 
reaction to anaphylaxis) 
Not applicable 
Prophylaxis and/or treatment per
institutional 
protocol/investigator 
discretion. 
Other (if applicable) 
Non-Clinical Safety (animal 
studies) 
BMS-986213 IB 
Not applicable. 
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Abbreviations: AE, adverse event; CT, computed tomography; IB, Investigator’s Brochure; IFU, instructions for use; 
IMAE, immune-mediated adverse event; IV, intravenous; MRI, magnetic resonance imaging; SC, subcutaneous. 
 
4 
OBJECTIVES AND ENDPOINTS 
Table 4-1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Cohort 1: Metastatic melanoma  
Primary 
Cohort 1: Metastatic melanoma  
• 
To evaluate participants’ preference for route 
of 
administration 
upon 
switching 
from 
nivolumab + relatlimab FDC IV to nivolumab 
+ relatlimab FDC SC  
Cohort 2: Resected melanoma  
• 
To evaluate participants’ preference for route 
of 
administration 
upon 
switching 
from 
nivolumab IV to nivolumab SC  
• 
Proportion of evaluable participants that prefer SC route 
of administration using the Patient Experience and 
Preference Questionnaire (Question 7) after Cycle 4 
Day 1 dose 
Cohort 2: Resected melanoma  
• 
Proportion of evaluable participants that prefer SC route 
of administration using the Patient Experience and 
Preference Questionnaire (Question 7) after Cycle 4 
Day 1 dose 
Secondary 
Cohort 1: Metastatic melanoma  
Secondary 
Cohort 1: Metastatic melanoma  
• 
To assess the safety and tolerability of 
nivolumab 
+ 
relatlimab 
FDC 
IV 
and 
nivolumab + relatlimab FDC SC  
Cohort 2: Resected melanoma  
• 
To assess the safety and tolerability of 
nivolumab SC and nivolumab IV  
• 
AEs, SAEs, treatment-related AEs, AEs leading to 
discontinuation, IMAEs, OESIs, injection/infusion 
related AEs, deaths and laboratory abnormalities  
Cohort 2: Resected melanoma  
• 
AEs, SAEs, treatment-related AEs, AEs leading to 
discontinuation, IMAEs, OESIs, injection/infusion 
related AEs, deaths and laboratory abnormalities  
Abbreviations: AE, adverse event; FDC, fixed dose combination; IMAE, immune-mediated adverse event; IV, 
intravenous; 
; OESI, other events of special interest ; SAE, serious adverse event. 
 
 
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Table 4-2: 
Main Estimands for the Primary and Key Secondary Endpoints 
Endpoint 
(Variable) 
Description 
Analysis 
Population 
Timeframe 
Summary 
Statistics 
Primary 
Cohort 1: Metastatic 
melanoma 
• 
Proportion of 
evaluable 
participants that 
prefer SC route of 
administration using 
the Patient 
Experience and 
Preference 
Questionnaire 
(Question 7) after 
Cycle 4 Day 1 dose 
• 
Cohort 2: Resected 
melanoma  
• Proportion of 
evaluable participants 
that prefer SC route of 
administration using 
the Patient Experience 
and Preference 
Questionnaire 
(Question 7) after 
Cycle 4 Day 1 dose 
Proportion of 
evaluable 
participants that 
prefer SC route of 
administration using 
the Patient 
Experience and 
Preference 
Questionnaire 
(Question 7) after 
Cycle 4 Day 1 dose 
After Cycle 4 Day 1 
dose 
Estimated 
proportion and exact 
95% CI 
Secondary 
 
• 
Cohort 1: Metastatic 
melanoma 
• 
AEs, SAEs, 
treatment-related 
AEs, AEs leading to 
discontinuation, 
IMAEs, OESIs, 
deaths and 
laboratory 
abnormalities 
• 
Cohort 2: Resected 
melanoma 
• AEs, SAEs, 
treatment-related 
AEs, AEs leading to 
discontinuation, 
IMAEs, OESIs, 
deaths and laboratory 
abnormalities 
All treated 
population 
Throughout the 
treatment period 
Descriptive 
proportion of 
participants  
Abbreviations: AE, adverse event; IMAE, immune-mediated adverse event; OESI, other events of special interest; 
SAE, serious adverse event; SC, subcutaneous. 
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For the primary and secondary endpoints, the treatment policy strategy will be used to address all 
intercurrent events. The occurrence of the intercurrent event is considered irrelevant, information 
after intercurrent event is used. 
5 
STUDY DESIGN 
5.1 
Overall Design 
CA2241044 is a Phase 2, open-label, 2-cohort study to evaluate patient preference for nivolumab 
SC or nivolumab + relatlimab FDC SC vs the IV formulations in participants with previously 
untreated Stage III (unresectable) or Stage IV (metastatic) melanoma (Cohort 1) and those with 
completely resected Stage IIB/C, III, or IV melanoma (Cohort 2).  
In Cohort 1, 
 treated adult participants with previously untreated metastatic or unresectable 
melanoma will receive nivolumab + relatlimab FDC IV for 2 treatment cycles followed by 
nivolumab + relatlimab FDC SC until withdrawal of consent, disease progression, unacceptable 
toxicity, lost to follow-up, death, study termination by the Sponsor, or a maximum treatment 
duration of 26 cycles or 2 years whichever comes first.  
In Cohort 2, 
 treated adult participants with completely resected Stage IIB/C, III, or IV 
melanoma will receive nivolumab IV for 2 treatment cycles followed by nivolumab SC until 
disease recurrence, unacceptable toxicity, withdrawal of consent for study treatment, lost to 
follow-up, death, study termination by the Sponsor, or a maximum treatment duration of 13 cycles 
or 1 year, whichever comes first.   
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5.1.1 
Screening Phase 
Screening will occur between Day -28 and Day -1. Participants will provide written informed 
consent to participate in the study before completing any protocol-specified procedures or 
evaluations not considered to be part of the participants’ standard care. After signing the informed 
consent form (ICF), participants will be evaluated based on the assessments outlined in the 
Schedule of Activities (SoA-Section 2) and inclusion and exclusion criteria within 
 (unless 
otherwise specified) prior to treatment assignment. 
 
 
 Re-enrollment after screen failure is allowed and requires reconsenting and a 
new participant number assignment. Participants who complete the Screening Period and meet the 
criteria for inclusion/exclusion will begin with the Treatment Period. 
5.1.2 
Treatment Period 
The Treatment Period begins at the time of treatment assignment (first day of treatment) and will 
end at the beginning of the Follow-up Period. Cycle length is 28 days. Treatment cycles will be 
counted from Cycle 1 Day 1 (C1D1) continuously regardless of dose interruptions or missed doses 
for both treatment arms. Participants will undergo safety and efficacy surveillance as defined in 
the SoA Section 2. 
Cohort 1 (SoA Table 2-3) 
Participants will receive 2 cycles of treatment with nivolumab + relatlimab FDC IV. Starting with 
Cycle 3, participants will receive nivolumab + relatlimab FDC SC. Participants will continue to 
receive study treatment until investigator-determined disease progression, unacceptable toxicity, 
withdrawal of consent, lost to follow-up, death, study termination by the Sponsor, or completion 
of up to 2 years (104 weeks) of treatment, whichever occurs first. 
 
 
 
 
  
Cohort 2 (SoA Table 2-4) 
Participants will receive 2 cycles of treatment with nivolumab IV. Starting with Cycle 3, 
participants will receive nivolumab SC. Participants will continue to receive study treatment until 
investigator-determined disease recurrence, unacceptable toxicity, withdrawal of consent, lost to 
follow-up, death, study termination by the Sponsor, or completion of up to 1 year (52 weeks) of 
treatment, whichever occurs first.   
5.1.3 
Follow-Up Period  
Follow-up assessments are to be performed as described in the SoA (Table 2-5). 
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Safety Follow-up Period 
Safety Follow-up will begin the day after the Treatment Period when the participant has completed 
their course of treatment or the decision to discontinue a participant from study treatment is made 
(ie, participants have discontinued study treatment). The Safety Follow-up Period consists of 
2 Follow-up Visits: 
 
 
 
 should be collected continuously using National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5 during the Safety 
Follow-up. 
For Cohort 1 - participants must be followed 
 after last dose of 
study treatment. Follow-up Visit 1 should occur 
 or can be 
performed on the date of discontinuation if that date is greater than 
 last dose. 
Follow-up Visit 2 occurs 
 from last dose of study treatment. 
Both follow-up visits should be conducted in person. 
For Cohort 2 - participants must be followed for at least 
 after last dose of 
study treatment. Follow-up Visit 1 should occur 
 from the last dose 
 or can be 
performed on the date of discontinuation if that date is greater than 
 after last dose. 
Follow-up Visit 2 occurs approximately 
 from last dose of study treatment. 
Both follow-up visits should be conducted in person. 
5.1.4 
Data Monitoring Committee and Other Committees 
A Data Monitoring Committee or other review committee will not be used in the study.   
5.2 
Number of Participants 
Approximately 
 participants will be enrolled in two cohorts of 
 treated participants each; 
 treated participants will be enrolled in Cohort 1 (metastatic melanoma) 
 
 treated participants will be enrolled in 
Cohort 2 (resected melanoma) 
 
. No replacement of discontinued participants will be performed.  
5.3 
End of Study Definition 
The start of the study is defined as the first participant’s first visit. 
The primary completion date is defined as the date on which the last data point is collected for the 
study’s primary endpoint (outcome). For this study, the last primary outcome for the primary 
endpoint is defined as the completion of the Patient Experience and Preference Questionnaire 
(PEPQ). 
End of study is defined as the last participant’s last visit, which will occur 
 from last 
treatment dose for Cohort 1 (nivolumab + relatlimab) and 
 from the last treatment dose 
for Cohort 2 (nivolumab). 
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A participant is considered to have completed the study if he/she has completed the last visit or 
the last procedure shown in the Schedule of Activities (Section 2), whichever occurs later.  
5.4 
Scientific Rationale for Study Design 
The pivotal Phase 2/3 CA224047 study demonstrated clinical benefit with nivolumab 
480 mg + relatlimab 160 mg IV FDC Q4W in participants with previously untreated metastatic or 
unresectable melanoma and has received FDA approval for the treatment of these patients. In 
Stage III/IV completely resected melanoma, adjuvant nivolumab is an established standard of care 
that is recognized in guidelines globally. In CA209238, adjuvant nivolumab demonstrated clinical 
benefit with an acceptable safety profile in patients with resected Stage IIIB/C or Stage IV 
melanoma (American Joint Committee on Cancer AJCC 7th edition). Recently, the Phase 3 
CA20976K study demonstrated statistically significant and clinically meaningful RFS benefit with 
adjuvant nivolumab versus placebo in patients with completely resected Stage IIB or IIC 
melanoma. With advancement in I-O therapies, cancer patients are surviving longer and hence 
enduring the burden of being on treatment for longer. Therefore, strategies to lessen this burden 
have the potential to improve the quality of life for patients and their caregivers. A faster SC 
injection as compared with IV infusion may allow for improved patient quality of life as well as 
efficiencies in healthcare resource utilization. 
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5.4.2 
Cohort 2: Resected Melanoma: 
5.4.2.1 
Rationale for Use of nivolumab 
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 CA209238, 
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.  
CA209238 randomly assigned patients with resected Stage IIIB, IIIC, or IV disease to receive 
nivolumab versus 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 versus 60.8% in the ipilimumab group. At 24 months, RFS was 62.6% in the nivolumab 
group versus 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 CA209238, the use of ipilimumab is no longer recommended in the adjuvant 
setting given the superiority of nivolumab coupled with less toxicity.  
For resected Stage IIB or IIC melanoma, the CA20976K study demonstrated statistically 
significant and clinically meaningful RFS benefit with adjuvant nivolumab versus placebo in 
patients with completely resected Stage IIB or IIC melanoma. CA20976K is a Phase 3 study in 
treatment-naive patients ≥ 12 years of age with completely resected Stage IIB/C melanoma with 
standard wide local excision and negative sentinel lymph node biopsy. Patients were randomized 
2:1 
. At the interim analysis 
with a minimum follow-up of 8 months, the primary endpoint was met, demonstrating improved 
RFS with nivolumab versus placebo (stratified HR 0.42 [95% CI: 0.30, 0.59] p<0.0001). The 
landmark 12-month RFS rate for nivolumab was 89% and 79% for the placebo arm. The RFS 
benefit with nivolumab was observed across prespecified subgroups, including age, sex, location 
of primary melanoma, T-category, disease stage, and melanoma subtype. The safety profile of 
nivolumab was consistent with previous reports. The results of CA20976K support nivolumab as 
an effective adjuvant treatment option in resected Stage IIB/C melanoma. 
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5.4.3 
Rationale for Patient Preference Endpoints 
Participants will be asked to complete the Patient Experience Questionnaire (PEQ) at the site 
immediately after Cycle 2 Day 1 following IV treatment administration, to assess patient 
experience of IV treatment, and the PEPQ at the site immediately after Cycle 4 Day 1 following 
SC treatment administration to assess experience of SC administration and preference between SC 
and IV treatment administration.30 (See Section 2 SoA). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. Patient preference has been shown to have 
an impact on adherence to treatment in many chronic conditions. Within oncology, patient 
preference has been associated with improved clinical outcomes and adherence to treatment.27 
Additionally, a recent study identified that in a metastatic melanoma patient population, 
considerations for patient preference of treatment can help patients get the full benefit of 
treatment.28  
In this study, patient preference using the PEPQ will be evaluated immediately after Cycle 4 Day 1. 
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5.5 
Justification of Dose 
5.5.1 
Nivolumab Clinical Pharmacology Summary 
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 IV infusion every 
2 or 3 weeks. Nivolumab clearance (CL) decreases over time, with a mean maximal reduction 
(% coefficient of variation [CV%]) from baseline values of 24.5% (47.6%) resulting in a geometric 
mean steady-state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; 
the decrease in CLss is not considered clinically relevant. nivolumab clearance does not decrease 
over time in patients with completely resected melanoma, as the geometric mean population 
clearance is 24% lower in this patient population compared with patients with metastatic 
melanoma at steady state. The geometric mean volume of distribution at steady state (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 Q2W, 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 Q2W. The predicted exposure (Cavg and Cmax) 
of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion. 
 
 
 
 
 
 
 
 
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5.5.3 
Justification of nivolumab + relatlimab FDC IV Dose 
The proposed dose of the FDC product is nivolumab 480 mg + relatlimab 160 mg Q4W. The dose 
and dosing regimen for this study were primarily based on the observed benefit/risk profile 
observed in metastatic melanoma participants from Study CA224047 and CA224020 PK, PD, and 
extensive nivolumab monotherapy clinical experience. 
Clinical efficacy and safety data from the pivotal Study CA224047 confirmed the positive 
benefit/risk profile of the proposed dose in adult melanoma participants. The benefit/risk of 
nivolumab 480 mg + relatlimab 160 mg Q4W regimen is supported by exposure-response (E-R) 
efficacy and E-R safety analyses performed using data from 1L and prior-I-O melanoma 
participants. 
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5.5.5 
Justification of nivolumab IV Dose 
The IV flat dose of nivolumab 480 mg was selected based on comprehensive PPK analyses and 
E-R data using Cavgd28 as the primary driver of efficacy across multiple tumor types. The IV
nivolumab 480 mg Q4W regimen presents a comparable benefit-risk profile as the IV nivolumab
3 mg/kg Q2W dosing regimen across multiple tumor types.
5.5.6 
Justification of nivolumab SC Dose 
PK data from participants enrolled in Study CA2098KX, where nivolumab 
 
 was administered SC with or without rHuPH20, and historical IV nivolumab data across 
several tumor types (data from approximately 3,000 patients) were used to characterize the 
absorption profile of nivolumab when given SC. PPK analysis estimated the typical value (90% 
CI) bioavailability to be 70% (66% to 74%) and first-order rate of absorption to be 0.250 (90%
CI: 0.225 to 0.274).16 All other PK parameters and effects of covariates on these parameters 
were consistent with those estimated previously with the IV nivolumab PPK model.
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Date: 24-May-2024 
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65 
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 the following criteria apply:  
6.1.1 
Inclusion Criteria for Cohort 1 
Participants are eligible to be included in the study only if all the following criteria apply: 
1) Signed Written Informed Consent 
a) Participants must have signed and dated an Institutional Review Board /Independent Ethics 
Committee 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. 
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b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study. 
2) Type of Participant and Target Disease Characteristics 
a) Participants must have an Eastern Cooperative Oncology Group performance status 
(ECOG PS) score of ≤ 1. 
b) Participants must have histologically confirmed Stage III (unresectable) or Stage IV 
(metastatic) melanoma, per the American Joint Committee on Cancer (AJCC) staging 
system (8th edition). 
c) Participants must be treatment-naïve (ie, no prior systemic anticancer therapy) for 
unresectable or metastatic melanoma. 
d) Participants are eligible regardless of BRAF status. Participants with known BRAF V600 
mutation status, or who consent to BRAF V600 mutation testing per local institutional 
standards during the Screening Period with the sample collected within 3 months prior to 
treatment assignment must report BRAF status. 
3) Age of Participant  
Participants must be ≥ 18 years of age at the time of consent.  
4) Reproductive Status 
a) Female Participants: 
i) Female participants must have documented proof that they are not of childbearing 
potential. 
Note: Women who are not of childbearing potential (as defined in Appendix 4) are 
exempt from contraceptive requirements.  
ii) WOCBP must have a negative highly sensitive serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) 
within 24 hours prior to the start of study intervention. An extension up to 72 hours 
prior to start of study treatment is permissible in situations where results cannot be 
obtained within the standard 24-hour window. 
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i) WOCBP must agree to follow instructions for method(s) of contraception as described 
below and included in the ICF. 
• WOCBP are permitted to use hormonal contraception methods (as described in Appendix 4). 
ii) 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 (with a 
failure rate of < 1% per year), with low user dependency, during the intervention 
period and for the duration of treatment with nivolumab and relatlimab plus 5 half-
lives of study treatment for a 
 post-treatment completion and 
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the 
same time period. 
 
6.1.2 
Inclusion Criteria for Cohort 2 
Participants are eligible to be included in the study only if all the following criteria apply: 
1) Signed Written Informed Consent 
a) Participants must have signed and dated an Institutional Review Board /Independent Ethics 
Committee 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 testing, and other requirements of the study. 
2) Type of Participant and Target Disease Characteristics 
a) Participants must have an (ECOG-PS) score of ≤ 1. 
b) Participants must be eligible for adjuvant therapy for melanoma.  
i) All participants must have completed surgical resection of Stage IIB/C, IIIA (> 1 mm 
tumor in lymph node)/B/C/D or stage IV (AJCC Cancer Staging, 8th edition) 
2.0
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Date: 24-May-2024 
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melanoma. All melanomas, except ocular and mucosal melanomas, are allowed 
regardless of primary site of disease.  
ii) Participants with complete melanoma resection within 12 weeks of treatment 
assignment. Participants must be surgically rendered free of disease with negative 
margins on resected specimens. Complete resection must be documented on surgical 
and pathology report. For central nervous system (CNS) lesion(s), documentation 
indicating that there has been complete resection of CNS lesion(s) will suffice as 
confirmation of negative margins. 
c) All participants must have disease-free status documented by a complete physical 
examination and imaging studies within 4 weeks prior to treatment assignment. Imaging 
studies must include computed tomography (CT) or magnetic resonance imaging (MRI) 
scans of the chest, abdomen, pelvis, and all known sites of resected disease, and brain MRI 
or CT (brain CT allowable if MRI is contraindicated or if there is no known history of 
resected brain lesions). 
3) Age of Participant  
Participants must be ≥ 18 years of age at the time of consent.  
4) Reproductive Status 
a) Female Participants: 
i) Female participants must have documented proof that they are not of childbearing 
potential. 
Note: Women who are not of childbearing potential (as defined in Appendix 4) are 
exempt from contraceptive requirements.  
ii) WOCBP must have a negative highly sensitive serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) 
within 24 hours prior to the start of study intervention. An extension up to 72 hours 
prior to start of study treatment is permissible in situations where results cannot be 
obtained within the standard 24-hour window. 
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i)
WOCBP must agree to follow instructions for method(s) of contraception as described
below and included in the ICF.
WOCBP are permitted to use hormonal contraception methods (as described in Appendix 4). 
i)
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 (with a
failure rate of < 1% per year), with low user dependency, during the intervention
period and for the duration of treatment with nivolumab and relatlimab plus 5 half-
lives of study treatment for a 
 post-treatment completion and
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the
same time period.
6.2 
Exclusion Criteria  
6.2.1 
Exclusion Criteria for Cohort 1 
Participants are excluded from the study if any of the following criteria apply: 
1) Medical Conditions
a) Participants must not have active brain metastases or leptomeningeal metastases.
b) Participants with brain disease treated with whole brain radiation are not eligible.
c) Participants must not have ocular or mucosal melanoma.
d) Participants must not have an active, known, or suspected autoimmune disease.
e) Participants may enroll with the following conditions:
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i) Type 1 diabetes mellitus. 
ii) Hypothyroidism only requiring hormone replacement therapy. 
iii) Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment. 
iv) Conditions not expected to recur in the absence of an external trigger. 
f) Participants must not have a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 
 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. 
g) Participants must not have a concurrent malignancy (present during screening) requiring 
treatment or history of prior malignancy active within 2 years prior to treatment 
assignment (ie, participants with a history of prior malignancy are eligible if treatment 
was completed at least 2 years before treatment assignment and the participant has no 
evidence of disease). Participants with history of prior early stage basal/squamous cell 
skin cancer or non-invasive or in situ cancers that have undergone definitive treatment at 
any time are also eligible. 
h) Participants must not have known human immunodeficiency virus (HIV) positive with an 
acquired immunodeficiency syndrome 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) for at least 4 weeks prior to treatment 
assignment as clinically indicated.  
ii) they continue on ART as clinically indicated while enrolled on study. 
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. (Refer to Appendix 8.) 
i) Participants must not have any serious or uncontrolled medical disorder that, in the 
opinion of the investigator in consultation with the BMS Medical Monitor, may increase 
the risk associated with study participation or study treatment administration, impair the 
ability of the participant to receive protocol therapy, or interfere with the interpretation of 
study results. 
j) Participants must not have previous SARS-CoV-2 infection either suspected or confirmed 
within 4 weeks prior to screening. Acute symptoms must have resolved and based on 
investigator assessment in consultation with the Medical Monitor, there are no sequelae 
that would place the participant at a higher risk of receiving investigational treatment. 
k) Participant has not recovered adequately from toxicity and/or complications from surgery 
prior to starting study treatment 
l) Participants must not have a history of myocarditis, regardless of etiology.  
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2) Reproductive Status 
a) Women who are breastfeeding. 
b) Women who are pregnant. 
3) Prior/Concomitant Therapy 
a) Participant must not have had prior treatment with an anti-PD-1 (except if given as adjuvant 
or neoadjuvant therapy for melanoma), anti- programmed death-ligand 1 (PD-L1), 
anti-programmed death-ligand 2 (PD-L2), anti-CTLA-4 antibody (except if given as 
adjuvant or neoadjuvant therapy for melanoma), or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways (except for interferon 
given as adjuvant or neoadjuvant therapy for melanoma) within 6 months prior to start of 
study treatment 
b) Participant must not have had prior treatment with relatlimab or any other lymphocyte 
activation gene-3 targeted agents. 
c) Inability to comply with restriction and prohibited treatments. 
d) Treatment with complementary medications (eg, herbal supplements or traditional Chinese 
medicines) to treat the disease under study within 2 weeks prior to first study treatment. 
Such medications are permitted if they are used as supportive care. 
e) 
. Participants must have 
recovered (ie, Grade ≤ 1 or at baseline) from radiation-related toxicities prior to first study 
treatment. 
f) Treatment with any live / attenuated vaccine within 30 days of first study treatment. 
g) Participants currently in other interventional trials, including those for coronavirus disease 
2019 (COVID-19), may not participate in BMS clinical trials until the protocol specific 
washout period is achieved. If a study participant has received an investigational 
COVID-19 vaccine or other investigational product designed to treat or prevent COVID-19 
prior to screening, treatment assignment must be delayed until the biologic impact of the 
vaccine or investigational product is stabilized, as determined by discussion between the 
investigator and the Medical Monitor. 
2.0
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5) Allergies and Adverse Drug Reactions 
a) Participants must not have a history of allergy or hypersensitivity to study intervention 
components. 
6) Other Exclusion Criteria 
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 Sponsor approval is required.) 
6.2.2 
Exclusion Criteria for Cohort 2 
Participants are excluded from the study if any of the following criteria apply: 
1) Medical Conditions 
a) Participants must not have active brain metastases or leptomeningeal metastases. 
 
b) Participants with brain disease treated with whole brain radiation are not eligible. 
c) Participants must not have ocular or mucosal melanoma. 
d) Participants must not have an active, known, or suspected autoimmune disease. 
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e) Participants may enroll with the following conditions: 
i) Type 1 diabetes mellitus. 
ii) Hypothyroidism only requiring hormone replacement therapy. 
iii) Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment. 
iv) Conditions not expected to recur in the absence of an external trigger. 
f) Participants must not have a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 
 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. 
g) Participants must not have a concurrent malignancy (present during screening) requiring 
treatment or history of prior malignancy active within 2 years prior to treatment assignment 
(ie, participants with a history of prior malignancy are eligible if treatment was completed 
at least 2 years before treatment assignment and the participant has no evidence of disease). 
Participants with history of prior early stage basal/squamous cell skin cancer or 
non-invasive or in situ cancers that have undergone definitive treatment at any time are 
also eligible. 
h) Participants must not have known human immunodeficiency virus (HIV) positive with an 
acquired immunodeficiency syndrome 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) for at least 4 weeks prior to treatment 
assignment as clinically indicated.  
ii) they continue on ART as clinically indicated while enrolled on study. 
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. (Refer to Appendix 8.) 
i) Participants must not have any serious or uncontrolled medical disorder that, in the opinion 
of the investigator in consultation with the BMS Medical Monitor, may increase the risk 
associated with study participation or study treatment administration, impair the ability of 
the participant to receive protocol therapy, or interfere with the interpretation of study 
results. 
j) Participants must not have previous SARS-CoV-2 infection either suspected or confirmed 
within 4 weeks prior to screening. Acute symptoms must have resolved and based on 
investigator assessment in consultation with the Medical Monitor, there are no sequelae 
that would place the participant at a higher risk of receiving investigational treatment. 
2) Reproductive Status 
a) Women who are breastfeeding. 
b) Women who are pregnant. 
3) Prior/Concomitant Therapy 
a) Participant must not have had prior treatment with an anti-PD-1 (except if given as adjuvant 
or neoadjuvant therapy for melanoma), anti- programmed death-ligand 1 (PD-L1), 
anti-programmed death-ligand 2 (PD-L2), anti-CTLA-4 antibody (except if given as 
2.0
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930207750
2.0
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Clinical Protocol 
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Protocol Amendment No. 01 
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74 
adjuvant or neoadjuvant therapy for melanoma), or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways (except for interferon 
given as adjuvant or neoadjuvant therapy for melanoma)  
b) Participant must not have had prior treatment with relatlimab or any other lymphocyte 
activation gene-3 targeted agents. 
c) Inability to comply with restriction and prohibited treatments. 
d) Treatment with complementary medications (eg, herbal supplements or traditional Chinese 
medicines) to treat the disease under study within 2 weeks prior to first study treatment. 
Such medications are permitted if they are used as supportive care. 
e) 
. Participants must have 
recovered (ie, Grade ≤ 1 or at baseline) from radiation-related toxicities prior to first study 
treatment. 
f) Treatment with any live / attenuated vaccine within 30 days of first study treatment. 
g) Participants currently in other interventional trials, including those for coronavirus disease 
2019 (COVID-19), may not participate in BMS clinical trials until the protocol specific 
washout period is achieved. If a study participant has received an investigational 
COVID-19 vaccine or other investigational product designed to treat or prevent COVID-19 
prior to screening, treatment assignment must be delayed until the biologic impact of the 
vaccine or investigational product is stabilized, as determined by discussion between the 
investigator and the Medical Monitor. 
2.0
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5) Allergies and Adverse Drug Reactions
Participants must not have a history of allergy or hypersensitivity to study intervention
components.
6) Participants must not have active brain metastases or leptomeningeal metastases.
7) Prior immunotherapy treatments for any prior malignancies are not permitted (such as, but not
limited to anti-PD-1, anti-PD-L1, PD-L2, or any other antibody or drug specifically targeting
T-cell co-stimulation or immune checkpoint pathways).
8) Other Exclusion Criteria
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
Sponsor approval is required.)
6.3 
Lifestyle Restrictions 
Not applicable. 
6.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently enrolled in the study/included in the analysis population.  
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants, to meet the Consolidated Standards of Reporting Trials 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 SAEs that occurred following consent. 
6.4.1 
Re-testing During Screening 
This study permits the re-enrollment of a participant who has discontinued the study as a screen 
failure (ie, participant has not been treated). If re-enrolled, the participant must be re-consented 
and assigned a new participant number from IRT. 
Re-testing of laboratory parameters and/or other assessments within any single screening or 
leading- period will be permitted (in addition to any parameters that require a confirmatory value). 
The most current result prior to treatment assignment is the value by which study inclusion will be 
assessed because it represents the participant’s most current clinical state. 
Laboratory parameters and/or assessments that are included in Table 2-1 and Table 2-2, Screening 
Procedural Outline, may be repeated in an effort to find all possible well-qualified participants. 
Consultation with the Medical Monitor may be needed to identify whether repeat testing of any 
particular parameter is clinically relevant. 
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nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
76 
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 IP as indicated in Table 7.1-1. 
An IP, also known as an Investigational Medicinal Product (IMP) in some regions, is defined as 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, used for an unauthorized 
indication, or when used to gain further information about the authorized form. 
In this protocol, the IPs are the following: 
Cohort 1: 
• nivolumab 480 mg + relatlimab 160 mg FDC IV  
• nivolumab 960 mg + relatlimab 320 mg FDC + 
 rHuPH20 SC 
 
Cohort 2:  
• nivolumab 480 mg IV 
• nivolumab 1200 mg + 
 rHuPH20 SC 
 
 
There are no non-IPs used in this study. 
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 
Non-IMPs/AxMPs. 
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Protocol Amendment No. 01 
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7.1 
Study Interventions Administered 
Table 7.1-1: 
Study Intervention(s) Administered 
Type/ 
Intervention 
Name/ 
Dose 
Formulation 
Unit Dose 
Strength(s) 
 
IMP/Non-
IMP/ AxMP 
Blinded or 
Open-label 
 
Sourcinga 
 
Packaging and 
Labeling 
 
Current/ 
Former 
Name(s) or 
Alias(es) 
 
Cohort 1 Metastatic Melanoma 
Drug/BMS-
986213/  
relatlimab/nivolu
mab/ solution for 
infusion  
 
 
 
 
 
 
IMP/ 
Open-label 
Provided 
centrally by 
the Sponsor 
Study 
intervention 
will be 
provided vials. 
Each vial will 
be labeled as 
required per 
country 
requirement. 
BMS-
986213; 
nivolumab + 
relatlimab 
FDC IV; 
Opdualag 
Drug/ 
nivolumab, 
relatlimab, 
rHuPH20/ 
(solution for 
injection) 
 
 
 
 
IMP/ 
Open-label  
 Provided 
centrally by 
the Sponsor 
Study 
intervention 
will be 
provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement. 
BMS-
986213; 
nivolumab + 
relatlimab + 
rHuPH20; 
FDC SC 
Cohort 2 – Resected Melanoma 
Drug/ 
nivolumab 
(solution for 
infusion) 
nivolumab 
(10 mg/mL) 
IMP/ 
Open-label  
 Provided 
centrally by 
the Sponsor 
Study 
intervention 
will be 
provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement.  
BMS-
936558/ 
nivolumab IV 
 
Drug/nivolumab 
and rHuPH20/ 
 (solution for 
injection) 
nivolumab  
 
 
 
IMP/ 
Open-label  
 Provided 
centrally by 
the Sponsor 
Study 
intervention 
provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement. 
BMS-986298 
nivolumab 
SC 
Abbreviations: AxMP, Auxiliary Medicinal Product; IMP, Investigational Medicinal Product; IV, intravenous; 
SC, subcutaneous; Non_IMP, Non-investigational Medicinal Product; SmPC, summary of product characteristics. 
a These products may be obtained by investigational sites as local commercial product in certain countries if allowed 
by local regulations. In these cases, products may be a different pack size/potency than listed in the table. These 
products should be prepared/stored/administered in accordance with the package insert or SmPC 
 
2.0
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Clinical Protocol 
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
78 
Table 7.1-2: 
Study Cohorts 
Cohort Title/ 
Cohort Type 
Intervention Description/ 
Dosage Levels 
Route of Administration/ 
Administration Time  
Cohort 1 Metastatic 
Melanoma/ 
Open Label 
Participants will receive  
nivolumab 480 mg + relatlimab 160 mg on 
Day 1 for first 2 cycles (28-day cycle). 
IV Infusion over 30 minutes 
Participants will receive  
nivolumab 960 mg + relatlimab 320 mg 
rHuPH20 
 beginning on Day 1 
of Cycle 3 for up to 2 years (28-day cycle). 
SC injection 
 
Cohort 2 Resected 
Melanoma/ 
Open Label 
participants will receive nivolumab 480 mg 
on Day 1 for first 2 cycles (28-day cycle). 
IV Infusion over 30 minutes 
Participants will receive nivolumab 
1200 mg + rHuPH20 
 beginning 
on Day 1 of Cycle 3 for up to 1 year (28-day 
cycle). 
SC injection 
 
7.1.1 
General Considerations 
Study treatment will be dispensed at the study visits as listed in Section 2 (Schedule of Activities). 
The selection and timing of dose for each participant is provided in Table 7.1-2. The selection, 
timing, and other parameters regarding dose administration for participants are further described 
as follows: 
Treatment cycles are 28 days in length (Q4W). 
Cohort 1 will receive nivolumab + relatlimab FDC IV on Day 1 of Cycle 1 and Cycle 2 
(± 3 days).  
Starting on Cycle 3 Day 1, nivolumab + relatlimab FDC will be administered SC Q4W ± 3 days 
on Day 1 of each treatment cycle until progression, unacceptable toxicity, withdrawal of consent, 
completion of treatment, lost to follow-up, death, or the end of study, whichever occurs first, up to 
2 years.  
Cohort 2 will receive nivolumab IV on Day 1 of Cycle 1 and Cycle 2 (± 3 days). 
Starting on Cycle 3 Day 1, nivolumab will be administered SC Q4W ± 3 days on Day 1 of each 
treatment cycle until disease recurrence, unacceptable toxicity, withdrawal of consent, lost to 
follow-up, completion of treatment, death, or the end of study, whichever occurs first, up to 1 year. 
Participants should begin study treatment within 3 calendar days of treatment assignment. 
•
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/local site reactions during
immunotherapy administration.
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
79 
• If an acute infusion/site reaction is noted, participants should be managed according to 
Section 7.4 
• Participants should receive study therapy until disease progression (Cohort 1) or recurrence 
(Cohort 2), unacceptable toxicity, lost to follow-up, death, withdrawal of consent, completion 
of treatment, or study termination by the sponsor, whichever comes first. 
• Doses of study therapy may be interrupted (for IV administration only), 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. 
 
7.1.2 
Intravenous Administration of nivolumab Combined with relatlimab 
Administration 
 
On Day 1 of Treatment Cycle 
 participants in Cohort 1 will 
receive an IV infusion of nivolumab and relatlimab FDC 
 
 
7.1.3 
Subcutaneous Administration of nivolumab Combined with relatlimab 
Administration 
 
, participants will be administered nivolumab + relatlimab SC Q4W 
±3 days on Day 1 of each treatment cycle until progression, unacceptable toxicity, withdrawal of 
consent, completion of treatment, death, or the end of study, whichever occurs first (as shown in 
SoA Table 2-3) up to 2 years.  
2.0
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Clinical Protocol 
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
80 
7.1.4 
Intravenous Administration of nivolumab 
  
Participants in Cohort 2 will initially receive nivolumab 480 mg administered 
 
, Q4W ± 3 days on Day 1 
 
 
 
 
 
7.1.5 
Subcutaneous Administration of nivolumab with rHuPH20 
 
 
, participants will be administered nivolumab SC Q4W ± 3 days on Day 1 
of each treatment cycle until recurrence, unacceptable toxicity, withdrawal of consent, completion 
of treatment, death, or the end of study, whichever occurs first (as shown in SoA Table 2-4) up to 
1 year.  
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Approved
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Clinical Protocol 
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Protocol Amendment No. 01 
Date: 24-May-2024 
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7.2 
Assignment to Study Intervention 
Each site user will receive login information and/or directions on how to access IRT. Specific 
instructions for using IRT will be provided to the investigational site in a separate document.  
During the screening visit, 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 
5-digit participant number which will be unique across all sites. Every participant who signs the 
informed consent form must be assigned a participant number in IRT. The investigator or designee 
will register the participant for treatment assignment by following the treatment assignment 
procedures established by BMS. The following information is required for treatment assignment:  
• Confirmation of informed consent 
• Year of birth 
• Gender at birth 
 
All enrolled participants will be assigned sequential participant numbers starting with 
 (eg, 
). 
 
. For example, the first participant screened (ie, enrolled) 
at site number 1 will have a PID of 
. 
Once it is determined that the participant meets the eligibility criteria following the screening visit, 
the investigative site will login to the IRT to enroll the participant. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable.   
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Clinical Protocol 
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Protocol Amendment No. 01 
Date: 24-May-2024 
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7.4 
Dosage Modification 
No dose modifications for either treatment are permitted. 
7.4.1 
Dose Delay Criteria for nivolumab and nivolumab + relatlimab FDC 
Dose delay criteria apply for all drug-related AEs graded using NCI-CTCAE v5.0 (regardless of 
whether the event is attributed to nivolumab, relatlimab, or rHuPH20). 
Delay administration of nivolumab IV or nivolumab + relatlimab FDC IV or nivolumab SC or 
nivolumab + relatlimab FDC SC if any of the delay criteria in Table 7.4.1-1 and Table 7.4.1-2 are 
met. 
Delay nivolumab IV or nivolumab + relatlimab FDC IV or nivolumab or nivolumab SC + 
relatlimab FDC SC dosing for any AE, laboratory abnormality, or intercurrent illness that in the 
judgment of the investigator, warrants delaying the dose of study medication. 
No dose escalations or reductions are permitted in the study.  
2.0
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2.0
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Approved
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Clinical Protocol 
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BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
83 
Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation nivolumab + relatlimab FDC 
Drug-Related Adverse Event 
(AE) per CTCAE V5.0 
Severity 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
Gastrointestinal 
Colitis or Diarrhea 
Grade 2 or 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 
2.0
Approved
930207750
2.0
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Approved
1.0
v

Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
84 
Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation nivolumab + relatlimab FDC 
Drug-Related Adverse Event 
(AE) per CTCAE V5.0 
Severity 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
Hepatic 
Aspartate aminotransferase 
(AST), alanine aminotransferase 
(ALT), or total bilirubin (T. Bili) 
increased 
AST or ALT > 3× and ≤5× upper limit of 
normal (ULN) or T. Bili >1.5× and ≤3× 
ULN, regardless of baseline value 
Delay dose 
Dosing may resume when laboratory 
values return to baseline. 
AST or ALT > 5× ULN or T. Bili > 3× 
ULN, regardless of baseline value 
Delay dose or 
permanently 
discontinue 
In most cases of AST or ALT > 5 × ULN, 
study treatment will be permanently 
discontinued. If the investigator determines a 
possible favorable benefit/risk ratio that 
warrants continuation of study treatment, a 
discussion between the investigator and the 
Medical Monitor/designee must occur and 
approval from Medical Monitor prior to 
resuming therapy. 
Concurrent AST or ALT > 3 × ULN and 
T. Bili > 2 × ULN, regardless of baseline 
value 
Permanently discontinue 
Endocrinopathy 
Adrenal Insufficiency 
Grade 2 adrenal insufficiency 
Delay dose 
Dosing may resume after adequately 
controlled with hormone replacement. 
Grade 3 or 4 adrenal insufficiency or 
adrenal crisis 
Delay dose or 
permanently 
discontinue 
Mandatory discussion with and approval from 
the Medical Monitor needed prior to resuming 
therapy. If adrenal insufficiency resolves or is 
adequately controlled with physiologic 
hormone replacement, participant may not 
require discontinuation of study intervention. 
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. 
2.0
Approved
930207750
2.0
v
Approved
1.0
v

Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
85 
Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation nivolumab + relatlimab FDC 
Drug-Related Adverse Event 
(AE) per CTCAE V5.0 
Severity 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
Hyperglycemia 
Grade 4 
Delay dose or 
permanently 
discontinue 
Mandatory discussion with and approval 
from the Medical Monitor needed prior to 
resuming therapy. If hyperglycemia resolves, 
or is adequately controlled with glucose-
controlling agents, participant may not 
require discontinuation of study intervention. 
Hypophysitis/Hypopituitarism 
Symptomatic Grade 1-3 that is also 
associated with corresponding abnormal 
lab and/or pituitary scan 
Delay dose 
Dosing may resume if endocrinopathy 
resolves to be asymptomatic, or is adequately 
controlled with only physiologic hormone 
replacement. 
Grade 4 
Delay dose or 
permanently 
discontinue 
Mandatory discussion with and approval from 
the Medical Monitor needed prior to resuming 
therapy. If endocrinopathy resolves or is 
adequately controlled with physiologic 
hormone replacement, participant may not 
require discontinuation of study intervention. 
Hyperthyroidism or 
Hypothyroidism 
Grade 2 or 3 
Delay dose 
Dosing may resume if endocrinopathy 
resolves to be asymptomatic, or is adequately 
controlled with only physiologic hormone 
replacement or other medical management. 
Grade 4 
Delay dose or 
permanently 
discontinue 
Mandatory discussion with and approval from 
the Medical Monitor needed prior to resuming 
therapy. If endocrinopathy resolves or is 
adequately controlled with physiologic 
hormone replacement or other medical 
management, participant may not require 
discontinuation of study intervention. 
Skin 
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 
2.0
Approved
930207750
2.0
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Approved
1.0
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
86 
Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation nivolumab + relatlimab FDC 
Drug-Related Adverse Event 
(AE) per CTCAE V5.0 
Severity 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
Rash 
Suspected Stevens-Johnson syndrome 
(SJS), toxic epidermal necrolysis (TEN) 
or drug reaction with eosinophilia and 
systemic symptoms (DRESS) 
Delay dose 
Dosing may resume if SJS, TEN, or DRESS 
is ruled out and rash reduces to is ≤10% 
body surface area 
Grade 4 rash or confirmed SJS, TEN, or 
DRESS 
Permanently discontinue 
Neurological 
Guillain-Barre Syndrome (GBS) 
Any Grade 
Permanently discontinue 
Myasthenia Gravis (MG) 
Any Grade 
Permanently discontinue 
Encephalitis 
Any Grade encephalitis 
Delay dose 
After workup for differential diagnosis, (ie, 
infection, tumor-related), if encephalitis is not 
drug-related, then dosing may resume when 
AE resolves 
Any Grade drug-related encephalitis 
Permanently discontinue 
Myelitis 
Any Grade myelitis 
Delay dose 
After workup for differential diagnosis, (ie, 
infection, tumor-related), if myelitis is not 
drug-related, then dosing may resume when 
AE resolves 
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 
2.0
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930207750
2.0
v
Approved
1.0
v

Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
87 
Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation nivolumab + relatlimab FDC 
Drug-Related Adverse Event 
(AE) per CTCAE V5.0 
Severity 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
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 
2.0
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930207750
2.0
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Approved
1.0
v

Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
88 
Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation nivolumab + relatlimab FDC 
Drug-Related Adverse Event 
(AE) per CTCAE V5.0 
Severity 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
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 intervention. 
Grade 3 or 4 uveitis 
Permanently discontinue 
Other Drug-Related AE (not 
listed above) 
Grade 2 non-skin AE, except fatigue 
Delay dose 
Dosing may resume when AE resolves to Grade 
≤ 1 or baseline value. 
Grade 3 AE - First occurrence lasting ≤ 7 
days 
Delay dose 
Dosing may resume when AE resolves to Grade 
≤ 1 or baseline value. 
Grade 3 AE - First occurrence lasting > 7 
days 
Permanently discontinue 
Recurrence of Grade 3 AE of any 
duration 
Permanently discontinue 
Grade 4 or Life-threatening adverse 
reaction 
Permanently discontinue 
2.0
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930207750
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Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
89 
Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation nivolumab + relatlimab FDC 
Drug-Related Adverse Event 
(AE) per CTCAE V5.0 
Severity 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
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 intervention: 
• 
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 
Injection 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; CTCAE v5.0, Common Terminology Criteria for Adverse 
Events version 5.0; DRESS, drug reaction with eosinophilia and systemic symptoms; FDC, fixed-dose combination; GBS, Guillain-Barre syndrome; MG, 
myasthenia gravis; SJS, Stevens-Johnson syndrome; T. Bili, total bilirubin; TEN, toxic epidermal necrolysis; ULN, upper limit of normal. 
 
 
2.0
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930207750
2.0
v
Approved
1.0
v

Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
90 
Table 7.4.1-2: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation of nivolumab 
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  
Nivolumab monotherapy: Delay dose 
Dosing may resume when AE resolves to baseline 
 
 
 Nivolumab monotherapy may be resumed when 
AE resolves to baseline. If Grade 3 diarrhea or 
colitis recurs while on nivolumab monotherapy, 
permanently discontinue 
Grade 4  
Permanently discontinue 
  
Renal 
Serum Creatinine Increased 
Grade 2 or 3  
Delay dose 
Dosing may resume when AE resolves to Grade ≤ 
1 or baseline value 
Grade 4  
Permanently discontinue 
  
Pulmonary 
Pneumonitis 
Grade 2  
Delay dose 
Dosing may resume after pneumonitis has resolved 
to ≤ Grade 1. 
Grade 3 or 4  
Permanently discontinue 
 
Hepatic 
 
Aspartate aminotransferase 
(AST), alanine 
aminotransferase (ALT), or 
total bilirubin (T.bili) increased 
AST or ALT > 3x and ≤5x 
upper limit of normal (ULN) 
or T.Bili >1.5x and ≤3x ULN, 
regardless of baseline value 
Delay dose 
Dosing may resume when laboratory values return 
to baseline. 
AST or ALT > 5 x ULN or T. 
bili > 3 x ULN, regardless of 
baseline value 
Delay dose or Permanently discontinue  
In most cases of AST or ALT > 5 x ULN, study 
treatment will be permanently discontinued. If the 
investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study 
treatment, a discussion between the investigator and 
the Medical Monitor/ designee must occur and 
approval from Medical Monitor prior to resuming 
therapy. 
2.0
Approved
930207750
2.0
v
Approved
1.0
v

Clinical Protocol 
CA2241044 
BMS-986213 
nivolumab + relatlimab FDC SC and nivolumab SC 
Protocol Amendment No. 01 
Date: 24-May-2024 
91 
Table 7.4.1-2: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation of nivolumab 
Drug-Related Adverse Event 
(AE) per CTCAE V5 
Severity  
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Concurrent AST or ALT > 3 x 
ULN and T.bili > 2 x ULN, 
regardless of baseline value 
Permanently discontinue  
  
Endocrinopathy 
Adrenal Insufficiency 
Grade 2 adrenal insufficiency 
Delay dose 
Dosing may resume after adequately controlled 
with hormone replacement. 
Grade 3 or 4 adrenal 
insufficiency or adrenal crisis 
Delay dose or permanently discontinue 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If adrenal insufficiency resolves or is adequately 
controlled with physiologic hormone replacement, 
participant may not require discontinuation of study 
drug. 
Hyperglycemia 
Hyperglycemia requiring 
initiation or change in daily 
management (Grade 2 or 3) 
Delay dose 
Dosing may resume if hyperglycemia resolves to 
Grade ≤1 or baseline value, or is adequately 
controlled with glucose-controlling agents. 
Grade 4 
Delay dose or permanently discontinue 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If hyperglycemia resolves, or is adequately 
controlled with glucose-controlling agents, 
participant may not require discontinuation of study 
drug. 
Hypophysitis/Hypopituitarism  
Symptomatic Grade 1-3 that is 
also associated with 
corresponding abnormal lab 
and/or pituitary scan 
Delay dose  
Dosing may resume if endocrinopathy resolves to 
be asymptomatic, or is adequately controlled with 
only physiologic hormone replacement. 
Grade 4 
Delay dose or permanently discontinue 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If endocrinopathy resolves or is adequately 
controlled with physiologic hormone replacement, 
participant may not require discontinuation of study 
drug. 
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. 
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Table 7.4.1-2: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation of nivolumab 
Drug-Related Adverse Event 
(AE) per CTCAE V5 
Severity  
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Grade 4 
Delay dose or permanently discontinue 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If endocrinopathy resolves or is adequately 
controlled with physiologic hormone replacement 
or other medical management, participant may not 
require discontinuation of study drug. 
Skin 
Rash 
Grade 2 rash covering >30% 
body surface area or Grade 3 
rash  
Delay dose  
Dosing may resume when rash reduces to ≤10% 
body surface area  
Suspected Stevens-Johnson 
syndrome (SJS), toxic 
epidermal necrolysis (TEN) or 
drug reaction with eosinophilia 
and systemic symptoms 
(DRESS) 
Delay dose 
Dosing may resume if SJS, TEN, or DRESS is 
ruled out and rash reduces to is ≤10% body surface 
area 
Grade 4 rash or confirmed 
SJS,TEN, or DRESS 
Permanently discontinue 
  
Neurological 
Guillain-Barre Syndrome 
(GBS) 
Any Grade 
Permanently discontinue 
 
Myasthenia Gravis (MG) 
Any Grade 
Permanently discontinue 
Encephalitis 
Any Grade encephalitis 
Delay dose  
After workup for differential diagnosis (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 
  
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Table 7.4.1-2: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation of nivolumab 
Drug-Related Adverse Event 
(AE) per CTCAE V5 
Severity  
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Neurological (other than GBS, 
MG, encephalitis, or myelitis) 
Grade 2 
Delay dose 
Dosing may resume when AE resolves to baseline  
Grade 3 or 4 
 
Permanently discontinue 
  
Myocarditis 
Myocarditis 
Symptoms induced from mild 
to moderate activity or 
exertion 
Delay dose 
Dosing may resume after myocarditis has resolved 
 
Severe or life threatening, with 
symptoms at rest or with 
minimal activity or exertion, 
and/or where intervention 
indicated. 
Permanently discontinue 
  
Other Clinical 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 
  
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 
  
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Table 7.4.1-2: 
Adverse Event Criteria for Delay, Resumption, and Discontinuation of nivolumab 
Drug-Related Adverse Event 
(AE) per CTCAE V5 
Severity  
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
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 
AEs, which in the judgement  
of the investigator, require 
delaying dose 
 N/A  
 Delay dose 
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 
 
  
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7.4.4 
Treatment of Related Infusion- and Injection-reactions 
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7.4.4.2 
Management of Local Infusion or Injection Site Reactions 
In the clinical experience with nivolumab IV, no tissue necrosis has been observed after accidental 
extravasations of nivolumab IV. The use of oral medications (eg, antihistamines, 
acetaminophen/paracetamol) and topically applied therapies such as cold packs and steroid or 
antihistamine creams or gels is allowed for the treatment of local injection reactions due to 
nivolumab SC (eg, swelling, erythema, pain, induration, local pruritus) and infusion local site 
reactions (local inflammation, necrosis due to drug extravasation) including those related to 
procedures (eg, hematoma). Local/institutional guidelines, if available, can be followed. 
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). 
These management strategies are applicable to both cohorts.  
7.4.4.3 
Management of Needle Stick Injuries 
In case of participant needle stick injuries, sites should follow recommended institutional 
guidelines. 
Initial measures should include the following: 
• Wash the exposed area right away with water and soap or using a skin disinfectant (antiseptic) 
such as rubbing alcohol or a hand sanitizer. 
• Seek immediate medical attention. 
• Notify the site staff. 
 
7.5 
Preparation/Handling/Storage/Accountability 
The IP/IMP 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/IMP is only dispensed to study 
participants. The IP/IMP 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 the Sponsor. If 
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concerns regarding the quality or appearance of the study intervention arise, the study intervention 
should not be dispensed, and the Sponsor should be contacted immediately. 
Study intervention not supplied by the Sponsor will be stored in accordance with the package 
insert. 
IP/IMP documentation (whether supplied by the Sponsor or not) must be maintained and must 
include 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 that 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. 
• Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply, prepare, or administer study intervention.  
• All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff. 
• The investigator, institution, head of the medical institution (where applicable), or authorized 
site staff is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition of records). 
• Further guidance and information for the final disposition of unused study interventions are 
provided in Appendix 2. 
 
7.6 
Study Intervention Compliance 
Study intervention compliance will be monitored by drug accountability as well as the participant’s 
medical record and eCRF. Drug accountability should be reviewed by the study site staff at each 
visit to confirm treatment compliance. The source data will be verified by the Site Monitor through 
regularly scheduled monitoring visits. 
7.7 
Concomitant Therapy 
Concomitant medications are recorded at treatment assignment and throughout the treatment phase 
of the study in the appropriate section of the eCRF. All medications (prescriptions and 
over-the-counter medications) continued at the start of the study or started during the study and 
different from the study treatment must be documented in the concomitant therapy section of the 
eCRF. Non-live COVID-19 vaccination is considered a simple concomitant medication within the 
study. However, the efficacy and safety of non-live vaccines (including non-live COVID-19 
vaccines) in participants receiving BMS-986213 is unknown. 
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7.7.2 
Other Restrictions and Precautions 
Participants are prohibited from joining another interventional clinical trial that includes systemic 
treatment with another investigational agent (IMP) while they are participating in this study. 
7.7.2.1 
Imaging Restrictions 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 
they should receive contrast and if so, which contrast agent and dose are appropriate. Specific to 
MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration rate 
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< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis; therefore, MRI 
contrast is contraindicated. In addition, participants may be excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc. Gentle hydration before and after IV contrast should 
follow local standard of care. The ultimate decision to perform MRI in an individual participant 
enrolled in this study rests with the site radiologist, the investigator, and standards set by the local 
Ethics Committee. 
7.7.4 
Antiviral Therapy 
Participants on antiviral therapy 
 should continue antiviral therapy during the study. 
Changing of dosage and regimens of antiviral therapy will be at the discretion of the investigator. 
 
. Adherence to current antiviral therapy should be 
assessed, and resistance testing performed according to local practices. 
 
 
 
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If a participant has documented virologic breakthrough due to antiviral resistance, then this should 
be managed based on standardized regional guidelines and treatment with study drug temporarily 
withheld. 
7.8 
Continued Access to Study Intervention After the End of the Study 
At the end of the study/period, the Sponsor will not continue to provide Sponsor-supplied study 
intervention to participants/investigators unless the Sponsor chooses to extend the study. The 
investigator should ensure that the participant receives appropriate standard of care to treat the 
condition under study. 
The Sponsor reserves the right to terminate access to Sponsor-supplied study intervention if any 
of the following occur: a) the study is terminated due to safety concerns; b) the development of 
nivolumab or nivolumab + relatlimab FDC is terminated for other reasons, including, but not 
limited to, lack of efficacy and/or not meeting the study objectives; or c) the participant can obtain 
medication from a government-sponsored or other health program. In all cases, the Sponsor will 
follow local regulations. 
8 
DISCONTINUATION CRITERIA 
8.1 
Discontinuation of Study Intervention 
Participants MUST discontinue IP/IMP 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. 
• Any clinical AE, laboratory test result 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 the Sponsor. 
• Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical illness (eg, infectious disease). (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.) 
• In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of 
the pregnancy, notify the Sponsor Medical Monitor or designee of this event. In most cases, 
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the study treatment will be permanently discontinued in an appropriate manner. (refer to 
Section 9.2.5). 
• Disease progression in the absence of clinical benefit as determined by the investigator. 
• Noncompliance of the participant with protocol-mandated procedures based on the judgment 
and agreement of both the investigator and Sponsor. 
• 
 
 
Refer to Section 2: 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: Schedule of Activities. 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. 
Discontinuation of nivolumab or nivolumab + relatlimab FDC SC and nivolumab or nivolumab + 
relatlimab FDC IV treatment must be permanently discontinued per criteria in Table 7.4.1-1 and 
Table 7.4.1-2 in Section 7.4. 
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8.3 
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 the participant to provide this information.  
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• 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. 
• Participants will be discontinued if new information regarding the efficacy or safety of SC 
treatments indicates a detrimental benefit/risk association compared to IV treatment.  
 
8.3.1 
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. 
• At the time of discontinuing from the study, if possible, an early termination visit should be 
conducted, as shown in the Schedule of Activities. See the Schedule of Activities 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 from both the study intervention and 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. 
 
8.4 
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 3 documented phone calls, faxes, or emails, as well as lack of response by participant 
to 1 registered mail letter. All attempts should be documented in the participant’s 
medical records. 
• If the investigator’s use of a third-party representative to assist in the follow-up portion of the 
study has been included in the participant’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining the participant’s 
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contact information or other public vital status data, such as public health registries and 
databases, 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, 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.  
• If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death. 
 
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 whether the participant should continue or discontinue 
treatment. 
• Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before treatment assignment. The investigator will 
maintain a screening log to record details of all participants screened and to confirm eligibility 
or record reasons for screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, complete 
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 time frame defined in the Schedule of Activities (Section 2). 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
• Perform additional measures, including non-study required laboratory tests, 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 intervention-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. 
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9.1 
Efficacy Surveillance 
9.1.1 
Imaging Assessment for the Study 
Study evaluations will take place outlined in Section 2 Schedule of Activities. 
Baseline or screening imaging assessment must be performed during the 
 Screening Period 
utilizing CT or MRI of the chest, abdomen, pelvis and brain MRI or CT (brain CT allowable if 
MRI is contraindicated or if there is no known history of resected brain lesions) and other clinically 
indicated sites as determined by the study investigator.  
Subsequent imaging assessment should be performed following local guidelines or as needed at 
the discretion of the investigator.  
9.1.2 
Investigator Assessment of Recurrence/Progression 
For metastatic melanoma: 
Tumor assessments should continue per local standards or guidelines irrespective of whether the 
dosing is delayed or discontinued. Changes in tumor measurements and tumor responses will be 
assessed by the same investigator or designee investigators must report once disease progression 
has been determined. The timepoint of disease progression should be reported on the eCRF based 
on the investigator’s assessment using RECIST v1.1 criteria to document any disease progression. 
For resected melanoma: 
Disease recurrence is defined as the appearance of one or more new tumor lesions which can be 
local, regional, or distant in location from the primary resected site. Specific criteria and definitions 
for diagnosing recurrence is based on local standards and guidelines. The date of recurrence is the 
first date when recurrence was observed regardless the method of assessment and should be 
documented in the eCRF. 
9.1.3 
Clinical Outcome Assessments  
The evaluation of clinical outcomes assessments, specifically patient-reported outcomes is an 
increasingly important aspect of clinical efficacy and patient experience in oncology trials. Such 
data provide an understanding of the impact of treatment from the participant’s perspective and 
offer insights into patient experience that may not be captured through physician reporting.  
 
 and the PEPQ at the site immediately following 
treatment administration at Cycle 4 Day 1 
 
  
The PEQ and PEPQ will be provided in the participant’s preferred language, if available, and will 
be administered via paper. This data will be recorded in the eCRF by the site. If exceptional 
circumstances preclude the continued administration of measures using planned modalities, then 
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alternate administration methods may be required, after consultation with the Sponsor or the 
Sponsor’s representative. 
9.1.3.1 
Patient Experience Questionnaire (PEQ) and Patient Experience and 
Preference Questionnaire (PEPQ) 
 
 
. Participants will then complete the PEPQ following treatment 
administration at Cycle 4 Day 1 to assess patient experience with SC treatment administration and 
preference between IV and SC treatment administration.30 
The PEQ and the PEPQ are identical questionnaires, with the exception of the single item to assess 
preference between route of treatment administration in the PEPQ, and not the PEQ. The PEPQ 
questionnaire was developed following discussions with clinicians and health economics and 
outcomes research specialists, regarding the concepts most important when considering patient 
preference with route of treatment administration. It is a patient self-complete questionnaire 
containing seven items, assessing patient perceptions regarding:  
 
The PEPQ has been implemented in clinical trials (CA209-8KX and CA209-76U). Patient 
qualitative interviews were embedded into both those clinical trials, where evidence of the content 
validity of the PEPQ was generated, indicating that the wording of items and response options is 
comprehensive and relevant to patients receiving SC treatment administration.  
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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. 
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 
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 v5.0 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 
Period and Frequency for Collecting AE and SAE Information 
For participants assigned to treatment and never treated with study intervention, collect SAEs 
 
 from the date of treatment assignment.  
All AEs and SAEs must be collected from the time of signing informed consent, including those 
thought to be associated with protocol-specified procedures, and must continue 
 
 following the last treatment 
administration. All AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection must be collected from the time of the participant’s signing the informed 
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consent until 
 for Cohort 1 and 
 for Cohort 2 following discontinuation of study 
treatment. 
The investigator must report any SAE that occurs after these periods and that is believed to be 
related to a study intervention or protocol-specified procedure (eg, imaging assessment, clinical 
blood draw). 
• All SAEs will be recorded and reported to the Sponsor or designee, without undue delay, but 
no later than within 24 hours of becoming aware of the events, as indicated in Appendix 3.  
• The investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of updated information being available. 
 
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
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 judgment in the context of known 
AEs, when appropriate for the program or protocol. 
Every AE must be assessed by the investigator to verify whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form. 
9.2.3 
Follow-up of AEs and SAEs 
• Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3). 
• Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study intervention and for those present at the end of study intervention as appropriate. 
• All identified non-serious AEs must be recorded and described on the non-serious AE page of 
the Case Report Form (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. 
 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs (as defined in Section 9.2: Adverse 
Events), 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 8.4: Lost to Follow-up). 
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Further information on follow-up procedures is given in Appendix 3. 
Additionally, all AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection will be followed 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 8.4) or for suspected cases, until SARS-CoV-2 infection is ruled-out. 
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 IB 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 suspected, unexpected serious adverse 
reaction (SUSAR) 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 
This section is not applicable for women not of child-bearing potential. 
If, following initiation of the study intervention, it is discovered that a participant is pregnant or 
may have been pregnant at the time of study intervention exposure, including 
 
 study intervention administration, the investigator must immediately notify the Sponsor 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to the Sponsor designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3. 
In all cases, the study intervention will be discontinued in an appropriate manner. 
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. 
After a pregnancy is confirmed, study treatment must be discontinued, and the participant 
followed. If, for whatever reason, the pregnancy has ended, as confirmed by negative serum 
pregnancy test, treatment may be resumed (at least 3 weeks and not greater than 6 weeks after the 
pregnancy has ended), following approvals of participant, sponsor, and IRB/EC, as applicable. 
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9.2.6 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the Adverse Events – 
Non-serious and Serious Events CRF page. 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 requires the participant to have study intervention 
discontinued or interrupted 
• Any laboratory test result abnormality that requires the participant to receive specific 
corrective therapy 
 
It is expected that, wherever possible, the clinical rather than the laboratory term will 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 test result 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). 
A potential DILI is defined as follows:  
• Aminotransferase (alanine aminotransferase or aspartate aminotransferase) elevation 
> 3× ULN 
AND 
• Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
• No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, 
, 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, 
, 
radiographic imaging, or any other potential safety assessment required or not required by the 
protocol should also be recorded as a non-serious 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 an SAE will be reported as SAEs (see Appendix 3). 
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In the event of an overdose, the investigator/treating physician should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the participant for AEs/SAEs and laboratory test result abnormalities  
• Document the quantity of the excess dose as well as the duration of the overdosing in the eCRF. 
 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
9.4 
Safety 
Planned time points for all safety assessments are listed in Section 2: Schedule of Activities. 
9.4.1 
Physical Examinations 
Refer to Section 2: Schedule of Activities. 
9.4.2 
Vital Signs 
Refer to Section 2: Schedule of Activities. 
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 the Schedule of 
Activities. 
 
Table 9.4.4-1: 
Clinical Laboratory Assessments 
Hematology 
Hemoglobin 
Hematocrit 
Total leukocyte count, including differential 
Platelet count 
Chemistry 
Aspartate aminotransferase 
Alanine aminotransferase  
Total bilirubin 
Alkaline phosphatase 
Gamma-glutamyl transferase only when 
alkaline phosphatase is ≥ Grade 2 
Lactate dehydrogenase  
Creatinine 
Blood urea nitrogen or serum urea 
Uric acid  
Glucose 
Albumin 
Sodium 
Potassium 
Chloride  
Calcium 
Phosphorus 
Thyroid-stimulating hormone (TSH), free T3 and free 
T4 - screening 
TSH, with reflexive fT3 and fT4 if TSH is abnormal - 
on treatment 
Creatine phosphokinase – at screening only and for 
Cohort 1 only 
Creatinine clearance (CrCl) – if used, at screening only  
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Table 9.4.4-1: 
Clinical Laboratory Assessments 
Urinalysis 
Protein 
Glucose 
Blood 
Leukocyte esterase 
Specific gravity 
pH 
Serology  
On Treatment : 
Participants with positive HBsAg (hepatitis B surface antigen) or positive anti-HBc (hepatitis B core antibody) - 
test HBV DNA up to 3 days before every dose. If Hepatitis B Reactivation> 1 log IU/mL increase in HBV DNA 
from screening baseline refer to Table 7.4.1-1 
HIV-1 and -2 antibodies (screening only; testing for HIV must be performed at sites where mandated by local 
requirements [see Appendix 8]). 
SARS-CoV-2 viral test (if clinically indicated) 
Other Analyses 
Pregnancy test (WOCBP only: screening, during treatment, and follow-up). 
Follicle stimulating hormone (screening only for women only, if needed to document post-menopausal status)  
Abbreviations: HIV, human immunodeficiency virus; WOCBP, women of childbearing potential. 
9.4.5 
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 per standard 
medical/clinical judgment. 
9.5 
Pharmacokinetics 
Not applicable.  
9.6 
Immunogenicity Assessments  
Not applicable. 
9.7 
Biomarkers 
9.7.1 
Germline Genetics 
Not applicable. 
9.7.2 
Other Biomarkers 
Not applicable. 
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9.8 
Optional Future Research 
This protocol will not include sample collection and/or residual sample storage for optional future 
research.  
10 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Hypotheses 
This is a descriptive study. No formal hypothesis testing will be performed. 
10.2 
Sample Size Determination 
Cohort 1 Metastatic melanoma: The primary objective of this cohort is to evaluate patient 
preference (Question 7 of the PEPQ) for route of administration upon switching from IV to SC. 
The primary endpoint is the proportion of participants who prefer the SC route of administration 
as assessed by PEPQ Question 7 after Cycle 4 Day 1. 
 
 participants are planned to be treated 
in Cohort 1, of which approximately 
 participants are expected to be evaluable for the primary 
endpoint. 
 The 
PEPQ Evaluable population is defined as all enrolled participants who have received two doses of 
nivolumab + relatlimab FDC IV, two doses of nivolumab + relatlimab FDC SC and have answered 
Question 7 of the PEPQ. 
Cohort 2 Resected melanoma: The primary objective of this cohort is to evaluate patient 
preference (Question 7 of the PEPQ) for route of administration upon switching from IV to SC. 
The primary endpoint is the proportion of participants who prefer the SC route of administration 
as assessed by PEPQ Question 7 after Cycle 4 Day 1. 
 
 participants are planned to be treated 
in Cohort 2, of which approximately 
 participants are expected to be evaluable for the primary 
endpoint. 
 The 
PEPQ Evaluable population is defined as all enrolled participants who have received two doses of 
both nivolumab IV, nivolumab SC and have answered Question 7 of the PEPQ.  
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10.3 
Analysis Sets 
For the purposes of analysis, the following populations are defined: 
Population 
Description 
All Screened 
Participants 
All participants who signed an ICF and registered into the study. This is the primary dataset 
for disposition. 
All Enrolled 
Participants 
All screened participants who meet study eligibility criteria and enroll in the study. This is the 
primary dataset for analyses of demography, protocol deviations, and baseline characteristics. 
All Treated 
Participants 
All enrolled participants who receive at least one dose of study intervention (on-study). This 
is the primary dataset for dosing and safety analyses. 
PEPQ Evaluable 
All treated participants who have received 2 doses of both IV and SC study treatments and 
have answered Question 7 of the PEPQ. 
Abbreviations: ICF, informed consent form; IV, Intravenous; PEPQ, Patient Experience and Preference 
Questionnaire; 
. 
 
10.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed, and it will include a more technical and 
detailed description of the statistical analyses described in this section, eg, the selection of 
participants to be included in the analyses, and procedures for accounting for missing, unused, and 
spurious data. This section is a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints. 
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10.4.1 
General Considerations 
All analyses will be descriptive in nature. Descriptive statistics including n (the corresponding 
sample size), means, medians, standard deviations, minimum, and maximum will be calculated for 
continuous variables, and categorical data will be summarized using frequency counts and 
percentages. 
 
  
10.4.2 
Primary Endpoint(s) 
Metastatic melanoma Cohort 1 
The primary endpoint is the proportion of evaluable participants that prefer nivolumab + relatlimab 
FDC SC using PEPQ (Question 7). Participants’ preference will be assessed using the single item 
in the PEPQ (Question 7) which asks participants to report their preferred route of treatment 
administration based on the PEPQ Evaluable population.  
Resected melanoma Cohort 2  
The primary endpoint is the proportion of evaluable participants that prefer nivolumab SC using 
PEPQ (Question 7). Participants’ preference will be assessed using the single item in the PEPQ 
(Question 7) which asks participants to report their preferred route of treatment administration 
based on the PEPQ Evaluable population.  
For both cohorts, the analyses will be descriptive, and the number and percentage of participants 
who report a preference for ‘IV infusion’, ‘SC injection’, or ‘no preference’ will be presented. 
 
 
. Participants who do not complete Question 7 of the PEPQ will be excluded from 
the PEPQ evaluable population. 
10.4.3 
Secondary Endpoint(s) 
For both cohorts, safety and tolerability will be measured by incidence of all AEs/SAEs, treatment-
related AEs including IMAEs, Other events of special interest (OESIs), AEs leading to 
discontinuation or death, laboratory abnormalities and injection/infusion-related AEs. All treated 
participant population will be used for safety and tolerability analyses. 
AEs will be coded using the Medical Dictionary for Regulatory Activities, and the most recent 
version of the dictionary at the time of the database lock will be used. AEs and laboratory values 
will be graded for severity according to the NCI-CTCAE version 5.0.  
Frequency distribution of treated participants with AE using the worst CTCAE grade will be 
presented. Participants will only be counted (1) once at the preferred term (PT) level, (2) once at 
the system organ class (SOC) level, and (3) once in the “total participant” row at their worst 
CTCAE grade, regardless of SOC or PT. 
The secondary endpoints for this study will be reported for each cohort and summarized by: 
overall treatment duration 
treatment switch period (Cycle 1-4) 
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route of administration 
 
 
10.4.5 
Other Safety Analyses 
Not applicable. 
10.4.6 
Other Analyses  
Not applicable. 
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11 
REFERENCES 
 
 
1  National 
Cancer 
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Cancer 
Statistics. 
https://www.cancer.gov/about-
cancer/understanding/statistics. Filename - national-cancer-institute-2020-cancer-statistics. 
2  Cancer Facts and Figures 2017. American Cancer Society. Atlanta, GA. 2017. 
3  Saiyed FK, Hamilton EC, Austin MT. Pediatric melanoma: incidence, treatment, and 
prognosis. Pediatric Health Med Ther 2017;8:39-45. 
4  Weiss SA, Wolchok JD, Sznol M. Immunotherapy of Melanoma: Facts and Hopes. Clin 
Cancer Res 2019;25:5191-5201. 
5  Hodi SF, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with 
metastatic melanoma. N Engl J Med 2010;363:711-23. 
6  Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemuafenib in melanoma 
with BRAF V600E mutation. N Engl J Med 2011;364:2507-16. 
7  Hauschild A, Grob JJ, Demidov LV, et al. Debrafenib in BRAF mutated metastatic melanoma: 
a multicentre, open-label, Phase 3 randomised controlled trial. Lancet 2012;380:358-65. 
8  BMS-986016: Relatlimab Investigator Brochure version 11.0, dated 12-Sep-2023. 
Bristol-Myers Squibb Company; 2021. Document Control No. 930071620. 
9  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. 
10  Efficacy of anti-LAG-3 antibody 19C7 in Sa1N tumor-bearing mice. (Study BDX-1408-251). 
Bristol-Myers Squibb Company; 2013. Document Control No. 930071265. 
11  Anti-tumor activity of anti-PD-1 and anti-LAG-3 antibodies alone and in combination in a 
SA1N fibrosarcoma tumor model (Study MDX-1106-059). Bristol-Myers Squibb Company; 
2013. Document Control No. 930054253. 
12  Confirmation of anti-tumor activity of anti-LAG-3 antibody alone and in combination with 
anti-PD-1 antibody in a Sa1N fibrosarcoma tumor model (Study BDX-1408-224). 
Bristol-Myers Squibb Company; 2013. Document Control No. 930071272. 
 
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15 Investigator Relatlimab + Nivolumab FDC Brochure BMS-986213 version 07, dated 
12-Jan-2024. Bristol-Myers Squibb Company; 2022. Document Control No. 930119921.
16  Investigator’s Brochure Nivolumab (subcutaneous) BMS-986298 version 06, dated 
03-Jul-2023. Bristol-Myers Squibb Company; 2021. Document Control No. 930128344.
17  Recombinant Human Hyaluronidase PH20 (rHuPH20) Investigator’s Brochure Edition 12.0, 
dated 04-Mar-2024. Halozyme, Inc; 2023. Document Control No. 930124324. 
18  Shivakumar SP, Anderson DR, Couban S. Catheter associated thrombosis in patients with 
malignancy. J Clin Oncol 2009;27:4858-64. 
19  Poorter RL, Lauw FN, Bemelman WA, et al. Complications of an implantable venous access 
device (Port-a-Cath) during intermittent continuous infusion chemotherapy. Eur J Cancer 
1996;32A:2262-6. 
20  De Cock E, Kritikou P, Sandoval M, et al. Time Savings with Rituximab Subcutaneous 
Injection versus Rituximab Intravenous Infusion: A Time and Motion Study in Eight 
Countries. PLOS ONE 2016;11(6):e0157957. 
21  Rummel M, Kim TM, Aversa F, et al. Preference for subcutaneous or intravenous 
administration of rituximab among patients with untreated CD20+ diffuse large B-cell 
lymphoma or follicular lymphoma: results from a prospective, randomized, open-label, 
crossover study (PrefMab). Ann Oncol 2017;28:836-42. 
22  Ismael G, Hegg R, Muehlbauer S, et al. Subcutaneous versus intravenous administration of 
(neo) adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer 
(HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 2012; 
13:869-78. 
23  Hussein AT, Schadendort D, Lipson EJ, et al. Relatlimab and Nivolumab versus Nivolumab 
in Untreated Advanced Melanoma. N Engl J Med 2022;386:24-34. 
24  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 
with previously untreated metastatic or unresectable melanoma. Bristol-Myers Squibb 
Company, 2021. Document Control No. 930168350. 
25  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). 
26  Investigator’s Brochure Nivolumab (intravenous) BMS-936558 MDX1106 ONO-4538 
version 22, dated 03-Jul-2023. Bristol-Myers Squibb Company; 2021. Document Control No. 
930038243. 
27  Shingler SL, Bennett BM, Cramer JA, et al. Treatment preference, adherence and outcomes in 
patients with cancer: literature review and development of a theoretical model. Curr Med Res 
Opin 2014;30(11), 2329-23 
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28  Mansfield C, Ndife B, Chen J, et al. Patient preferences for treatment of metastatic melanoma. 
Future Oncol 2019;15(11), 1255-68. 
30  Stull, D. E., Leidy, N. K., Parasuraman, B., & Chassany, O. (2009). Optimal recall periods for 
patient-reported outcomes: challenges and potential solutions. Current medical research and 
opinion, 25(4), 929-942. 
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APPENDICES 
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APPENDIX 1 
ABBREVIATIONS 
Term 
Definition 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ART 
antiretroviral therapy 
BICR 
blinded independent central review 
BMS 
Bristol-Myers Squibb Company 
CI 
confidence interval 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRF 
Case Report Form, paper or electronic 
CSR 
Clinical Study Report 
CT 
computed tomography 
DNA 
deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EU 
European Union 
FDA 
US Food and Drug Administration 
FDC 
fixed-dose combination 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMAE 
Immune mediate adverse event 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
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Term 
Definition 
IRT 
Interactive Response Technology 
IU 
international unit 
IUS 
intrauterine system 
IV 
intravenous(ly) 
LAG-3 
lymphocyte activation gene-3 
mAb 
monoclonal antibody 
MRI 
magnetic resonance imaging 
OESI 
Other events of special interest 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 1 
PEQ 
Patient Experience Questionnaire 
PEPQ 
Patient Experience and Preference Questionnaire 
PFS 
progression-free survival 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SOP 
Standard Operating Procedure 
ULN 
Upper limit of normal 
US 
United States 
WOCBP 
women of childbearing potential 
WNOCBP 
women not of childbearing potential 
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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 
the 
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, 1 or more of the following: (1) the rights, physical safety, or mental integrity 
of 1 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 (US) Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
European Union (EU) Directive 2001/20/EC
•
European Regulation 536/2014 for clinical studies (if applicable)
•
European Medical Device Regulation 2017/745 for clinical device research (if applicable)
•
the IRB/IEC
•
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, 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 the following: 
•
IRB/IEC
•
Regulatory authority(ies), if applicable according to 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, by the local Health Authority must be sent to Bristol-Myers 
Squibb Company (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 study and for 1 year 
after completion of the study. 
RECRUITMENT AND INFORMED CONSENT PROCEDURES 
Potential participants may be identified by the recruiting investigational team (called “site”) within 
the affiliated clinic/hospital, and/or group practice, through their own chart/database review, using 
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the inclusion/exclusion criteria defined by the protocol. Potential participants may also be referred 
to the site by medical doctors from surrounding hospitals/practices or directly contact one of 
the investigative ‘sites’ following study and site identification through a public registry, such as 
clinicaltrials.gov or euclinicaltrials.eu. The investigator has access to the participant's medical file, 
so, the medical data will remain confidential without the sponsor having access to them. 
Recruitment material will also be utilized as an additional tool to recruit participants per local 
regulations and requirements.  
The principal investigator or sub-investigator, or a qualified designee of the investigator's research 
team will approach potential participants to discuss the option of participating in the clinical trial 
and the consent process. Informed consent will be obtained by the principal investigator or a 
qualified delegate on the principal investigator's research team from each participant prior to 
enrolment into the study. The participant will be provided the opportunity to read the information 
sheet and consent form and have all their questions and concerns addressed before giving consent 
in writing.  
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.  
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 and answer all questions regarding the study.
•
Inform the participant that his/her participation is voluntary. The participant will be required
to sign a statement of informed consent that meets the requirements of 21 CFR Part 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 the participant to inquire about the details of the study.
•
Obtain an ICF signed and personally dated by the participant and by the person who conducted
the informed consent discussion.
•
Include a statement in the participant’s medical record that written informed consent was
obtained before the 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 the participant to the most current version of the ICF(s) during his/her participation.
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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 of all pertinent aspects of the study and of any new information relevant
to the participant’s willingness to continue participation in the study. This communication
should be documented.
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participant’s signed 
ICF, and, in the US, the participant’s signed HIPAA authorization. 
The ICF must also include a statement that BMS and local and foreign regulatory authorities have 
direct access to participant records.  
If informed consent is initially given by a participant’s 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. 
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 Case Report Form (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.
•
Definition of what constitutes source data and its origin can be found in the source data location
list/map or equivalent document.
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. 
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Such systems may include, but are not limited to, electronic medical records/electronic health 
records, adverse event (AE) tracking/reporting, protocol-required assessments, and/or drug 
accountability records. 
When paper records from such systems are used in place of an electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original.  
STUDY INTERVENTION RECORDS 
Records for study intervention (whether supplied by BMS, its vendors, or the site) must 
substantiate study intervention integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
BMS/designee or a Health Authority. 
If 
Then 
Supplied by BMS (or its 
vendors) 
Records or logs must comply with applicable regulations and 
guidelines and should include the following: 
•
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
•
non-study 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 per the Delegation of
Authority Form
Sourced by site and not 
supplied by BMS or its 
vendors 
(examples 
include 
Investigational 
Product sourced from the 
site’s 
stock 
or 
commercial supply or a 
specialty pharmacy) 
The investigator or designee accepts responsibility for documenting 
traceability and study intervention integrity in accordance with 
requirements applicable under law and the standard operating 
procedures/standards of the sourcing pharmacy 
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BMS or its designee will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements. 
CASE REPORT FORMS 
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents, or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory test result 
abnormalities that are reported or identified during 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 serious adverse events (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 are 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 non-compliance 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. 
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Certain CRF electronic files may serve as source documents. 
In addition, the study may be evaluated by the Sponsor or designee internal auditors and 
government inspectors who must be allowed access to CRFs, source documents, other study files, 
and study facilities. BMS audit reports will be kept confidential. 
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities 
and promptly forward copies of inspection reports to the Sponsor or designee.  
RECORDS RETENTION 
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or its designee, whichever is longer. 
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 INTERVENTION 
For this study, study interventions (those supplied by BMS or a vendor or sourced by the 
investigator), such as partially used study intervention containers, vials, and syringes, may be 
destroyed on site.  
If 
Then 
Study interventions 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 intervention 
containers must be immediately destroyed as required for 
safety or to meet local regulations (eg, cytotoxic or biologic 
agents). 
Partially used study interventions and/or empty containers 
may 
be 
destroyed 
after 
proper 
reconciliation 
and 
documentation. However, unused Investigational Medicinal 
Product must be reconciled by the site monitor/clinical 
research associate prior to destruction. 
If study interventions will be returned, the return will be 
arranged by the responsible study monitor. 
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If 
Then 
Study interventions sourced by 
site, not supplied by BMS (or its 
vendors; eg, study interventions 
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 interventions provided by BMS (or its vendors). Destruction of non-study 
interventions sourced by the site, not supplied by BMS, is solely the responsibility of the 
investigator or designee.  
STUDY AND SITE 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, the following: 
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For study termination: 
•
Discontinuation of further study intervention development
For site termination: 
•
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 or no recruitment (evaluated after a reasonable amount of time) of participants by
the investigator
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 ensure 
appropriate participant therapy and/or follow-up. 
DISSEMINATION OF CLINICAL STUDY DATA 
To benefit potential study participants, patients, health care 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 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. 
In the European Union (EU, the summary of results and summary for laypersons will be submitted 
within 1 year of the end of trial in the EU/European Economic Area and third countries. 
CLINICAL STUDY REPORT 
A Signatory Investigator must be selected to sign the Clinical Study Report (CSR). 
For each CSR related to this protocol, the following criteria will be used to select the Signatory 
Investigator: 
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator
•
Study Steering Committee chair or designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to the Sponsor or designee. 
Any publications or abstracts arising from this study must adhere to the publication requirements 
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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 period set forth in the CTAg. 
Scientific publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
Principal Investigator, sub-investigator, or any other member of the study staff without the prior 
written consent of the Sponsor. 
Authorship of publications at the Sponsor is aligned with the criteria of the International 
Committee of Medical Journal Editors (ICMJE; www.icmje.org). Authorship selection is based on 
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)
2) Drafting the work or revising it critically for important intellectual content
3) Final approval of the version to be published
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 the 
Sponsor 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 occurring in a clinical investigation participant after signing of 
informed consent, whether or not considered related to the study intervention. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
test result), symptom, or disease temporally associated with the study intervention 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 sign
measurements), including those that worsen from baseline, considered clinically significant
in the medical and scientific judgment of the investigator. Note that abnormal laboratory test
results or other safety assessment findings 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
the condition 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 iinvestigator),
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).
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DEFINITION OF SAE 
If an event is not an AE per the definition above, then it cannot be an SAE, even if serious 
conditions are met. 
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 that hypothetically might have caused death if it were 
more severe). 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below). 
NOTE:  
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
A visit to the emergency department or other hospital department < 24 hours that does not
result in admission (unless considered an important medical or life-threatening event).
•
Elective surgery that was planned prior to signing consent.
•
Admissions 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 enrollment
in 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 results 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 department 
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 
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medical event. (See Section 9.2.7: Potential Drug-induced Liver Injury of the protocol for the 
definition of a potential DILI.)  
Pregnancy and DILI must follow the same transmission timing and processes to BMS as those 
used for SAEs. (See Section 9.2.5: Pregnancy of the protocol 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 1 of the criteria used when determining regulatory reporting
requirements.
Assessment of Intensity 
The investigator will make an assessment of grade for each AE and SAE according to the NCI-
CTCAE version 5.0. 
Follow-up of AEs and SAEs 
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports must include the same investigator term[s] initially reported.)  
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If an ongoing SAE changes in its intensity or relationship to study intervention or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or the designee) using the same procedure used for transmitting the initial SAE report. 
All AEs/SAEs must be followed to resolution or stabilization. 
REPORTING OF SAES TO SPONSOR OR DESIGNEE 
•
SAEs, whether related or not related to study intervention, and pregnancies must be reported
to BMS (or the designee) promptly and not to exceed 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 the designee).
♦In this case, the paper form is transmitted via email or confirmed fax 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 fax transmission.
SAE Email Address: worldwide.safety@BMS.com 
SAE Fax 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 Women of Childbearing 
Potential (WOCBP) 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: Inclusion Criteria of the protocol. Only the contraception 
methods as described in Section 6.1: Inclusion Criteria of the protocol are acceptable for this study. 
DEFINITIONS 
Women 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
•
Pre-menopausal 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. 
•
Post-menopausal female
−
A post-menopausal state is defined as 12 months of amenorrhea in a woman over the age
of 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 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 
judgment 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
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.
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End of Relevant Systemic Exposure 
End of relevant systemic exposure is the time point at which the study intervention (Investigational 
Medicinal Product [IP/IMP] and other study interventions ie, Non-IMP/AxMP required for study) 
or any active major metabolites have decreased to a concentration that is no longer considered 
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 study 
intervention 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 in which 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 in which
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 in which hormonal contraception is permitted by the study protocol.)b
•
Intrauterine device.
•
Intrauterine system (IUS). (This method of contraception can only be used by WOCBP
participants in studies in which hormonal contraception is permitted by the study
protocol.)b,c
•
Bilateral tubal occlusion.
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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.
•
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 intervention.
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 of the protocol.
•
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, post-ovulation
methods), withdrawal (coitus interruptus), spermicides only, and lactation 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 intervention, which may reduce the
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the Investigational Medicinal Product 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 Section 6.1: Inclusion Criteria 
 
 
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 Section 6.1: Inclusion Criteria and 
 
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.
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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 in which hormonal contraception is prohibited.)
Unacceptable Methods of Contraception 
•
Periodic abstinence (calendar, symptothermal, post-ovulation 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: Pregnancy of the protocol and Appendix 3. 
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APPENDIX 6 
ECOG PERFORMANCE STATUS SCALE AND CONVERSION 
FORM  
ECOG a 
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 a light or sedentary nature, eg, light housework, office work  
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours  
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours  
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair  
5 
Dead 
a Reference: Oken MM, Creech RH, et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol 1982; 5: 649655. 
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APPENDIX 7 
AJCC MELANOMA STAGING (CANCER STAGING MANUAL 
8TH   EDITION)  
[From AJCC Cancer Staging Manual, 8th Edition. Amin MB, Edge S, Greene F, Byrd DR, 
Brookland RK, Washington MK, et al. editors. Springer International Publishing. 2017 (pages 577 
& 578)]  
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 
Tis (melanoma in situ) 
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 
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APPENDIX 8 
COUNTRY SPECIFIC REQUIREMENTS/DIFFERENCES 
Cohort 1:  
Original Language 
Country-specific Language or Differences 
Criteria for exclusion of HIV-positive 
participants in any country where 
exclusion of HIV-positive participants 
is locally mandated.  
Section 6.2 Exclusion  
Criteria, criterion 1) h)  
“Participants must not have 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:  
•
they have received antiretroviral therapy (ART) for at least 4 weeks
prior to randomization as clinically indicated while enrolled on study.
•
they continue on ART as clinically indicated while enrolled on
study.
•
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 (Refer to Appendix 9.)” to be replaced with “Positive test for HIV."
Section 2 Flow Chart/Time and Events 
Schedule, Tables 2-1 and 2-2: 
Screening Assessments - Laboratory 
Tests  
Add “HIV” to the list of laboratory tests.
USA 
Section 2-1 Screening Procedural 
Outline  
None.  
Added a row, Demography and Participant Characteristics. 
None. 
Section 10.4 Statistical Analyses 
None. 
Added the following text:  
“A description of the participant population will be included in the CSR, 
including subgroups of age, gender, gender identity, race, and other study-
specific populations and demographic characteristics. A description of 
participant disposition will also be included in the CSR.”  
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APPENDIX 9 
PRODUCT QUALITY ISSUES 
DEFINITIONS: STUDY INTERVENTION DEFECTS Study intervention defects may be related to 
component, product, or packaging and labeling issues prior to or during use. The list below 
includes, but is not limited to, descriptions of product complaints in these 3 categories that should 
be reported as a defect:  
•
Component Issue: Defect in container or dosing mechanism of the investigational product (IP).
The component defect may be damaged, missing, or broken.
Product Issue (related to drug appearance, solution): Defect in the product itself. The product 
appearance has visual imperfections such as foreign particles, crystallization, discoloration, 
turbidity, insufficient volume, or anything that is not consistent to the product description in the 
IFU.  
•
Packaging/Labeling Issue: Defect in the packaging or labeling of the study drug. The
packaging (carton or tamper-evident seal) or labeling defects may be damaged or unreadable,
or the label may be missing.
REPORTING PRODUCT QUALITY ISSUES 
Issues that call into question study intervention defects or study intervention device malfunctions 
(eg, IMP safety, purity, potency, quality, and identity [eg, evidence of suspected tampering of 
product]), device failed to activate, labelling issues) must be reported to the Sponsor using the 
following 
  within one business day and no longer 
than three calendar days (upon clinical site’s identification or time of receipt from study 
participants receiving treatment at home).  
This includes suspected quality issues of components co-packaged with the drug, labelling, IMP 
device/drug combination products, and medical devices.  
In the event of a suspected product quality issue, the immediate action to be taken by the site is to 
quarantine the affected product. Do not dispose of the product unless retention presents a risk to 
personnel (eg, cytotoxic, risk of injury from broken glass or sharps). When reporting, provide as 
much product information as possible. Suspected IMP quality issues will be investigated, and a 
response will be provided back to the investigational site.  
Site staff will be asked to send back malfunctioning devices to the depot or local sponsor company 
according to local guidance/regulations.  
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