A Phase I/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered Alone and in Combination With Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Advanced Solid Tumors
Phase: PHASE1
Conditions: Neoplasms by Site
Sponsor: Bristol-Myers Squibb

Official Title of Study:  
A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of 
Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered Alone and in Combination with Anti-PD-1 
Monoclonal Antibody (Nivolumab, BMS-936558) in Advanced Solid Tumors 
 
 
NCT Number: NCT01968109 
Document Date (Date in which document was last revised): February 16, 2024  
 
 
 

Page:
1
Protocol Number:
CA224020
IND Number:
117607
EU Trial Number
2023-508067-70
Date:
10-Jul-2013
Revised Date:
16-Feb-2024
CLINICAL PROTOCOL CA224020
A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and 
Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered Alone and in 
Combination with Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Advanced
Solid Tumors
Protocol Amendment: 15
Incorporates Administrative Letters 08 and 09
Clinical Trial Physician -
Medical Monitor
Bristol-Myers Squibb
Bristol-Myers Squibb
Route de Perreux 1
3401 Princeton Pike
2017 Boudry, Switzerland
Lawrence Township, NJ 08648
Telephone (office): 
Telephone: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
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Protocol Amendment No. 15
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2
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, e.g., a Contract Research 
Organization (CRO).
 
 
 
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Protocol Amendment No. 15
Date: 16-Feb-2024
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DOCUMENT HISTORY
Document
Date of 
Issue
Summary of Change
Protocol
Amendment 15
16-Feb-2024
Incorporates Administrative Letters 08 and 09 and the following changes:

Updated the Post Study Access to Therapy section to include rollover
option.

Removed female partner contraception requirements to align with the
latest relatlimab/nivolumab contraceptive guidance.

Replaced the EudraCT number by EU Trial Number, and the legal
framework Directive 2001/20/EC by Regulation 536/2014.
Administrative 
Letter 09
25-Jan-2024
Updated study personnel information and updated nivolumab packaging
(BMS-936558-01).
Administrative 
Letter 08
12-May-
2023
Updated study personnel information.
Protocol
Amendment 14
28-Oct-2022
Incorporates the following changes: 

Clarified the study duration for patients remaining on treatment beyond 5
years.

Updated contraceptive language.

Added COVID-19 vaccination language.

Removed rechallenge period. Patients currently receiving rechallenge
treatment will be allowed to continue and patients currently in
rechallenge-eligible Survival Follow-up as of this Protocol Amendment
remain eligible for rechallenge.

Limited PK/immunogenicity collection maximum to up to 24 months of
treatment and removed PK/immunogenicity collections upon the
occurrence of ≥ Grade 3 AEs.

Addition of Appendix 8: Country Specific Requirements/Differences,
which includes France and Italy (Site Specific Amendment 9 and 10) in
the list of countries.
Protocol
Amendment 13
29-Jul-2021
Incorporates the following changes:

Provided information on the background/rationale for this amendment.
 
 
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Protocol Amendment No. 15
Date: 16-Feb-2024
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Document
Date of 
Issue
Summary of Change
Revised 
Protocol 12
05-Feb-2020
Incorporates the following changes:

Typographical and grammatical errors were corrected, and edits were
made for consistency and clarity.

Added DOR as secondary objective for Part E.

Clarified when survival follow-up visits will be scheduled.

PK and Biomarker samples will be taken coincident with the occurrence
of a study drug-related Grade 3 adverse event.

When recent archival samples are submitted at baseline,

Clarified that for subjects who discontinue at the investigator’s discretion
with CR, PR, or SD, imaging must be performed every 12 weeks until
disease progression.
Added information to bring in line with current program standards and 
template language.
Revised 
Protocol 11
01-Oct-2019
Incorporates the following changes:

Typographical and grammatical errors were corrected, and edits were
made for consistency and clarity.

Updated information about the safety of BMS-986016 480 mg +
nivolumab 480 mg Q4W dosing regimen

Removed from Treatment period references to up to twelve 8-week
treatment cycles.

Removed confirmed complete response and completion of the maximum
number of twelve 8 week cycles from discontinuation criteria

Removed from re-challenge period statement that subjects could receive
therapy for up to 6 additional eight-week cycles

Changed criteria for Adjuvant/Neoadjuvant therapy in Part D1, D2, and
E.

Added the following criterion to Part E for melanoma participants that
have not received prior systemic anticancer therapy for unresectable or
metastatic melanoma:  Uveal melanoma subjects are NOT eligible

Outlined procedures for tumor assessments done outside of scheduled
assessments, if clinically indicated.
Revised 
Protocol 10
15-Feb-2019
Incorporates the following changes:

Added four additional Part B combination dosing cohorts: 480 mg BMS-
986016 (relatlimab) + 480 mg nivolumab, 960 mg BMS 986016 + 480 mg
nivolumab, 1440 mg BMS-986016 + 480 mg nivolumab, and 1600 mg
BMS-986016 + 480 mg nivolumab every four weeks (Q4W).

Changed the dose escalation statistical methodology from 3+3+3 to an
adaptive Bayesian Logistic Regression Model (BLRM) Copula design for
Part B.

Changed DLT period from 8 weeks to 6 weeks.
 
 
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Protocol Amendment No. 15
Date: 16-Feb-2024
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Document
Date of 
Issue
Summary of Change

Added Part E, exposure response evaluation cohorts (untreated metastatic
melanoma and subjects who experienced progression on prior anti-PD-1
therapy).
Administrative 
Letter 07
18-Oct-2018
Study personnel updates
Revised 
Protocol 09
31-Jan-2018
Incorporates Administrative Letters 05 - 06 and the following changes:

The testing of the nivolumab/relatlimab fix dose combination (FDC) drug
product into Part D1 has been added.

Compare the safety of the FDC drug product with co-administration of
relatlimab and nivolumab.

Additional analyses are added/clarified to assess PK of the FDC drug
product as well as confirm the efficacy and safety of the every four-week
dosing schedule.
Administrative 
Letter 06
19-Jan-2018
Clarify language regarding the mandatory tissue collection requirements for
clinical trial participation.
Administrative 
Letter 05
14-Sep-2017
Correction to numbering of Inclusion Criteria
Revised 
Protocol 08
31-Jul-2017
Incorporates Administrative Letter 04 and the following changes:

Added a bladder cohort to Part C and added Part D (melanoma prior IO
expansion cohorts ) to the study design,

Introduced co-administration to Part D

Updated to allow adolescent subjects (age 12 and above) to enroll in Parts
C and D.

Modified inclusion/exclusion criteria

Updated statistical section and made administrative changes as applicable
Administrative 
Letter 04
01-Mar-2017

Clarified biopsy requirements and updated inclusion criteria for Non-
small cell lung cancer (NSCLC) naive to IO 
Revised 
protocol 07
20-Dec-2016
Incorporates Amendment 11
Amendment 11
20-Dec-2016
The following changes were made:

Updated nivolumab and BMS 986016 safety information

Added a Q4W dosing regimen in Part B of the study

Updated dose delay guidelines and study discontinuation criteria to align
with nivolumab program

Modified inclusion/exclusion criteria for Part C of study

Modified to mandate fresh tumor biopsy collection from every subject

Updated statistical section and made administrative changes as applicable
Revised 
protocol 06
25-May-
2016
Incorporates Amendment 07 and Administrative letter 03
 
 
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Protocol Amendment No. 15
Date: 16-Feb-2024
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Document
Date of 
Issue
Summary of Change
Amendment 07
25-May-
2016
The following changes were made:

Revision of exclusion criteria regarding cardiovascular history

Addition of echocardiogram and troponin level monitoring at baseline

Addition of ECG and troponin level monitoring through Cycle 1

Correction of typographical errors
Revised 
protocol 05
12-Feb-2016
Incorporates Amendment 06 and Administrative letter 02
Amendment 06
12-Feb-2016
The following changes were made: 

Revised study design to remove Parts D, E, F and G, and updated Part C
expansion cohort populations.

Updated DLT criteria

Included adaptive language for dose selection for Part C of the study

Nivolumab infusion time was reduced from 60 minutes to 30 minutes
starting for Part C of the study

Updated statistical sections, to align with revised study design
Administrative 
letter 02
20-Nov-2015
Change of Medical Monitor/Study Director
Revised 
protocol 04
24-Aug-2015
Incorporates Amendment 04
Amendment 04
24-Aug-2015
The following changes were made:

Revised study design to include new Parts/cohorts and updated expansion
cohort populations; introduced adaptive design of Stage 1 and Stage 2.

Updated biomarker and pharmacokinetic collections

Updated anti-LAG-3 and nivolumab safety information

Updated statistical sections to reflect new study design
Revised 
protocol 03
08-Sep-2014
Incorporates Amendment 03 and Administrative letter 01
Amendment 03
08-Sep-2014
The following changes were made:

Revised the starting dose of anti-LAG-3 in the first combination cohort of
Part B from 3 mg to 20 mg.

Removed the 3 mg anti-LAG-3/240 mg nivolumab cohort in Part B
Administrative 
letter 01
16-Jul-2014
Addition of EUDRACT number and minor clerical edits.
Revised 
Protocol 02
23-May-
2014
Incorporates Amendment 02
Amendment 02
23-May-
2014
The following changes were made:

Addition of fourth additional subject at beginning of each dose level

Revision of inclusion and exclusion criteria

Updated WOCBP definition and contraception methods, and  revised
Appendix 1

Revised DLT criteria
 
 
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Document
Date of 
Issue
Summary of Change

Added study drug dosing instructions for combination of anti-LAG-3 and
nivolumab.

Incorporated new biomarker sample collections for Part C of study

Revised subject criteria for Part B and expansion cohorts in Part C of
study

Modified PK and ADA Table 5.5.1-1

Added Appendix 4- Nivolumab Management Algorithms
Revised 
Protocol 01
11-Sep-2013
Incorporates Amendment 01
Amendment 01
11-Sep-2013
The following changes were made:

Addition of Grade 4 anemia to dose-limiting toxicity criteria

Addition of neurological examination performed by a neurologist for
subjects in Part B or C who develop study drug-related Grade 2 or higher
neurological AEs

Extension of vital sign monitoring on Cycle 1 Day 1 from 60 minutes to
120 minutes for subjects in the first cohort in Part B

Modifications to inclusion criteria to specify that subjects in all parts of
the study must have an incurable solid malignancy and that subjects in
Parts B and C may have refused standard therapy for advanced or
metastatic disease
Original 
Protocol
10-Jul-2013
Not applicable
 
 
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 15:
The study protocol has been updated to describe potential options post-CA224020 closure for 
1) participants remaining on treatment to continue to receive study treatment, and 2) participants
in rechallenge-eligible Survival Follow-up to remain eligible to receive rechallenge study
treatment for up to 5 years from their first dose. This includes the option to participate in a Bristol-
Myers Squibb sponsored rollover trial.
Additionally, this revised protocol reflects the changes included in approved administrative letters 
08 and 09 and are not included in the summary of key changes listed below. 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 15
Section Number & Title
Description of Change
Brief Rationale
Title Page
Replaced EudraCT number by EU 
Trial Number.
Applied the new
administrative reference 
to comply with EU 
Clinical Trial
Regulation (EU CTR),
following the transition 
to EU CTR.
Added Sponsor location for 
Research and Development.
To update address.
Section 2.1: Good Clinical 
Practice
Replaced the European Union 
Directive 2001/20/EC by 
European Union Regulation 
536/2014.
Applied the new
administrative reference 
to comply with EU CTR,
following the transition 
to EU CTR.
Section 3.2: Post Study 
Access to Therapy
Updated to include options for 
continued study treatment after 
the conclusion of CA224020 
study.
To allow participants 
remaining on treatment
an option to continue 
treatment post CA224020 
study, and participants in 
rechallenge-eligible 
Survival Follow-up an 
option to remain eligible 
for a rechallenge 
treatment for up to 5 
years from the first dose.
Section 3.3.1: Inclusion 
Criteria
Criterion (3)(g): Added language
that pregnancy reporting from 
female partners of childbearing 
potential is not required. 
For consistency with 
Sponsor asset language. 
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 15
Section Number & Title
Description of Change
Brief Rationale
Section 3.6: Post Treatment 
Study Follow up
Removed the Study Follow-up 
after study treatment 
discontinuation in a rollover 
study.
Text removed because no 
further collection of 
survival follow-up data 
via a rollover study is 
planned.
Section 6.4: Pregnancy
Removed the last paragraph 
pertaining to female partner 
contraception requirements.  
Aligned with latest 
relatlimab/nivolumab 
contraceptive guidance.
Throughout
Minor formatting and 
typographical corrections.
Minor, therefore not 
summarized.
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SYNOPSIS
Clinical Protocol CA224020
Protocol Title: A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety, 
Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered 
Alone and in Combination with Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in 
Advanced Solid Tumors
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with 
Investigational Product(s):
BMS-986016 (anti–lymphocyte activation gene 3 [LAG-3] antibody) is supplied as a sterile 10-
mg/mL formulation to be administered as an intravenous (IV) infusion.
Nivolumab (BMS-936558) is available as a sterile 10-mg/mL formulation to be administered as 
an IV infusion.
BMS-986213 (relatlimab 80 mg/nivolumab 240 mg vial) is available as a 16-mg/mL fixed-dose 
combination (FDC) drug product. It contains relatlimab and nivolumab at a protein-mass ratio of 
1:3 in a single vial. 
In Part A, monotherapy dose escalation, BMS-986016 will be administered at doses of 20, 80, 240, 
and 800 mg once every 2 weeks (Q2W), in 8-week cycles.
In Part A1, monotherapy cohort expansion, BMS-986016 will be administered at the maximum 
administered dose (MAD) of 800 mg as determined in Part A. Study therapy will be administered 
once Q2W, in 8-week cycles.
In Part B, dose escalation of combination with nivolumab administered by sequential infusion, 
nivolumab will be administered at a dose of either 80 mg or 240 mg followed by infusion of 
BMS-986016 at doses of 20, 80, and 240 mg, once Q2W, in 8-week cycles. This part of the study 
will also have a dose escalation with a nivolumab dose of 480 mg followed by infusion of 
BMS-986016 at doses of 160, 240, 320, 480, 960, 1440, and 1600 mg once every 4 weeks (Q4W), 
in 8-week cycles. 
In Part C, cohort expansion of combination with nivolumab administered by sequential infusion, 
nivolumab and BMS-986016 will be administered at the combination doses selected from Part B, 
which may represent the maximum tolerated dose (MTD), MAD, or an alternative dose selected 
from dose escalation. Study therapy will be administered once Q2W or Q4W with infusion of 
nivolumab first followed by BMS-986016 administration, in 8-week cycles.
In Part D, melanoma prior immuno-oncology (IO) extended expansion cohorts, most subjects will 
receive coadministration of BMS-986016 and nivolumab in a single IV bag at 2 different select 
doses, either at Q2W or Q4W, in 8-week cycles; some subjects will receive BMS-986213 FDC 
product. Part D1 employs focused eligibility criteria to build upon eligible subjects from the Part C 
melanoma prior IO cohort. If subjects do not meet the more focused eligibility of Part D1, they 
may be eligible for Part D2, which is more flexible in the allowed prior therapies and performance 
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status. Part D2 will test safety and efficacy in this broader patient population and will employ the 
more convenient Q4W dosing in 2 different dose combinations.
In Parts C, D, and E, adolescents (12 to < 18 years of age) weighing less than 40 kg will be dosed 
based on weight (1 mg/kg BMS-986016 and 3 mg/kg of nivolumab Q2W, 2 mg/kg BMS-986016 
and 6 mg/kg of nivolumab Q4W, and 6 mg/kg BMS-986016 and 6 mg/kg of nivolumab Q4W) up 
to maximum doses of the respective adult flat doses. 
In Part E advanced melanoma, exposure response evaluation cohorts, subjects will receive 
coadministration of BMS-986016 and nivolumab in a single IV bag at different select doses, Q4W, 
in 8-week cycles.
Study Phase: Phase 1/2a
Research Hypotheses: It is anticipated that anti-LAG-3 antibody (BMS-986016), administered 
as a single agent or in combination with anti-programmed cell death protein 1 (PD-1) antibody 
(nivolumab), will demonstrate adequate safety and tolerability, as well as a favorable benefit-risk 
profile, to support further clinical testing. No prospective hypotheses are being formally evaluated. 
Part D1: Treatment with BMS-986016 in combination with nivolumab will lead to clinical benefit, 
as demonstrated by a clinically meaningful objective response rate (ORR), including durable 
responses with substantial magnitude of tumor burden reduction, in melanoma subjects who 
progressed while on anti-PD-1 antibody therapies.
Part D1: Treatment with BMS-986213 (FDC) will demonstrate no clinically relevant differences 
in safety relative to coadministration of nivolumab and BMS-986016.
Part E: Treatment with BMS-986016 in combination with nivolumab (coadministration) will lead 
to clinical benefit in melanoma subjects. This will be demonstrated by higher doses of relatlimab 
(eg, 480 mg BMS 986016 + 480 mg nivolumab Q4W) producing greater clinical benefit, 
manifested by a clinically meaningful ORR, including durability of response and substantial 
magnitude of tumor burden reduction.
Objectives:
Primary Objectives: 
Parts A and B: 
The primary objective is to determine the safety, tolerability, dose-limiting toxicities (DLTs), and 
MTD of BMS-986016 administered alone and in combination with nivolumab in subjects with 
advanced solid tumors.
Part A1: 
The primary objective of BMS-986016 monotherapy cohort expansion is to gather additional 
safety, tolerability, and preliminary efficacy information of BMS-986016 monotherapy.
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Part C: 
The primary objective is to further establish adequate safety and tolerability of BMS-986016 in 
combination with nivolumab administered sequentially.
The coprimary objective in Dose Expansion Part C is to investigate the preliminary efficacy of 
BMS-986016 in combination with nivolumab as measured by ORR, disease control rate (DCR), 
and duration of response (DOR) in multiple tumor types.
Part D: 
The primary objective in Part D is to assess safety and tolerability of a more convenient dosing 
regimen (ie, coadministration and Q4W dosing interval).
Part D1-Q2W: The coprimary objective in Part D1-Q2W is to demonstrate preliminary clinical 
evidence of the treatment effect, measured by ORR, as determined by Blinded Independent Central 
Review (BICR) using Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1 that 
may represent substantial improvement over available therapies in advanced melanoma subjects 
with LAG-3 expression who progressed while on anti-PD-1 antibody therapies.
Part D1-Q4W: The primary objective in Part D1-Q4W is to evaluate the difference in safety of 
coadministration relative to FDC as measured by the incidence of adverse events (AEs) in the 
Broad Scope Medical Dictionary for Regulatory Activities (MedDRA) Anaphylactic Reaction 
Standardized MedDRA Query (SMQ) occurring within 2 days after dosing in advanced melanoma 
subjects who progressed while on anti-PD-1 antibody therapies. 
Part D1-Q4W: The coprimary objective in Part D1-Q4W is to confirm with Q4W dosing of 
BMS-986016 160 mg in combination with nivolumab 480 mg the safety of the Q2W dosing of 
BMS-986016 80 mg in combination with nivolumab 240 mg in advanced melanoma subjects who 
progressed while on anti-PD-1 antibody therapies.
Part E:
The primary objective of Part E is to demonstrate that the 480 mg BMS 986016 + 480 mg 
nivolumab Q4W dosing regimen provides significantly greater clinical benefit, manifested as an 
increased ORR, to participants as compared with the 160 mg BMS 986016 + 480 mg nivolumab 
Q4W dose by interdose cohort comparison in melanoma participants who have not received prior 
systemic anticancer therapy for unresectable or metastatic melanoma and to historical control for 
melanoma participants who experienced disease progression on prior anti-PD-1 therapy. 
Secondary Objectives:
The secondary objectives are:
To characterize the pharmacokinetics (PK) of BMS-986016 administered alone and in 
combination with nivolumab
To investigate the preliminary ORR and/or DCR of BMS-986016 administered alone and in 
combination with nivolumab in subjects with advanced solid tumors in Parts A and B, Dose 
Escalation 
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To characterize the immunogenicity of BMS-986016 administered alone and in combination with 
nivolumab
In Parts A and B, to assess the effect of BMS-986016 administered alone and in combination with 
nivolumab on QTc
Part D1:
To evaluate DOR, DCR, and progression-free survival (PFS) rates at prespecified time points (eg, 
24 weeks) based on BICR assessments using RECIST v1.1 in advanced melanoma subjects with 
LAG-3 expression who progressed while on anti-PD-1 antibody therapies
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
BICR assessments using RECIST v1.1 in advanced melanoma subjects with a lack of LAG-3 
expression and overall, regardless of LAG-3 expression
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
Investigator assessments using RECIST v1.1 in advanced melanoma subjects with LAG-3 
expression, a lack of LAG-3 expression, and overall regardless of LAG-3 expression
To assess the 1-year and 2-year landmark overall survival (OS) in advanced melanoma subjects 
with LAG-3 expression, a lack of LAG-3 expression, and overall regardless of LAG-3 expression
Part D1-Q4W: To confirm with Q4W dosing of BMS-986016 160 mg in combination with 
nivolumab 480 mg the efficacy of the Q2W dosing of BMS-986016 80 mg in combination with 
nivolumab 240 mg in advanced melanoma subjects who progressed while on anti-PD-1 antibody 
therapies
Part D1-Q4W: To evaluate the difference in safety of coadministration relative to FDC as 
measured by the incidence of AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ 
and the incidence of the select AEs in the hypersensitivity/infusion reaction category occurring 
within 2 days after dosing during the combination in advanced melanoma subjects who progressed 
while on anti-PD-1 antibody therapies
Part D1-Q4W: To evaluate Grade 3 - 5 AE incidence rate (drug related and all causality) defined 
using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.0 criteria
Part D1-Q4W: To determine PK comparisons of nivolumab and BMS-986016 administered as 
FDC to that of coadministered nivolumab and BMS-986016
Part D1: To assess PK of nivolumab and BMS-986016 in Part D1-Q4W dosing and Part D1-Q2W 
dosing
Part D2:
To assess safety and tolerability of more convenient dosing regimen in a wider range of population 
in advanced melanoma subjects who progressed while on anti-PD-1/PD-L1 antibody therapies
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
BICR assessments using RECIST v1.1 in a wider range of population in advanced melanoma 
subjects with LAG-3 expression, a lack of LAG-3 expression, and overall regardless of LAG-3 
expression
Protocol Amendment No. 15
Date: 16-Feb-2024
13
19.0
Approved
930071758
18.0
v
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v

Clinical Protocol
CA224020
BMS-986016
relatlimab
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
Investigator assessments using RECIST v1.1 in a wider range of population in advanced melanoma 
subjects with LAG-3 expression, a lack of LAG-3 expression, and overall regardless of LAG-3 
expression
To assess the 1-year and 2-year landmark OS in advanced melanoma subjects with LAG-3 
expression, a lack of LAG-3 expression, and overall regardless of LAG-3 expression
Part E:
To evaluate the clinical benefit of the 480 mg BMS-986016 + 480 mg nivolumab Q4W dosing 
regimen using DOR in melanoma participants who have not received prior systemic anticancer 
therapy for unresectable or metastatic melanoma and for melanoma participants who experienced 
disease progression on prior anti-PD-1 therapy
Exploratory Objectives:
To assess the pharmacodynamic effects of BMS-986016 alone and in combination with nivolumab 
based on select biomarkers in the peripheral blood and tumor biopsy specimens
To assess the 1-year and 2-year landmark OS in subjects treated with BMS-986016 alone and in 
combination with nivolumab
To characterize nivolumab PK and immunogenicity when administered in combination with BMS-
986016
To explore exposure-response relationships in subjects treated with BMS-986016 as monotherapy 
or in combination with nivolumab
To investigate the relationship between clinical efficacy and peripheral and tumor biomarkers
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
iRECIST assessments based on BICR
To predict milestone survival at 1 year and 2 years using tumor growth dynamic-survival model
Study Design:
This is a Phase 1/2a, open-label study of BMS-986016 administered as a single agent and in 
combination with nivolumab to subjects with advanced solid tumors. 
Part A and Part B consist of a 3 + 3 + 3 dose escalation design and, implemented in site-specific 
amendment #15 (dated 13 August 2018) and superseding the 3 + 3+ 3 dose escalation design, the 
Bayesian Logistic Regression Model (BLRM)-Copula design (for Part B only), evaluating 
BMS-986016 administered as a single agent (Part A) or in combination with nivolumab (Part B) 
as sequential infusions in subjects with advanced solid tumors. Treatment in Part B will be initiated 
upon the decision to escalate to the third dose cohort in Part A (in accordance with dose escalation 
rules); subsequently, escalation in the 2 parts will proceed in parallel. Testing of the Q2W and 
Protocol Amendment No. 15
Date: 16-Feb-2024
14
19.0
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18.0
v
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v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Q4W dosing schedules in Part B can proceed concurrently with independent escalation decisions 
based upon review of the current total safety experience and following consultation and agreement 
between Investigators and the Sponsor. Treatment in Part B will be initiated after the decision is 
made to escalate to the third dose cohort in Part A (in accordance with dose escalation rules). 
Part A1 consists of cohort expansion with BMS-986016 monotherapy in 2 disease-restricted 
cohorts of approximately 6-12 subjects each. Treatment in Part A1 will be initiated at the MAD 
determined in Part A (ie, 800 mg). The dose selected for Part A1 will not exceed the MAD in Part 
A, but dose selection may change according to assessment of other data, including toxicities and 
PK and pharmacodynamic data from Parts A and A1. Subjects in Part A1 may cross over to 
combination therapy with nivolumab and BMS-986016 in sequential infusion if they meet 
predefined criteria. 
Part C consists of cohort expansion in disease-restricted cohorts using a multistage approach, 
treated with sequential infusion of nivolumab and BMS-986016. Cohorts deemed futile (see 
sample size section for further details) at Stage 1 will be discontinued, whereas those deemed 
promising may be expanded further up to 90 to 120 subjects in total after careful evaluation of all 
available data, including the totality of efficacy, safety profile, and PK/pharmacodynamics. 
Otherwise, additional subjects may be treated to collect more data during Stage 2 in order to make 
decisions for further expansion. The doses selected for Part C will not exceed the Part B MTD or 
MAD, and specific doses selected may incorporate assessment of other data, including toxicities 
and PK and pharmacodynamic data from Parts A and B. Subjects in Part C cannot cross over to 
Part A1 either.
Part D consists of melanoma subjects who progressed on prior IO therapy. There is a Part D1 and 
a Part D2 within Part D. Most subjects in Part D will receive coadministration of BMS-986016 
and nivolumab. Part D1 employs a focused set of eligibility criteria to build upon eligible subjects 
from the Part C melanoma prior IO cohort with the primary goal of testing the efficacy of 80 mg 
BMS-986016 + 240 mg nivolumab Q2W regimen. Enrollment may continue until the following 
criteria are met: (a) 90 efficacy-evaluable LAG-3-positive subjects have been treated, (b) 60 
efficacy-evaluable LAG-3-positive and BRAF wild-type subjects have been treated, and (c) 60 
efficacy-evaluable LAG-3-positive and ipilimumab-pretreated subjects have been treated. Part D1 
will also have 2 other cohorts: 1) 160 mg BMS-986016 with 480 mg of nivolumab Q4W 
coadministration and 2) BMS-986213 (relatlimab 160 mg/nivolumab 480 mg) Q4W.
If subjects do not meet the more focused eligibility of Part D1, they may be eligible for Part D2, 
which is more flexible with respect to the allowed prior therapies and performance status. Part D2 
will test safety and efficacy in this broader patient population and will employ the more convenient 
Q4W dosing in 2 different dose combinations (160 mg BMS-986016 + 480 mg nivolumab and 
subsequently 240 mg BMS-986016 + 480 mg of nivolumab). Adolescents (12 to < 18 years of 
age) weighing less than 40 kg will receive body weight-based dosing, equivalent to the conversion 
from a median adult weight of 80 kg (1 mg/kg BMS-986016 and 3 mg/kg of nivolumab Q2W, 2 
mg/kg BMS-986016 and 6 mg/kg of nivolumab Q4W, or 6 mg/kg BMS-986016 and 6 mg/kg of 
nivolumab Q4W for corresponding fixed doses of 80/240 Q2W, 160/480 Q4W, and 240/480 Q4W, 
respectively). This adolescent dosing scheme also applies to BMS-986213. The doses and schedule 
Protocol Amendment No. 15
Date: 16-Feb-2024
15
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Clinical Protocol
CA224020
BMS-986016
relatlimab
selected for Part D will not exceed the Part B MTD or MAD, and dosing of the cohorts may be 
altered in collaboration between the Investigators and Sponsor, based upon the overall ongoing 
study data, including evaluation of toxicities, PK, and pharmacodynamics. A schematic of the 
study is provided in Figure 1.
Part E consists of advanced melanoma participants. Two cohorts of melanoma participants will 
be enrolled in Part E: melanoma participants who experienced disease progression on prior 
anti-PD-1 therapy and melanoma participants who have not received prior systemic anticancer 
therapy for unresectable or metastatic melanoma. In Part E, melanoma participants will be 
administered either 160 mg BMS-986016 with 480 mg of nivolumab Q4W or 480 mg BMS-
986016 with 480 mg of nivolumab Q4W; the specific dosing regimen will be dependent on 1) 
whether the subject had progressive disease on an earlier anti-PD-1 therapy and 2) randomization.
Figure 1:
Study Schematic
Sequential = sequential administration of nivolumab first, followed by BMS-986016 infusion within 15 to 30 minutes 
of completing nivolumab infusion. For doses of 960 mg relatlimab + 480 mg nivolumab Q4W and higher doses, BMS-
986016 infusion should be administered no sooner than 30 minutes following completion of nivolumab infusion. 
IO = immuno-oncology agents (such as, but not limited to, anti-cytotoxic T lymphocyte–associated antigen 4 (CTLA-
4), antiPD-1, antiPD-L1, antiPD-L2, anti-KIR, anti-CD137, anti-LAG-3, and/or anti-OX40 antibodies).
* Subsequent to site-specific amendment #15 (dated 13 August 2018), the dose escalation design was changed to
BLRM-Copula from the 3 + 3 + 3 design.
Protocol Amendment No. 15
Date: 16-Feb-2024
16
19.0
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930071758
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Figure 2:
Part D
Figure 3:
Part E
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Part E consists of advanced melanoma participants. Two cohorts of melanoma participants will be 
enrolled in Part E: melanoma participants who experienced disease progression on prior anti-PD-1 
therapy and melanoma participants who have not received prior systemic anticancer therapy for 
unresectable or metastatic melanoma.
Melanoma participants who experienced disease progression on prior anti-PD-1 therapy will all 
receive 480 mg BMS 986016 + 480 mg nivolumab Q4W dose regimen.
Melanoma participants who have not received prior systemic anticancer therapy for unresectable 
or metastatic melanoma will be randomized to 1 of the 2 following treatment arms:
160 mg BMS-986016 + 480 mg nivolumab Q4W
480 mg BMS 986016 + 480 mg nivolumab Q4W
Subjects will complete up to 4 periods of the study: Screening (up to 28 days), Treatment, 
Clinical Follow-up (135 days), and Survival Follow-up (up to 5 years following the first dose of 
study drug). Two independent periods, Crossover and Rechallenge may be conducted in selected 
cases at progression. As of Protocol Amendment 14, rechallenge is not permitted.
In the Treatment Period, each treatment cycle comprises 4 doses of either BMS-986016 alone 
(Parts A and A1) or in combination with nivolumab (Part B and C except bladder cohort), 
administered on Days 1, 15, 29, and 43 of each treatment cycle. 
 
 
 
. In Parts B and C when 
both study drugs are given as sequential infusion, nivolumab will be given first, followed by BMS-
986016 within 15 to 30 minutes of completing the infusion of nivolumab. In Part B, for doses of 
960 mg relatlimab + 480 mg nivolumab Q4W and higher doses, BMS-986016 infusion should be 
administered no sooner than 30 minutes following completion of nivolumab infusion. Part D, the 
melanoma prior IO extended expansion, will have 2 sections: Part D1 will have a focused 
eligibility criteria with a cohort of 80 mg of BMS-986016 with 240 mg nivolumab Q2W, a cohort 
of 160 mg BMS-986016 with 480 mg of nivolumab Q4W, and a cohort of BMS-986213 (160 mg 
relatlimab/480 mg nivolumab) Q4W; Part D2 will have an expanded eligibility criteria with 
2 cohorts in sequence: 160 mg BMS-986016 with 480 mg of nivolumab Q4W and 240 mg 
BMS-986016 and 480 mg of nivolumab Q4W. In Part D, study drugs are given as a 
coadministration or single infusion of BMS-986213 over approximately 60 minutes. In Part E, 
melanoma subjects will be administered either 160 mg BMS-986016 with 480 mg of nivolumab
Q4W or 480 mg BMS-986016 with 480 mg of nivolumab Q4W; the specific dosing regimen will 
be dependent on whether the subject previously received anti-PD-1 therapy in the advanced, 
unresectable, or metastatic setting and had progressive disease on that earlier treatment regimen 
and randomization, as previously described. Adolescents (12 to < 18 years of age) weighing less 
than 40 kg will be dosed based on weight (1 mg/kg BMS-986016 and 3 mg/kg of nivolumab Q2W, 
2 mg/kg BMS-986016 and 6 mg/kg of nivolumab Q4W, or 6 mg/kg BMS-986016 and 6 mg/kg of 
nivolumab Q4W). In Parts C, D, and E, Q4W dosing, BMS-986016 and nivolumab will be 
Protocol Amendment No. 15
Date: 16-Feb-2024
18
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Clinical Protocol
CA224020
BMS-986016
relatlimab
administered on Days 1 and 29 of each treatment cycle; visits will occur every 2 weeks to assess 
safety for the first cycle of treatment, and thereafter visits will only be on Day 1 and Day 29 of 
each subsequent cycle. 
 
 
 
 
 Tumor response will be evaluated using RECIST v1.1. Subjects will be allowed 
to continue study therapy until the first occurrence of either: 1) progressive disease (PD), 2) 
clinical deterioration, and/or 3) meeting other criteria for discontinuation (Section 3.5). Treatment 
beyond progression may be allowed in select subjects with initial RECIST v1.1-defined PD who 
are receiving clinical benefit as assessed by the Investigator, tolerating treatment, and meeting 
other criteria specified in Section 4.3.4. Subjects who discontinue treatment will enter a 135-day 
Clinical Follow-up period.
After completion of the Clinical Follow-up period, subjects will enter the Survival Follow-up 
period. During this period, clinic visits or telephone contact every 12 weeks will be performed to 
assess survival status. Survival follow-up visits will be scheduled based on the last clinical follow-
up visit. The duration of this period may continue for up to 5 years from the first dose. Diagnostic 
imaging must be performed every 8 weeks until disease progression. For subjects who 
discontinue treatment at the Investigator’s discretion with a complete response (CR), partial 
response (PR), or stable disease (SD) by RECIST v1.1, imaging must be performed every 12 
weeks until disease progression. If subjects progress during the Clinical Follow-up period or the 
Survival Follow-up period, they could further receive therapy with BMS-986016 alone or in 
combination therapy (Rechallenge period) as long as the benefit-risk ratio is considered favorable 
by the Investigator and the Medical Monitor and eligibility criteria are met (Section 3.1.2.4). The 
rechallenge-eligible Survival Follow-up period may continue for up to 5 years from the first dose 
of study drug. The original dose and schedule and protocol rules would apply accordingly. Subjects 
will not be rechallenged a second time. Collection of archival tissue (baseline) and tumor biopsies 
(baseline and on-treatment) will be optional for subjects enrolled for rechallenge. PK and 
biomarker monitoring will be limited (Sections 5.5 and 5.7). As of Protocol Amendment 14, 
rechallenge is not permitted. All subjects who discontinue primary study treatment following 
implementation of Protocol Amendment 14 will not be eligible for rechallenge. Subjects currently 
receiving rechallenge treatment will be allowed to continue, and subjects currently in the 
rechallenge-eligible Survival Follow-up as of this Protocol Amendment remain eligible for 
rechallenge.
For patients remaining on treatment beyond 5 years, subjects may continue on study treatment, as 
long as the benefit-risk ratio is considered favorable by the Investigator and continues to meet the 
criteria outlined in the protocol.
Also, subjects receiving therapy with BMS-986016 alone in expansion Part A1 may cross over to 
combination therapy at confirmed progression (Section 3.1.2.1).
A study schematic is shown in Figure 4.
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Figure 4:
Detailed Study Schematic
1 Treatment beyond progression may be considered in select subjects as described in Section 4.3.4.
2 Diagnostic imaging must be performed every 8 weeks until disease progression, and in subjects who discontinue 
study treatment at the Investigator’s discretion with a CR, PR, or SD via RECIST 1.1, imaging must be performed 
every 12 weeks until disease progression.
3 For treatment visits in Parts B and C where BMS-986016 and nivolumab are administered sequentially, nivolumab 
will be administered first over 30 minutes, followed by BMS-986016 administration within 15 to 30 minutes after 
completion of the nivolumab infusion. For doses of 960 mg relatlimab + 480 mg nivolumab Q4W, BMS-986016 
infusion should be administered no sooner than 30 minutes following completion of nivolumab infusion.
4 Note the 6-week DLT period will be initiated with the 960 mg BMS-986016 dose level.
Note: As of Protocol Amendment 14, rechallenge is not permitted.
Study Parts:
Dose Escalation Part A: In Part A, a 3 + 3 + 3 design will be used to assess the safety of 
BMS-986016 given as single agent. A fourth subject may be enrolled at the beginning of a dose 
escalation cohort following agreement between the Investigator and the Sponsor/Medical Monitor, 
if the subject is able to start the first day of dosing within approximately 1 week of the third subject 
in the same dose escalation cohort. The dosages during dose escalation are provided in Table 1. 
Three subjects (or 4, if applicable) will initially be treated in each dose cohort; in Dose Cohort 1, 
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
each of the first 3 subjects (or 4, if applicable) will be designated as sentinel subjects and will begin 
treatment at least 5 days apart. Subjects in subsequent cohorts will not be required to observe the 
5-day interval between treatment start dates. 
Dose escalation in Part A will proceed as follows: if none of the 3 (or 4, if applicable) subjects 
experience a DLT, a new cohort of 3 subjects (or 4, if applicable) will be treated at the next higher 
dose level. If 1 of 3 (or 4, if applicable) subjects experiences a DLT, that cohort will be expanded 
to 6 subjects (or 7, if applicable). If 2 of 6 (or 7, if applicable) subjects experience a DLT, that 
cohort will be expanded to 9 subjects. If 2 of 3 (or 4, if applicable), 3 of 6 (or 7, if applicable), 
or 3 of 9 subjects experience DLTs within a cohort, then that dose level will be determined to 
have exceeded the MTD.
Table 1:
Dose Escalation and Dose Expansion Schedules for Part A and Part 
A1 BMS 986016 Monotherapy
Part A Dose Escalation Cohort Number
Total Subjects
BMS-986016 Dose
(IV; mg)
1
n = approximately 3-9
20
2
n = approximately 3-9
80
3
n = approximately 3-9
240
4
n = approximately 3-9
800
Total
N = approximately 12-36
Part A1: Dose Expansion Cohorts
Non-small cell lung cancer (NSCLC): prior 
anti-PD-1 or PD-L1 therapy alloweda
n = approximately 6-12
800
Renal cell carcinoma (RCC): prior anti-PD-1 or 
PD-L1 therapy alloweda
n = approximately 6-12
800
Total
N = approximately 12-24
a See Section 3.3 for detailed eligibility criteria.
Prior to declaring the MTD (or MAD), and in consultation with Investigators, the Sponsor has the 
option to expand any cohort previously established to be safe in order to obtain additional 
experience or to investigate dose levels intermediate to those defined in the protocol. Dose 
escalation rules (cohort size, observation for DLTs, etc.) will apply to these expanded or additional 
cohorts. A maximum of 9 subjects will be enrolled in any additional or expanded dose cohorts.
Cohort Expansion Monotherapy (Part A1): The purpose of cohort expansion is to gather 
additional safety, tolerability, preliminary efficacy, PK, and pharmacodynamic information of 
BMS-986016 monotherapy. The doses selected for Part A1 will not exceed the MTD or MAD in 
Part A but may incorporate assessment of other data, including toxicities and PK and 
pharmacodynamic data from Part A. Doses to be considered may include doses intermediate to 
those evaluated in Part A, if recommended by the Investigators and the Sponsor. Modeling may 
Protocol Amendment No. 15
Date: 16-Feb-2024
21
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Clinical Protocol
CA224020
BMS-986016
relatlimab
be used to help inform the selection of the combination dose level to carry forward in Part A1 if a 
dose below the MTD is chosen. Two expansion cohorts will be restricted to the tumor types listed 
in Table 1. 
Subjects in Part A1 may cross over to Part C if all of the following criteria are met: 1) subject has 
confirmed disease progression (Investigator-assessed RECIST 1.1-defined progression confirmed 
at least 4 weeks after the initial tumor assessment showing progression; 2) subject has not 
experienced BMS-986016related AEs leading to permanent discontinuation; 3) subject is not 
continuing to derive any clinical benefit from BMS-986016 single-agent therapy as assessed by 
the Investigator; 4) the individual case has been discussed with the Medical Monitor prior to 
crossover (Section 3.1.2.1); 5) at least an 8-week period in between the last dose of monotherapy 
and the first dose of combination therapy. Subjects will not be rechallenged a second time. As of 
Protocol Amendment 14, rechallenge is not permitted. Subjects crossing over to combination 
therapy will start treatment at Cycle 1 Day 1 as described for subjects in Part C. Subjects who cross 
over will receive combination therapy in sequential infusion at the doses that have been declared 
safe in dose escalation and/or dose expansion parts at the time of crossover. The original protocol 
rules will apply accordingly. Subjects who crossed over and subsequently have an objective 
response in combination therapy will not be considered in the decision making for Part C 
proceeding to Stage 2. Subjects in Part C cannot cross over to Part A1.
Dose Escalation Sequential (Part B): Treatment in Part B will be initiated upon the decision to 
escalate to the third dose cohort in Part A in accordance with dose escalation rules. Subsequently, 
escalation in the 2 parts will proceed in parallel. Treatment assignments for subjects eligible for 
both Part A and Part B will alternate between the 2 parts, with consecutively treated subjects 
assigned to different parts through interactive voice response system, whenever possible. If there 
are no openings available in the part to which the subject would be assigned by this algorithm, 
then the subject will be assigned to the next open cohort or part.
In Part B, a 3 + 3 + 3 design or BLRM-Copula design, effective with site-specific amendment #15 
(dated 13 August 2018), will also be used to assess the safety of BMS-986016 given in 
combination with nivolumab as a sequential infusion Q2W and Q4W. A fourth subject may be 
enrolled at the beginning of a dose escalation cohort following agreement between the Investigator 
and the Sponsor/Medical Monitor, if subject is able to start the first day of dosing within 
approximately 1 week of the third subject in the same dose escalation cohort. The potential dose 
levels evaluated during dose escalation are provided in Table 2. Intermediate and lower dose levels 
may be assessed following agreement between the Investigator and the Sponsor/Medical Monitor 
based upon ongoing review of safety data. As in Part A, each of the first 3 subjects (or 4, if 
applicable) in the first dose cohort in Part B will be designated as sentinel subjects and will begin 
treatment at least 5 days apart.
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 2:
Dose Escalation Schedule for Part B — BMS-986016 in Combination 
with Nivolumab Q2W and Q4W
Dose Cohort 
Number
Total Subjects
BMS-986016 Dose 
(IV; mg)
Nivolumab Dose
(IV; mg)
Dose Escalation Schedule for Part B — BMS-986016 in Combination with Nivolumab 
Q2W Dosing
1
n = approximately 3-9
20
80
2
n = approximately 3-9
20
240
3
n = approximately 3-9
80
240
Intermediate 
n = approximately 3-9
160
240
4
n = approximately 3-9
240
240
Dose Escalation Schedule for Part B — BMS-986016 in Combination with Nivolumab 
Q4W Dosing
1
n = approximately 3-9
160
480
2
n = approximately 3-9
240
480
3
n = approximately 3-9
320
480
4
n = approximately 3-12
480
480
5
n = approximately 3-15
960
480
6
n = approximately 3-15
1440
480
7
n = approximately 3-15
1600
480
Total
N = approximately 36-120
In Part B, if the MTD is exceeded in Dose Cohort 2, the subsequent cohort will be treated with 80 
mg of BMS-986016 and 80 mg of nivolumab. If this dose combination is found to be safe, and 
following consultation and agreement between Investigators and the Sponsor, escalation may 
proceed at the previously defined BMS-986016 doses, maintaining the nivolumab dose at 80 mg, 
or an intermediate dose level. Testing of the Q2W and Q4W dosing schedules can proceed 
concurrently with independent escalation decisions based upon review of the current total safety 
experience and following consultation and agreement between Investigators and the Sponsor.
Prior to declaring the MTD (or MAD), and in consultation with Investigators, the Sponsor has the 
option to expand any cohort previously established to be safe in order to obtain additional 
experience or to investigate dose levels intermediate to those defined in the protocol. Dose 
escalation rules (cohort size, observation for DLTs, etc.) will apply to these expanded or additional 
cohorts. A maximum of 9 subjects will be enrolled in any additional or expanded dose cohorts.
Cohort Expansion Sequential (Part C): The purpose of cohort expansion is to gather additional 
safety, tolerability, preliminary efficacy, PK, and pharmacodynamic information in subjects 
treated with sequential infusion of nivolumab first, followed by administration of BMS-986016. 
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
The initial doses selected for specific Part C cohorts will not exceed the MTD or MAD in Part B 
but may incorporate consideration of other data, including (but not necessarily limited to) 
toxicities, PK, and pharmacodynamic data from Parts A and B and can be chosen while additional 
Part B dose escalation cohorts continue to be explored. Part C expansion cohort doses to be 
considered will include those doses shown to be safe in Part B (or intermediate to those doses) as 
recommended by the Investigators and the Sponsor. Dosing of subsequent patients within an 
expansion cohort, or between cohorts, can be increased (if deemed safe in Part B) or decreased 
(based upon ongoing reviews of the totality of the safety data), all to be decided in agreement 
between the Investigators and the Sponsor. There will be no dose adjustments for individual 
subjects. 
In Part C, a multistage design will be used to assess treatment efficacy. Cohorts deemed futile at 
Stage 1 will be discontinued, whereas those deemed promising may be expanded up to 90 to 120 
subjects in total after careful evaluation of all available data, including the totality of efficacy, 
safety profile, and PK/pharmacodynamics. Otherwise, additional subjects may be treated to collect 
more data during Stage 2 in order to make a decision for further expansion. Enrollment to Stage 2 
or further expansion in a given cohort can continue even if the other cohorts are still in Stage 1. 
Subjects who crossed over to combination therapy in Part A1 and subsequently have an objective 
response will not be considered in the decision making for Part C. Subjects in Part C cannot cross 
over to Part A1 either. 
All Cohort Expansion Parts (Parts A1, C, D, and E)
Continuous evaluation of toxicity events in the cohort expansions will be performed throughout 
enrollment in the expansion cohorts. If, at any time, the aggregate rate of treatment-related 
toxicities meeting DLT criteria exceeds 33% across all subjects treated in any of these cohort 
expansions, the findings will be discussed, and further enrollment must be interrupted in that 
particular cohort and other relevant cohorts. Depending on the nature and grade of the toxicity, 
and after assessing the benefit-risk ratio, a new dose(s) for all cohorts may be initiated at a 
previously tested lower dose level or at a dose level intermediate to previously tested lower dose 
levels.
Rechallenge in Dose Escalation (Parts A, B, and E) and Cohort Expansion (Parts A1, C, and 
D)
If, after discontinuing study treatment at the Investigator’s discretion, subjects that have disease 
progression during the Clinical Follow-up period or the Survival Follow-up period, subjects could 
further receive therapy with BMS-986016 alone or in combination therapy (Rechallenge) as long 
as the benefit-risk ratio is considered favorable by the Investigator and the Medical Monitor and 
the following eligibility criteria are met: 1) subject has confirmed disease progression 
(Investigator-assessed RECIST 1.1-defined progression confirmed at least 4 weeks after the initial 
tumor assessment showing progression; 2) subject has not experienced BMS-986016related AEs 
leading to permanent discontinuation. The rechallenge-eligible Survival Follow-up may continue 
for up to 5 years from the first dose of study drug. The original dose and schedule of therapy and 
protocol rules will apply. For the rechallenge, collection of archival tissue (baseline) and tumor 
Protocol Amendment No. 15
Date: 16-Feb-2024
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v

Clinical Protocol
CA224020
BMS-986016
relatlimab
biopsies (baseline and on-therapy) will be optional for subjects crossing over, and PK and 
biomarker monitoring will be limited (Sections 5.5 and 5.7). As of Protocol Amendment 14, 
rechallenge is not permitted. All subjects who discontinue primary study treatment following 
implementation of Protocol Amendment 14 will not be eligible for rechallenge. Subjects currently 
receiving rechallenge treatment will be allowed to continue, and subjects currently in the 
rechallenge-eligible Survival Follow-up as of this protocol amendment remain eligible for
rechallenge.
Subjects who are rechallenged and who subsequently have an objective response will not be 
included in the primary analysis of efficacy. Responses to rechallenge will be evaluated in a 
separate analysis. Subjects will not be rechallenged a second time.
Part D Melanoma Prior IO Extended Expansion Coadministration or Treatment with FDC 
(BMS-986213)
In Part D, advanced melanoma subjects with progression on prior anti-PD-1 therapy will be 
enrolled into 2 subparts, D1 and D2, based on eligibility criteria. If eligible for the focused (more 
restricted eligibility) D1 subpart, subjects will be randomized across 3 arms:
Arm 1: relatlimab 80 mg + nivolumab 240 mg given by coadministration Q2W
Arm 2: relatlimab 160 mg + nivolumab 480 mg given by coadministration Q4W
Arm 3: BMS-986213 (relatlimab 160 mg/nivolumab 480 mg) given Q4W; BMS-986213 contains 
both relatlimab and nivolumab in the same solution at a ratio of 1:3 (relatlimab:nivolumab)
Part E Exposure Response Evaluation (Coadministration)
Two cohorts of melanoma subjects will be enrolled in Part E: melanoma participants who 
experienced disease progression on prior anti-PD-1 therapy and melanoma participants who have 
not received prior systemic anticancer therapy for advanced, unresectable, or metastatic 
melanoma. Melanoma participants who experienced disease progression on prior anti-PD-1 
therapy in the advanced, unresectable, or metastatic setting will only receive 480 mg BMS 986016 
+ 480 mg nivolumab Q4W. Melanoma participants who have not received prior systemic 
anticancer therapy for locally advanced, unresectable, or metastatic melanoma will be randomized 
to 1 of the following 2 treatment arms:
160 mg BMS-986016 + 480 mg nivolumab Q4W
480 mg BMS-986016 + 480 mg nivolumab Q4W
Randomization will be unblinded. Enrollment and randomization to Arm 1 may continue until the 
following criteria are met: (a) 90 efficacy-evaluable LAG-3-positive subjects have been treated, 
(b) 60 efficacy-evaluable LAG-3-positive and BRAF wild-type subjects have been treated, and (c) 
60 efficacy-evaluable LAG-3-positive and ipilimumab-pretreated subjects have been treated. 
Enrollment and randomization across Arms 2 and 3 may continue until the following criteria are 
met: (a) 90 efficacy-evaluable LAG-3-positive subjects have been treated, (b) 60 efficacy-
evaluable LAG-3-positive and BRAF wild-type subjects have been treated, and (c) 60 efficacy-
evaluable LAG-3-positive and ipilimumab-pretreated subjects have been treated. Prior to Revised 
Protocol Amendment No. 15
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Protocol 09, Part D1 subjects are being enrolled only into Arm 1. Subsequent to activation of this 
revised protocol, and until the enrollment to Arm 1 is completed, subjects in Part D1 will be 
randomized 1:1:1 across the 3 arms. Once enrollment to Arm 1 is completed, subjects will be 
randomized 1:1 to Arms 2 and 3. If enrollment to Arms 2 and 3 is completed prior to Arm 1, then 
enrollment to Arm 1 will be completed as a single arm. Prior to the start of randomization, a safety 
lead-in will be conducted with BMS-986213 (see Section 3.1.2.5). If subjects do not meet the more 
focused eligibility of Part D1, they may be eligible for Part D2, which is more flexible with respect 
to the allowed prior therapies and performance status. Part D2 will test safety and efficacy in this 
broader patient population and will employ the more convenient Q4W coadministration dosing. 
Initial dosing will be 160 mg BMS-986016 + 480 mg nivolumab. Once further safety is established 
at the BMS-986016 160 mg + nivolumab 480 mg dose, subsequently enrolled subjects will be 
treated with BMS-986016 240 mg + nivolumab 480 mg. The doses and schedule selected for Part 
D will not exceed the Part B MTD or MAD, and dosing of the cohorts may be altered in 
collaboration between the Investigators and Sponsor based upon the overall ongoing study data, 
including assessment of toxicities, PK, and pharmacodynamics. There will be no dose adjustments 
for individual subjects. Expansion cohorts in Part D will be restricted to advanced melanoma 
subjects (Section 3). Efficacy analyses are described in Section 8.4.2.
Dose-limiting Toxicities: BMS-986016 has the potential to augment the frequency and severity 
of previously described AEs associated with nivolumab or to produce new toxicities. For the 
purpose of guiding decisions regarding dose escalation in Parts A and B, DLTs will be determined 
based on the incidence, intensity, and duration of AEs that are related to study drug and that occur 
within 42 days (6 weeks) of initiation of study drug. The severity of AEs will be graded according 
to NCI CTCAE v4.0.
No intrasubject dose escalations are allowed. Subjects who withdraw from the study during the 
DLT evaluation interval for reasons other than a DLT may be replaced at the same dose level. In 
the case that an infusion cannot be administered at a scheduled visit during the DLT evaluation 
interval, it must be administered as soon as possible. Subjects may be dosed no more frequently 
than every 12 days in the Q2W regimen and no more frequently than every 25 days in the Q4W 
regimen and no more than 3 days from scheduled dose. If an infusion cannot be administered at a 
scheduled visit, it should be administered as soon as possible. Subsequent dosing visits will follow 
every 2 weeks or every 4 weeks after the delayed dose. A dose given more than 3 days after the 
intended dose date will be considered a delay. A maximum delay of 6 weeks between doses is 
allowed. Longer delays may be allowed following discussion with the Medical Monitor. For Q4W 
dosing cycles, subjects may be dosed within a 3 day window. For the purpose of making decisions 
on dose escalation from a safety perspective, subjects will be considered evaluable if they have 
received 3 out of the 4 scheduled BMS-986016 doses in Part A (or 3 out of 4 schedules BMS-
986016 and nivolumab doses in Part B Q2W dosing or 2 out of 2 scheduled BMS-986016 and 
nivolumab doses in Part B Q4W dosing) through the 6-week observation period, only if the 1 
missed dose was secondary to progressive disease or nonmedical reasons. Unevaluable subjects 
may be replaced at the same dose level.
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For the purpose of subject management, potential DLTs that occur at any time, whether during 
dose escalation (Parts A, B) or cohort expansion (Parts A1, C, D) will result in all study drug(s) 
being held pending evaluation of the event’s relatedness to study drug, severity, duration, and in 
accordance with Section 4.3.2. Subjects must meet criteria for retreatment prior to reinitiation of 
study treatment (see Section 4.3.3). Any DLT that occurs after the initial 6-week DLT observation 
period, and after dosing in the next higher dose cohort has begun, will be accounted for and 
factored into the BLRM-Copula model in a post-hoc manner. Additionally, as a practical matter, 
it should be noted that the BLRM-Copula model, based on the absence of DLTs at a preceding 
dose level, may dictate that an entire dose level cohort be skipped.
Duration of Study: Subjects will be allowed to continue on therapy until PD, until clinical 
deterioration, or until meeting criteria for discontinuation as described in Section 3.5. Patients who 
discontinue treatment before 5 years will complete a 135-day clinical follow-up period, and a 
survival follow-up period for up to 5 years after the first dose. Patients who continue study 
treatment for longer than 5 years will complete a 135-day clinical follow-up period once the criteria 
for treatment discontinuation are met, but will not participate in a survival follow-up period. The 
study will end when all patients have completed their respective follow-up periods. The original 
dose, schedule, and protocol rules would apply. 
If a subject has disease progression during the Clinical Follow-up period or the Survival Follow-
up period, the subject could further receive therapy with BMS-986016 alone or in combination 
therapy (Rechallenge) as long as they meet eligibility criteria and the benefit-risk ratio is 
considered favorable by the Investigator and the Medical Monitor. The rechallenge-eligible 
Survival Follow-up may continue for up to 5 years from the first dose of study drug. The original 
dose and schedule and protocol rules would apply accordingly. Subjects will not be rechallenged 
a second time. As of Protocol Amendment 14, rechallenge is not permitted. All subjects who 
discontinue primary study treatment following implementation of Protocol Amendment 14 will 
not be eligible for rechallenge. Subjects currently receiving rechallenge treatment will be allowed 
to continue, and subjects currently in the rechallenge-eligible Survival Follow-up as of this 
protocol amendment remain eligible for rechallenge.
Number of Subjects: Approximately up to 1200 subjects may be dosed (up to approximately 100 
subjects during dose escalation Parts A and B, approximately 300 subjects in Part C cohort 
expansions, and approximately 550 subjects in Part D and approximately 225 subjects in Part E ). 
Study Population: For Parts A, B, C, D, and E, males and females 18 years at the time of 
informed consent. Additionally, for Parts C (melanoma only), D, and E, males and females 12 
years at the time of informed consent if local regulations and/or institutional policies allow for 
participants < 18 years of age (pediatric population). All subjects must have histologic or cytologic 
confirmation of advanced, nonresectable, or metastatic solid tumors and measureable disease who 
meet all eligibility criteria will be eligible to participate in the study. Unless otherwise stated in 
the inclusion/exclusion criteria for each study part, subjects must be naive to prior IO agents such 
as, but not limited to, anti-CTLA-4, anti-PD-1, or anti-PD-L1; anti-PD-L2, anti-KIR, anti-CD137, 
anti-LAG-3, and/or anti-OX40 antibodies.
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Dose Escalation-Monotherapy (Part A): Subjects with any solid tumor type (with the exception 
of primary central nervous system [CNS] tumors or with CNS metastases as the only site of active 
disease) are eligible to enroll. Subjects must not have prior exposure to IOs.
Dose Expansion-Monotherapy (Part A1): Subjects with 1) NSCLC with prior anti-PD-1 or 
PD-L1 therapy allowed; 2) Subjects with renal cell carcinoma with prior anti-PD-1 or PD-L1 
therapy allowed. 
Dose Escalation-Sequential Infusion (Part B): Subjects with any solid tumor type (with the 
exception of primary CNS tumors or with CNS metastases as the only site of active disease) were 
eligible to enroll in the first 2 cohorts. Subjects naive to IOs, subjects with melanoma progressing 
while on or after anti-CTLA-4 and/or anti-PD-1/anti-PD-L1 antibody therapy, and subjects with 
NSCLC progressing while on anti-PD-1 or anti-PD-L1 antibody therapy as their most recent are 
allowed (full criteria described in Section 3.3.1) were also eligible in the first 2 cohorts. 
For subsequent cohorts, eligible tumor types (and all subtypes) will include: 1) NSCLC naive to 
IOs; 2) NSCLC whose disease progresses while on therapy with anti-PD-1 (limited to nivolumab 
or pembrolizumab) or anti-PD-L1 antibody therapy; 3) melanoma first line; 4) melanoma 
progressing while on or after receiving anti-CTLA-4 and/or anti-PD-1 (limited to nivolumab or 
pembrolizumab)/anti-PD-L1 antibody therapies; 5) RCC naive to IOs; 6) other tumors naive to IO 
agents, including head and neck, gastric, hepatocellular, cervical, ovarian, bladder, and colorectal 
cancers. Participants must also weigh 40 kg. Subjects can have received anti-PD-1 (limited to 
nivolumab or pembrolizumab) or anti-PD-L1 antibody but cannot have had therapy discontinued 
due to serious and/or life-threatening anti PD-1 or anti-PD-L1 antibody related to toxicity.
Cohort Expansion - Sequential Infusion (Part C): Tumor types include: 1) melanoma first line; 
2) RCC naive to IO; 3) squamous cell carcinoma head and neck (SCCHN) naive to IO; 4) NSCLC 
naive to IO; 5) NSCLC whose disease progressed while on or after therapy with anti-PD-1 or anti-
PD-L1 antibody as most recent therapy; 6) gastric cancer naive to IO; 7) hepatocellular carcinoma 
(HCC) naive to IO; 8) melanoma previously progressed on anti-PD-1/anti-PD-L1 antibody alone 
or anti-PD-1/anti-PD-L1 antibody in combination with anti-CTLA-4 antibody therapy; and 9) 
bladder cancer naive to IO.
Part D Melanoma Prior IO Extended Expansion - Coadministration (BMS-986016 and 
Nivolumab): Tumor types include unresectable or metastatic advanced melanoma. Part D1, 
Focused Eligibility Criteria: 1) documented progression while on a prior anti-PD-1 (limited to 
nivolumab and pembrolizumab) containing regimen (monotherapy or combination therapy). 
Documentation of prior anti-PD-1 therapy should include start, stop, and progression dates of the 
prior anti-PD-1 therapy with unequivocal progression and a radiological progression date no more 
than 3 months after the last dose of anti-PD-1 therapy; 2) only 1 line of a prior anti-PD-1 (limited 
to nivolumab or pembrolizumab) containing regimen is allowed; 3) BRAF wild-type and mutant 
subjects are eligible; 4) if BRAF mutant, progression on a single line of a BRAF inhibitor, 
administered with or without a MEK inhibitor, is required; 5) Eastern Cooperative Oncology 
Group performance status (ECOG PS) 0-1. Part D2 Expanded Eligibility Cohort: 1) anti-PD-L1 
therapy or combination-containing regimen can substitute for anti-PD-1 therapy (limited to 
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nivolumab or pembrolizumab); 2) BRAF wild-type and mutant subjects are eligible, but prior 
targeted BRAF therapy is not required; 3) ECOG PS 0-2. Please see Section 3.3 for full eligibility 
criteria.
Part E Exposure Response Evaluation in Melanoma Participants: Eligibility for melanoma 
participants who experienced disease progression on prior anti-PD-1 therapy: 1) documented 
progression while on a prior anti-PD-1 (limited to nivolumab and pembrolizumab) containing 
regimen (monotherapy or combination therapy). Documentation of prior anti-PD-1 therapy should 
include start, stop, and progression dates of the prior anti-PD-1 therapy with unequivocal
progression, and a radiological progression date no more than 3 months after the last dose of 
anti-PD-1 therapy; 2) only 1 line of a prior anti-PD-1 (limited to nivolumab or pembrolizumab) 
containing regimen is allowed; 3) BRAF wild-type and mutant subjects are eligible; 4) if BRAF 
mutant, progression on a single line of a BRAF inhibitor, administered with or without a MEK 
inhibitor, is required; 5) ECOG PS 0-1.
Eligibility for melanoma participants who have not received prior systemic anticancer therapy for 
unresectable or metastatic melanoma: Participants must have an ECOG PS 1/Lansky 
Performance Score 80% for minors (ages 12-17) ONLY and 2) histologically confirmed Stage 
III (unresectable) or Stage IV melanoma, as per American Joint Committee on Cancer staging 
system.
As of Protocol Amendment 14, no contraception requirements for relatlimab and nivolumab are 
necessary for male participants. 
Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of 
contraception for the duration of treatment with nivolumab and relatlimab, plus 5 half-lives of 
study treatment, for a total of 5 months post-treatment completion and agree not to donate eggs 
(ova, oocytes) for the purpose of reproduction for the same time period (refer to Appendix 1).
Investigators shall counsel WOCBP on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. Investigators shall advise WOCBP on the use of highly 
effective methods of contraception. Highly effective methods of contraception have a failure rate 
of < 1% per year when used consistently and correctly (see Appendix 1).  
Please see Section 3.3 for full eligibility criteria and additional details regarding prior lines of 
treatments.
Study Assessments:
Safety Outcome Measures: Safety assessments will be based on medical review of AE reports and 
the results of vital sign measurements, electrocardiograms (ECGs), physical examinations, and 
clinical laboratory tests. AEs will be assessed continuously during the study and for 135 days after 
the last treatment. AEs will be coded using the most current version of MedDRA and reviewed for 
potential significance and importance. Both AEs and laboratory tests will be graded using the NCI 
CTCAE v4.0.
Efficacy Measures: Disease assessment using computed tomography (CT) and/or magnetic 
resonance imaging (MRI), as appropriate, will be performed at baseline and every 8 weeks 
regardless of dose delays during the treatment period after first dose of study medication. Tumor 
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responses will be determined by the Investigator for subjects with adequate data as defined by 
RECIST v1.1. For selected disease cohorts in Part C, tumor responses will also be determined by 
BICR using RECIST v1.1. Diagnostic imaging must be performed every 12 weeks, until 
disease progression, in subjects who discontinue treatment at the Investigator’s discretion 
with a confirmed CR, PR, or SD by RECIST v1.1.
Pharmacokinetic Measures: Serial serum samples will be collected from all subjects at specified 
time points to evaluate concentrations of BMS-986016 and nivolumab. PK parameters such as 
Cmax, Ctrough, Tmax, AUC(TAU), CLT, and AI will be derived from serum concentration vs 
time data. Sparse serum samples will be collected from subjects in Parts B and C to evaluate 
concentrations of nivolumab. As per Protocol Amendment 14, PK sample collection upon the 
occurrence of a ≥ Grade 3 AE is not required. 
Immunogenicity Measures: Serum samples to evaluate development of positive antidrug antibody 
(ADA) response to BMS-986016 and nivolumab will be collected at specified time points.
Biomarker Measures: The sample collection and biomarker assessment strategy is designed to 
address mechanisms of action, pharmacodynamic changes associated with BMS-986016, and the 
potential identification of predictive safety and efficacy biomarkers associated with BMS-986016, 
and to evaluate potential mechanisms of resistance to BMS-986016 and nivolumab. To address 
these key questions, peripheral blood, serum, and biopsy samples will be collected prior to and 
during study drug treatment during this study.
Statistical Considerations: Sample Size: 
Dose Escalation (Parts A and B)
Sample size at each dose depends on observed toxicity and cannot be precisely determined. Part 
A will have 3 to 9 subjects in each cohort. Part B will have 3 to 15 subjects in each cohort.
In the Part B dose escalation using BLRM-Copula, the sample size at each dose depends on 
observed toxicity and posterior inference. Initially, approximately 3 subjects will be treated at the 
starting dose level (using the new BLRM-Copula design) of BMS-986016 in combination with 
nivolumab. Due to the potential for early discontinuation, an additional subject(s) may be enrolled 
to ensure approximately 3 evaluable subjects at each dose level.
Cohort tolerability assessment and subsequent dose recommendation will occur when 2 evaluable 
subjects within a set have completed the DLT evaluation period. If the potential DLT occurring in 
any third evaluable subject regarding the specific dose level does not influence the dose 
recommendation by BLRM-Copula, the BLRM-Copula recommended next dose level may 
proceed without waiting for the third subject to complete the corresponding DLT observation 
period, after discussion and agreement between Sponsor and Investigators. Continuous 
reassessment of dose recommendation by BLRM-Copula in the combination phase will be carried 
out at each dose level.
During dose escalation, BLRM could recommend escalating to the next dose or skipping an entire 
dose level altogether. In that case, a new cohort of approximately 3 subjects will be treated at the 
recommended new dose. BLRM could also recommend staying at the same dose level, in which 
case an additional increment of approximately 3 subjects will be treated at that dose. At least 6 
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DLT-evaluable subjects will be treated in the selected dose cohort(s) chosen for expansion. Up to 
15 subjects may be treated at any dose level for further evaluation of safety and 
pharmacodynamic/PK parameters as required.
Cohort Expansion Monotherapy (Part A1)
A sample size of 6 subjects per cohort allows for estimation of the proportion of subjects with 
objective response (ie, best overall response [BOR] of CR + PR) within a cohort such that the 
maximum distance between the estimated rate and either limit of the exact 2-sided 95% Clopper-
Pearson confidence interval (CI) is 47.5%.
A sample size of 12 subjects per cohort allows for estimation of the proportion of subjects with 
objective response (ie, BOR of CR + PR) within a cohort such that the maximum distance between 
the estimated rate and either limit of the exact 2-sided 95% Clopper-Pearson CI is 32.2%.
Cohort Expansion (Part C)
The objective of this expansion in combination with nivolumab is to support further clinical testing 
by demonstrating adequate safety and tolerability as well as favorable benefit-risk by assessing 
preliminary efficacy measured by ORR and other clinically relevant efficacy measures such as 
DOR and DCR. However, the sample size is strictly based on efficacy, specifically based on the 
target ORR relative to historic ORR.
Disease- and prior IO therapy-restricted cohorts will be investigated in the Part C cohort 
expansion: NSCLC progressing on IO therapy; melanoma progressing on anti-PD-1/anti-PD-L1; 
RCC naive to IO therapies; NSCLC naive to IO therapies; melanoma first line; SCCHN naive to 
IO therapies; gastric cancer naive to IO therapies; HCC naive to IO therapies; and bladder 
(urothelial) cancer naive to IO therapies. The NSCLC progressing on IO therapy cohort will be 
analyzed as a whole and as 2 separate subgroups, refractory and relapsed, as defined in 
Section 3.3.1. All disease cohorts will be handled independently, and there will be no multiplicity 
adjustment.
A multistage design will be used as a guide for each expansion cohort in order to decide whether 
the treatment of BMS-986016 in combination with nivolumab warrants more extensive 
development. At first, a 2-stage design with a reasonable false positive rate (eg, < 10%) and false 
negative rate (eg, < 10%) will be used for the decision making based on assumptions of true (target) 
and historic/standard-of-care response rate for each cohort. The assumed historic and target 
response rates may change over time and may need to be adjusted by the time of response data 
from this study are available. Using a 2-stage design provides an option to stop early for futility as 
well as a signal of preliminary antitumor activity for strong-go early on. Enrollment may continue 
into Stage 2 while the planned number of subjects for Stage 1 is followed for efficacy-evaluable 
tumor assessments. There will be no stopping of a disease cohort for efficacy, although early plan 
for the next stage of clinical development may be initiated. 
The ORRs considered to be of clinical value for further expansion of selected populations, sample 
size, and operational characteristics of using a 2-stage design, as an example, are provided in Table 
3, although this is not for statistical hypothesis testing.
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Once there is preliminary evidence of the treatment effect that may represent substantial 
improvement over available therapies, sufficient additional subjects will be treated to demonstrate 
a substantial and clinically meaningful effect in ORR that is supported by duration of the effect. 
The total sample size at this stage will be determined based on the ability to produce a CI, which 
would exclude an ORR of the historic response, and to provide sufficient information for a reliable 
understanding of the safety profile. With 90 to 120 subjects in total, this design yields a less than 
5% of 2-sided Type I error rate and at least 80% power depending on tumor type with specified 
historic/standard of care and target rates. Table 4 summarizes the 95% exact CI for various 
observed ORRs with sample sizes of 90, 100, and 120.
Table 3:
Example of a 2-stage Design Characteristics
Cohort
Historic/
Target 
Rate (%)
Stage
Cum
Sample 
Size
Conclude 
Futility if 
Ra
Conclude 
Efficacy
if R
PETb for 
Futility 
(%)
PEEc for 
Efficacy 
(%)
Gastric
IO naive
10/30
1
2
15
26
1
5
4
6
55
70
HCC
IO naive
Melanoma 
progressed on 
anti-PD-1/PD-
L1
RCC
IO naive
25/50
1
2
11
26
2
9
6
10
46
50
NSCLC IO 
refractory
5/20
1
2
12
37
0
3
3
4
54
44
NSCLC IO 
relapsed
NSCLC
1/2L, IO naive
20/45
1
2
14
25
3
7
7
8
70
45
Melanoma
1L
40/65
1
2
13
28
5
14
10
15
57
28
SCCHN
IO naive
__________
Bladder
IO naive
20/40
1
2
20
36
4
10
8
11
63
58
a R is the cumulative number of responses at the end of stage.
b PET: probability of early termination.
c PEE: probability of early expansion.
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Table 4:
Observed ORR with Exact 95% CI
Sample Size
Number of Responses
ORR
95% Exact CI
90
18
27
32
37
46
20%
30%
36%
41%
51%
[12.3%, 29.8%]
[20.8%, 40.6%]
[25.7%, 46.4%]
[30.8%, 52.0%]
[40.4%, 61.8%]
100
20
30
35
40
50
20%
30%
35%
40%
50%
[12.7%, 29.2%]
[21.2%, 40.0%]
[25.7%, 45.2%]
[30.3%, 50.3%]
[39.8%, 60.2%]
120
24
36
42
48
60
20%
30%
35%
40%
50%
[13.3%, 28.3%]
[22.0%, 39.0%]
[26.5%, 44.2%]
[31.2%, 49.3%]
[40.7%, 59.3%]
Melanoma Prior IO Extended Expansion (Part D) 
The objective of this expansion in melanoma subjects whose disease is progressing while receiving 
anti-PD-1 (anti-PD-L1 allowed in Part D2) antibody therapies is to assess safety and tolerability 
of more convenient dosing regimen (ie, coadministration and Q4W dosing interval) and 
demonstrate preliminary clinical evidence of the treatment effect measured by ORR, as determined 
by BICR, that may represent substantial improvement over available therapies in subjects with 
LAG-3 expression (Part D1).
Melanoma Prior IO Extended Expansion (Part D1-Q2W)
Data from Part C melanoma subjects who progressed while receiving anti-PD-1 antibody therapies 
demonstrated preliminary evidence that subjects with LAG-3 expression are more likely to 
respond to treatment of BMS-986016 in combination with nivolumab. The biomarker prevalence 
using the initial 1% cut (ie, LAG-3 expression 1%) is estimated to be approximately 60% in this 
patient population.
In order to establish safety and tolerability of a more convenient dosing regimen and further 
characterize an enriched responder population, approximately a total of 150 subjects who meet the 
eligibility criteria for Part D1 will be treated with BMS-986016 80 mg + nivolumab 240 mg Q2W 
coadministered. A sample size of 150 is expected to provide approximately 90 subjects with 
LAG-3 expression using the initial cutoff of 1% and provide reasonable precision to examine the 
enrichment of patient population with LAG-3 expression.
Since the optimal LAG-3 biomarker cutpoint is not well known prior to the study, several different 
cutoffs may be explored, and, depending on the prevalence of the LAG-3 biomarker-positive using 
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these cutoffs, the initial total sample size may be modified in order to have an adequate precision 
for demonstrating preliminary clinical evidence of the treatment effect in the LAG-3 
biomarker-positive population (ie, approximately 90 subjects). Although evaluation of the cutpoint 
will be based on the ORR, the decision of the cutpoint will be based on the totality of the efficacy 
data, including DOR and DCR.
Additionally, in an effort of exploring enriched patient population in advanced melanoma subjects 
who progressed while on anti-PD-1 antibody therapies in Part D1, other potential predictive 
biomarkers such as BRAF mutation status may be explored. Approximately 60 subjects among the 
90 subjects with LAG-3 expression in Part D1 are expected to be BRAF wild-type.
For the purpose of demonstrating preliminary clinical evidence of the treatment effect, the primary 
efficacy population will be subjects with LAG-3 expression who progressed while on anti-PD-1 
antibody therapies and receive BMS-986016 80 mg + nivolumab 240 mg Q2W in Part D1. A 
portion of subjects in Part C who meet the eligibility criteria of Part D1 will be included in a 
sensitivity analysis to further strengthen the evidence. 
The sample size of 90 subjects with LAG-3 expression was determined based on the ability to 
produce a CI, which would exclude an ORR of the historic response, and to provide sufficient 
information for a reliable understanding of the safety profile.
There is no standard of care for advanced melanoma patients that have progressed during prior 
anti-PD-1 therapy; thus, the demonstration of effective and tolerable therapy in these patients 
remains a large unmet need. The only published or reported studies in this clinical setting employ 
anti-CTLA-4 therapy, namely ipilimumab, and they are small retrospective or exploratory ad hoc 
analyses. The patient population characteristics and results of ipilimumab monotherapy in these 
studies are listed in Table 5 below. There have been no prospective studies defining the benefit of 
anti-CTLA-4 therapy after disease progression during anti-PD1 therapy.
Table 5:
Ipilimumab After Prior Anti-PD-1 Therapy
Study Population
ORR/CI/DOR
Toxicity
Source
Retrospective: Sequential treatment of 
anti-PD-1 (all progressed on clinical 
trials), then ipilimumab. 10% BRAF 
mutant. 42% with PD as BOR to prior 
anti-PD-1. 10% prior ipilimumab 
(response not reported).
10% (4/40 PRs)
No CI reported
DOR not reported
55% received all 4 doses 
of ipilimumab
35% had Grade 3-5 
immune-related (ir)AE; 
1 drug-related death due 
to pneumonitis
Bowyer et al
10.1038/bjc.2016
.107
Retrospective: Documented 
progression on prior anti-PD1 as per 
RECIST v1.1 (details not provided). 
15% BRAF mutant. 51% with PD as 
BOR to prior anti-PD1. 26% prior 
ipilimumab (response not reported).
16% (7/43 PRs)
No CI reported
DOR not reported
Median DoDC 7 
months 
95% CI (2.8-22.8) 
months
53% received all 4 doses 
of ipilimumab (33% did 
not due to toxicity) 
Rates of irAEs were not 
reported
Zimmer et al
10.1016/j.ejca.20
17.01.009
Exploratory post-hoc analysis of 
patients who received ipilimumab 
13% (3 CRs and 10 
PRs out of 97 patients)
Not reported
Long et al
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Table 5:
Ipilimumab After Prior Anti-PD-1 Therapy
Study Population
ORR/CI/DOR
Toxicity
Source
sequentially after pembrolizumab (91% 
with documented progression). Data 
from subsequent therapies case report 
forms. 16% BRAF mutant. 62% with 
PD as BOR to prior anti-PD1. 
No CI reported
DOR not reported
KEYNOTE-006 
presentation at 
Society for 
Melanoma 
Research 
November 6-9, 
2016
All treated subjects - nivolumab 
crossover to ipilimumab (the subjects 
randomized to nivolumab who received 
ipilimumab as subsequent therapy). 
56% with PD as BOR to prior anti-PD-
1.
10% (7/68 PRs)
95% CI (4.2%, 20.1%)
DOR not reported
Not reported
CA209066 study
Unpublished 
analysis
Combined analyses employing a standard response evaluable population definition across the 
multiple small studies of ipilimumab monotherapy in the setting of prior anti-PD1 therapy reveals 
an approximate 12% ORR. Durability of these responses is poorly documented.
In heavily pretreated patients, where clinical benefit is observed in only a subset of the population, 
safety is a significant concern. The reported rates of Grade 3 (or greater) TRAEs of approximately 
35% from single-agent ipilimumab after anti-PD-1 therapy limits the overall utility of this 
approach.59
The majority of our patient population (approximately 60%) has also been previously treated with 
anti-CTLA-4 therapy. There are no reported effective therapies in this setting. In addition, 
antitumor responses with continued anti-PD1 therapy after initial progression on anti-PD1 therapy 
is relatively rare, with estimates of incidence of approximately 5%.60 Thus, given a study 
population in which all subjects have progressed during prior anti-PD1 therapy, and the majority 
have received prior anti-CTLA-4 therapy as well, it is reasonable to target an ORR that excludes 
10% as a lower bound within a 95% CI.
Table 6:
Observed ORR with Exact 95% CI for Cohort D
Sample Size
Number of Responses
ORR
95% Exact CI
60
12
15
18
20%
25%
30%
[10.8%, 32.3%]
[14.7%, 37.9%]
[18.9%, 43.2%]
90
16
18
20
18%
20%
22%
[10.5%, 27.3%]
[12.3%, 29.8%]
[14.1%, 32.2%]
120
20
24
27
17%
20%
23%
[10.5%, 24.6%]
[13.3%, 28.3%]
[15.4%, 31.0%]
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Table 6:
Observed ORR with Exact 95% CI for Cohort D
Sample Size
Number of Responses
ORR
95% Exact CI
150
24
27
30
16%
18%
20%
[10.5%, 22.9%]
[12.2%, 25.1%]
[13.9%, 27.3%]
220
26
29
32
12%
13%
15%
[7.9%, 16.8%]
[9.0%, 18.4%]
[10.2%, 19.9%]
Melanoma Prior IO Focused Eligibility Expansion (Part D1-Q4W)
The coprimary objective in Part D1-Q4W is to evaluate the difference in safety between 
coadministration relative to FDC as measured by the incidence of AEs in the Broad Scope 
MedDRA Anaphylactic Reaction SMQ occurring within 2 days after dosing during the 
combination and to confirm with Q4W dosing of BMS-986016 160 mg in combination with 
nivolumab 480 mg the safety of the BMS-986016 80 mg in combination with nivolumab 240 mg 
Q2W in advanced melanoma subjects who progressed while on anti-PD-1 antibody therapies (see 
Appendix 5).
Prior to Revised Protocol 09, subjects are being enrolled into a single arm: Part D1 BMS-986016 
80 mg + nivolumab 240 mg Q2W. Subsequent to this amendment, and until the enrollment to Part 
D1 BMS-986016 80 mg + nivolumab 240 mg Q2W is completed, subjects in Part D1 will be 
randomized 1:1:1 to Part D1 BMS-986016 80 mg + nivolumab 240 mg Q2W, Part D1 BMS-
986016 160 mg + nivolumab 480 mg Q4W coadministration, or Part D1 BMS-986213 (relatlimab 
160 mg/nivolumab 480 mg) Q4W. Once the enrollment to Part D1 BMS-986016 80 mg + 
nivolumab 240 mg Q2W is completed, subjects will be randomized 1:1 to Part D1 BMS-986016 
160 mg + nivolumab 480 mg Q4W coadministration or Part D1 BMS-986213 (relatlimab 160 
mg/nivolumab 480 mg) Q4W arms. If enrollment to Q4W arms is completed prior to arm BMS-
986016 80 mg + nivolumab 240 mg Q2W arm, then enrollment to arm BMS-986016 80 mg + 
nivolumab 240 mg Q2W will be completed as a single arm.
Approximately 150 subjects will be randomized to the 2 treatment arms: Part D1 BMS-986016 
160 mg + nivolumab 480 mg Q4W coadministration and Part D1 BMS-986213 (relatlimab 160 
mg/nivolumab 480 mg) Q4W. This number of treated subjects was chosen to achieve a sufficient 
level of precision for a descriptive analysis to estimate the difference in rates of AEs in the Broad 
Scope MedDRA Anaphylactic Reaction SMQ between the 2 treatment arms. Seventy-five treated 
subjects per arm will allow estimation of the rate difference within 95% confidence limits of 15% 
or less and will be supplemented by a qualitative clinical assessment of the type and severity of 
events to evaluate benefit-risk. 
From the Q2W expansion cohorts in Part C of the current study, AEs in the MedDRA Anaphylactic 
Reaction SMQ (Broad Scope) with onset within 2 days after sequential dosing of nivolumab 240 
mg combined with BMS-986016 80 mg were reported in 14% of treated subjects. In Part D1, if 
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the observed rate of these events is equal to 14% among 75 treated subjects in each arm, and then 
the 95% CI for the difference in rates between arms will be (-11.1%, 11.1%). 
Table 7 shows the precision that the sample size of 75 treated subjects per arm in Part D1-Q4W
and 150 treated subjects each in Part D1-Q2W and Part D1-Q4W dosing will provide for 
estimating rates and rate differences between the treatment arms under different assumed observed 
rates. Enrollment and randomization across treatment arms Part D1 BMS-986016 160 mg + 
nivolumab 480 mg Q4W coadministration and Part D1 BMS-986213 (relatlimab 
160 mg/nivolumab 480 mg) Q4W may continue until the following criteria are met: (a) 90 
efficacy-evaluable LAG-3-positive subjects have been treated, (b) 60 efficacy-evaluable 
LAG-3-positive and BRAF wild-type subjects have been treated, and (c) 60 efficacy-evaluable 
LAG-3-positive and ipilimumab-pretreated subjects have been treated. 
Table 7:
95% CI for Rate Differences When Observed in 75 Subjects per Arm 
and 150 Subjects per Dosing Regimen
75 Subjects per Arm
Coadministration Arm
Fixed Dose Combination
Arm
Rate Difference (95% CI)
14%
14%
0% (-11.1%, 11.1%)
14%
12%
2% (-8.8%, 12.8%)
16%
14%
2% (-9.4%, 13.4%)
18%
16%
2% (-10%, 14%)
20%
18%
2% (-10.6%, 14.6%)
150 Subjects Each in Part D1-Q4W and Part D1-Q2W 
Q2W
Q4W
Rate Difference (95% CI)
14% 
14%
0% (-7.9%, 7.9%)
14%
12%
2% (-5.6%, 9.6%)
16%
14%
2% (-6.1%, 10.1%)
18%
16%
2% (-6.5%, 10.5%)
20%
18%
2% (-6.9%, 10.9%)
Also, with 75 subjects per arm, there is a 99% probability that the 95% CI for the geometric mean 
ratio of Cmax of FDC to coadministration is wholly contained within [0.8, 1.25]. log(Cmax) is 
assumed to follow a normal distribution and, with intrasubject coefficients of variation, is assumed 
to be no greater than 30%.
Melanoma Prior IO Expanded Eligibility (Part D2)
Part D2 will have expanded eligibility criteria with 2 cohorts in sequence: 160 mg BMS-986016 
with 480 mg of nivolumab Q4W and 240 mg BMS-986016 with 480 mg of nivolumab Q4W. 
Subjects in Part D2 on average will have a worse performance status and be more heavily 
pretreated. Approximately 30 subjects will be initially treated with 160 mg BMS-986016 with 480 
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mg of nivolumab Q4W. Once this dose level is deemed safe, approximately up to 220 additional 
subjects will be treated with either 160 mg BMS-986016 with 480 mg or 240 mg BMS-986016 
with 480 mg of nivolumab Q4W to establish safety and efficacy in this broader group of melanoma 
patients. With 30 subjects, there is approximately 96% chance to observe at least 1 occurrence of 
any AE that would occur with a 10% incidence in the population from which the sample is drawn. 
With 250 subjects, there is approximately 92% chance to observe at least 1 occurrence of any AE 
that would occur with a 1% incidence in the population from which the sample is drawn. Safety 
and efficacy data will be collected as in the other cohorts, and the data will be used as supportive 
evidence of safety and efficacy of the combination therapy.
Exposure/Response Expansion Q4W Dosing (Part E)
In Part E, 2 disease cohorts will be investigated: melanoma participants who experienced disease 
progression on prior anti-PD-1 therapy and melanoma participants who have not received prior 
systemic anticancer therapy for advanced, unresectable, or metastatic melanoma. The objective of 
this expansion is to support further clinical testing at higher dose of relatlimab in combination with 
nivolumab by demonstrating adequate safety and tolerability as well as favorable benefit-risk by 
assessing preliminary efficacy measured by ORR and other clinically relevant efficacy measures, 
such as DOR and DCR. However, the sample size is based on efficacy, specifically based on the 
target ORR relative to the ORR observed at the lower dose of relatlimab in combination with 
nivolumab. Both disease cohorts will be handled independently, and there will be no multiplicity 
adjustment. The sample size of the melanoma participants who experienced disease progression 
on prior anti-PD-1 therapy cohort is based on the comparison of the ORR of subjects who receive 
480 mg BMS 986016 + 480 mg nivolumab Q4W vs the benchmark observed ORR of subjects who 
received 80 mg BMS 986016 + 240 mg nivolumab Q2W from the historical control in this study. 
A sample size of 75 melanoma participants who experienced disease progression on prior anti-PD-
1 therapy will provide approximately 85% power for testing the ORR difference with a 2-sided 
alpha of 0.1, assuming ORR of 25% and 10% in the 480 mg BMS 986016 + 480 mg nivolumab 
Q4W arm and in the historical control arm, respectively.
The sample size of the melanoma participants who have not received prior systemic anticancer 
therapy for unresectable or metastatic melanoma cohort is based on the comparison of the ORR of 
subjects who receive 480 mg BMS 986016 + 480 mg nivolumab Q4W vs the ORR of subjects 
who receive 160 mg BMS 986016 + 480 mg nivolumab Q4W. A sample size of 150 melanoma 
subjects who have not received prior systemic anticancer therapy for advanced, unresectable, or 
metastatic melanoma, randomized in a 1:1 ratio in 2 arms, will provide approximately 81% power 
for testing the ORR difference with a 2-sided alpha of 0.1, assuming ORR of 67% and 47% in the 
480 mg BMS 986016 + 480 mg nivolumab Q4W arm and in the 160 mg BMS 986016 + 480 mg 
nivolumab Q4W arm, respectively.
Endpoints: 
Primary Endpoint:
The primary endpoint of this Phase 1/2a study is safety as measured by the rate of AEs, serious 
AEs (SAEs), and AEs leading to discontinuation of treatment, deaths, and laboratory 
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abnormalities, assessed during treatment and for up to for 135 days after the last treatment. All 
subjects who receive at least 1 dose of BMS-986016 or nivolumab will be analyzed for safety. 
In Part C, the coprimary endpoints are ORR, DCR, and DOR by BICR using RECIST v1.1, where 
applicable, in selected disease cohorts.
In Part D1-Q2W, the coprimary endpoint is efficacy measured by ORR, as determined by BICR 
using RECIST v1.1, in advanced melanoma subjects with LAG-3 expression who progressed 
while on anti-PD-1 antibody therapies.
The primary endpoint in Part D1-Q4W of the study is the incidence of AEs in the Broad Scope 
MedDRA Anaphylactic Reaction SMQ occurring within 2 days after dosing. This incidence rate 
is defined as number of subjects who experienced at least 1 AE in the MedDRA Anaphylactic 
Reaction broad scope SMQ with onset on the day of or within 2 days after any study therapy 
infusion divided by number of treated subjects. The terms included in the MedDRA Anaphylactic 
Reaction SMQ based on the most current MedDRA version will be listed in the statistical analysis 
plan.
Secondary Endpoints:
Efficacy: The BOR, ORR, DCR, DOR, and PFS rates at prespecified time points by BICR when 
not designated as the primary in Parts C and D, and by the Investigator assessments using RECIST 
v1.1 are secondary endpoints. Additionally, the 1-year and 2-year landmark OS in Part D and DOR 
in Part E are secondary endpoints.
Pharmacokinetics: Select BMS-986016 PK parameters, such as Cmax, Ctrough, Tmax, AUC 
(TAU), CLT, and AI, will be assessed from concentration-time data during Cycle 1 and Cycle 3.
Immunogenicity: Incidence of ADA to either BMS-986016 or nivolumab will be assessed during 
treatment and for up to 135 days after their last treatment in post-treatment follow-up or for a 
maximum of up to 24 months of treatment, whichever comes first.
ECG: In Parts A and B, QTc will be assessed by a central reader for ECG collected at follow-up 
Visit 1, as well as on Day 1 of Cycle 1 and Cycle 3 at the predose and 4-hour postdose time points. 
In Part D1-Q4W, PK of nivolumab and BMS-986016 coadministered will be assessed and 
compared to that of FDC of relatlimab and nivolumab. PK will be measured using serum 
concentration-time data. PK of nivolumab and BMS-986016 in Part D1-Q4W and Part D1-Q2W 
will also be assessed.
Exploratory Endpoints:
Biomarkers:
 
 
 Biomarker endpoints from tumor biopsies may include, but will not be 
limited to, 
 
 
 expression of LAG-3, 
 and PD-L1. 
 
 
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Pharmacokinetics: PK parameters will include nivolumab concentration-time data at select 
trough (Ctrough) and end-of-infusion (EOI) time points based on measurements collected for up 
to 135 days during the post-treatment follow-up or for a maximum of up to 24 months of treatment, 
whichever comes first.
Efficacy: The BOR, ORR, DCR, DOR, and PFS rates at prespecified time points will be explored 
by iRECIST assessments based on BICR. Landmark 1-year and 2-year OS rates will be assessed 
as exploratory efficacy endpoints in the study (except for Part D). 
Analyses:
Unless otherwise specified, data from Part A (monotherapy dose escalation) and Part A1 
(monotherapy dose expansion) will be presented separately from data collected in Parts B, C, and 
D (combination therapy). Safety data from the dose escalation phase will be summarized by dose 
and across all doses. Safety data from the dose expansion phase will be summarized for each 
disease cohort and overall by dose and across doses. Efficacy data from the dose expansion phase 
will be summarized for each disease cohort by dose and across doses. Efficacy data from the dose 
escalation phase will be summarized by dose and listed by tumor type.
Safety: All subjects who receive study drug therapy will be included in the analysis of safety 
endpoints. All recorded AEs will be coded according to the most current version of MedDRA and 
be graded using NCI CTCAE v4.0. AEs will be listed, and subjects with AEs will be summarized 
based on the event with worst CTCAE grade by system organ class (SOC) and preferred term (PT), 
counting once at the PT term level and once at the SOC level, for each dose, dosing regimen, and 
overall. The incidence of AEs in the Broad and Narrow Scope MedDRA Anaphylactic Reaction 
SMQ and select AEs in hypersensitivity/infusion reaction category occurring within 2 days after 
dosing by treatment arm, the difference in rates between arms, and the corresponding 95% CIs will 
be reported descriptively. The CIs for the rate estimates will be based on the Clopper-Pearson 
method. Vital signs and clinical laboratory test results will be listed and summarized by treatment. 
Any significant physical examination findings and results of clinical laboratory tests will be listed. 
Any ECG abnormalities identified by the Investigator will be listed. In Parts A and B, ECG will 
be assessed by a central reader at specific time points. All ECG data analyses, including summaries 
of each ECG parameters, frequency distributions of subjects’ maximum values/changes, and 
scatter plots, will be performed following the current practice of ECG data analysis. Concentration-
response analysis may be performed using mixed effect model, if appropriate. The details of ECG 
data analysis will be provided in the statistical analysis plan. 
Efficacy Analyses: Individual BOR, DOR, and PFS will be determined based on RECIST v1.1 
criteria for the primary and secondary analyses. iRECIST will be used as an exploratory analysis 
in Parts C and D and for exploratory analyses in other parts of the study. BOR outcomes will be 
summarized using frequency tables together with 2-sided 95% CIs. Time-to-event distribution (eg, 
PFS and DOR) will be estimated using Kaplan-Meier method. When appropriate, the median along 
with 95% CI will be provided using Brookmeyer and Crowley methodology (using log-log 
transformation for constructing the CIs). Rates at fixed time points (eg, PFS rate at 24 weeks and 
OS at 1 and 2 years) will be derived from the Kaplan-Meier estimate, and corresponding CI will 
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be derived based on Greenwood formula. Confidence intervals for binomial proportions will be 
derived using the Clopper-Pearson method.
For the purpose of demonstrating preliminary clinical evidence of the treatment effect in advanced 
melanoma subjects who progressed while on receiving anti-PD-1 antibody therapies, the primary 
efficacy population will be subjects with LAG-3 expression who progressed while on anti-PD-1 
antibody therapies in Part D1 and receive BMS-986016 80 mg + nivolumab 240 mg Q2W. A 
portion of subjects in Part C who meet the eligibility criteria of Part D1 will be included in the 
sensitivity analysis to further strengthen the evidence. Efficacy analysis will also be performed for 
subjects with a lack of LAG-3 expression and also for all treated subjects regardless of LAG-3 
expression to support the treatment effect of the combination therapy.
Initial cutpoint for the purpose of exploring an enriched population is LAG-3 expression 1%. 
However, as the optimal biomarker cutpoint is not well known prior to the study, several different 
cutoffs may be explored other than the initial cutpoint of 1% by examining receiver operating 
characteristics curves using the ORR, although the decision of the cutpoint will be based on the 
totality of the efficacy data, including DOR and DCR. Details of methodology will be described 
in the statistical analysis plan prior to any data exploration in Part D.
In an effort to explore an enriched patient population in advanced melanoma subjects who 
progressed while on anti-PD-1 antibody therapies in Part D1, other potential predictive biomarkers 
such as BRAF mutation status may be explored.
Subsequently, efficacy analysis for Part D1-Q4W will be done similarly to that for Part D1-Q2W. 
If the outcome of BOR in the Part D1-Q4W is deemed similar to that of the Part D1-Q2W, data 
from both Part D1-Q2W and Part D1-Q4W may be combined to strengthen the evidence.
Efficacy analysis for Part D2 will be done similarly to that for Part D1.
Pharmacokinetics: PK parameters for BMS-986016 will be calculated using noncompartmental 
analyses. Summary statistics will be tabulated for the PK parameters of BMS-986016 by treatment 
and study day/cycle. To describe the association of these parameters with dose of BMS-986016, 
scatter plots of Cmax and AUC(TAU) vs dose may be provided for each day measured. Dose 
proportionality of BMS-986016 when administered alone or coadministered with nivolumab may 
also be assessed based on a power model. Nivolumab end-of-infusion and trough (Ctrough) 
concentrations will be tabulated by treatment using summary statistics. 
Nivolumab concentration-time data at scheduled trough (Ctrough) and end-of-infusion time points 
will be evaluated as an exploratory endpoint. Measurements will be collected on-treatment (up to 
12 cycles) and for up to 135 days during the post-treatment follow-up or for a maximum of up to 
24 months of treatment, whichever comes first. Model-predicted milestone survival at 1 year and 
2 years using all available longitudinal tumor response data based on historical IO treatment-based 
tumor growth dynamic-survival relationship similarly to PFS data analysis. In Part D1-Q4W, PK 
comparisons will be summarized using descriptive summary statistics, and the point estimate and 
CI of geometric mean ratios of Cmax and AUC(TAU) will be presented to compare nivolumab 
and BMS-986016 administered as FDC to that of coadministered nivolumab and BMS-986016. 
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PK parameters will also be summarized using descriptive summary statistics for nivolumab and 
BMS-986016 administered in Part D1-Q2W and Part D1-Q4W dosing.
Immunogenicity Analyses: A listing will be provided for all available immunogenicity data. A 
baseline ADA-positive subject is defined as a subject with positive seroconversion detected in the 
last sample before initiation of treatment. An ADA-positive subject is a subject with at least 1 
ADA-positive sample relative to baseline after initiation of the treatment. For each drug, frequency 
distribution of baseline ADA-positive subjects and ADA-positive subjects after initiation of the 
treatment will be summarized. To examine the potential relationship between immunogenicity and 
safety, a table summarizing the frequency and type of AEs of special interest may be explored by 
immunogenicity status. In addition, potential relationships between immunogenicity and efficacy 
and/or PK may also be explored.
Biomarker Analyses: The pharmacodynamic effect in subjects who undergo biopsy will be 
assessed using summary statistics and plots. 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 15: ............................ 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 15 ................ 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale for Nivolumab Therapy ........................................................... 
1.1.2 LAG-3 and T Cell Exhaustion .................................................................. 
1.1.3 Rationale for Anti-LAG-3 Antibody (BMS-986016) Therapy .................. 
 
 
1.1.5 Summary .................................................................................................. 
1.1.6 Rationale for Part D Expansion .............................................................. 
1.1.7 Rationale for Part E (Melanoma Expansion) .......................................... 
1.1.8 Parts C, D, and E (Melanoma Only) Rationale for Inclusion of 
Adolescents ................................................................................................. 
1.1.9 Rationale for Dose Selection ................................................................... 
1.1.9.1 Rationale for Flat Dosing ............................................................... 
1.1.9.2 Part A — BMS-986016 Dose .......................................................... 
1.1.9.3 Part B — BMS-986016 Dose (Applies to Only a Subset of Sites 1-6)
............................................................................................................... 
1.1.9.4 Parts B, C — Nivolumab and Combination Dosing - Sequential 
Infusion ................................................................................................. 
1.1.9.5 Rationale for 30-minute Nivolumab Infusion ................................. 
1.1.9.6 Part D: Coadministration or Fixed-dose Combination .................. 
1.1.9.7 Part E: Coadministration of BMS-986016 and Nivolumab ............ 
1.1.9.8 Dose Rationale for Adolescents ...................................................... 
1.2 Research Hypotheses ........................................................................................ 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.4.1 BMS-986016 (Anti-LAG-3 Antibody) ...................................................... 
1.4.1.1 Nonclinical Pharmacology ............................................................. 
1.4.1.2 Toxicity ............................................................................................ 
1.4.1.3 Nonclinical Metabolism and Pharmacokinetics ............................. 
1.4.1.4 Clinical Pharmacology and Safety ................................................. 
1.4.2 Nivolumab (BMS-936558, Anti-PD-1 Antibody) ..................................... 
1.4.2.1 Nonclinical Pharmacology, Metabolism, and Pharmacokinetics ... 
1.4.2.2 Clinical Safety ................................................................................. 
1.4.2.3 Clinical Pharmacokinetics .............................................................. 
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1.4.2.4 Clinical Activity .............................................................................. 
 
1.4.3 BMS-986213 (Fixed-dose Combination Product) ................................... 
 
1.5 Overall Benefit-risk Assessment ....................................................................... 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
 
2.1 Good Clinical Practice ...................................................................................... 
 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
 
2.3 Informed Consent.............................................................................................. 
 
3 INVESTIGATIONAL PLAN .................................................................................... 
 
3.1 Study Design and Duration ............................................................................... 
 
3.1.1 Dose Escalation ....................................................................................... 
 
3.1.1.1 Part A - Monotherapy ..................................................................... 
 
3.1.1.2 Part B - Sequential Infusion ............................................................ 
 
3.1.2 Cohort Expansion .................................................................................... 
 
3.1.2.1 Cohort Expansion (Part A1) - Monotherapy .................................. 
 
3.1.2.2 Cohort Expansion (Part C) - Sequential Infusion........................... 
 
3.1.2.3 All Cohort Expansion Parts (A1, C, D, and E) ............................... 
 
3.1.2.4 Rechallenge in Dose Escalation (Parts A and B) and Cohort 
Expansion Parts (A1, C, D, and E) ....................................................... 
 
3.1.2.5 Part D Melanoma Prior IO Extended Expansion (Coadministration 
or Treatment with Fixed-dose Combination [BMS-986213]) .............. 
 
3.1.2.6 Part E Exposure Response Evaluation (Coadministration) ........... 
 
3.1.3 Dose-limiting Toxicities ........................................................................... 
 
3.1.3.1 Rationale for 6-week DLT Period in Part B ................................... 
 
3.2 Post Study Access to Therapy ........................................................................... 
 
3.3 Study Population ............................................................................................... 
 
3.3.1 Inclusion Criteria ..................................................................................... 
 
3.3.2 Exclusion Criteria .................................................................................... 
 
3.3.3 Women of Childbearing Potential ........................................................... 
 
3.4 Concomitant Treatments ................................................................................... 
 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
 
3.4.2 Other Restrictions and Precautions ......................................................... 
 
3.4.3 Permitted Therapy ................................................................................... 
 
3.4.3.1 Palliative Radiotherapy .................................................................. 
 
3.4.4 Treatment of BMS-986016, Nivolumab-related Infusion Reactions ........ 
 
3.5 Discontinuation of Subjects From Treatment ................................................... 
 
3.6 Post Treatment Study Follow-up ...................................................................... 
 
3.6.1 Withdrawal of Consent ............................................................................ 
 
3.6.2 Lost to Follow-up ..................................................................................... 
 
4 TREATMENTS ......................................................................................................... 
 
4.1 Study Treatments .............................................................................................. 
 
4.1.1 Investigational Product ............................................................................ 
 
4.1.2 Noninvestigational Product ..................................................................... 
 
4.1.3 Handling and Dispensing ........................................................................ 
 
4.2 Method of Assigning Subject Identification ..................................................... 
 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
 
4.3.1 Guidelines for Dose Modification ............................................................ 
 
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4.3.1.1 Intrasubject Dose Escalation .......................................................... 
 
4.3.1.2 Dose Reductions.............................................................................. 
 
4.3.2 Dose Delay Criteria ................................................................................. 
 
4.3.3 Criteria to Resume Treatment After Dose Delay ..................................... 
 
4.3.4 Treatment Beyond Disease Progression .................................................. 
 
4.3.5 Guidelines for Permanent Discontinuation ............................................. 
 
4.4 Blinding/Unblinding ......................................................................................... 
 
4.5 Treatment Compliance ...................................................................................... 
 
4.6 Destruction and Return of Study Drug ............................................................. 
 
4.6.1 Destruction of Study Drug ....................................................................... 
 
4.6.2 Return of Study Drug ............................................................................... 
 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
 
5.2 Study Materials ................................................................................................. 
 
5.3 Safety Assessments ........................................................................................... 
 
5.3.1 Laboratory Test Assessments ................................................................... 
 
5.4 Efficacy Assessments ........................................................................................ 
 
5.4.1 Imaging Assessment for the Study............................................................ 
 
5.4.2 Efficacy Assessment for the Study ............................................................ 
 
5.4.3 Primary Efficacy Assessment ................................................................... 
 
5.4.4 Secondary Efficacy Assessments .............................................................. 
 
5.4.5 Exploratory Efficacy Assessments ........................................................... 
 
5.5 Pharmacokinetic Assessments .......................................................................... 
 
5.5.1 Pharmacokinetics: Collection and Processing ........................................ 
 
5.5.2 Pharmacokinetic Sample Analyses .......................................................... 
 
5.6 Biomarker Assessments .................................................................................... 
 
5.7 Exploratory Biomarker Assessments ................................................................ 
 
5.7.1 Soluble Biomarkers (Serum Biomarkers) ................................................ 
 
5.7.2 Antitumor Antibodies (Serum Biomarkers) .............................................. 
 
 
 
 
 
 
 
5.7.9 Tumor Biopsy Analysis ............................................................................ 
 
5.7.10 Tumor-based Biomarker Measures........................................................ 
 
5.7.11 Additional Research Collection ............................................................. 
 
5.8 Outcomes Research Assessments ..................................................................... 
 
5.9 Other Assessments ............................................................................................ 
 
5.9.1 Immunogenicity Assessments ................................................................... 
 
5.10 Results of Central Assessments ...................................................................... 
 
6 ADVERSE EVENTS ................................................................................................. 
 
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6.1 Serious Adverse Events .................................................................................... 
 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
 
6.2 Nonserious Adverse Events .............................................................................. 
 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
 
6.3 Laboratory Test Result Abnormalities .............................................................. 
 
6.4 Pregnancy .......................................................................................................... 
 
6.5 Overdose ........................................................................................................... 
 
6.6 Potential Drug-induced Liver Injury ................................................................. 
 
6.7 Other Safety Considerations ............................................................................. 
 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
 
7.1 Data Monitoring Committee ............................................................................. 
 
7.2 Blinded Independent Central Review Committee ............................................ 
 
8 STATISTICAL CONSIDERATIONS....................................................................... 
 
8.1 Sample Size Determination ............................................................................... 
 
8.1.1 Dose Escalation (Parts A and B ) ............................................................ 
 
8.1.2 Cohort Expansion Monotherapy (Part A1).............................................. 
 
8.1.3 Cohort Expansion (Part C) ...................................................................... 
 
8.1.4 Melanoma Prior IO Extended Expansion (Part D) ................................. 
 
8.1.4.1 Melanoma Prior IO Extended Expansion (Part D1-Q2W) ............. 
 
8.1.4.2 Melanoma Prior IO Focused Eligibility Expansion (Part D1-Q4W)
............................................................................................................... 
 
8.1.4.3 Melanoma Prior IO Expanded Eligibility Expansion (Part D2) .... 
 
8.1.5 Exposure/Response Expansion Q4W Dosing (Part E) ............................ 
 
8.2 Populations for Analyses .................................................................................. 
 
8.3 Endpoints .......................................................................................................... 
 
8.3.1 Primary Endpoints ................................................................................... 
 
8.3.2 Secondary Endpoints ............................................................................... 
 
8.3.2.1 Pharmacokinetics ............................................................................ 
 
8.3.2.2 Efficacy ........................................................................................... 
 
8.3.2.3 Immunogenicity ............................................................................... 
 
8.3.2.4 Centrally Read ECGs (Parts A and B) ........................................... 
 
8.3.2.5 Safety ............................................................................................... 
 
8.3.3 Exploratory Endpoints ............................................................................. 
 
8.3.3.1 Biomarkers ...................................................................................... 
 
8.3.3.2 Pharmacokinetics ............................................................................ 
 
8.3.3.3 Efficacy ........................................................................................... 
 
8.4 Analyses ............................................................................................................ 
 
8.4.1 Demographics and Baseline Characteristics........................................... 
 
8.4.2 Efficacy Analyses ..................................................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.5 Biomarker Analyses ................................................................................. 
 
8.4.6 Exploratory Biomarker Analyses ............................................................. 
 
8.4.7 Outcomes Research Analyses .................................................................. 
 
8.4.8 Other Analyses ......................................................................................... 
 
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8.4.8.1 Immunogenicity Analyses ............................................................... 
 
8.5 Interim Analyses ............................................................................................... 
 
9 STUDY MANAGEMENT ........................................................................................ 
 
9.1 Compliance ....................................................................................................... 
 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
 
9.1.2 Monitoring ............................................................................................... 
 
9.1.3 Investigational Site Training.................................................................... 
 
9.2 Records ............................................................................................................. 
 
9.2.1 Records Retention .................................................................................... 
 
9.2.2 Study Drug Records ................................................................................. 
 
9.2.3 Case Report Forms .................................................................................. 
 
9.3 Clinical Study Report and Publications ............................................................ 
 
10 GLOSSARY OF TERMS ........................................................................................ 
 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
12 REFERENCES ........................................................................................................ 
 
APPENDIX 1 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 2 RECIST 1.1 ........................................................................................... 
 
APPENDIX 3 ECOG, KARNOFSKY, AND LANSKY PERFORMANCE STATUS
................................................................................................................................. 
 
APPENDIX 4 MANAGEMENT ALGORITHMS ....................................................... 
 
APPENDIX 5 MEDDRA ANAPHYLACTIC REACTIONS ...................................... 
 
APPENDIX 6 STATISTICAL METHODOLOGY ..................................................... 
 
APPENDIX 7 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
APPENDIX 8 COUNTRY SPECIFIC REQUIREMENTS/DIFFERENCES .............. 
 
 
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1
INTRODUCTION AND STUDY RATIONALE
Patients with metastatic or refractory solid tumors have very poor prognosis.1 Despite advances in 
multimodal therapy, increases in overall survival (OS) in this patient population have been limited. 
To address this unmet medical need, compounds that have novel mechanisms of action will be 
evaluated in clinical studies with the goal of achieving better response rates and improved OS.
The use of immunotherapy in the treatment of cancer is based on the premise that tumors evade 
the endogenous immune response by being recognized as self, and not non-self. Tumors develop 
immune resistance using different mechanisms; the goal of immunotherapy is to counteract these 
resistance mechanisms, allowing the endogenous immune system to reject tumors. The recent 
success of immune-modulating agents in patients with refractory solid tumors has provided 
proof-of-concept of the efficacy of immune system activation as a therapeutic modality. 
Specifically, patients with metastatic melanoma had an increase in OS when treated with the anti-
cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) antibody, ipilimumab.2 Moreover, the 
same patient population treated with the combination of ipilimumab and an anti–programmed cell 
death protein 1 (PD-1) antibody (nivolumab) achieved an unprecedented 53% response rate and 
prolonged responses.3 These data suggest that combination therapy with immune-modulating 
agents may achieve more robust and prolonged responses than single-agent therapy in select cancer 
types and deserves to be further explored.
1.1
Study Rationale
1.1.1
Rationale for Nivolumab Therapy
Programmed cell death 1 is a cell surface signaling receptor that plays a critical role in the 
regulation of T cell activation and tolerance.4 It is a type I transmembrane protein and, together 
with B and T lymphocyte attenuator (BTLA), CTLA-4, inducible T cell costimulator (ICOS), and 
CD28, makes up the CD28 family of T cell costimulatory receptors. PD-1 is primarily expressed 
on activated T cells, B cells, and myeloid cells.5 It is also expressed on natural killer (NK) cells.6
Binding of PD-1 by its ligands PD-L1 and PD-L2 results in phosphorylation of the tyrosine residue 
in the proximal intracellular immune receptor tyrosine inhibitory domain, followed by recruitment 
of the phosphatase SHP-2, eventually resulting in downregulation of T cell activation. One 
important role of PD-1 is to limit the activity of T cells in peripheral tissues at the time of an 
inflammatory response to infection, thus limiting the development of autoimmunity.7 Evidence of 
this negative regulatory role comes from the finding that PD-1deficient mice develop lupus-like 
autoimmune diseases, including arthritis and nephritis, along with cardiomyopathy.8,9 In the tumor 
setting, the consequence is the development of immune resistance within the tumor 
microenvironment.
PD-1 is highly expressed on tumor-infiltrating lymphocytes (TILs), and its ligands are upregulated 
on the cell surface of many different tumors.10 Multiple murine cancer models have demonstrated 
that binding of ligand to PD-1 results in immune evasion. In addition, blockade of this interaction 
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results in antitumor activity. These findings provided the rationale for testing PD-1 pathway 
blockade in clinical trials.
Nivolumab is a fully human monoclonal antibody (mAb) that binds to PD-1 with nanomolar 
affinity and a high degree of specificity, thus precluding binding of PD-1 to its ligands PD-L1 and 
PD-L2.11 Nivolumab does not bind other related family members, such as BTLA, CTLA-4, ICOS, 
or CD28. Results from clinical trials have demonstrated complete response (CR), partial response 
(PR), and mixed response in patients with advanced solid tumors treated with nivolumab 
monotherapy, including all tumor types chosen for expansion in this study: non-small cell lung 
cancer (NSCLC), melanoma, renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), 
squamous cell carcinoma of the head and neck (SCCHN), gastric cancer, and bladder cancer 
(Section 1.4.2.4).
1.1.2
LAG-3 and T Cell Exhaustion 
Lymphocyte activation gene 3 (LAG-3; CD223) is also a type I transmembrane protein that is 
expressed on the cell surface of activated CD4+ and CD8+ T cells and subsets of NK and dendritic 
cells.12,13 LAG-3 is closely related to CD4, which is a co-receptor for T helper cell activation. Both 
molecules have 4 extracellular Ig-like domains and require binding to their ligand, 
 
, for their functional activity. In contrast to CD4, 
LAG-3 is only expressed on the cell surface of activated T cells, and its cleavage from the cell 
surface terminates LAG-3 signaling. LAG-3 can also be found as a soluble protein, but it does not 
bind to 
, and its function is unknown.
It has been reported that LAG-3 plays an important role in promoting regulatory T cell (Treg) 
activity and in negatively regulating T cell activation and proliferation.14 Both natural and induced 
Treg express increased LAG-3, which is required for their maximal suppressive function.15,16
Furthermore, ectopic expression of LAG-3 on CD4+ effector T cells reduced their proliferative 
capacity and conferred on them regulatory potential against third-party T cells.16 Recent studies 
have also shown that high LAG-3 expression on exhausted lymphocytic choriomeningitis virus-
specific CD8+ T cells contributes to their unresponsive state and limits CD8+ T cell antitumor 
responses.17,18 In fact, LAG-3 maintained tolerance to self and tumor antigens via direct effects 
on CD8+ T cells in 2 murine models.18
Immune tolerance observed in the setting of tumor development and tumor recurrence, however, 
seems to be mediated by the coexpression of various T cell negative regulatory receptors, not 
solely from LAG-3. Data from chronic viral infection models,17,18,19 knockout mice,20,21,22 tumor 
recurrence models,23 and, to a more limited extent, human cancer patients23,24,25 support a model 
wherein T cells that are continuously exposed to antigen become progressively inactivated through 
a process termed “exhaustion.” Exhausted T cells are characterized by the expression of T cell 
negative regulatory receptors, predominantly CTLA-4, PD-1, and LAG-3, whose action is to limit 
the cell’s ability to proliferate, produce cytokines, and kill target cells and/or to increase Treg 
activity. However, the timing and sequence of expression of these molecules in the development 
and recurrence of tumors have not been fully characterized. 
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It is hypothesized that CTLA-4 acts as the dominant off-switch for tolerance, but it is the strong 
synergy between the PD-1 and LAG-3 inhibitory pathways that seems to mediate tolerance to both 
self and tumor antigens.20,21,23 Whereas CTLA-4 knockout mice die prematurely from multiorgan 
inflammation,26 PD-1 and LAG-3 single knockout mice present minimal immunopathologic 
sequelae.21 In contrast, dual knockout mice (LAG-3-/-PD-1-/-) abrogate self-tolerance with 
resultant autoimmune infiltrates in multiple organs and even lethality.20,21 These dual knockout 
mice also show markedly increased survival from and clearance of multiple transplantable 
tumors.20
Conversely, extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ T 
cells has been shown in distinct transplantable tumors and samples from melanoma, RCC, HNC, 
NSCLC, and ovarian cancer patients.23,27,28,29,30,31,32 Blockade of PD-1/PD-L1 interactions has 
been successfully used to restore antitumor immunity in preclinical and clinical studies. But the 
simultaneous blockade of PD-1 and LAG-3 pathways on T cells may exert an even more robust 
antitumoral immunity in naive as well as in recurrent tumors due to the possibility of reversing 
LAG-3–mediated T cell exhaustion. In 2 syngeneic mice models, for example, dual anti–LAG-
3/anti–PD-1 antibody therapy is able to cure most mice of established tumors that are largely 
resistant to single antibody treatment.20 Furthermore, recurrent tumors from a melanoma mouse 
model with increased Treg cell numbers and increased expression of checkpoint inhibitors PD-1, 
LAG-3, T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif 
domains, and T cell immunoglobulin domain and mucin domain 3 can be controlled by depletion 
of Tregs (via FoxP3-DTR) plus the administration of anti–PD-L1 antibody. But more importantly, 
tumor regression of these recurrent tumors can also be accomplished with the combination of 
anti-PD-L1 plus anti-LAG-3 antibodies (C9B7W mAb), which also increases T cell activity.23
Given the literature supporting synergistic activity of nivolumab and anti–LAG-3 antibody in viral 
models, it is hypothesized that this combination could have antitumor effects in virally related 
cancers, including human papilloma virus (HPV)-related tumors such as HPV+ head and neck 
cancer (HNC). Recent evidence has shown a role of immune inhibitory receptors 
(eg, PD-1/PD-L1) in the adaptive immune resistance seen in HNCs associated with HPV. In these 
cancers with high lymphocytic infiltration, there is PD-1 expression on the majority of CD8+ TILs 
and PD-L1 expression on both tumor cells and tumor-associated macrophages.19 In a recent 
analysis, 33% to 47% of head and neck tumors showed a T cell-inflamed phenotype (TCIP) similar 
to melanoma, based on a gene expression signature. Interestingly, 75% of HPV (+) tumors showed
a TCIP, compared with 23% of HPV (-) tumors.28 Furthermore, various checkpoint molecules 
were universally coexpressed in these TCIP tumors, including PD-1, CTLA-4, LAG-3, PD-L2, 
and indoleamine 2,3-dioxygenase, as shown in gene expression analysis. Altogether, these data 
support a role for the PD-1:PD-L1 pathway in T cell exhaustion leading to both persistence of 
HPV infection and malignant progression in HNC patients. It is then possible that LAG-3 may 
also play a role in virally induced T cell exhaustion in these patients. Gastric cancer is another 
exploratory tumor suitable for T cell-directed therapy based on preliminary objective responses 
observed in patients treated with anti-PD-L1 antibody therapy.33 In addition, LAG-3 expression 
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1% by immunohistochemistry (IHC) has been documented in ~35% of gastric cancer samples.29
A subtype of gastric cancer is also associated with Epstein-Barr virus (EBV) infection.34 This 
subtype is characterized by massive lymphocyte infiltration, better prognosis than EBV-negative
tumors, and worldwide distribution, particularly in Asia. So, similar to HNC, the expression of 
checkpoint inhibitors may be leading to the persistence of EBV infection and/or malignant 
progression of these tumors which could be halted by T cell-directed therapy.
Hepatocellular carcinoma is another virally associated tumor suitable for combination therapy with 
BMS-986016 and nivolumab. On one hand, it has been shown that LAG-3 is selectively 
upregulated on tumor-infiltrating CD8+ T cells and that HBV-specific CD8+ TILs have an 
impaired effector function in subjects with HCC.35 Furthermore, T cell–directed therapy with anti-
CTLA-4 antibody (tremelimumab; NCT01008358)36 or with nivolumab in HCC subjects has 
displayed an acceptable safety profile as well as antitumor and antiviral activity in clinical studies. 
In a Phase I trial,31 nivolumab produced durable responses across all dose levels and HCC cohorts 
(objective response rate [ORR] 19%), with a favorable 12-month OS rate of 62%, regardless of 
the underlying viral status.
Checkpoint molecules are also key immunomodulators in RCC, particularly PD-1 and LAG-3. By 
IHC, it has been documented that LAG-3 expression 1% is found in ~60% of RCC samples. 
 has demonstrated that PD-1 and LAG-3 were expressed by a significantly higher 
percentage of CD8+ TILs as compared with 
 
obtained from RCC patients or healthy individuals.36 Also, subjects with RCC primary tumors and 
lung metastases associated with extensive CD8+ T cell infiltrate were correlated with poor 
prognosis only if they had high expression of LAG-3 and PD-L2.37 Finally, nivolumab produced 
durable responses across all doses (ORR 29%), with a favorable 3-year OS rate of 52%.38
The efficacy and improved OS obtained with nivolumab in second-line treatment of squamous 
NSCLC has led to its recent approval in the US.39 Nivolumab has also demonstrated a significant 
OS benefit in nonsquamous tumors in the CheckMate 057 trial.32 So, considering that 
approximately 47% of the immune infiltrate in NSCLC is PD-L1 positive and that these tumors 
also express other immune checkpoints such as LAG-3, TIM3, B7-H3, B7-H4, and CTLA-4,40 it 
is possible that dual blockade could improve the outcomes already seen with nivolumab single 
agent in these subjects.
More recently, nivolumab has received accelerated approval for locally advanced and metastatic 
urothelial carcinoma in the setting of advanced disease progression during or following platinum-
containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing 
treatment. The accelerated approval was based on an ORR of 19.6% with a 10-month duration of 
response (DOR).41 Despite clinical activity of PD-1/PD-L1–targeted therapy in this disease, most 
patients do not benefit, and resistance mechanisms remain poorly characterized. LAG-3 expression 
and PD-L1 expression were both highly positively correlated with CD8A expression within 
inflamed urothelial carcinomas, providing a strong rationale for combination therapy.42
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Altogether, these data argue strongly that dual blockade of the PD-1 and LAG-3 pathways could 
be a promising combinatorial strategy for multiple malignancies. 
1.1.3
Rationale for Anti-LAG-3 Antibody (BMS-986016) Therapy
BMS-986016 (relatlimab; these terms are interchangeably used throughout the document) is a fully 
human antibody specific for human LAG-3 that was isolated from immunized transgenic mice 
expressing human immunoglobulin genes. It is expressed as an IgG4 isotype antibody that includes 
a stabilizing hinge mutation (S228P) for attenuated Fc receptor binding in order to reduce or 
eliminate the possibility of antibody- or complement-mediated target cell killing. BMS-986016 
binds to a defined epitope on LAG-3 with high affinity (Kd, 0.25 to 0.5 nM) and specificity and 
potently blocks the interaction of LAG-3 with its ligand, 
 (IC50, 0.7 nM). The 
antibody exhibits potent in vitro functional activity in reversing LAG-3mediated inhibition of an 
antigen-specific murine T cell hybridoma overexpressing human LAG-3 (IC50, 1 nM). In addition, 
BMS-986016 enhances activation of human T cells in superantigen stimulation assays when added 
alone or in combination with nivolumab (antiPD-1 antibody).
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1.1.5
Summary
Combined inhibition of T cell checkpoint molecules, such as CTLA-4, PD-1, and LAG-3, in 
preclinical models provides synergistic improvement in T cell activity, control of virus replication, 
and tumor inhibition in animal models. These observations led to the discovery of one of the key 
signature molecules associated with T cell exhaustion, the negative T cell regulator, LAG-3, and 
to the development of the antagonistic LAG-3 antibody, BMS-986016. 
An initial evaluation of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics 
will be conducted with an escalation arm of BMS-986016 monotherapy. It is proposed that this 
antibody should be considered for the treatment of multiple malignancies in combination with 
nivolumab (an antiPD-1 antibody) as a T cell-core therapy with the aim to: 1) increase the 
number, type, and DORs in tumors known to respond to T cell checkpoint inhibitors; 2) rescue an 
adaptive response where patients are refractory to T cell checkpoint inhibitors and have progressed 
clinically; and/or 3) enhance the antitumor immunity in malignancies associated with chronic viral 
infections (eg, HPV, EBV, HCV, HBV, etc). 
1.1.6
Rationale for Part D Expansion
As of the cutoff date of 15-Jun-2017, preliminary proof-of-concept efficacy has been revealed in 
the Part C combination treatment expansion cohort of advanced melanoma with prior treatment 
with anti-PD-1/PD-L1. All subjects were treated with BMS-986016 80 mg + nivolumab 240 mg 
every 2 weeks (Q2W). The overall ORR was 11.5% (7/61 response evaluable), with a disease 
control rate (DCR) of 49%. Biomarker analyses suggested that subjects whose TIL expressed more 
LAG-3 had a higher response rate, with a greater than 3-fold increase in ORR observed in subjects 
with evidence of LAG-3 expression in at least 1% of nucleated cells within the tumor margin, 
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compared with less than 1% LAG-3 expression (18.2% [6/33] and 5.0% [1/20], respectively). PD-
L1 expression did not appear to enrich for response. The treatment group had the following 
characteristics: 1) most subjects had M1C disease (68%), 2) the cohort was heavily pretreated 
(77% with 2 or more prior therapies and 57% with prior anti-CTLA-4 therapy), 3) all subjects had 
progressed while receiving anti-PD-1/PD-L1, and 4) progressive disease (PD) was the best 
response to prior anti-PD-1/PD-L1 in 46% of subjects. Overall, anti-LAG-3 (BMS-986016) in 
combination with nivolumab demonstrated encouraging initial efficacy with a safety profile 
similar to nivolumab monotherapy.43
Based on initial efficacy signal in advanced melanoma subjects who progressed on anti-
PD-1/PD-L1 therapy, additional subjects in this subset population for further clinical testing are 
justified. Assessment in this population will be extended in 2 subparts: Part D1 and D2. D1 will 
test the combination in a focused eligibility population, whereas D2 will allow assessment in a 
broader population under expanded eligibility criteria.
Given the improved response rate in subjects whose tumor-associated immune cells express more 
LAG-3, efficacy analysis in Part D1 will be the primary focus. Subjects whose tumors are 
LAG-3 negative will also be evaluated to determine the role of LAG-3 expression on the antitumor 
activity of BMS-986016. Part D2 will explore safety and efficacy in a broader patient population, 
including those with Eastern Cooperative Oncology Group performance status (ECOG PS) up to 
2 and among those with a more diverse set of prior therapies.
1.1.7
Rationale for Part E (Melanoma Expansion)
At the time of incorporation of Part E into this protocol, the majority of the melanoma patients 
evaluated within the BMS-986016 clinical development program have been treated with the 
BMS-986016 160 mg + nivolumab 480 mg every 4 weeks (Q4W) dosing regimen or BMS-986016 
80 mg + nivolumab 240 mg Q2W dosing regimen. Although preliminary evidence indicates that 
BMS-986016 160 mg + nivolumab 480 mg Q4W is a reasonable dose, it is possible that higher 
doses may produce additional clinical benefit for melanoma participants. Accordingly, in an effort 
to more fully elucidate the dose-response curve in melanoma participants, Part E of this protocol 
includes the evaluation of the BMS-986016 480 mg + nivolumab 480 mg Q4W dosing regimen. 
The BMS-986016 480 mg + nivolumab 480 mg Q4W dosing regimen has been evaluated in Part 
B (Dose Escalation with DLT Criteria) of this study. Seven (7) subjects were treated, and no DLTs 
were observed.29 Accordingly, the BMS-986016 480 mg + nivolumab 480 mg Q4W dosing 
regimen was determined by the Principal Investigators conducting Part B to have an acceptable 
safety profile that warranted dose escalation to the BMS-986016 960 mg + nivolumab 480 mg 
Q4W dosing regimen. Subsequently, the BMS-986016 960 mg + nivolumab 480 mg Q4W dosing 
regimen was evaluated. Three (3) subjects were treated, and there were no DLTs. Accordingly, the 
BMS-986016 960 mg + nivolumab 480 mg Q4W dosing regimen was determined by the Principal 
Investigators conducting Part B to have an acceptable safety profile that warranted dose escalation 
to the BMS-986016 1440 mg + nivolumab 480 mg Q4W dosing regimen.
Melanoma participants who experienced disease progression on anti-PD-1 therapy and melanoma 
participants with previously untreated metastatic or unresectable disease will be included in Part 
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E. More specifically, these 2 participant cohorts are defined, respectively, as an advanced 
melanoma participant who has progressed (radiologically confirmed) on prior anti-PD-1 therapy 
within 3 months of the last anti-PD-1 dose and an advanced melanoma participant who has not 
received prior systemic anticancer therapy for unresectable or metastatic melanoma. Please refer 
to Section 3.3 of this protocol for complete definitions of these participant cohorts and details on 
applicable inclusion/exclusion criteria.
In participants who experienced disease progression on prior anti-PD-1 therapy, only the BMS-
986016 480 mg + nivolumab 480 mg Q4W dosing regimen will be evaluated. In the cohort of 
participants who have not received prior systemic anticancer therapy for unresectable or metastatic 
melanoma, both the BMS-986016 160 mg + nivolumab 480 mg Q4W and the BMS-986016 480 
mg + nivolumab 480 mg Q4W dosing regimens will be evaluated. 
The rationale for limiting the cohort of participants who experienced disease progression on 
anti-PD-1 therapy cohort to only the BMS-986016 480 mg + nivolumab 480 mg Q4W dosing 
regimen is that there is substantial clinical experience in melanoma participants who experienced 
disease progression on anti-PD-1 therapy with the BMS-986016 160 mg + nivolumab 480 mg 
Q4W dosing regimen. That substantial clinical experience will be used as a historical control for 
the purpose of elucidating the dose-response curve in this cohort of melanoma subjects. For the 
cohort of participants who have not received prior systemic anticancer therapy for unresectable or 
metastatic melanoma, where the clinical experience is more limited, participants will be 
randomized to 1 of the 2 dosing regimens.
1.1.8
Parts C, D, and E (Melanoma Only) Rationale for Inclusion of 
Adolescents
Patients under 18 years of age have often been excluded from adult oncology trials because of 
safety or regulatory concerns; a practice that leads to delays in pediatric studies. Separate adult 
and pediatric cancer centers, distinct cooperative research groups, and oncologists specializing in 
different populations do not often conduct unified adult–pediatric clinical trials or 
drug-development programs.44
Although rare, the incidence of childhood and adolescent melanoma in the United States has been 
increasing in the past 35 years. This trend is most prominent in the adolescent age range, 
specifically those 15 to 19 years of age. Single-center and industry-sponsored trials often exclude 
advanced melanoma adolescent patients for historical or empiric reasons. A recent genomic 
analysis of pediatric melanoma demonstrates that conventional melanoma in children and 
adolescents shares many of the genomic features that have been described in adult melanoma, 
including BRAF mutations. The abstract of this genomic analysis advocated for the opportunity 
for pediatric patients to be enrolled in pharmaceutically sponsored trials that incorporate novel 
agents. Many pediatric subjects who are diagnosed with melanoma are referred to and treated by 
medical oncologists vs pediatric oncologists, due to divergent expertise in the field.45
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1.1.9
Rationale for Dose Selection
CA224020 currently consists of 6 parts. Part A and Part B consist of a 3 + 3 + 3 dose escalation 
design and, implemented in site-specific amendment #15 (dated 13 August 2018) and superseding 
the 3 + 3+ 3 dose escalation design, the Bayesian Logistic Regression Model (BLRM)-Copula 
design, with BMS-986016 administered as a single agent (Part A) or in combination with 
nivolumab as sequential infusion (Part B) in subjects with advanced solid tumors. Part A1 consists 
of expansion cohorts of approximately 6 to 12 subjects in each disease-restricted population, with 
BMS-986016 monotherapy. Part C consists of expansion cohorts of approximately 25 to 40 
subjects each in disease-restricted populations (and further expansion of up to approximately 90 
to 120 subjects in selected cohorts based upon safety and efficacy profiles), with BMS-986016 
administered in combination with nivolumab as sequential infusions. Part D consists of advanced 
melanoma subjects with progression on prior anti-PD-1 therapy enrolled into 2 subgroups based 
upon eligibility criteria. Part E consists of both melanoma participants who experienced disease 
progression on prior anti-PD-1 therapy and melanoma participants who have not received prior 
systemic anticancer therapy for unresectable or metastatic melanoma. The sequential infusion of 
BMS-986016 and nivolumab will be administered in Parts A, A1, B and C. In Part D, subjects will 
be administered BMS-986016 and nivolumab coadministration or BMS-986213 (fixed-dose 
combination [FDC] relatlimab/nivolumab at a 1:3 ratio in a single vial). In Part E, subjects will be 
administered BMS-986016 and nivolumab as a coadministration. See Section 4.1.1 for details.
1.1.9.1
Rationale for Flat Dosing
Therapeutic mAbs doses have been routinely calculated on a body size basis with a perception that 
this approach may reduce intersubject variability in drug exposure compared with a flat dose 
approach. However, recent analyses of marketed and experimental mAbs have demonstrated that 
body weight-based dosing did not always offer advantages over flat dosing in reducing exposure 
variability.46,47 Since the magnitude of the impact of body weight on the human PK of BMS-
986016 is not yet determined and it is unknown if body size-based dosing would increase or 
decrease intersubject variability, this study will utilize a flat dose escalation and expansion since 
it is the simpler of the 2 approaches and may result in fewer dosing errors. The impact of body 
weight on the PK of nivolumab is small, and the dose-response relationship is relatively shallow 
near the 3-mg/kg dose level, indicating that nivolumab can also be administered as a flat dose in 
combination with BMS-986016 in this study. 
Flat doses for this study have been normalized for an average 80-kg adult cancer patient. A dataset 
from the nivolumab program used for preliminary population PK contained 325 subjects with a 
median weight of 81 kg. This value aligns well with a study by Bai et al, which found a median
weight of 78 kg in 2519 adult patients with rheumatoid arthritis, breast cancer, colorectal cancer, 
NSCLC, ovarian cancer, and non-Hodgkin’s lymphoma.46
Additionally, BMS-986016 flat dose of 20 to 800 mg as monotherapy and up to 480 mg in 
combination with nivolumab (both given Q2W) has been studied across the 40 to 120 kg weight 
range in adults.
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1.1.9.2
Part A — BMS-986016 Dose
The first-in-human dose selected for this study is based on all available nonclinical data. 
To balance the potential for pharmacologic activity and reasonable safety in this cancer patient 
population, a dose of 20 mg (0.25 mg/kg) was selected as the starting dose in monotherapy 
(Arm A). This dose is less than 1/10 of the human equivalent dose (HED) of the no-observed-
adverse-effect level (NOAEL) in the 4-week toxicity study (636 mg; 8.0 mg/kg) and is below the 
HED after a linear adjustment of the NOAEL target exposure for the highest affinity difference 
estimate of 265-fold (24 mg; 0.30 mg/kg) between activated human and cynomolgus T cells. No 
additional safety factor was added to the affinity-adjusted calculation because a linear adjustment 
is expected to be a conservative approach. Based on the model from the mouse efficacy data, this 
dose has the potential to have antitumor activity in humans. The calculated safety multiple for the 
20-mg (0.25 mg/kg) dose is 315-fold based on the NOAEL of 100 mg/kg/week in the 4-week
repeat-dose monkey study without accounting for affinity differences. In addition, a staggered 
dosing (sentinel subject) approach will be used in the first dose cohort, as described in Section 
3.1.1.1. The top dose of 800 mg (10 mg/kg) is projected to have the potential for 71% to 179% 
TGI from the most sensitive model in mouse. 
1.1.9.3
Part B — BMS-986016 Dose (Applies to Only a Subset of Sites 1-6)
Administrative Note: Only a limited number of sites are conducting Part B of this protocol. Each 
investigational site that is participating in Part B will receive an administrative letter from BMS 
confirming their participation in Part B that can be submitted to their respective Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC).
The starting doses for Part B were selected based on all nonclinical data available from studies of 
the combination and BMS-986016 monotherapy and on emerging clinical safety and PK data from 
Part A monotherapy. In the 4-week repeated-dose Good Laboratory Practice (GLP) toxicology 
study, a dose of 100 mg/kg/week of BMS-986016 + 50 mg/kg/week nivolumab was considered 
the severely toxic dose in 10% of the animals (STD10; refer to Section 1.4.1.2). The same approach 
to identifying HEDs as described for monotherapy was used. Using a linear adjustment of the 
STD10 for a 265-fold affinity difference results in a dose of 20 mg (~0.3 mg/kg). 
Pharmacokinetic data from Part A monotherapy suggested that subjects treated at 20 mg 
BMS-986016 (flat dose) have significant lower exposure compare to exposure associated with
toxicity in the GLP toxicology study with 100 mg/kg/week of BMS-986016 + 50 mg/kg/week 
nivolumab in cynomolgus monkey. Furthermore, BMS-986016 monotherapy was well tolerated 
in subjects treated with up to 800 mg BMS-986016 (flat dose) in Part A. The only high-grade 
related toxicity was an asymptomatic, self-limited, G3 lipase elevation in 1 subject treated at 20 
mg flat dose. Therefore, the proposed starting dose for BMS-986016 in combination with 
nivolumab in Part B was 20 mg (~0.3 mg/kg) given Q2W. This dose cohort was initiated after the 
decision was made to escalate to the third dose cohort in Part A (monotherapy) in accordance with 
the dose escalation rules. Delaying initiation of the first dose cohort in Part B until after evaluation 
of the first 2 cohorts in Part A (ie, up to 80 mg flat dose) provided additional clinical safety data 
with single-agent BMS-986016 at doses 4-fold higher than the 20-mg dose prior to administration 
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of the combination. In addition, a staggered dosing (sentinel subject) approach will be used in the 
first dose cohort as described in Section 3.1.1.2. 
While the majority of assessments in this study have been and will be conducted using Q2W 
dosing, a Q4W dosing regimen will also be assessed in this study. Specifically, extending the 
dosing interval to Q4W provides numerous benefits to patients, including increased flexibility 
between clinical visits compared with Q2W. 
The initial Q4W dose escalation (3 + 3 + 3 design) is as follows: 160, 240, and 320 mg. Upon 
completion of safety evaluation from these initial dose escalations, additional higher doses, 
including 480, 960, 1440, and 1600 mg Q4W, will be evaluated to assess a maximum tolerated 
dose (MTD). Proposed higher doses of 480 to 1600 mg Q4W are predicted to provide a 
dose-proportional increase in exposure by following linear PK. The top dose of 1600 mg is 
predicted to provide steady state average concentrations similar (< 5%) to the maximum 
administered dose (MAD) of 800 mg Q2W in human and steady state maximum observed 
concentration (Cmaxss) well below the observed exposure at the NOAEL dose in the 3-month 
repeat-dose toxicity studies in cynomolgus monkeys. 
 
 
 (Section 1.4.1.4). The increment of 
subsequent dose levels after the initial 320-mg dose level can be modified based on the BLRM-
Copula recommendation.
1.1.9.4
Parts B, C — Nivolumab and Combination Dosing - Sequential Infusion
As mentioned previously, a dose of 100 mg/kg/week of BMS-986016 + 50 mg/kg/week nivolumab 
was considered the STD10 in the 4-week toxicity study. Known human nivolumab PK parameters 
were used to calculate the HED. The same approach to identifying HEDs as described for 
monotherapy was used. With an added 10-fold safety factor, the maximum recommended starting 
dose based on the STD10 is 320 mg (~4 mg/kg) in humans. The starting nivolumab dose for 
subjects in Part B is 80 mg (1 mg/kg) Q2W. All subsequent cohorts on Q2W schedule are planned 
to be administered 240 mg of nivolumab, which is equivalent to the well-tolerated global 
nivolumab monotherapy Phase 3 dose 3 mg/kg Q2W.11 Most recently, the nivolumab dosage 
regimen was modified to a flat 240 mg Q2W as monotherapy for melanoma, NSCLC, and RCC in 
the US.11 [USPI (Appendix 1)] In Part B with Q2W dose escalation cohorts, doses will be 
administered sequentially as nivolumab intravenous (IV) infusion over 60 minutes, followed by 
BMS-986016 infusion over 60 minutes.
In Part B, for the less frequent dosing regimen (Q4W), nivolumab dose of 480 mg will be 
administered in combination with BMS-986016. Based on PK modeling and simulations, while 
480 mg Q4W is predicted to provide greater (approximately 40%) maximum steady state 
concentrations and lower (approximately 20%) steady state trough concentrations, these exposures 
are predicted to be within the exposure ranges observed at doses up to 10 mg/kg Q2W used in the 
Phase 1 nivolumab clinical program and are not considered to put subjects at increased risk. Similar
to the nivolumab Q2W dosing monotherapy regimen, the exposures predicted following 
administration of nivolumab 480 mg Q4W are on the flat part of the exposure-response curves for 
previously investigated tumors (ie, melanoma and NSCLC) and are not predicted to affect efficacy. 
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Based on these data, nivolumab 480 mg Q4W is expected to have similar efficacy and safety 
profiles to nivolumab 240 mg or 3 mg/kg Q2W.48
The dosing and schedule for subjects in Part C will be agreed upon by Investigators and the 
Sponsor based upon dosing shown to be safe in Part B. In Part B and Part C, the sequential infusion 
of both drugs will start with nivolumab administration first, followed by infusion of BMS-986016. 
Based upon review of the available safety, PK, 
 
, Part C expansions commenced at combination dosing of 80 mg BMS-986016 and 240 mg 
nivolumab Q2W (see Section 1.4.1.4.2 of this protocol and the BMS-986016 Investigator 
Brochure [IB]).29 The planned treatment for the bladder immuno-oncology (IO)-naive cohort will 
be sequential dosing of 160 mg BMS-986016 with 480 mg nivolumab Q4W. However, if 160 mg 
BMS-986016 with 480 mg nivolumab Q4W is deemed not safe, then the 80 mg BMS-986016 with 
240 mg nivolumab Q2W regimen will be given.
1.1.9.5
Rationale for 30-minute Nivolumab Infusion
Administration of nivolumab using a 30-minute infusion time has been evaluated in subjects with 
cancer and was shown to be safe.49
1.1.9.6
Part D: Coadministration or Fixed-dose Combination 
In Part D, advanced melanoma subjects with progression on prior anti-PD-1 therapy will be 
enrolled in 2 subgroups based on eligibility criteria. If eligible for the focused D1 group, subjects 
will be randomized across 3 arms (see Section 3.1.2.5 for details):
Arm 1: BMS-986016 80 mg + nivolumab 240 mg given by coadministration Q2W
Arm 2: BMS-986016 160 mg + nivolumab 480 mg given by coadministration Q4W
Arm 3: BMS-986213 (relatlimab 160 mg/nivolumab 480 mg) given Q4W; BMS-986213 contains 
both relatlimab and nivolumab in the same solution at a ratio of 1:3
The expanded eligibility Part D2 cohort will all be treated using the more convenient Q4W dosing 
in 2 different dose combinations: 160 mg BMS-986016 + 480 mg of nivolumab and subsequently 
240 mg BMS-986016 + 480 mg of nivolumab (described in Section 3.1). The combination 
treatment in Part D2 will be coadministered. 
The less frequent dosing regimen given Q4W was selected based on model predicted PK, 
 and acceptable safety profile up to BMS-986016 160 mg + nivolumab 240 mg 
given Q2W in this study and ongoing study CA224022. BMS-986016 160 mg + nivolumab 
480 mg Q4W is predicted to provide similar steady state BMS-986016 exposure (ie, steady state 
average concentration [Cavgss]) 
 comparable to the levels achieved when 
BMS-986016 80 mg + nivolumab 240 is dosed Q2W. BMS-986016 240 mg + nivolumab 480 mg 
Q4W is predicted to maintain steady state exposure (ie, Cavgss) 
 below the 
levels achieved when BMS-986016 160 mg + nivolumab 240 mg is given Q2W, a dose shown to 
be tolerable in Part B. In addition, confirmation of the predicted safety of BMS-986016 240 mg + 
nivolumab 480 mg Q4W is ongoing, and employment of this dose will commence upon 
appropriate safety assessment in Part B. If BMS-986016 240 mg + nivolumab 480 mg Q4W is 
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considered toxic based on Section 3.1.2.3, then further expansion will resume at BMS-986016 160 
mg + nivolumab 240 mg Q2W.
For coadministration treatments, BMS-986016 and nivolumab will be mixed in same 
infusion bag and will be administered over approximately 60 minutes. The decrease in 
infusion time will allow for increased convenience for patients, doctors, nursing staff, other 
health-care staff members, and pharmacists. Key advantages of a coadministration of this 
combination are as follows:
Patients benefit from reduced infusion time and less time in the clinic and/or doctor’s office
Increased ease of administration
Pharmacists require less time in preparation of the IV solution to be administered to the patient
For the FDC drug product (BMS-986213) treatment, BMS-986213 will be administered over 
approximately 60 minutes. The advantages of the use of a single-vial drug product include easier 
and more rapid administration and infusion preparation, as well as decreased opportunity for 
dosing and administration errors.
Although coadministration and treatment with the FDC drug product (BMS-986213) would result 
in overlapping time of maximum observed concentration (Tmax) for BMS-986016 and nivolumab, 
the PK and exposure of both agent will be the same as when administered sequentially. Therefore, 
sequential administration vs coadministration (ie, single infusion bag) vs BMS-986213 (FDC) 
administration is not expected to impact the overall safety profile.
1.1.9.7
Part E: Coadministration of BMS-986016 and Nivolumab
Part E consists of advanced melanoma participants. Two cohorts of melanoma participants will be 
enrolled in Part E: melanoma participants who experienced disease progression on prior anti-PD-1 
therapy and melanoma participants who have not received prior systemic anticancer therapy for 
unresectable or metastatic melanoma. Melanoma participants who experienced disease 
progression on prior anti-PD-1 therapy will only receive 480 mg BMS-986016 + 480 mg 
nivolumab Q4W. Melanoma participants who have not received prior systemic anticancer therapy 
for unresectable or metastatic melanoma will be randomized to 1 of 2 treatment arms:

160 mg BMS-986016 + 480 mg nivolumab Q4W

480 mg BMS-986016 + 480 mg nivolumab Q4W
Administration of 480 mg BMS-986016 + 480 mg nivolumab Q4W to participants in Part E is 
warranted based on an acceptable safety profile of this dose being established in Part B (ie, Dose 
Escalation with DLT Criteria) of this study; see Section 1.1.7 for details. 
BMS-986016 and nivolumab will be mixed in same infusion bag and will be administered over 
approximately 60 minutes. The decrease in infusion time will allow for increased convenience for 
patients, doctors, nursing staff, other health-care staff members, and pharmacists. Key advantages 
of a coadministration of this combination are as follows:
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Patients benefit from reduced infusion time and less time in the clinic and/or doctor’s office
Increased ease of administration
Pharmacists require less time in preparation of the IV solution to be administered to the patient
1.1.9.8
Dose Rationale for Adolescents
The PK of drugs and many therapeutics proteins has been shown to be similar between adolescents 
and adults once the effect of body size on PK is taken into consideration.50,51 Therefore, in general, 
adult doses would expected to achieve similar systemic exposures in adolescents. In this study,
BMS-986016 in combination with nivolumab was administered as a flat dosing in adults; therefore, 
a minimum body weight threshold in adolescents (40 kg) is defined to receive the same adult 
flat dose to prevent exceeding target adult exposures. Adolescent subjects < 40 kg body weight 
will be given body weight–based dosing, equivalent to the conversion from a median adult weight 
of 80 kg. Therefore, the weight-based doses are 1 mg/kg BMS-986016 and 3 mg/kg nivolumab 
Q2W, 2 mg/kg BMS-986016 and 6 mg/kg nivolumab Q4W, and 6 mg/kg BMS-986016 and 
6 mg/kg nivolumab Q4W for corresponding fixed doses of 80/240 Q2W, 160/480 Q4W, and 
480/480 Q4W, respectively. This adolescent dosing scheme also applies to BMS-986213.
1.2
Research Hypotheses 
It is anticipated that antiLAG-3 antibody (BMS-986016, relatlimab), administered as a single 
agent or in combination with antiPD-1 antibody (nivolumab) will demonstrate adequate safety 
and tolerability, as well as a favorable benefit-risk profile, to support further clinical testing. No 
prospective hypotheses are being formally evaluated.
Part D1: Treatment with BMS-986016 in combination with nivolumab will lead to clinical benefit, 
as demonstrated by a clinically meaningful ORR, including durable responses with substantial 
magnitude of tumor burden reduction in melanoma subjects who progressed while on anti-PD-1 
antibody therapies.
Part D1: Treatment with BMS-986213 (FDC) will demonstrate no clinically relevant differences 
in safety relative to coadministration of nivolumab and BMS-986016.
Part E: Treatment with BMS-986016 in combination with nivolumab (coadministration) will lead 
to clinical benefit in melanoma subjects. This will be demonstrated by higher doses of relatlimab 
(eg, 480 mg BMS-986016 + 480 mg nivolumab Q4W) producing greater clinical benefit, as 
manifested by a clinically meaningful ORR, including durability of response and substantial 
magnitude of tumor burden reduction.
1.3
Objectives
1.3.1
Primary Objectives
Parts A and B:
The primary objective of Parts A and B is to determine the safety, tolerability, dose-limiting 
toxicities (DLTs), and MTD of BMS-986016 administered alone and in combination with 
nivolumab in subjects with advanced solid tumors.
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Part A1:
The primary objective of BMS-986016 monotherapy cohort expansion is to gather additional 
safety, tolerability, and preliminary efficacy information of BMS-986016 monotherapy.
Part C:
The primary objective is to further establish adequate safety and tolerability of BMS-986016 in 
combination with nivolumab administered sequentially.
The coprimary objective in Dose Expansion Part C is to investigate the preliminary efficacy of 
BMS-986016 in combination with nivolumab as measured by ORR, DCR, and DOR in multiple 
solid tumor types.
Part D:
The primary objective in Part D is to assess safety and tolerability of a more convenient dosing 
regimen (ie, coadministration and Q4W dosing interval).
Part D1-Q2W: The coprimary objective in Part D1-Q2W is to demonstrate preliminary clinical 
evidence of the treatment effect, measured by ORR, as determined by Blinded Independent Central 
Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, that 
may represent substantial improvement over available therapies in advanced melanoma subjects 
with LAG-3 expression who progressed while on anti-PD-1 antibody therapies.
Part D1-Q4W: The primary objective in Part D1-Q4W is to evaluate the difference in safety of 
coadministration relative to FDC as measured by the incidence of adverse events (AEs) in the 
Broad Scope Medical Dictionary for Regulatory Activities (MedDRA) Anaphylactic Reaction 
Standardized MedDRA Query (SMQ) occurring within 2 days after dosing in advanced melanoma 
subjects who progressed while on anti-PD-1 antibody therapies (see Appendix 5).
Part D1-Q4W: The coprimary objective in Part D1-Q4W is to confirm with Q4W dosing of BMS-
986016 160 mg in combination with nivolumab 480 mg the safety of the Q2W dosing of BMS-
986016 80 mg in combination with nivolumab 240 mg in advanced melanoma subjects who 
progressed while on anti-PD-1 antibody therapies.
Part E:
The primary objective of Part E is to demonstrate that the 480 mg BMS-986016 + 480 mg 
nivolumab Q4W dosing regimen provides significantly greater clinical benefit, manifested as an 
increased ORR, to participants as compared with the 160 mg BMS-986016 + 480 mg nivolumab 
Q4W dose by interdose cohort comparison in melanoma participants who have not received prior 
systemic anticancer therapy for unresectable or metastatic melanoma and to historical control for 
melanoma participants who experienced disease progression on prior anti-PD-1 therapy.
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1.3.2
Secondary Objectives
The secondary objectives are:
To characterize the PK of BMS-986016 administered alone and in combination with nivolumab.
To investigate the preliminary ORR and/or DCR of BMS-986016 administered alone and in 
combination with nivolumab in subjects with advanced solid tumors in Parts A and B, Dose 
Escalation. 
To characterize the immunogenicity of BMS-986016 administered alone and in combination with 
nivolumab.
In Parts A and B, to assess the effect of BMS-986016 administered alone and in combination with 
nivolumab on QTc.
Part D1:
To evaluate DOR, DCR, and progression-free survival (PFS) rates at prespecified time points (eg, 
24 weeks) based on BICR assessments using RECIST v1.1 in advanced melanoma subjects with 
LAG-3 expression who progressed while on anti-PD-1 antibody therapies. 
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
BICR assessments using RECIST v1.1 in advanced melanoma subjects with a lack of LAG-3 
expression and overall regardless of LAG-3 expression.
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
investigator assessments using RECIST v1.1 in advanced melanoma subjects with LAG-3 
expression, a lack of LAG-3 expression, and overall regardless of LAG-3 expression.
To assess the 1-year and 2-year landmark OS in advanced melanoma subjects with LAG-3 
expression, a lack of LAG-3 expression, and overall regardless of LAG-3 expression.
Part D1-Q4W: To confirm with Q4W dosing of BMS-986016 160 mg in combination with 
nivolumab 480 mg the efficacy of the Q2W dosing of BMS-986016 80 mg in combination with 
nivolumab 240 mg in advanced melanoma subjects with LAG-3 expression who progressed while 
on anti-PD-1 antibody therapies.
Part D1-Q4W: To evaluate the difference in safety of coadministration relative to FDC as 
measured by the incidence of AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ 
and the incidence of the select AEs in the Hypersensitivity/Infusion Reaction category occurring 
within 2 days after dosing during the combination in advanced melanoma subjects who progressed 
while on anti-PD-1 antibody therapies (see Appendix 5).
Part D1-Q4W: To evaluate Grade 3 - 5 AE incidence rate (drug related and all causality) defined 
using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.0 criteria.
Part D1-Q4W: To determine PK comparisons of nivolumab and BMS-986016 administered as 
FDC to that of coadministered nivolumab and BMS-986016.
Part D1: To assess PK of nivolumab and BMS-986016 in Part D1-Q4W dosing and Part D1-Q2W 
dosing.
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Part D2:
To assess safety and tolerability of more convenient dosing regimen in a wider range of population 
in advanced melanoma subjects who progressed while on anti-PD-1/PD-L1 antibody therapies.
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
BICR assessments using RECIST v1.1 in a wider range of population in advanced melanoma 
subjects with LAG-3 expression, a lack of LAG-3 expression, and overall regardless of LAG-3 
expression.
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
investigator assessments using RECIST v1.1 in a wider range of population in advanced melanoma 
subjects with LAG-3 expression, a lack of LAG-3 expression, and overall regardless of LAG-3 
expression.
To assess the 1-year and 2-year landmark OS in advanced melanoma subjects with LAG-3 
expression, a lack of LAG-3 expression, and overall regardless of LAG-3 expression.
Part E:
To evaluate the clinical benefit of the 480 mg BMS-986016 + 480 mg nivolumab Q4W dosing 
regimen using DOR in melanoma participants who have not received prior systemic anticancer 
therapy for unresectable or metastatic melanoma and for melanoma participants who experienced 
disease progression on prior anti-PD-1 therapy.
1.3.3
Exploratory Objectives
Exploratory objectives are:
To assess the pharmacodynamic effects of BMS-986016 alone and in combination with nivolumab 
based on select biomarkers in the peripheral blood and tumor biopsy specimens. 
 
To assess the 1-year and 2-year landmark OS in subjects treated with BMS-986016 alone and in 
combination with nivolumab.
To characterize nivolumab PK and immunogenicity when administered in combination with BMS-
986016. 
To explore exposure-response relationships in subjects treated with BMS-986016 as monotherapy 
or in combination with nivolumab.
To investigate the relationship between clinical efficacy and peripheral and tumor biomarkers.
To evaluate ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
iRECIST assessments based on BICR.
To predict milestone survival at 1 year and 2 years using tumor growth dynamic-survival model.
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1.4
Product Development Background
Information for nivolumab (BMS-936558, antiPD-1 antibody), BMS-986016 (relatlimab, 
antiLAG-3 antibody), and BMS-986213 (relatlimab/nivolumab) is provided in the sections 
below; additional details are provided in the respective IBs.11,29,53
1.4.1
BMS-986016 (AntiLAG-3 Antibody)
1.4.1.1
Nonclinical Pharmacology
The ability of BMS-986016 to bind recombinant human LAG-3 antigen was determined using 
Biacore and enzyme-linked immunosorbent assay (ELISA). Binding to human and primate 
LAG-3+ transfectants and to activated human or primate T cells was measured using flow 
cytometric and Scatchard analyses. BMS-986016 binds to human LAG-3 with high affinity 
(Kd, 0.12 to 0.5 nM) and inhibits the binding of LAG-3 to cells expressing its ligand, 
 
(IC50, 0.67 nM). BMS-986016 binds to cynomolgus LAG-3 on transfected Chinese hamster 
ovary cells and on activated cynomolgus T cells with a lower affinity (EC50, 21.5 to 34.3 nM) 
than to activated human T cells. A high concentration of BMS-986016, in the absence of secondary 
costimulation, elicits no measurable cytokine response from cultured human peripheral blood cells, 
nor does the drug mediate measurable antibody-dependent or complement-dependent killing of 
target cells. BMS-986016 promotes the activation of an antigen-specific mouse T cell hybridoma 
expressing human LAG-3 in co-culture with an 
-positive antigen-presenting cell. In 
addition, BMS-986016 enhances activation of human T cells in superantigen stimulation assays 
when added alone or in combination with nivolumab (antiPD-1 antibody). Detailed information 
can be found in the current version of the BMS-986016 IB.29
1.4.1.2
Toxicity
The nonclinical toxicology package for BMS-986016 consists of the following studies: 
1) Four-week Intermittent (QW) Intravenous Exploratory Combination Pharmacodynamic and 
Toxicity Study in Cynomolgus Monkeys with Anti-LAG-3.1 Antibody (a precursor of the 
anti-LAG-3.5 antibody) and Nivolumab
2) GLP-compliant Four-week Intravenous Combination Toxicity Study in Cynomolgus Monkeys 
with a 6-week Recovery with BMS-986016 and Nivolumab
3) GLP-compliant Three-month Intravenous Toxicity Study in Cynomolgus Monkeys with BMS-
986016
The key results were as follows:  

Single-agent BMS-986016 administered at up to 100 mg/kg/week did not result in adverse 
changes. 

Combined administration of BMS-986016 and nivolumab (100 and 50 mg/kg/week, 
respectively) resulted in moribundity of 1 male out of 9 monkeys on study Day 29. From 
Days 26 to 29, this monkey presented with elevated body temperature, shivers, red or clear 
nasal discharge, fecal changes (unformed, scant, or absent feces), decreased feeding 
behavior, mild dehydration, sneezing, decreased activity, and hunched posture. After 
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2 days of veterinary care and antibiotic treatment, this animal did not show any 
improvement and was euthanized on Day 29 for poor clinical condition. There were no 
remarkable gross necropsy findings. Histopathological findings in this monkey included 
slight lymphoplasmacytic inflammation of the choroid plexus; minimal to moderate 
lymphohistiocytic inflammation of the vasculature of the brain parenchyma, meninges, and 
spinal cord (cervical and lumbar); and minimal to moderate mixed cell inflammation of the 
epididymes, seminal vesicles, and testes. Clinical pathology changes indicated decreases
in red blood cell count, hemoglobin concentration, and hematocrit whose cause was unclear 
and an increase in fibrinogen correlating with the inflammation observed in the central 
nervous system (CNS) and male reproductive tract. 

Additional 
histopathological 
findings 
upon 
combination 
administration 
of 
BMS-986016 and nivolumab (100 and 50 mg/kg/week, respectively) were limited to 
minimal to slight nonreversible lymphoplasmacytic inflammation of the choroid plexus in 
the brain in 7 of 8 remaining monkeys and minimal lymphohistiocytic inflammation of the 
vasculature of the brain parenchyma in 1 of 8 remaining monkeys, whose reversibility 
could not be assessed.

NOAEL for single-agent BMS-986016 was considered to be 100 mg/kg/week (mean area 
under the concentration-time curve (AUC)[0-168h] = 474,000 gh/mL); NOAEL for 
single-agent nivolumab was considered to be 50 mg/kg/week (mean AUC[0-168h] = 
193,000 gh/mL); NOAEL for combination of BMS-986016 and nivolumab was not 
determined. 

However, the combination therapy was generally well tolerated, and clinical signs of 
toxicity were observed in only 1 of 9 monkeys (approximately 10%). Therefore, 
100/50 mg/kg/week 
BMS-986016/nivolumab 
(mean 
BMS-986016 
AUC[0-168h] 
= 514,000 μgh/mL; mean nivolumab AUC[0-168h] = 182,000 μgh/mL) was considered 
the STD10.

The doses administered (100 mg/kg BMS-986016 and 50 mg/kg nivolumab) are 10 times 
higher than the maximum doses proposed for the current study.

In GLP-compliant toxicity studies up to 3 months in duration, single-agent BMS-986016 
administered at up to 100 mg/kg/week did not result in adverse changes. In the 3-month
study, 1 male monkey at 30 mg/kg exhibited transient clinical observations that were
considered to be secondary to antidrug antibodies (ADAs) and, therefore, were not factored 
in determining the NOAEL. The NOAEL was considered to be 100 mg/kg/week (mean 
AUC[0-168h] = 1,180,000 μgh/mL)
4) GLP-compliant Tissue Cross-reactivity Study in Human and Select Cynomolgus Monkey 
Tissues with BMS-986016. 

Positive staining with BMS-986016-FITC was observed in the plasma membrane or 
plasma membrane granules of mononuclear leukocytes of most human tissues, including 
lymphoid tissues and hematopoietic cells of the bone marrow. In addition, staining with 
BMS-986016-FITC was observed in the cytoplasm of the human pituitary endocrine cell 
epithelium. Although BMS-986016 is not expected to have access to the cytoplasmic 
compartment in vivo and the repeat-dose toxicology studies in monkeys showed no effects 
on the pituitary gland, these findings may be of clinical significance and will be monitored. 
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
In Vitro Cytokine Release and Lymphocyte Activation Assessment with BMS-986016 
Using Human 

BMS-986016 did not induce cytokine release when presented to human 
 regardless 
of concentration, donor, or incubation time. The levels of cytokines observed were either 
at or near the assay lower limits of quantification, with no evidence of dose dependence or 
pattern across donors (interleukin [IL]-1, IL-2, IL-5, IL-10, IL-12p70, and interferon 
gamma [IFN-) or were generally overlapping with cytokine levels from 
 
incubated with negative controls (IL-6, IL-8, TNF-). 

Consistent with the lack of cytokine release, there was no evidence that
BMS-986016 induced T or NK cell activation, as measured by surface expression of CD25 
and CD69. Expression levels of these markers on T and NK cells following stimulation 
with BMS-986016 were similar to those observed upon stimulation with negative controls. 

Overall, these data indicate that BMS-986016 does not possess agonistic potential to induce 
either T or NK cellular activation or cytokine release.
Refer to the current BMS-986016 IB or additional information regarding nonclinical toxicity of 
BMS-986016.
1.4.1.3
Nonclinical Metabolism and Pharmacokinetics
In accordance with regulatory guidelines for biotechnology-derived pharmaceuticals,52 no 
metabolism studies with BMS-986016 have been conducted in animals. The expected in vivo 
degradation of mAbs is to small peptides and amino acids via biochemical pathways that are 
independent of cytochrome P450 enzymes.
BMS-986016 demonstrated favorable PK properties in cynomolgus monkeys. From both 
single-dose and repeat-dose IV PK studies, BMS-986016 decayed bi-exponentially, and the 
exposure was approximately dose proportional. The systemic clearance (CLTp) ranges from 
0.12 to 0.22 mL/h/kg and a terminal half-life (T-HALF) 133 to 414 hours. The volume of 
distribution at steady state was 62 to 72 mL/kg, suggesting limited distribution outside the plasma. 
AntiBMS-986016 antibodies were detected in some monkeys, but the presence of 
antiBMS-986016 antibodies appeared to have no impact on BMS-986016 exposure.
1.4.1.4
Clinical Pharmacology and Safety
1.4.1.4.1
Clinical Pharmacology
Relatlimab PK was well described by a 2-compartment model with time-varying linear and 
nonlinear clearance. The time-varying linear clearance was described by an empirical Emax 
model. The baseline covariate effects of body weight, sex, albumin, and lactate dehydrogenase 
(LDH) on baseline clearance and body weight on central volume of distribution were found to be 
statistically significant. The baseline covariate effects of race, age, ECOG PS, hepatic function, 
renal function, tumor type, and coadministration with nivolumab on relatlimab PK were not 
statistically significant. 
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Currently available data suggest that the immunogenicity rate of anti-relatlimab antibodies is 
approximately 7% and 21% when administered alone and in combination with nivolumab, 
respectively. A neutralizing antibody assay is currently being developed to further assess 
neutralizing potential of anti-relatlimab antibodies. The clinical significance of immunogenicity 
will be assessed using all available data on efficacy, safety, and time of immunogenicity 
occurrence.
1.4.1.4.2
Clinical Safety
Safety information is presented in detail in the BMS-986016 IB and focuses primarily on 
information obtained from Phase 1/2a studies (Studies CA224020 [advanced solid tumors] and 
CA224022 [advanced hematologic malignancies], as well a Phase 1 study conducted in Japan 
[Study CA224034]). As of the clinical data cutoff date of 18-Jun-2018, 942 subjects have been 
treated with relatlimab monotherapy or relatlimab in combination with nivolumab in these 
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3 ongoing studies. The large majority of the BMS-986016 safety data are derived from study 
CA224020, in which 837 total subjects have been treated, 25 with BMS-986016 monotherapy and 
812 in combination with nivolumab.
Overall, the safety profile of relatlimab in combination with nivolumab is manageable in the 
3 ongoing studies with combination therapy, with no MTD reached at the tested doses up to
960 mg relatlimab/480 mg nivolumab (Q4W). As of the clinical cutoff date of 18 June 2018, there 
was no dose relationship between the incidence, severity, or causality of AEs and combination 
therapy (see Section 5.5.1, Section 5.5.2, and Section 5.5.3 of the BMS-986016 IB). Most AEs 
were of low grade (Grade 1 to 2). A total of 91 out of the 876 subjects receiving combination 
therapy experienced a drug-related serious AE (SAE). Twenty Grade 1 and 31 Grade 2 infusion-
related reactions were reported during infusion of the study drug and were manageable using the 
updated protocol guidelines. 
In Studies CA224020, CA224022, and CA224034, a total of 273 deaths occurred in subjects 
treated with combination therapy (62 deaths within 30 days of last dose, 218 deaths within 
135 days of last dose, and 55 deaths occurring > 135 days after last dose of study drug). A total of 
19 subjects died for reasons other than disease progression. In Study CA224020, causes of death 
were reported as study drug toxicity in 3 subjects (Grade 5 dyspnea, Grade 4 myocarditis, and 
Grade 3 pneumonitis), unknown in 1 subject, and “other” in 13 subjects. In Study CA224022, 1 
subject died due to an unknown cause, and 1 subject died due to a cause listed as “other.” All other 
deaths were due to complications of disease progression and were considered by the Investigator 
to be not related to study drug.
1.4.1.4.3
Clinical Efficacy - Monotherapy (Part A) Versus Combination Therapy 
(Part B): CA224020 Study 
Response Evaluation Criteria In Solid Tumors v1.1 criteria were used in Study CA224020 to 
evaluate response to treatment. As of the cutoff date of 15-Jun-2017, 25 subjects were treated with 
BMS-986016 monotherapy. In Part A, no responses were observed in subjects with advanced solid 
tumors treated with BMS-986016 monotherapy. 
 
 
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As of the 16 June 2017 cutoff date, 262 subjects were treated with BMS-986016/nivolumab 
combination therapy in Part C. Preliminary proof-of-concept efficacy has been revealed in Part C 
of Study CA224020 in the combination treatment expansion cohort of advanced melanoma with 
prior treatment with anti-PD-1/PD-L1. The treatment group had the following characteristics: 1) 
most subjects had M1C disease (68%), 2) the cohort was heavily pretreated (77% with 2 or more 
prior therapies and 57% with prior anti-CTLA-4 therapy), 3) all subjects had progressed while 
receiving anti-PD-1/PD-L1, and 4) PD was the best response to prior anti-PD-1/PD-L1 in 46% of 
subjects. All subjects were treated with 80 mg BMS-986016/ 240 mg nivolumab Q2W. The 
overall ORR was 11.5% (7/61, response evaluable) with a DCR of 49%. Biomarker analyses 
suggested that subjects whose TIL expressed more LAG-3 had a higher response rate, with a 
greater than 3-fold increase in ORR observed in subjects with evidence of LAG-3 expression in at 
least 1% of nucleated cells within the tumor margin, compared with less than 1% LAG-3 
expression (18.2% [6/33] and 5.0% [1/20], respectively). PD-L1 expression did not appear to 
enrich for response.
These data were presented at the 2017 annual ESMO conference.43
1.4.2
Nivolumab (BMS-936558, AntiPD-1 Antibody)
1.4.2.1
Nonclinical Pharmacology, Metabolism, and Pharmacokinetics
Nivolumab is a fully human, IgG4 (kappa) isotype mAb that binds to PD-1. Additional details are 
provided in the current version of the nivolumab (BMS-936558) IB and OPDIVO(nivolumab) 
package insert.11,49
1.4.2.2
Clinical Safety 
Nivolumab has been studied in over 17,700 subjects and is widely approved in multiple 
indications. Extensive details on the safety profile of nivolumab are available in the IB11 and 
OPDIVO package insert49 and will not be repeated herein.
1.4.2.3
Clinical Pharmacokinetics 
Details are provided in the current version of the nivolumab (BMS-936558) IB and OPDIVO 
package insert.11,49
1.4.2.4
Clinical Activity 
Nivolumab has demonstrated clinical activity in subjects with a variety of malignancies, including 
melanoma, NSCLC, RCC, urothelial carcinoma, SCLC, gastric and esophageal cancer, HCC, 
colorectal cancer, glioblastoma, Merkel cell carcinoma, and combined malignant tumors as 
described in the nivolumab IB (detailed in Section 5.4),11 appendices (USPI [Appendix 1]) and 
Summary of Product Characteristics (SmPC [Appendix 2]), and OPDIVO package insert.49
1.4.3
BMS-986213 (Fixed-dose Combination Product)
BMS-986213 contains both relatlimab and nivolumab in protein-mass ratio 1:3 in a single vial. 
Additional details including the formulation are provided in the current version of BMS-936213 
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1.5
Overall Benefit-risk Assessment 
This section summarizes the potential risks of treatment with relatlimab alone and in combination 
with nivolumab and the specific tests, observations, and precautions that are required in clinical
studies.
As of the clinical cutoff date of 18-Jun-2018, across 3 safety studies (Studies CA224020, 
CA224022, and CA224034), relatlimab monotherapy has been administered to 66 subjects across 
doses: 20 mg (8 subjects), 80 mg (13 subjects), 240 mg (27 subjects), and 800 mg (18 subjects) 
relatlimab flat dose Q2W. The safety profile of relatlimab monotherapy appears manageable, with 
no MTD reached. The MAD was 800 mg Q2W. Following administration of up to 800 mg 
relatlimab flat dose in Study CA224022, AEs were mainly Grade 1 and Grade 2, with 4 drug-
related Grade 3 to 4 events (anemia, amylase increased, and lipase increased following 
administration of 240 mg relatlimab, and aseptic meningitis following administration of 800 mg 
relatlimab). All AEs were reversible or manageable (in the setting of immune-mediated endocrine 
events) by withholding drug administration and following treatment algorithms specified in the 
protocols where applicable. There were 5 Grade 1 to Grade 2 infusion-related reactions with 
relatlimab monotherapy (1 in Study CA224020, 4 in Study CA224022, and 0 in Study CA224034), 
which were manageable and reversible with recommended treatment guidelines in the protocol. 
There were 4 drug-related SAEs in monotherapy: Grade 3 pneumonitis, Grade 2 pneumonitis, and 
Grade 3 allergic reaction in monotherapy in Study CA224020 at a dose of 800 mg relatlimab Q2W; 
and Grade 3 aseptic meningitis in monotherapy in Study CA224022 at a dose of 800 mg relatlimab 
Q2W. There was no apparent relationship in the incidence, severity, or causality of AEs to 
relatlimab at these dose levels. A total of 27 subjects died due to malignant neoplasm progression 
following relatlimab monotherapy (19 in Study CA224020, 7 in Study CA224022, and 1 in Study 
CA224034).
As of the clinical cutoff date of 18-Jun-2018, treatment with relatlimab in combination with 
nivolumab has been administered to 876 subjects in Studies CA224020 (812 subjects), CA224022 
(45 subjects), and CA224034 (19 subjects). The safety profile of relatlimab combined with 
nivolumab is manageable, with currently no MTD reached, as combination dose evaluation 
remains ongoing.
Across Studies CA224020, CA224022, and CA224034 for both monotherapy and combination 
therapy, drug-related AEs were reported in 528 subjects. The most frequent drug-related AEs 
included fatigue, decreased appetite, pruritus, diarrhea, rash, rash maculopapular, anemia, 
asthenia, hypothyroidism, and hyperthyroidism. The types of drug-related AEs, as well as the rates 
of drug-related AEs, appeared comparable to historical nivolumab monotherapy rates. All drug-
related AEs, except for 1 Grade 4 myocarditis (240 mg relatlimab/240 mg nivolumab Q2W) as 
well as 1 Grade 4 potential drug-induced liver injury (DILI), 1 Grade 5 dyspnea, and 1 Grade 3 
pneumonitis (all at a dose level of 80 mg relatlimab/240 mg nivolumab Q2W), were reversible or 
manageable by withholding study drug administration, providing standard medical care, and/or 
following immune-related AE (irAE) algorithms.29
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There is risk associated with tumor biopsies, including bleeding, infection, and pain. While there 
is no direct benefit to subjects who undergo these procedures, there is significant potential that 
data generated from these samples will guide the further development of these compounds and 
may be of direct benefit for others with advanced solid tumors. In particular, emerging evidence 
from tissue analysis is showing an enrichment of response in subjects expressing higher LAG-3 
protein levels in tumor-associated immune cells.
The potential direct benefit to subjects who participate in the CA224020 study is that both single-
agent and combined therapy with these investigational agents may result in a greater proportion of 
subjects with stabilization of disease, objective response, or increased DOR than those observed 
with nivolumab monotherapy. It is also possible that combination therapy may reverse LAG-3-
mediated T cell exhaustion and achieve responses in 1) tumor types known to be unresponsive to 
nivolumab, 2) tumors refractory to anti-CTLA-4 and anti-PD-1 or anti-PD-L1 antibody therapy, 
and/or 3) virally associated tumors. In fact, multiple RECIST v1.1–defined clinical responses have 
been observed with BMS-986016 in combination with nivolumab, both in the immunotherapy 
naive as well as the anti-PD-1 resistant setting. More specifically, updated disclosure of the initial 
efficacy at ESMO 2017 showed an ORR of 11.5% in advanced melanoma subjects that have 
progressed on prior anti-PD-1/PD-L1, with an even more encouraging ORR of 18% in subjects 
with significant LAG-3 expression in tumor-associated immune cells. Thus, the potential for direct 
benefit in subjects with few if any alternative treatment options has been initially demonstrated, 
warranting continued evaluation of the combination across tumor types.
Lastly, the FDC drug product BMS-986213, with both relatlimab and nivolumab administered 
from the same vial, offers increased ease and speed of preparation with decreased opportunity for 
dosing errors. Given the theoretical risk of infusion reactions with the new formulation, an acute 
safety lead-in will be employed with continued monitoring for 1 hour after the completion of all 
infusions.
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The effect of coronavirus disease 2019 (COVID-19) vaccines in participants taking relatlimab in 
combination with nivolumab is unknown. BMS has given consideration regarding the benefit-risk 
of COVID-19 vaccination during participation in BMS-986016 (relatlimab) and BMS-936558 
(nivolumab) clinical trials. Based on the review of current available data and evidence to date, 
knowledge of the mechanisms of action of the COVID-19 vaccines and relatlimab in combination 
with nivolumab investigational medicinal product (IMP), a biological or pharmacological 
interaction occurring between the vaccine and the IMP that would negatively impact the benefit-
risk for participants in BMS relatlimab in combination with nivolumab clinical trials is not 
expected; however, data will continue to be reviewed. Therefore, at this time, a COVID-19 vaccine 
given to subjects in this trial is considered a concomitant medication with no interaction.
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CA224020
BMS-986016
relatlimab
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with: 

Consensus ethical principles from international guidelines, including the Declaration of
Helsinki and Council for International Organizations of Medical Sciences (CIOMS)
International Ethical Guidelines Good Clinical Practice (GCP);

as defined by the International Council for Harmonisation (ICH); and

in accordance with the ethical principles underlying European Union Regulation 536/2014,

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50), and

applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subjects’ informed consent forms (ICFs) will receive approval/favorable opinion by 
IRB/IEC and regulatory authorities according to applicable local regulations prior to initiation of 
the study.
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) immediately. A 
serious breach is a breach of the conditions and principles of GCP (occurring in any country) in 
connection with the study or the protocol, which is likely to affect, to a significant degree, the 
safety or physical or mental integrity of 1 or more subjects of the study or the scientific value of 
the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the Investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The Investigator 
or BMS should also provide the IRB/IEC with a copy of the IB or product labeling information to 
be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates, and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
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In situations where consent cannot be given to subjects, their legally acceptable representatives are 
clearly and fully informed about the purpose, potential risks, and other critical issues regarding 
clinical studies in which the subject volunteers to participate. 
BMS will provide the Investigator with an appropriate (ie, global or local) sample ICF, which will 
include all elements required by ICH, GCP, and applicable regulatory requirements. The sample 
ICF will adhere to the ethical principles that have their origin in the Declaration of Helsinki.
Investigators must:
Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
nontechnical and easily understood. 
Allow time necessary for subject or subject’s legally acceptable representative to inquire about the 
details of the study.
Obtain an ICF signed and personally dated by the subject or the subject’s legally acceptable 
representative and by the person who conducted the informed consent discussion. 
Obtain the IRB/IEC’s written approval/favorable opinion of the written ICF and any other 
information to be provided to the subjects prior to the beginning of the study and after any revisions 
are completed for new information.
If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian and the subject subsequently becomes capable of making and communicating his or her 
informed consent during the study, consent must additionally be obtained from the subject.
Revise the ICF whenever important new information becomes available that is relevant to the 
subject’s consent. The Investigator, or a person designated by the Investigator, should fully inform 
the subject or the subject’s legally acceptable representative or legal guardian of all pertinent 
aspects of the study and of any new information relevant to the subject’s willingness to continue 
participation in the study. This communication should be documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects’ signed ICF and, in 
the US, the subjects’ signed Health Insurance Portability and Accountability Act (HIPAA) 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the ICF approved for the study prior to 
clinical study participation. The explicit wish of a minor, who is capable of forming an opinion 
and assessing this information to refuse participation in, or to be withdrawn from, the clinical study 
at any time, should be considered by the Investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
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CA224020
BMS-986016
relatlimab
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 1/2a, open-label study of BMS-986016 (relatlimab) administered as a single agent 
and in combination with nivolumab to subjects with advanced solid tumors. Part A and Part B
consist of a 3 + 3 + 3 dose escalation design and, implemented in the site-specific amendment #15 
(dated 13 August 2018) and superseding the 3+3+3 dose escalation design, the BLRM-Copula 
design (for Part B only), evaluating BMS-986016 administered as a single agent (Part A) or in 
combination with nivolumab (Part B) as sequential infusions in subjects with advanced solid 
tumors. Treatment in Part B will be initiated upon the decision to escalate to the third dose cohort 
in Part A (in accordance with dose escalation rules); subsequently, escalation in the 2 parts will 
proceed in parallel. Testing of the Q2W and Q4W dosing schedules in Part B can proceed 
concurrently, with independent escalation decisions based upon review of the current total safety 
experience and following consultation and agreement between Investigators and the Sponsor.
Part A1 consists of cohort expansion with BMS-986016 monotherapy in 2 disease-restricted 
cohorts of approximately 6 to 12 subjects each. Treatment in Part A1 will be initiated at the MAD
determined in Part A (ie, 800 mg). The dose selected for Part A1 will not exceed the MAD in Part 
A, but dose selection may change according to assessment of other data, including toxicities and 
PK and pharmacodynamic data from Parts A and A1. Subjects in Part A1 who progress on 
monotherapy may cross over to combination therapy with nivolumab and BMS-986016 as long as 
they meet eligibility criteria and the benefit-risk ratio is considered favorable by the Investigator 
and the Medical Monitor. Subjects will receive combination therapy in sequential infusion at the 
doses that have been declared safe in dose escalation or dose expansion parts at the time of 
crossover. The original protocol rules will apply accordingly. Combination therapy may thus be 
administered for up to 12 additional 8-week cycles according to the protocol rules. Collection of 
archival tissue (baseline) and tumor biopsies (baseline and on-therapy) will be optional for subjects 
crossing over, and PK and biomarker monitoring will be limited (Sections 5.5 and 5.7). 
Part B treatment will be initiated after the decision is made to escalate to the third dose cohort in 
Part A (in accordance with dose escalation rules). See Section 3.1.1.2.
Part C consists of cohort expansion in disease-restricted cohorts using a multistage approach, 
treated with sequential infusion of nivolumab and BMS-986016. Cohorts deemed futile 
(Section 8.1.2) at Stage 1 will be discontinued. Cohorts deemed promising may be expanded 
further up to 90 to 120 subjects in total after careful evaluation of all available data, including the 
totality of efficacy, safety profile, and PK/pharmacodynamics. Otherwise, additional subjects may 
be treated to collect more data during Stage 2 in order to make decision for further expansion. The 
doses and schedule selected for Part C will not exceed the Part B MTD or MAD, and specific doses 
selected may incorporate assessment of other data including toxicities, PK, and pharmacodynamic 
data from Parts A and B. Subjects who crossed over to combination therapy in Part A1 and 
subsequently have an objective response will not be considered in the decision making for Part C. 
Subjects in Part C cannot cross over to Part A1 either. A study schematic for Parts A-C is provided 
in Figure 3.1-1.
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Part D consists of melanoma subjects who progressed on prior IO therapy. There is a Part D1 and 
a Part D2 within Part D. Most subjects in Part D will receive coadministration of BMS-986016 
and nivolumab. Part D1 employs a focused eligibility to build upon eligible subjects from the 
Part C melanoma prior IO cohort, with the primary goal of testing the efficacy of 80 mg BMS-
986016 + 240 mg nivolumab Q2W. Enrollment may continue until the following criteria are met: 
(a) 90 efficacy-evaluable LAG-3–positive subjects have been treated, (b) 60 efficacy-evaluable
LAG-3–positive and BRAF wild-type (WT) subjects have been treated, and (c) 60 efficacy-
evaluable LAG-3–positive and ipilimumab pretreated subjects have been treated. Part D1 will also
have 2 other cohorts: 1) 160 mg BMS-986016 with 480 mg of nivolumab Q4W coadministration
and 2) a cohort of BMS-986213 (relatlimab 160 mg/nivolumab 480 mg) Q4W. If subjects do not
meet the more focused eligibility of Part D1, they may be eligible for Part D2, which is more
flexible with respect to the allowed prior therapies and performance status. Part D2 will test safety
and efficacy in this broader patient population and will employ the more convenient Q4W dosing
in 2 different dose combinations (160 mg BMS-986016 + 480 mg nivolumab, and subsequently,
240 mg BMS-986016 + 480 mg of nivolumab). Adolescents (12 to < 18 years of age) weighing
less than 40 kg will receive weight-based dosing (see Section 1.1.9.8). The doses and schedule
selected for Part D will not exceed the Part B MTD or MAD, and dosing of the cohorts may be
altered in collaboration between the Investigators and Sponsor, based upon the overall ongoing
study data, including toxicities, PK, and pharmacodynamics. A schematic of Part D is provided in
Figure 3.1-2.
Figure 3.1-1:
CA224020 Study Schematic
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Sequential = sequential administration of nivolumab first followed by BMS-986016 infusion within 15 to 30 
minutes of completing nivolumab infusion. For doses of 960 mg relatlimab + 480 mg nivolumab Q4W and higher 
doses, BMS-986016 infusion should be administered no sooner than 30 minutes following completion of nivolumab 
infusion.
IO = immuno-oncology agents (such as, but not limited to, anti-CTLA-4, antiPD-1, antiPD-L1, antiPD-L2, anti-
KIR, anti-CD137, anti-LAG-3, and/or anti-OX40 antibodies).
* Subsequent to site-specific amendment #15 (dated 13 August 2018), the dose escalation design was changed to 
BLRM-Copula from the 3 + 3 + 3 design.
Figure 3.1-2:
Part D
Part E consists of advanced melanoma participants. Two cohorts of melanoma participants will be 
enrolled in Part E:  melanoma participants who experienced disease progression on prior anti-PD-1 
therapy and melanoma participants who have not received prior systemic anticancer therapy for 
unresectable or metastatic melanoma.  
Melanoma participants who experienced disease progression on prior anti-PD-1 therapy will all 
receive the 480 mg BMS-986016 + 480 mg nivolumab Q4W dose regimen.
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Melanoma participants who have not have not received prior systemic anticancer therapy for 
unresectable or metastatic melanoma will be randomized to 1 of the 2 following treatment arms:

160 mg BMS-986016 + 480 mg nivolumab Q4W

480 mg BMS-986016 + 480 mg nivolumab Q4W
A schematic for Part E is presented in Figure 3.1-3.
Figure 3.1-3:
Part E
Subjects will complete up to 4 periods of the study:  Screening (up to 28 days), Treatment, 
Clinical Follow-up (135 days), and Survival Follow-up (up to 5 years following the first dose of 
study drug). Two independent periods, Crossover and Rechallenge, may be conducted in selected 
cases upon disease progression. As of Protocol Amendment 14, rechallenge is not permitted.
In the Treatment Period, each treatment cycle comprises 4 doses of either BMS-986016 alone 
(Parts A and A1) or in combination with nivolumab (Part B and C except bladder cohort), 
administered on Days 1, 15, 29, and 43 of each treatment cycle. 
 
 
 
 In Parts B and C, 
when both study drugs are given as sequential infusion, nivolumab will be given first, followed by 
BMS-986016 within 15 to 30 minutes of completing the infusion of nivolumab. In Part B, for 
doses of 960 mg relatlimab + 480 mg nivolumab Q4W and higher doses, BMS-986016 infusion 
should be administered no sooner than 30 minutes following completion of nivolumab infusion. 
Part D, the melanoma prior IO extended expansion, will have 2 sections: Part D1 will have a 
focused eligibility criteria with a cohort of 80 mg of BMS-986016 with 240 mg nivolumab Q2W, 
a cohort of 160 mg BMS-986016 with 480 mg of nivolumab Q4W, and a cohort of BMS-986213 
(relatlimab 160 mg/nivolumab 480 mg) Q4W; and Part D2 will have an expanded eligibility 
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relatlimab
criteria with 2 cohorts in sequence, 160 mg BMS-986016 with 480 mg of nivolumab Q4W and 
240 mg BMS-986016 and 480 mg of nivolumab Q4W. In Part D, both study drugs are given as a 
coadministration or as FDC over approximately 60 minutes.
In Part E, melanoma subjects will be administered either 160 mg BMS-986016 with 480 mg 
nivolumab Q4W or 480 mg BMS-986016 with 480 mg of nivolumab Q4W; the specific dosing 
regimen will be dependent on 1) whether the subject previously received anti-PD-1 therapy in the 
advanced, unresectable, or metastatic setting and had PD on that earlier treatment regimen; and 2) 
randomization, as previously described. 
Adolescents (12 to < 18 years of age) weighing less than 40 kg will be dosed based on weight 
(1 mg/kg BMS-986016 and 3 mg/kg nivolumab Q2W, 2 mg/kg BMS-986016 and 6 mg/kg 
nivolumab Q4W, or 6 mg/kg BMS-986016 and 6 mg/kg nivolumab Q4W. In Parts C, D, and E, 
Q4W dosing, BMS-986016 and nivolumab will be administered on Days 1 and 29 of each 
treatment cycle; visits will occur every 2 weeks to assess safety for the first cycle of treatment, and 
thereafter visits will only be on Day 1 and Day 29 of each subsequent cycle. 
 
 
 
 
 Tumor 
response will be evaluated using RECIST v1.1. 
Subjects will be allowed to continue study therapy until the first occurrence of either 1) PD, 2) 
clinical deterioration, and/or 3) meeting other criteria for discontinuation. Refer to Section 3.5 for 
additional details. Treatment beyond progression should be considered in select participants with 
initial RECIST v1.1-defined PD who are receiving clinical benefit as assessed by the Investigator, 
tolerating treatment, and meeting other criteria specified in Section 4.3.4. Follow-up imaging 
should be obtained to confirm progression where appropriate (see Section 5.1). Subjects who 
discontinue treatment will enter a 135-day Clinical Follow-up period.
After completion of the Clinical Follow-up period, subjects enter the Survival Follow-up period. 
During this period, clinic visits or telephone contact every 12 weeks will be performed to assess 
survival status. Survival follow-up visits will be scheduled based on the last clinical follow-up 
visit. Diagnostic imaging must be performed every 8 weeks until disease progression. For 
subjects who discontinue treatment at the Investigator’s discretion with a CR, PR, or stable 
disease (SD) by RECIST v1.1, imaging must be performed every 12 weeks until disease 
progression. The duration of this period may continue for up to 5 years from the first dose.
For patients remaining on treatment beyond 5 years, subjects may continue on study treatment, as 
long as the benefit-risk ratio is considered favorable by the Investigator and continues to meet the 
criteria outlined in the protocol. Patients who discontinue treatment before 5 years will complete 
a 135-day clinical follow-up period, and a survival follow-up period for up to 5 years after the first 
dose. Patients who continue study treatment for longer than 5 years will complete a 135-day 
clinical follow-up period once the criteria for treatment discontinuation are met, but will not 
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participate in a survival follow-up period. The study will end when all patients have completed 
their respective follow-up periods. The original dose, schedule and protocol rules would apply.
If subjects progress during the Clinical Follow-up period or the Survival Follow-up period, they 
could further receive therapy with BMS-986016 alone or in combination therapy (Rechallenge 
period) as long as the benefit-risk ratio is considered favorable by the Investigator and the Medical 
Monitor and eligibility criteria is met (Section 3.1.2.4). The rechallenge-eligible Survival Follow-
up may continue for up to 5 years from the first dose of study drug. The original dose, schedule, 
and protocol rules would apply. Subjects will not be rechallenged a second time. Collection of 
archival tissue (baseline) and tumor biopsies (baseline and on-treatment) will be optional for 
subjects enrolled for rechallenge. Pharmacokinetic and biomarker monitoring will be limited 
(Sections 5.5 and 5.7). As of Protocol Amendment 14, rechallenge is not permitted. All subjects 
who discontinue primary study treatment following implementation of Protocol Amendment 14 
will not be eligible for rechallenge. Subjects currently receiving rechallenge treatment will be 
allowed to continue, and subjects currently in the rechallenge-eligible Survival Follow-up as of 
this Protocol Amendment remain eligible for rechallenge. 
Also, subjects receiving therapy with BMS-986016 alone in expansion Part A1 may cross over to 
combination therapy at confirmed progression (Section 3.1.2.1). 
A study schematic is provided in Figure 3.1-4.
Figure 3.1-4:
Detailed Study Schematic
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1 Treatment beyond progression may be considered in select subjects as described in Section 4.3.4.
2 Diagnostic imaging must be performed every 8 weeks until disease progression, and in subjects who discontinue 
study treatment at the Investigator’s discretion with a CR, PR, or SD via RECIST v1.1, imaging must be performed 
every 12 weeks until disease progression.
3 For treatment visits in Parts B and C where BMS-986016 (relatlimab) and nivolumab are administered sequentially, 
nivolumab will be administered first over 30 minutes, followed by BMS-986016 administration within 15 to 30 
minutes after completion of the nivolumab infusion. For doses of 960 mg relatlimab + 480 mg nivolumab Q4W, 
BMS-986016 infusion should be administered no sooner than 30 minutes following completion of nivolumab 
infusion.
4 Note the 6-week DLT period will be initiated after completion of the 480 mg BMS-986016 dose level.
Note: As of Protocol Amendment 14, rechallenge is not permitted.
Assessments, 
including 
physical 
examinations, 
vital 
sign 
measurements, 
12-lead 
electrocardiogram (ECG), and clinical laboratory evaluations, will be performed at selected times 
throughout the dosing interval. Subjects will be closely monitored for AEs throughout the study. 
Blood samples will be collected for up to 4 hours following the start of study drug administration 
for PK analysis. 
Subjects will be allowed to continue on therapy until PD, clinical deterioration, or meeting criteria 
for discontinuation. Patients who discontinue treatment before 5 years will complete a 135-day 
clinical follow-up period, and a survival follow-up period for up to 5 years after the first dose. 
Patients who continue study treatment for longer than 5 years will complete a 135-day clinical 
follow-up period once the criteria for treatment discontinuation are met, but will not participate in 
a survival follow-up period. The study will end when all patients have completed their respective 
follow-up periods. Additional OS analysis may be conducted periodically until end of study.
3.1.1
Dose Escalation
3.1.1.1
Part A - Monotherapy
In Part A, a 3 + 3 + 3 design will be used to assess the safety of BMS-986016 given as single agent. 
A fourth subject may be enrolled at the beginning of a dose escalation cohort following agreement 
between the Investigator and the Sponsor/Medical Monitor, if the subject is able to start the first 
day of dosing within approximately 1 week of the third subject in the same dose escalation cohort.
The dosages during dose escalation are provided in Figure 3.1-1 and Table 3.1.1.1-1.
Three subjects (or 4, if applicable) will initially be treated in each dose cohort; in Dose Cohort 1, 
each of the first 3 subjects (or 4, if applicable) will be designated as sentinel subjects and will begin 
treatment at least 5 days apart. Subjects in subsequent cohorts will not be required to observe the 
5-day interval between treatment start dates. 
Dose escalation in Part A will proceed as follows:  
If 0 of the first 3 (or 4, if applicable) subjects experiences a DLT within the DLT evaluation 
interval, a new cohort of 3 subjects (or 4, if applicable) will be treated at the next higher dose level. 
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If 1 of 3 (or 4, if applicable) subjects experiences a DLT within the DLT evaluation interval, that 
cohort will be expanded to 6 subjects (or 7, if applicable).
If 2 of 6 (or 7, if applicable) subjects experience a DLT within the DLT evaluation interval, that 
cohort will be expanded to 9 subjects. 
If 2 of 3 (or 4, if applicable), 3 of 6 (or 7, if applicable), or 3 of 9 subjects experience DLTs 
within a dose cohort during the DLT evaluation interval, then that dose level will be determined 
to have exceeded the MTD.
Table 3.1.1.1-1:
Dose Escalation and Dose Expansion Schedules for Part A
and Part A1 BMS-986016 Monotherapy
Part A Dose Escalation Cohort Number
Total Subjects
BMS-986016 Dose 
(IV; mg)
1
n = approximately 3-9
20
2
n = approximately 3-9
80
3
n = approximately 3-9
240
4
n = approximately 3-9
800
Total
N = approximately 12-36
Part A1 Dose Expansion Cohorts
NSCLC: prior anti-PD-1 or PD-L1
therapy alloweda
n = approximately 6-12
800 
RCC: prior anti-PD-1 or PD-L1 therapy 
alloweda
n = approximately 6-12
800
Total
N = approximately 12-24
a See Section 3.3 for detailed eligibility criteria.
Prior to declaring the MTD (or MAD), and in consultation with Investigators, the Sponsor has the 
option to expand any cohort previously established to be safe in order to obtain additional 
experience or to investigate dose levels intermediate to those defined in the protocol. Dose 
escalation rules (cohort size, DLT evaluation interval, cohort expansion criteria, etc.) will apply to 
these expanded or additional cohorts. A maximum of 9 subjects will be enrolled in any additional 
or expanded dose cohorts.
No within-subject dose escalations will be permitted. If a dose level is found to exceed the MTD, 
subjects enrolled in that dose level may be treated at a lower dose following consultation and 
agreement between Investigators and the Sponsor.
3.1.1.2
Part B - Sequential Infusion
Treatment in Part B will be initiated after the decision is made to escalate to the third dose cohort 
in Part A (in accordance with dose escalation rules). Subsequently, escalation in the 2 parts will 
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proceed in parallel. Treatment assignments for subjects eligible for both Part A and Part B will 
alternate between the 2 parts, with consecutively treated subjects assigned to different parts 
through interactive voice response system (IVRS) whenever possible. If there are no openings 
available in the part to which the subject would be assigned by this algorithm, then the subject will 
be assigned to the next open cohort or part.
As in Part A, a 3 + 3 + 3 design, or a BLRM-Copula design, as implemented in the site-specific 
amendment #15 (dated 13 August 2018) and superseding the 3 + 3 + 3 dose escalation design will 
also be used in Part B to assess the safety of BMS-986016 given in combination with nivolumab 
as a sequential infusion. A fourth subject may be enrolled at the beginning of a dose escalation 
cohort following agreement between the Investigator and the Sponsor/Medical Monitor, if the 
subject is able to start the first day of dosing within approximately 1 week of the third subject in 
the same dose escalation cohort. The potential dose levels evaluated during dose escalation are 
provided in Table 3.1.1.2-1. Intermediate and lower dose levels may be assessed following 
agreement between the Investigator and the Sponsor/Medical Monitor based upon ongoing review 
of safety data.
Table 3.1.1.2-1:
Dose Escalation Schedule for Part B — BMS-986016 in 
Combination with Nivolumab Q2W and Q4W
Dose Cohort 
Number
Total Subjects
BMS-986016 
Dose (IV; mg)
Nivolumab Dose 
(IV; mg)
Dose Escalation Schedule for Part B — BMS-986016 in Combination with Nivolumab 
Q2W Dosing
1
n = approximately 3-9
20
80
2
n = approximately 3-9
20
240
3
n = approximately 3-9
80
240
Intermediate 
n = approximately 3-9
160
240
4
n = approximately 3-9
240
240
Dose Escalation Schedule for Part B — BMS-986016 in Combination with Nivolumab 
Q4W Dosing
1
n = approximately 3-9
160
480
2
n = approximately 3-9
240
480
3
n = approximately 3-9
320
480
4
n = approximately 3-12
480
480
5
n =  approximately 3-15
960
480
6
n =  approximately 3-15
1440
480
7
n =  approximately 3-15
1600
480
Total
N = approximately 36-120
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Three subjects (or 4, if applicable) will be treated initially in each dose cohort; in Dose Cohort 1, 
each of the first 3 subjects (or 4, if applicable), designated as sentinel subjects, will begin treatment 
at least 5 days apart. Subjects in subsequent cohorts will not be required to observe the 5-day 
interval between treatment start dates. 
In Part B, if the MTD is exceeded in Dose Cohort 2, the potential subsequent cohort will be treated 
with 80 mg BMS-986016 and 80 mg nivolumab. If this dose combination is found to be safe, 
following consultation and agreement between Investigators and the Sponsor, escalation may 
proceed at the previously defined BMS-986016 doses, maintaining the nivolumab dose at 80 mg, 
or an intermediate dose level. Testing of the Q2W and Q4W dosing schedules can proceed 
concurrently with independent escalation decisions based upon review of the current total safety 
experience and following consultation and agreement between Investigators and the Sponsor.
Prior to declaring the MTD (or MAD), and in consultation with Investigators, the Sponsor has the 
option to expand any cohort previously established to be safe in order to obtain additional 
experience or to investigate dose levels intermediate to those defined in the protocol. Dose 
escalation rules (cohort size, DLT evaluation interval, cohort expansion criteria, etc.) will apply to 
these expanded or additional cohorts. A maximum of 9 (or 15, in case of BLRM-Copula) subjects 
will be enrolled in any additional or expanded dose cohorts.
No within-subject dose escalations will be permitted. If a dose level is found to exceed the MTD, 
subjects enrolled in that dose level may be reduced to a lower dose following consultation and 
agreement between Investigators and the Sponsor.
3.1.2
Cohort Expansion
3.1.2.1
Cohort Expansion (Part A1) - Monotherapy
The purpose of cohort expansion is to gather additional safety, tolerability, preliminary efficacy, 
PK, and pharmacodynamic information of BMS-986016 monotherapy. The doses selected for Part 
A1 will not exceed the MTD or MAD in Part A but may incorporate assessment of other data, 
including toxicities and PK and pharmacodynamic data from Part A. Doses to be considered may 
include doses intermediate to those evaluated in Part A, if recommended by the Investigators and 
the Sponsor. Two expansion cohorts will be restricted to the tumor types listed in Table 3.1.1.1-1. 
Subjects with PD in Part A1 may cross over to combination therapy with sequential infusion of 
nivolumab and BMS-986016 if the following criteria are met: 1) subject has confirmed disease 
progression (investigator-assessed RECIST v1.1–defined progression confirmed at least 4 weeks 
after the initial tumor assessment showing progression); 2) subject has not experienced BMS-
986016–related AEs leading to permanent discontinuation; 3) subject is not continuing to derive 
any clinical benefit from BMS-986016 single-agent therapy as assessed by the Investigator; 4) the 
individual case has been discussed with the Medical Monitor prior to crossover; 5) at least an 8-
week period between the last dose of monotherapy and the first dose of combination therapy. 
Subjects crossing over to combination therapy will start treatment at Cycle 1 Day 1 as described 
for subjects in Part C. Subjects who cross over will receive combination therapy in sequential 
infusion at the doses that have been declared safe in dose escalation and/or dose expansion parts 
at the time of crossover. The original protocol rules will apply accordingly. Combination therapy 
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may thus be administered for up to 12 additional 8-week cycles according to the protocol rules. 
Subjects who crossed over and subsequently have an objective response in combination therapy 
will not be considered in the decision making for Part C. Subjects in Part C cannot cross over to 
Part A1.
Collection of archival tissue (baseline) and tumor biopsies (baseline and on-therapy) will be 
optional in subjects crossing over, and PK and biomarker monitoring will be limited (Sections 5.5
and 5.7).
3.1.2.2
Cohort Expansion (Part C) - Sequential Infusion
The purpose of cohort expansion is to gather additional safety, tolerability, preliminary efficacy, 
PK, and pharmacodynamic information in subjects treated with sequential infusion of nivolumab 
followed by administration of BMS-986016. The initial doses selected for specific Part C cohorts 
will not exceed the MTD (or MAD if no MTD is determined) in Part B but may incorporate 
consideration of other data, including (but not necessarily limited to) toxicities, PK, and 
pharmacodynamic data from Parts A and B and can be chosen while additional Part B dose 
escalation cohorts continue to be explored. Part C expansion cohort doses to be considered will 
include those doses shown to be safe in Part B (or intermediate to those doses) as recommended 
by the Investigators and the Sponsor. Dosing of subsequent patients within an expansion cohort, 
or between cohorts, can be increased (if deemed safe in Part B) or decreased (based upon ongoing 
reviews of the totality of the safety data), all to be decided in agreement between the Investigators 
and the Sponsor. There will be no dose adjustments for individual subjects. Expansion cohorts in 
Part C will be restricted to 7 tumor types in 8 cohorts (Section 3.1). Efficacy analyses in all cohorts 
will be guided by a multistage evaluation approach. Cohorts deemed futile at Stage 1 will be 
discontinued, whereas those deemed promising may be expanded up to 90 to 120 subjects in total 
after careful evaluation of all available data, including the totality of efficacy, safety profile, and 
PK/pharmacodynamics (Section 8.1.2). Otherwise, additional subjects may be treated to collect 
more data during Stage 2 in order to make a decision for further expansion. Enrollment to Stage 2 
or further expansion in a given cohort can continue even if the other cohorts are still in Stage 1. 
Subjects who crossed over to combination therapy in Part A1 and subsequently have an objective 
response will not be considered in the decision making for Part C. Subjects in Part C cannot 
crossover to Part A1 either. 
3.1.2.3
All Cohort Expansion Parts (A1, C, D, and E)
Continuous evaluation of toxicity events in the cohort expansions will be performed throughout 
enrollment in the expansion cohorts. Not applicable as per Protocol Amendment 14: Safety 
conference calls with the BMS Medical Monitor, Investigators, and representatives of the Sponsor 
are being held regularly during conduct of the study. In addition, separate BMS Medical Safety 
Teams routinely review safety signals across the BMS-986016 and nivolumab programs. If, at any 
time, the aggregate rate of treatment-related toxicities meeting DLT criteria exceeds 33% across 
all subjects treated in any of these cohort expansions, the findings will be discussed and further 
enrollment must be interrupted in that particular cohort and other relevant cohorts. Depending on 
the nature and grade of the toxicity and after assessing the benefit-risk ratio, a new dose(s) for all 
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cohorts may be initiated at a previously tested lower dose level or at a dose level intermediate to 
previously tested lower dose levels.
3.1.2.4
Rechallenge in Dose Escalation (Parts A and B) and Cohort Expansion 
Parts (A1, C, D, and E)
If, after discontinuing study treatment at the Investigator’s discretion, subjects progress during the 
Clinical Follow-up period or the Survival Follow-up period, subjects could further receive therapy 
with BMS-986016 alone or in combination therapy (Rechallenge) as long as the benefit-risk ratio 
is considered favorable by the Investigator and the Medical Monitor and the following eligibility 
criteria are met: 1) subject has confirmed disease progression (Investigator-assessed RECIST 
v1.1–defined progression confirmed at least 4 weeks after the initial tumor assessment showing 
progression); 2) subject has not experienced BMS-986016–related AEs leading to permanent 
discontinuation. The rechallenge-eligible Survival Follow-up may continue for up to 5 years from 
the first dose of study drug. The original dose and schedule of therapy and protocol rules will 
apply. For the rechallenge, collection of archival tissue (baseline) and tumor biopsies (baseline and 
on-therapy) will be optional and PK and biomarker monitoring will be limited (Sections 5.5 and 
5.7). As of Protocol Amendment 14, rechallenge is not permitted. All subjects who discontinue 
primary study treatment following implementation of Protocol Amendment 14 will not be eligible 
for rechallenge. Subjects currently receiving rechallenge treatment will be allowed to continue, 
and subjects currently in the rechallenge-eligible Survival Follow-up as of this protocol 
amendment remain eligible for rechallenge.
Subjects who are rechallenged and who subsequently have an objective response will not be 
included in the primary analysis of efficacy. Responses to rechallenge will be evaluated in a 
separate analysis. Subjects will not be rechallenged a second time.
3.1.2.5
Part D Melanoma Prior IO Extended Expansion (Coadministration or 
Treatment with Fixed-dose Combination [BMS-986213])
In Part D, advanced melanoma subjects with progression on prior anti-PD-1 therapy will be 
enrolled into 2 subparts, D1 and D2, based on eligibility criteria. If eligible for the focused (more 
restricted eligibility) D1 subpart, subjects will be randomized across 3 arms:
Arm 1: BMS-986016 80 mg + nivolumab 240 mg given by coadministration Q2W
Arm 2: BMS-986016 160 mg + nivolumab 480 mg given by coadministration Q4W
Arm 3: BMS-986213 (relatlimab 160 mg/nivolumab 480 mg) given Q4W; BMS-986213 contains 
both relatlimab and nivolumab in the same solution at a ratio of 1:3 (relatlimab:nivolumab)
Randomization will be unblinded. Enrollment and randomization to Arm 1 may continue until the 
following criteria are met: (a) 90 efficacy-evaluable LAG-3–positive subjects have been treated, 
(b) 60 efficacy-evaluable LAG-3–positive and BRAF WT subjects have been treated, and (c) 60
efficacy-evaluable LAG3–positive and ipilimumab-pretreated subjects have been treated.
Enrollment and randomization across Arms 2 and 3 may continue until the following criteria are 
met: (a) 90 efficacy-evaluable LAG-3–positive subjects have been treated, (b) 60 efficacy-
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evaluable LAG-3–positive and BRAF WT subjects have been treated, and (c) 60 efficacy-
evaluable LAG-3–positive and ipilimumab-pretreated subjects have been treated. 
Prior to Revised Protocol 09, Part D1 subjects are being enrolled only into Arm 1. Subsequent to 
activation of this revised protocol and until the enrollment to Arm 1 is completed, subjects in Part 
D1 will be randomized 1:1:1 across the 3 arms. Once enrollment to Arm 1 is completed, subjects 
will be randomized 1:1 to Arms 2 and 3. If enrollment to Arms 2 and 3 is completed prior to Arm 
1, then enrollment to Arm 1 will be completed as a single arm. Prior to the start of randomization, 
a safety lead-in will be conducted with BMS-986213.
If subjects do not meet the more focused eligibility of Part D1, they may be eligible for Part D2, 
which is more flexible with respect to the allowed prior therapies and performance status. Part D2 
will test safety and efficacy in this broader patient population and will employ the more convenient 
Q4W combination coadministration dosing. Initial dosing will be 160 mg BMS-986016 + 480 mg 
nivolumab. Once further safety is established at the BMS-986016 160 mg + nivolumab 480 mg 
dose (see Section 8.1.4), subsequently enrolled subjects may be treated with BMS-986016 240 mg 
+ nivolumab 480 mg. The doses and schedule selected for Part D will not exceed the Part B MTD
or MAD, and dosing of the cohorts may be altered in collaboration between the Investigators and
Sponsor, based upon the overall ongoing study data, including toxicities, PK, and
pharmacodynamics.
There will be no dose adjustments for individual subjects. Expansion cohorts in Part D will be 
restricted to advanced melanoma subjects (Section 3). Efficacy analyses are described in 
Section 8.4.2. 
Part D1 Safety Lead-in 
Given the theoretical risk of infusion reactions with the administration of the BMS-986213, a 
safety lead-in will be employed for the first (up to) 9 subjects enrolling into subpart D1 and prior 
to the start of randomization.
The lead-in will follow a 3 + 3 + 3 design to monitor any potential Grade 3 or 4 infusion reactions 
that may occur as a result of coadministration of both drugs. Three subjects will be treated in each 
cohort. There will be no time interval restrictions for patients to begin treatment within a cohort.  
If 0 to 1 of the first 3 subjects experiences a Grade 3 or 4 infusion reaction, then the cohort will be 
expanded to 6 subjects. If 2 of 6 subjects experience a Grade 3 or 4 infusion reaction, the cohort 
will be expanded to 9 subjects. If 2 of 3, 3 of 6, or 3 of 9 subjects experience Grade 3 or 4 
infusion reactions, then the safety of BMS-986213 then further treatments with BMS-986213 will 
be held until further evaluation can be performed and randomization to the 2 coadministration arms 
may commence. If no more than 1 of 6 subjects, or 2 of 9, experience a Grade 3 or 4 reaction, 
randomization across all 3 arms will commence.  
The infusion reaction observation period will be 48 hours. 
Subjects will be instructed to contact the site regarding any potential infusion reaction symptoms.
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the BMS Medical 
Monitor and reported as an SAE if it meets the criteria. Infusion reactions should be graded 
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according to NCI CTCAE v4.0 guidelines. Prior to allowing dosing of each subsequent cohort, 
sites will be contacted to confirm that there has been no report of serious reactions.
For the management of infusion reactions, please refer to the treatment guidelines outlined in
Section 3.4.4.
The above enrollment plan will be executed by setting enrollment/treatment caps for each cohort 
in IVRS.
3.1.2.6
Part E Exposure Response Evaluation (Coadministration)
Two cohorts of melanoma subjects will be enrolled in Part E: melanoma participants who 
experienced disease progression on prior anti-PD-1 therapy and melanoma participants who have 
not received prior systemic anticancer therapy for unresectable or metastatic melanoma.
Melanoma participants who experienced disease progression on prior anti-PD-1 therapy in the 
advanced, unresectable, or metastatic setting will only receive 480 mg BMS-986016 + 480 mg 
nivolumab Q4W. Melanoma participants who have not received prior systemic anticancer therapy 
for locally advanced, unresectable, or metastatic melanoma will be randomized to 1 of the 
following 2 treatment arms:

160 mg BMS-986016 + 480 mg nivolumab Q4W

480 mg BMS-986016 + 480 mg nivolumab Q4W
3.1.3
Dose-limiting Toxicities
BMS-986016 has the potential to augment the frequency and severity of previously described AEs 
associated with nivolumab or to produce new toxicities. For the purpose of guiding decisions 
regarding dose escalation in Parts A and B DLT will be determined based on the incidence, 
intensity, and duration of AEs that are related to study drug and that occur within 42 days (6 weeks) 
of initiation of study drug. The severity of AEs will be graded according to NCI CTCAE v4.0.
For the purpose of subject management, potential DLTs that occur at any time, whether during 
dose escalation (Parts A and B or cohort expansion Parts A1, C, and D) will result in all study 
drug(s) being held pending evaluation of the event’s relatedness to study drug, severity, and 
duration, and in accordance with Section 4.3.2. Subjects must meet criteria for retreatment prior 
to reinitiation of study treatment (see Section 4.3.3). Any DLT that occurs after the initial 6-week 
DLT observation period, and after dosing in the next higher dose cohort has begun, will be 
accounted for and factored into the BLRM-Copula model in a post hoc manner. Additionally, as a 
practical matter, it should be noted that the BLRM-Copula model, based on the absence of DLTs 
at a preceding dose level, may dictate that an entire dose level cohort be skipped.
3.1.3.1
Rationale for 6-week DLT Period in Part B
The identification of acute DLTs that occur after administration of a study drug is critical for 
ensuring the safety of the patients enrolled in a clinical trial. The length of the DLT period is 
initially established based on the availability of preclinical data. Yet, when extensive clinical data 
become available, the benefit-risk evaluation used to define the appropriate DLT period must be 
reevaluated and should incorporate a critical analysis of all clinical and preclinical data.
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Accordingly, for Part B, the DLT period will be reduced from 8 weeks to 6 weeks, effective with 
Revised Protocol #10, in light of the availability of extensive clinical data from ongoing clinical 
studies. As of the clinical cutoff date of 18-Jun-2018, treatment with relatlimab in combination 
with nivolumab has been administered to 876 subjects in studies CA224020 (812 subjects), 
CA224022 (45 subjects), and CA224034 (19 subjects). The integrated safety determination is that 
the AE profile of the combination of relatlimab and nivolumab is similar to nivolumab 
monotherapy. Additionally, a review of the 7 DLTs that have been observed in Study CA224020 
to date demonstrates that the median time to onset was 4 weeks.
Effects of Prolonged DLT Period in a Population with Advanced Cancer
The target populations for Phase 1/2a oncology studies are characterized by patients with advanced 
stage disease. As a consequence, a relevant group of patients will progress rapidly after initiation 
of study drug. Across the ongoing studies CA224020 and CA224022, with BMS-986016 
administered as monotherapy or in combination with nivolumab, 24% (9/38) of the subjects 
enrolled in dose escalation cohorts experienced disease progression between Week 4 and 8 of the 
DLT period, whereas only 2/38 (5%) of the subjects progressed between Week 1 and 4. It is 
important to note that a subject that progresses during the DLT period is no longer evaluable for 
the purposes of safety evaluation of the dose cohort and a new replacement subject must be 
enrolled in the same dose cohort in order to complete the safety evaluation for that dose cohort. 
In summary, the review of the safety data from the ongoing studies strongly suggests that a 6-week 
DLT period will be an appropriate time frame to capture the acute, treatment-related AEs and to 
ensure the safety of the patients enrolled in Part B of this clinical trial. Furthermore, this DLT 
period revision will limit the number of patients who need to be replaced due to PD occurring 
between Weeks 6 and 8.
Hepatic, nonhematologic, and hematologic DLTs are defined separately as outlined below. 
Hepatic DLT
Any of the following drug-related events will be considered a hepatic DLT (non-HCC subjects):
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 8 upper limit of normal 
(ULN), regardless of duration, or
ALT or AST > 5 and 8 ULN that fails to return to Grade 1 within 2 weeks despite medical 
intervention, or 
Total bilirubin > 5 ULN, or 
Potential DILI event (Section 6.6)
For subjects with HCC, hepatic DLT criteria differ due to intrinsic involvement of the liver. In 
addition, for subjects with hepatitis B or hepatitis C, it is possible that virological breakthrough 
may occur, leading to temporary hepatic abnormalities. In these cases, subjects who regain 
virologic control may be allowed to resume study therapy after agreement between the Investigator 
and Sponsor.
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Any of the following events will be considered a hepatic DLT for subjects with HCC:
ALT or AST > 15 x ULN, regardless of duration
ALT or AST > 10 x ULN for greater than 2 weeks
Total bilirubin > 8 x ULN regardless of duration for subjects with elevated bilirubin at study entry 
or > 5 x ULN for subjects with normal bilirubin at study entry
Potential DILI event for HCC (Section 6.6)
Nonhematologic DLT
Any of the following drug-related events will be considered a nonhematologic DLT:
Any Grade 2 immune-related eye pain or reduction in visual acuity that requires systemic 
treatment, or
Any Grade 2 eye pain or reduction in visual acuity that does not respond to topical therapy and 
that does not improve to Grade 1 within 2 weeks of initiation of topical therapy, or
Any Grade 3 nonhepatic or nonhematologic toxicity with the exceptions noted below.
The following Grade 3 or 4 nonhematologic events will not be considered DLTs:
Grade 3 electrolyte abnormality (and Grade 4 hyperglycemia) that lasts < 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical intervention
Grade 3 or 4 increase in amylase and/or lipase that is not associated with symptoms or clinical 
manifestations of pancreatitis
Grade 3 nausea or vomiting that lasts < 48 hours and resolves to Grade 1 either spontaneously or 
with conventional medical intervention
Grade 3 diarrhea that lasts < 72 hours, does not result in hospitalization, and resolves to Grade 1 
either spontaneously or with conventional medical intervention
Grade 3 fever that lasts < 72 hours and is not associated with hemodynamic compromise (including 
hypotension or clinical or laboratory evidence of end organ perfusion impairment) 
Grade 3 endocrinopathy that is well controlled by hormone replacement therapy (HRT)
Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or suspected 
tumor)
Grade 3 fatigue for less than 7 days
Grade 3 rash meeting the following criteria: 1) improves to Grade 1 within 2 weeks, 2) does not 
limit self-care, and 3) is not associated with infection
Grade 3 troponin not associated with any other sign of cardiac toxicity (as determined by a cardiac 
evaluation)
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Definition of Hematologic DLT
Any of the following drug-related events will be considered a hematologic DLT:
Grade 4 febrile neutropenia of any duration 
Grade 4 neutropenia that lasts > 5 days 
Grade 4 thrombocytopenia 
Grade 4 anemia
Any Grade 3 thrombocytopenia associated with clinically significant bleeding
Any Grade 3 febrile neutropenia that lasts > 48 hours 
Any Grade 3 hemolysis
In the event that study drug cannot be administered at a scheduled visit during the DLT evaluation 
interval, it must be administered as soon as possible. Subjects may be dosed no less than 12 days 
in the Q2W regimen and 25 days in the Q4W regimen from the previous dose and no more than 3 
days from scheduled dose. If an infusion cannot be administered at a scheduled visit, it should be 
administered as soon as possible. Subsequent dosing visits will follow every 2 weeks or every 4 
weeks after the delayed dose. A dose given more than 3 days after the intended dose date will be 
considered a delay. A maximum delay of 6 weeks between doses is allowed. Longer delays may 
be allowed following discussion with the Medical Monitor. 
For Q4W dosing regimen, subjects may be dosed within a +/- 3 day window. For the purpose of 
making decisions on dose escalation from a safety perspective, subjects will be considered 
evaluable if they have received 3 out of the 4 scheduled BMS-986016 doses in Part A (or 3 out of 
4 scheduled BMS-986016 and nivolumab doses in Part B Q2W dosing). Subjects will be 
considered evaluable if they have received 2 out of 2 scheduled BMS-986016 and nivolumab doses 
in Part B Q4W dosing. Unevaluable subjects may be replaced at the same dose level.
3.2
Post Study Access to Therapy
At the conclusion of the study, participants who continue to demonstrate clinical benefit (including 
participants remaining on study treatment and participants in rechallenge-eligible follow-up who 
are within 5 years from first dose) may be eligible to receive BMS-supplied study treatment for 
the maximum treatment duration specified in Section 3.1. Study treatment would be provided via 
a rollover study requiring approval by the responsible Health Authority and Ethics Committee, or,
if appropriate, through another mechanism at the discretion of BMS.
3.3
Study Population
For entry into the study, the following criteria MUST be met prior to dosing on Day 1. No 
exceptions will be granted. Retesting of laboratory parameters and/or other assessments within any 
single Screening or Lead-in period will be permitted (in addition to any parameters that require a 
confirmatory value).
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3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The subject must sign and date the IRB/IEC-approved written ICF prior to the performance 
of any study-related procedures that are not considered part of standard of care.
b) Consent for tumor biopsy samples
i)
Parts A and B (Dose Escalation):  
(1) During the screening period, all participants must have tumor tissue submitted, 
 
 
. Subjects who do not meet these criteria 
are not eligible. However, subjects whose screening biopsy yields inadequate tissue 
quantity or quality will not be ineligible on this basis alone. The acquisition of 
existing formalin-fixed paraffin-embedded (FFPE) tumor tissue, either a block or 
unstained slides, for performance of correlative studies should also be collected if 
available. Subjects unable to provide pretreatment tumor tissue or who do not have 
accessible lesions are not eligible.
ii) Parts A1, C, D, and E (Cohort Expansions): 
(1) During the screening period, all participants must have tumor tissue submitted, 
 
 
. Subjects who do not meet these criteria 
are not eligible. However, subjects whose screening biopsy yields inadequate tissue 
quantity or quality will not be ineligible on this basis alone. The acquisition of 
existing FFPE tumor tissue, either a block or unstained slides, for performance of 
correlative studies should also be collected if available. Subjects unable to provide 
pretreatment tumor tissue or who do not have accessible lesions are not eligible. 
(2) Not applicable per Protocol Amendment 11.
iii) If there is only 1 measurable lesion and a core-needle biopsy is done (instead of 
excisional), the lesion may be used as measurable lesion. If there are more than 1 
measurable lesions, the lesion being biopsied should not be a target lesion.
iv) Not applicable per Revised Protocol 11. In lieu of a biopsy during screening, 
acceptable MANDATORY pretreatment biopsies include 
 
 or from an unresectable 
primary tumor lesion that has not been previously irradiated and if no intervening 
treatments have been administered between the time of biopsy/surgery and study entry.
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2) Target Population
a) Subjects must have histologic or cytologic confirmation of an incurable solid malignancy 
that is advanced (metastatic and/or unresectable):
i)
Part A: Dose Escalation BMS-986016 Monotherapy 
(1) All solid tumor histologies will be permitted except for subjects with primary CNS 
tumors. 
(2) Only subjects without prior exposure to IO agents such as, but not limited to, anti-
CTLA-4, antiPD-1, antiPD-L1, antiPD-L2, anti-KIR, anti-CD137, or anti-OX40 
antibodies, are allowed.
(3) Subjects must have received, and then progressed or been intolerant to, at least 1 
standard treatment regimen in the advanced or metastatic setting, if such a therapy 
exists.
ii) Part B: Dose Escalation BMS-986016 + nivolumab
(1) Not applicable as per Revised Protocol 10, see inclusion (7) and (8). Selected solid 
tumor histologies naive to IO agents such as, but not limited to, anti-CTLA-4, anti-
PD-1, anti-PD-L1, antiPD-L2, anti-KIR, anti-CD137, anti-LAG-3, or anti-OX40 
antibodies, will be permitted except for subjects with primary CNS tumors. Selected 
tumor types (and all subtypes) include melanoma first line; RCC; NSCLC first, 
second, or third line; HNC (any histology); gastric (includes gastroesophageal 
junction) cancer; and hepatocellular, cervical, ovarian, colorectal, and bladder 
cancers. 
(2) Not applicable per Protocol Amendment 02.
(3) NSCLC subjects progressing while on or after therapy with antiPD-1 or antiPD-
L1 antibody (for Part B this does not need to be the most recent therapy).
(a) Not applicable per Protocol Amendment 02.
(b) Cannot have had therapy discontinued due to serious and/or life-threatening 
antiPD-1 or antiPD-L1 antibody-related toxicity (eg, DLT in prior study) per 
Investigator’s assessment in consultation with the BMS Medical Monitor.
(c) Not applicable per Protocol Amendment 02.
(d) Not applicable as per Revised Protocol 10. Cannot have had prior exposure to 
other IOs, such as, but not limited to, antiPD-L2, anti-KIR, anti-CD137, anti-
LAG-3, or anti-OX40 antibodies. Prior anti-CTLA-4 antibody therapy is 
allowed.
(e) Subjects with targetable epidermal growth factor receptor (EGFR) or anaplastic 
lymphoma kinase (ALK) genetic aberrations must have previously received 
prior targeted therapy.
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(4) Melanoma subjects whose disease is progressing while on or after receiving 
anti-CTLA-4 and/or anti-PD-1/anti-PD-L1 antibody therapies 
(a) Anti-CTLA-4 and/or anti-PD-1 or anti-PD-L1 antibody therapies could have 
been received in sequential or combination regimens, as well as in combination 
with BRAF inhibitors, with or without MEK inhibitors.
(b) Last dose of antibody therapy must have been received 30 days of first dose 
of study medication.
(c) Cannot have had therapy discontinued due to serious and/or life-threatening 
antibody-related toxicity (eg, DLT in prior study) per Investigator’s assessment 
in consultation with the BMS Medical Monitor.
(d) Not applicable as per Revised Protocol 10. Cannot have had prior exposure to 
any IOs other than anti-CTLA-4 and/or anti-PD-1/anti-PD-L1 antibody 
therapy. Prior IL-2 and interferon (IFN) therapy is allowed.
(5) Subjects must have received, and then progressed or been intolerant to, at least 1 
standard treatment regimen or refused standard therapy in the advanced or metastatic 
setting, if such a therapy exists, except for NSCLC and melanoma, where treatment 
as first-line therapy is allowed.
(a) For first-line NSCLC subjects: The drug regimen with the highest likelihood of 
benefit with toxicity deemed acceptable to both the physician and the patient 
should be given as initial therapy for advanced lung cancer. Subjects should be 
offered chemotherapy if appropriate and available. Patients may refuse these 
standard treatments. The reason for why a subject does not receive standard 
first-line metastatic therapy must be documented. Subjects with targetable 
EGFR or ALK genetic aberrations must have previously received prior targeted 
therapy.
(b) For first-line melanoma subjects: The following prior adjuvant or neoadjuvant 
melanoma therapies are allowed if all related AEs have either returned to 
baseline or stabilized:
(i) Anti-PD-1 or anti-CTLA-4 therapy with at least 6 months between the last 
dose and date of disease recurrence.
(ii) Interferon therapy with the last dose at least 6 weeks prior to randomization.
(c) For first-line NSCLC subjects: Prior adjuvant or neoadjuvant chemotherapy, or 
definitive chemo/radiation, is permitted as long as the last administration of the 
prior regimen occurred at least 6 months prior to enrollment; while prior IO 
therapies are not allowed.
(6) Weight 40 kg.
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(7) Selected tumor types (and all subtypes) include melanoma; RCC; NSCLC; HNC
(any histology); gastric (includes gastroesophageal junction) cancer; and
hepatocellular, cervical, ovarian, colorectal, and bladder cancers.
(8) Cannot have had therapy discontinued due to serious and/or life-threatening
anti-PD-1 or anti-PD-L1 antibody-related toxicity.
iii) Part C: Cohort Expansion Sequential Dosing
(1) The following groups will be enrolled:
(a) Melanoma – first line:
(i) Untreated, histologically confirmed unresectable Stage III or Stage IV
melanoma, as per American Joint Committee on Cancer (AJCC) staging
system.
(ii) Both BRAF V600 wild-type and mutant melanomas are allowed and mutation
status must be documented.
(iii)Prior adjuvant or neoadjuvant melanoma therapy is permitted if it was
completed at least 6 weeks prior to enrollment and all related AEs have either
returned to baseline or stabilized. Note that adjuvant or neoadjuvant cytokine
(IL-2 or IFN) therapy is allowed but other IO therapies such as, but not limited
to, anti-CTLA-4, anti-PD-1, anti-PD-L1, antiPD-L2, anti-KIR, anti-CD137,
anti-LAG-3, or anti-OX40 antibodies are not allowed.
(iv)Uveal melanoma subjects are not eligible.
(b) RCC - naive to IOs
(i) Histology must have a clear-cell component.
(ii) Subjects must have received at least 1, but not more than 2, prior anti-
angiogenic therapy regimens (including, but not limited to, sunitinib,
sorafenib, pazopanib, axitinib, tivozanib, everolimus, temsirolimus, and
bevacizumab) in the advanced or metastatic setting.
(iii)No more than 3 total previous regimens of systemic therapy are allowed,
including cytokines (IL-2 or IFN), vaccine therapy, and cytotoxic
chemotherapy drugs, and disease progression during or after the last treatment
regimen and within 6 months before study enrollment.
(iv)Subjects cannot have had prior exposure to noncytokine IO therapies such as,
but not limited to, anti-CTLA-4, anti-PD-1, anti-PD-L1, antiPD-L2, anti-
KIR, anti-CD137, anti-LAG-3, or anti-OX40 antibodies.
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(c) NSCLC  - naive to IOs: first, second, or third line
(i) First line:
a.
Subjects with histologically confirmed Stage IIIB who have progressed
following definitive concurrent chemoradiation, Stage IV, or recurrent
NSCLC who are not amenable to potentially curative surgical resection
or concurrent chemoradiation,54 squamous or nonsquamous histology.
b. Prior adjuvant treatments (except IO therapies) are allowed as long as
there was a 6-month interval between last adjuvant treatment dose and
diagnosis of advanced disease. Prior definitive chemoradiation for
locally advanced disease is also permitted as long as the last
administration of chemotherapy or radiotherapy (whichever was given
last) occurred at least 6 months prior to enrollment.
c.
NOTE: The drug regimen with the highest likelihood of benefit with
toxicity deemed acceptable to both the physician and the patient should
be given as initial therapy for advanced lung cancer. Subjects should be
offered chemotherapy if appropriate and available. Patients may refuse
these standard chemotherapy treatments. The reason for why a subject
does not receive standard first-line metastatic therapy must be
documented.
d. Subjects with targetable EGFR or ALK genetic aberrations must have
previously received targeted therapy.
(ii) Second or third line:
a.
Subjects with histologically or cytologically documented locally
advanced NSCLC who present with Stage IIIB/Stage IV or recurrent or
PD following multimodality therapy (radiation therapy, surgical
resection, or definitive chemoradiation therapy for locally advanced
disease).
b. Subjects who will receive study therapy as second line of treatment:
Subjects must have experienced disease recurrence or progression
during or after 1 prior platinum doublet-based chemotherapy regimen
for advanced or metastatic disease.
First-line therapy is defined as therapy used to treat advanced disease.
Each subsequent line of therapy is preceded by disease progression. A
switch of an agent within a regimen in order to manage toxicity does not
define the start of a new line of therapy. Subjects must have received at
least 2 cycles of platinum doublet-based chemotherapy before
discontinuation for toxicity.
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Experimental therapies when given as separate regimen are considered 
as a separate line of therapy.
Maintenance therapy following platinum doublet-based chemotherapy 
is not considered as a separate regimen of therapy and could comprise 
continuation of 1 or more of the agents used in the first-line therapy 
regimen or switch to another non cross-resistant agent. The initiation of 
maintenance therapy requires the lack of PD with front-line therapy.
Treatment given for locally advanced disease is not considered as a line 
of therapy for advanced disease. Subjects with recurrent disease > 6 
months after platinum-containing adjuvant, neoadjuvant, or definitive 
chemoradiation therapy given for locally advanced disease who also 
subsequently progressed during or after a platinum doublet-based 
regimen given to treat the recurrence are eligible.
Subjects who received platinum-containing adjuvant, neoadjuvant, or 
definitive chemoradiation therapy given for locally advanced disease 
and developed recurrent (local or metastatic) disease within 6 months of 
completing therapy are eligible.
Adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery 
and/or radiation therapy) followed by recurrent or metastatic disease 
within 6 months of completing therapy is considered as first-line therapy 
for advanced disease.
Subjects with targetable EGFR or ALK genetic aberrations must have 
previously received targeted therapy.
c.
Subjects who will receive study therapy as third line of treatment must
have experienced disease recurrence or progression during or after a
separate EGFR or ALK tyrosine kinase inhibitor (TKI) regimen in
addition to 1 prior platinum doublet-based chemotherapy regimen
(regardless of order of administration).
Subjects who received an EGFR TKI (erlotinib, gefitinib, or
experimental) in addition to a platinum-based chemotherapy must have
a tumor with a known activating EGFR mutation.
Subjects with a tumor with EGFR wild-type or unknown EGFR
mutation status who received an EGFR TKI after failure of a prior
platinum-based chemotherapy are excluded.
Subjects who received an ALK inhibitor (crizotinib or experimental) in
addition to a platinum-based chemotherapy must have a tumor with a
known ALK translocation.
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(d) NSCLC subjects progressing while on or after therapy with antiPD-1 or
antiPD-L1 antibody as most recent therapy
(i) Squamous or nonsquamous histology.
(ii) This cohort includes 2 separate subgroups: 1) primary refractory disease:
defined as those subjects that progressed within the first 12 weeks of the prior
antiPD-1 or antiPD-L1 antibody therapy and 2) relapsed disease: defined
as those subjects that do not meet the criterion for primary refractory disease.
(iii)Subjects should not have discontinued antibody therapy due to serious and/or
life-threatening toxicity (eg, DLT in prior study) per Investigator’s
assessment in consultation with the BMS Medical Monitor.
(iv)These subjects cannot have had prior exposure to any other IOs such as, but
not limited to, antiPD-L2, anti-KIR, anti-CD137, anti-LAG-3, or anti-OX40
antibodies. Prior anti-CTLA-4 antibody therapy is allowed.
(v) Subjects with targetable EGFR or ALK genetic aberrations must have
previously received prior targeted therapy.
(vi)All available scans on the most recent prior anti-PD-1 containing regimen,
including the baseline scan (prior to starting anti-PD-1) and scans after the
last dose of anti-PD-1 but before the start of any intervening therapy may be
collected and submitted to a third-party imaging vendor.
(e) HNC – naive to IOs
(i) Histology restricted to SCCHN from any of the following primary sites only:
oral cavity, oropharynx, hypopharynx, and larynx.
(ii) Subjects are eligible regardless of HPV status.
(iii)Subjects must have metastatic or recurrent SCCHN that is not amenable to
therapy with curative intent (surgery or radiation therapy with or without
chemotherapy). Subjects who refuse potentially curative salvage surgery for
recurrent disease are ineligible. Subjects must have tumor progression or
recurrence after prior platinum-containing systemic therapy for recurrent or
metastatic disease. In addition, subjects who have progressed within 6 months
of platinum-based therapy used as part of concurrent chemoradiation
(definitive or adjuvant therapy) are also eligible. Thus, for subjects where
platinum-based therapy was used only in the adjuvant (ie, with radiation after
surgery) or primary (ie, with radiation) setting, only patients with recurrence
within 6 months of completing platinum will be eligible.
(iv)Subjects cannot have had prior exposure to IO therapies such as, but not
limited to, anti-CTLA-4, anti-PD-1, anti-PD-L1, antiPD-L2, anti-KIR, anti-
CD137, anti-LAG-3, or anti-OX40 antibodies.
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(f) Not applicable per Protocol Amendment 04.
(g) Melanoma - previously progressed on anti-PD-1/ anti-PD-L1 antibody therapy
(i) Prior anti-PD-1/anti-PD-L1 antibody alone or in any combination with 
anti-CTLA-4 antibody therapy, BRAF, and/or MEK inhibitors are allowed.
(ii) Subjects should not have discontinued antibody therapy due to serious and/or 
life-threatening toxicity (eg, DLT in prior study) per Investigator’s 
assessment in consultation with the BMS Medical Monitor.
(iii)Subjects cannot have had prior exposure to IOs therapies including, but not 
limited to, antiPD-L2, anti-KIR, anti-CD137, anti-LAG-3, or anti-OX40 
antibodies. IO therapies including, but not limited to, anti-CTLA-4, 
anti-PD-1, anti-PD-L1 antibody therapies, or IL-2 and IFN cytokine therapies 
are allowed.
(iv)Prior adjuvant or neoadjuvant therapy with cytokines (IL-2 or IFN) or 
anti-CTLA-4 antibodies is allowed.
(v) Uveal melanoma subjects are not eligible.
(vi)All available scans on the most recent prior anti-PD-1–containing regimen, 
including the baseline scan (prior to starting anti-PD-1) and scans after the 
last dose of anti-PD-1 but before the start of any intervening therapy may be 
collected and submitted to BICR.
(h) Gastric adenocarcinoma (includes gastroesophageal junction) – naive to IOs
(i) HER-2(+) and HER-2(-) subjects will be allowed.
(ii) Subjects cannot have had prior exposure to IO therapies such as, but not 
limited to, anti-CTLA-4, anti-PD-1, anti-PD-L1, antiPD-L2, anti-KIR, anti-
CD137, anti-LAG-3, or anti-OX40 antibodies.
(i) HCC – naive to IOs
(i) Child-Pugh score of 6 points or less (ie, Child-Pugh A).
(ii) Without history of encephalopathy, clinically significant ascites (within 1 
year of enrollment), or clinically significant variceal bleeding (within 6 
months of enrollment).
(iii) Subjects with or without viral infection (uninfected, HCV-infected, and 
HBV-infected) are eligible. 
(iv) Disease not amenable for management with curative intent by surgery or 
local therapeutic measures.
(v) Subjects with radiological diagnosis may be enrolled for screening in the 
study, but histological confirmation is mandatory prior to initiation of study 
therapy.
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(vi) Subjects with chronic HBV infection must have a HBV DNA viral load 
< 100 IU/mL at screening. In addition, they must be on antiviral therapy per 
regional standard of care guidelines prior to initiation of study therapy. If not 
on antiviral therapy at screening, then the subjects must initiate treatment per 
regional standard of care guidelines at the time of consent. All subjects 
enrolled in the HBV cohort must continue antiviral therapy for the duration 
of the study. Both HBeAg positive and negative subjects will be included. 
Subjects with hepatitis B infection must not have coinfection with hepatitis C 
or hepatitis D (must obtain hepatitis D antibody testing).
(vii) Subjects cannot have had prior exposure to IO therapies such as, but not 
limited to, anti-CTLA-4, anti-PD-1, anti-PD-L1, antiPD-L2, anti-KIR, anti-
CD137, anti-LAG-3, or anti-OX40 antibodies.
(viii) Fibrolamellar and sarcomatoid histologies are not eligible.
(j) Bladder carcinoma – naive to IOs
(i) Histological or cytological evidence of metastatic or surgically unresectable 
transitional cell carcinoma of the urothelium involving the bladder, urethra, 
ureter, or renal pelvis.
(ii) Subjects must have metastatic or surgically unresectable (cT4b, or any N+ 
[N1-3], or any M-1) disease.
(iii)Visceral disease is allowed.
(iv)Subjects must have progression or recurrence after treatment: i) with at least 
1 platinum-containing chemotherapy regimen for metastatic or surgically 
unresectable locally advanced urothelial cancer, or ii) within 12 months of 
peri-operative (neoadjuvant or adjuvant) treatment with a platinum agent in 
the setting of cystectomy for localized muscle-invasive urothelial cancer.
(v) Subjects cannot have had prior exposure to IO therapies such as, but not 
limited to, anti-CTLA-4, anti-PD-1, anti-PD-L1, antiPD-L2, anti-KIR, anti-
CD137, anti-LAG-3, or anti-OX40 antibodies.
(vi)No limit to the number of therapies.
(2) Prior lines of therapy (applies to all Part C subjects except those treated as first-line 
NSCLC and first-line melanoma): Subjects must have received, and then progressed 
or been intolerant to, at least 1 standard treatment regimen in the advanced or 
metastatic setting, if such a therapy exists or refused standard treatment (refusal must 
be documented). Number of maximum allowed prior systemic treatment regimens 
in the advanced or metastatic setting based on cohort: NSCLC progressing on prior 
IO = 3 lines, unless targetable EGFR or ALK genomic tumor aberrations, then 4 
lines are allowed; melanoma progressing on prior IO = 3 lines, unless targetable 
BRAF V600 mutation, then 4 lines are allowed; gastric = no limit; HNC = 2 prior 
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lines; HCC = no limit. For RCC and NSCLC IO-naive cohorts, see criteria in 
individual cohort eligibility sections above.
iv) Part A1: Cohort Expansion – Monotherapy 
(1) The following groups will be enrolled: 
(a) NSCLC: Subjects whose disease progressed while on or after therapy with an 
approved antiPD-1 or antiPD-L1-containing regimen. There is no limit on 
other prior therapies. Subjects should have not discontinued immunotherapy 
due to serious and/or life-threatening toxicity (eg, DLT in prior study) per 
Investigator’s assessment in consultation with the BMS Medical Monitor. 
Subjects must also have progressed on, been intolerant to, or refused at least 1 
chemotherapy-containing regimen in the advanced or metastatic setting. 
Subjects with targetable EGFR or ALK genetic aberrations must have 
previously received and progressed on, or have been intolerant to, prior targeted 
therapy.
(b) RCC: Subjects whose disease progressed while on or after therapy with an 
approved anti-PD-1 or anti-PD-L1-containing regimen. There is no limit on 
other prior therapies. Subjects should have not discontinued immunotherapy 
due to serious and/or life-threatening toxicity (eg, DLT in prior study) per 
Investigator’s assessment in consultation with the BMS Medical Monitor. 
Subjects must have progressed on, or been intolerant to, at least 1 prior anti-
angiogenic therapy regimen (including, but not limited to, sunitinib, sorafenib, 
pazopanib, axitinib, tivozanib, everolimus, temsirolimus, and bevacizumab).
(2) Subjects must have received, and then progressed or been intolerant to, at least 1 
standard treatment regimen or refuse standard therapy in the advanced or metastatic 
setting, if such a therapy exists.
v) Part D1: Melanoma Prior IO Extended Expansion - Focused Eligibility Cohort
(1) Must have measurable disease by computed tomography (CT) or magnetic 
resonance imaging (MRI) and documented progression while on a prior 
anti-PD-1-containing regimen (monotherapy or combination therapy) in the 
advanced unresectable or metastatic setting.
(a) Documentation should include start, stop, and progression dates of anti-PD-1 
therapy (limited to nivolumab or pembrolizumab) with unequivocal progression 
and a progression date no more than 3 months after the last dose of anti-PD-1 
therapy (limited to nivolumab or pembrolizumab).
(b) All available scans on the most recent anti-PD-1–containing regimen (limited 
to nivolumab or pembrolizumab), including the baseline scan (prior to starting 
anti-PD-1) and scans after the last dose of anti-PD-1 but before the start of any 
intervening therapy, will be collected and submitted to a third-party imaging 
vendor (see Section 5.4 and Table 5.1-1).
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(c) There are no restrictions on the prior anti-PD-1 (limited to nivolumab or
pembrolizumab) combination partners.
(d) Only 1 line of a prior anti-PD-1–containing regimen (limited to nivolumab or
pembrolizumab) is allowed. See 2) Target Population b) below for more detail
on the definition of “a line of a prior anti-PD-1–containing regimen (limited to
nivolumab or pembrolizumab).”
(e) Prior anti-LAG-3 or anti-PD-L1 therapy is not allowed.
(2) BRAF wild-type and mutant subjects are eligible.
(a) BRAF status must be known.
(b) BRAF mutant subjects must have been treated with, and progressed on, 1 prior
line of a BRAF inhibitor, administered with or without a MEK inhibitor, in the
advanced unresectable or metastatic setting.
(c) Only 1 line of a BRAF inhibitor, administered with or without a MEK inhibitor,
in the advanced unresectable or metastatic setting is allowed.
(3) Adjuvant/neoadjuvant therapy
Adjuvant (or neoadjuvant) anti-PD-1 or anti-PD-L1 therapy is not allowed. 
Other adjuvant (or neoadjuvant) melanoma therapies, including anti-CTLA-4, 
are allowed. 
(a) Not applicable per Revised Protocol 11. Anti-PD-1 or anti-CTLA-4 therapy
with at least 6 months between the last dose and date of disease recurrence.
(b) Not applicable per Revised Protocol 11. Interferon therapy with the last dose
at least 6 weeks prior to randomization.
(4) No limit to the number of prior therapies (except as noted above).
(5) Uveal melanoma subjects are NOT eligible.
(6) ECOG PS 0-1/Lansky Performance Score 80% for minors ONLY.
vi) Part D2: Melanoma Prior IO Extended Expansion – Expanded Eligibility Cohort
(1) Anti-PD-L1 therapy or combination-containing regimen can substitute for anti-PD-1
therapy (limited to nivolumab or pembrolizumab).
(2) Must have documented progression while on a prior anti-PD-1–containing regimen
(monotherapy or combination therapy).
(a) Documentation on prior anti-PD-1–containing therapy (limited to nivolumab or
pembrolizumab) should include start, stop, and progression dates of prior anti-
PD-1 therapy with unequivocal progression and a progression date no more than
3 months after the last dose of anti-PD-1 therapy.
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(b) All available scans on the most recent prior anti-PD-1–containing regimen 
(limited to nivolumab or pembrolizumab), including the baseline scan (prior to 
starting anti-PD-1) and scans after the last dose of anti-PD-1 but before the start 
of any intervening therapy, will be collected and submitted to a central imaging 
vendor (see Section 5.4 and Table 5.1-1).
(c) Patients with prior adjuvant or neoadjuvant anti-PD-1 therapy are allowed as 
long as 1 of the 2 conditions is met: 1) progression occurred during or within 6 
months of the last dose of adjuvant anti-PD-1 therapy, or 2) there has been 
subsequent progression on additional anti-PD-1 therapy in the metastatic 
setting.
(i) Not applicable per Revised Protocol 11. Anti-PD-1 or anti-CTLA-4 therapy 
with at least 6 months between the last dose and date of disease recurrence.
(ii) Not applicable per Revised Protocol 11. Interferon therapy with the last dose 
at least 6 weeks prior to randomization.
(d) Multiple prior lines of anti-PD-1–containing regimens are allowed.
(3) BRAF wild-type and mutant subjects are eligible.
(a) BRAF status must be known.
(b) Multiple prior lines of BRAF inhibitor administered with or without a MEK 
inhibitor are allowed.
(4) No limit to the number of prior therapies.
(5) Uveal melanoma subjects are NOT eligible.
(6) ECOG PS 0-2/Lansky Performance Score 60% for minors ONLY.
(7) Subject does not qualify for Part D1.
vii)Part E: Exposure Response Evaluation in Melanoma Participants
(1) Melanoma participants who experienced disease progression on prior 
anti-PD-1 therapy: Must have measurable disease by CT or MRI and documented 
progression while on a prior anti-PD-1–containing regimen (monotherapy or 
combination therapy) in the advanced unresectable or metastatic setting.
(a) Documentation should include start, stop, and progression dates of anti-PD-1 
therapy (limited to nivolumab or pembrolizumab) with unequivocal progression 
and a progression date no more than 3 months after the last dose of anti-PD-1 
therapy (limited to nivolumab or pembrolizumab).
(b) All available scans on the most recent anti-PD-1–containing regimen (limited 
to nivolumab or pembrolizumab), including the baseline scan (prior to starting 
anti-PD-1) and scans after the last dose of anti-PD-1 but before the start of any 
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intervening therapy, will be collected and submitted to a third-party imaging 
vendor (see Section 5.4 and Table 5.1-1).
(c) There are no restrictions on the prior anti-PD-1 (limited to nivolumab or
pembrolizumab) combination partners.
(d) Only 1 line of a prior, anti-PD-1–containing regimen (limited to nivolumab or
pembrolizumab) is allowed. See 2) Target Population b) below for more detail
on the definition of “a line of a prior anti-PD-1–containing regimen (limited to
nivolumab or pembrolizumab).”
(e) Prior anti-LAG-3 or anti-PD-L1 therapy is not allowed.
(f) BRAF wild-type and mutant subjects are eligible.
(i) BRAF status must be known.
(ii) BRAF mutant subjects must have been treated with, and progressed on, 1
prior line of a BRAF inhibitor, administered with or without a MEK inhibitor,
in the advanced unresectable or metastatic setting.
(iii)Only 1 line of a BRAF inhibitor, administered with or without a MEK
inhibitor, in the advanced unresectable or metastatic setting is allowed.
(g) Adjuvant/neoadjuvant therapy
(i) Not applicable per Revised Protocol 11. Anti-PD-1 or anti-CTLA-4 therapy
with at least 6 months between the last dose and date of disease recurrence.
(ii) Not applicable per Revised Protocol 11. Interferon therapy with the last dose
at least 6 weeks prior to randomization.
(iii)Adjuvant (or neoadjuvant) anti-PD-1 or anti-PD-L1 therapy is not allowed.
Other adjuvant (or neoadjuvant) melanoma therapies, including anti-CTLA-4,
are allowed.
(h) No limit to the number of prior therapies (except as noted above).
(i) Uveal melanoma subjects are NOT eligible.
(j) ECOG PS 0-1/Lansky Performance Score 80% for minors ONLY.
(2) Melanoma participants who have not received prior systemic anticancer
therapy for unresectable or metastatic melanoma:
(a) Participants must have an ECOG PS 1/Lansky Performance Score ≥80% for
minors (aged 12 to 17 years) ONLY (for details, see Appendix 3).
(b) Participants must have histologically confirmed Stage III (unresectable) or
Stage IV melanoma, per the AJCC staging system.
(c) Participants must not have had prior systemic anticancer therapy for
unresectable or metastatic melanoma.
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(d) The following prior adjuvant or neoadjuvant melanoma therapies are allowed 
if all related AEs have either returned to baseline or stabilized:
(i) Anti-PD-1 or anti-CTLA-4 therapy with at least 6 months between the last 
dose and date of recurrence.
(ii) Interferon therapy with the last dose at least 6 weeks prior to randomization
(iii)BRAF- or MEK-inhibitor–containing regimens with at least 6 months 
between the last dose and date of recurrence.
(e) Participants must have measurable disease by CT or MRI per RECIST v1.1 
criteria (for details, see Appendix 2).
(f) Participants must have known BRAF V600 mutation status or consent to BRAF 
V600 mutation testing per local institutional standards during the screening 
period.
(g) Prior radiotherapy must have completed at least 2 weeks prior to study 
treatment administration.
(h) Uveal melanoma subjects are NOT eligible.
b) In subjects with prior treatment regimens, the following are not considered separate 
lines of treatment: 1) addition of a compound to an ongoing regimen, 2) restarting the 
same regimen after a drug holiday, or 3) switching from IV to oral therapy. In 
addition, 4) a switch between nivolumab and pembrolizumab within a regimen in 
order to manage toxicity, or for reason of patient convenience, institutional practice 
standards, or insurance coverage does not define the start of a new line of therapy. A 
consult with the Medical Monitor on individual cases is highly recommended where 
there is uncertainty. Maintenance therapy is not considered as a separate regimen of 
therapy and could comprise continuation of 1 or more of the agents used in the 
effective treatment regimen or switch to another non cross-resistant agent. The 
initiation of maintenance therapy requires the lack of PD with the effective treatment 
regimen.
c) Presence of at least 1 lesion with measurable disease as defined by RECIST v1.1 criteria 
for response assessment. Subjects with lesions in a previously irradiated field as the sole 
site of measurable disease will be permitted to enroll provided that the lesion(s) have 
demonstrated clear progression prior to the time of informed consent and can be measured 
accurately.
d) ECOG PS 0 or 1; Lansky Performance Score 80%. For RCC subjects ONLY: Karnofsky 
Performance Score (KPS) 80%. Note: Exception Part D2 ECOG PS 0 to 2; Lansky 
Performance Score 60% (Appendix 3).
e) Life expectancy of 12 weeks at the time of informed consent per Investigator assessment.
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f)
Adequate organ function as defined by the following:
i)
White blood cells 2000/L (stable and off any growth factor within 4 weeks of first 
study drug administration)
ii) Neutrophils 1500/L (stable and off any growth factor within 4 weeks of first study 
drug administration)
iii) Platelets 100 (60 for HCC) 103/L (transfusion to achieve this level is not 
permitted within 2 weeks of first study drug administration)
iv) Hemoglobin 8.5 g/dL (transfusion to achieve this level is not permitted within 
2 weeks of first study drug administration)
v) Creatinine < 1.5 ULN or creatinine clearance 40 mL/min (Cockcroft-Gault 
formula)
vi) ALT and AST 3 ULN (5 ULN for HCC)
vii) Lipase and amylase < 1.5 ULN
viii) Total bilirubin 1.5 ULN (except subjects with Gilbert’s Syndrome, who must have 
normal direct bilirubin) [3 mg/dL for HCC]
ix) Normal thyroid function or stable on hormone supplementation per Investigator 
assessment
x) Albumin 2.8 g/dl
xi) Not applicable per Revised Protocol 08. See exclusion 2o.
g) Ability to comply with treatment, PK, and pharmacodynamic sample collection and 
required study follow-up.
h) Subject re-enrollment:  This study permits the re-enrollment of a subject who has 
discontinued the study as a pretreatment failure (ie, subject has not been randomized/has 
not been treated). If re-enrolled, the subject must be reconsented.
i)
Left ventricular ejection fraction (LVEF) assessment with documented LVEF 50% by 
either transthoracic echocardiogram (TTE) or multigated acquisition scan (MUGA) (TTE 
preferred test) within 6 months from first study drug administration.
3) Age and Reproductive Status
a) For Parts A, B, C, D, and E males and females, 18 years at the time of informed consent. 
Additionally, for Parts C (melanoma only), D, and E, males and females 12 years at the 
time of informed consent if local regulations and/or institutional policies allow for 
participants < 18 years of age (pediatric population). If pediatric population is not allowed 
to participate, then 18 years applies.
b) Not applicable as per Protocol Amendment 14: Women of childbearing potential 
(WOCBP) must agree to follow instructions for method(s) of contraception for the duration 
of treatment with BMS-986016 plus 5 half-lives of BMS-986016 (135 days) plus 30 days 
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(duration of ovulatory cycle) for a total of 165 days (24 weeks) after completion of 
treatment.
c) As per Protocol Amendment 14: Women of childbearing potential (WOCBP) must agree 
to follow instructions for method(s) of contraception for the duration of treatment with 
nivolumab and relatlimab plus 5 half-lives of study treatment for a total of 5 months post-
treatment completion and agree not to donate eggs (ova, oocytes) for the purpose of 
reproduction for the same time period. Investigators shall counsel WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP on the use of highly effective methods of contraception. 
Highly effective methods of contraception have a failure rate of < 1% per year when used 
consistently and correctly (see Appendix 1).
d) Women of childbearing potential must have a negative serum or urine pregnancy test (urine 
pregnancy test: minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [hCG]) within 24 hours prior to the start of study drug.
e) Women must not be breastfeeding.
f)
Not applicable as per Protocol Amendment 14: Men who are sexually active with 
WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with BMS-986016 plus 5 half-lives of BMS-986016 (135 days) plus 90 days 
(duration of sperm turnover) for a total of 225 days (33 weeks) after completion of 
treatment. This criterion applies to azoospermic males as well. In addition, male 
participants must be willing to refrain from sperm donation during this time.
a.
Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an 
unexpected pregnancy. Investigators shall advise WOCBP and male subjects who 
are sexually active with WOCBP on the use of highly effective methods of 
contraception. Highly effective methods of contraception have a failure rate of 
< 1% per year when used consistently and correctly. 
b. At a minimum, subjects must agree to the use of 2 methods of contraception, with 
one method being highly effective and the other being either highly effective or less 
effective as listed in Appendix 1. 
g) Note as of Protocol Amendment 14: No contraception requirements for nivolumab and 
relatlimab are necessary for male participants. Therefore, pregnancy reporting from female 
partners of childbearing potential is not required.
h) WOCBP who are continuously not heterosexually active are exempt from contraceptive 
requirements. However, WOCBP who abstain from heterosexual activity on a continuous 
basis must still undergo pregnancy testing as described in this protocol.
3.3.2
Exclusion Criteria
1) Target Disease Exceptions
a) Subjects with known or suspected CNS metastases or with the CNS as the only site of 
active disease are excluded with the following exceptions: 
i)
Subjects with controlled brain metastases will be allowed to enroll. Controlled brain 
metastases are defined as those with no radiographic progression for at least 4 weeks 
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after radiation and/or surgical treatment at the time of consent. Subjects must have been 
off of steroids for at least 2 weeks prior to informed consent and have no new or 
progressive neurological signs and symptoms.
ii) Subjects with signs or symptoms of brain metastases are not eligible unless brain
metastases are ruled out by CT or MRI.
b) Not applicable as per Revised Protocol 09. Participation in any prior clinical study with
nivolumab, including subjects in comparator arms, in which OS is listed as the primary or
coprimary endpoint and which has not completed analysis based on the primary endpoint.
2) Medical History and Concurrent Diseases
a) Prior malignancy active within the previous 3 years, except for locally curable cancers
that have been apparently cured, such as basal or squamous cell skin cancer, superficial
bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
b) Subjects with an active, known or suspected autoimmune disease. Subjects with type I
diabetes mellitus, hypothyroidism only requiring HRT, skin disorders (such as vitiligo,
psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger are permitted to enroll.
c) A known or underlying medical condition that, in the opinion of the Investigator or
Sponsor, could make the administration of study drug hazardous to the subject or could
adversely affect the ability of the subject to comply with or tolerate study.
d) Requirement for daily supplemental oxygen.
e) Uncontrolled or significant cardiovascular disease including, but not limited to, any of the
following:
i)
Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months
prior to consent
ii) Uncontrolled angina within the 3 months prior to consent
iii) Any history of clinically significant arrhythmias (such as poorly controlled atrial
fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
iv) QTc prolongation > 480 msec
v) History of other clinically significant cardiovascular disease (ie, cardiomyopathy,
congestive heart failure with New York Heart Association functional classification
III-IV, pericarditis, significant pericardial effusion, significant coronary stent
occlusion, poorly controlled venous thrombosis, etc)
vi) Cardiovascular disease–related requirement for daily supplemental oxygen
vii) History of 2 or more MIs OR 2 or more coronary revascularization procedures
(regardless of the number of stent placements during each procedure)
viii) Subjects with history of myocarditis, regardless of etiology
f)
A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior
to informed consent.
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g) Positive blood screen for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites 
where mandated locally. 
h) Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating 
presence of virus, eg, hepatitis B surface antigen (HBsAg; Australia antigen) positive or 
hepatitis C antibody positive (except if HCV-RNA negative) (does not apply to HCC 
subjects)
i)
Not applicable per Revised Protocol 08.
ii) Not applicable per Revised Protocol 08.
iii) Not applicable per Revised Protocol 08.
i)
Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal 
therapy 7 days prior to initiation of study drug therapy 
j)
Any other significant acute or chronic medical illness
k) Subjects who are unable to undergo venipuncture and/or tolerate venous access
l)
Any other sound medical, psychiatric, and/or social reason as determined by the 
Investigator
m) Any of the following procedures or medications:
i)
Within 2 weeks prior to time of study treatment: 
(1) Systemic or topical corticosteroids at immunosuppressive doses (> 10 mg/day of 
prednisone or equivalent). Inhaled or topical steroids, and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease.
(2) Palliative radiation or gamma knife radiosurgery
(3) Not applicable per Protocol Amendment 02. 
ii) Within 4 weeks prior to study drug administration:
(1) Any cytotoxic drug. Exposure to any noncytotoxic drug within 4 weeks or 5 half-
lives (whichever is shorter) is prohibited. If 5 half-lives is shorter than 4 weeks, 
agreement with Sponsor/Medical Monitor is mandatory.
(2) Not applicable per Protocol Amendment 05.
(3) Receipt of a live/attenuated vaccine within 30 days of first treatment
(4) Allergen hyposensitization therapy
(5) Growth factors, eg, granulocyte-colony stimulating factor, granulocyte macrophage-
colony stimulating factor, erythropoietin
(6) Major surgery
(7) Not applicable per Protocol Amendment 11. 
iii) Not applicable per Protocol Amendment 04.
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n) Subjects with history of life-threatening toxicity related to prior immune therapy (eg, anti-
CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting
T cell costimulation or immune checkpoint pathways) except those that are unlikely to
reoccur with standard countermeasures (eg, HRT after endocrinopathy)
o) Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Troponin levels between > 1 to 2 x
ULN will be permitted if a repeat assessment remains 2 x ULN and subject undergoes a
cardiac evaluation.
p) Prior treatment with LAG-3 targeted agents
q) Not applicable as per Revised Protocol 09. Adolescents weighing < 30 kg
3) Allergies and Adverse Drug Reaction
a) History of allergy to antiPD-1 or antiPD-L1 antibody therapy or to other mAbs or related
compounds or to any of their components (eg, history of severe hypersensitivity reactions
to drugs formulated with polysorbate 80)
b) History of allergy or hypersensitivity to study drug components
4) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical
(eg, infectious disease) illness
c) Inability to comply with restrictions and prohibited activities and treatments as listed in
Section 3.4
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential are defined as any female who have experienced menarche and 
who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not 
postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 in 
the absence of other biological or physiological causes. In addition, females under the age of 55 
must have a documented serum follicle-stimulating hormone (FSH) level > 40 mIU/mL to confirm 
menopause.
Females treated with HRT are likely to have artificially suppressed FSH levels and may require a 
washout period in order to obtain a physiologic FSH level. The duration of the washout period is 
a function of the type of HRT used. The duration of the washout period below are suggested 
guidelines and the investigators should use their judgment in checking serum FSH levels. If the 
serum FSH level is > 40 mIU/mL at any time during the washout period, the woman can be 
considered postmenopausal.
1 week minimum for vaginal hormonal products (rings, creams, gels)
4 week minimum for transdermal products
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8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study:
Immunosuppressive agents unless they are utilized to treat an AE or as specified in Sections 3.4.3
and 3.4.4
Concurrent administration of any anticancer therapies (investigational or approved) in the 
Treatment period, with the exception of subjects in Clinical Follow-up period as well as the 
Survival period of the study.
Use of growth factors should be discussed with BMS Medical Monitor.
Use of allergen hyposensitization therapy.
Palliative radiotherapy is permitted only under certain conditions as described in Section 3.4.3.
3.4.2
Other Restrictions and Precautions
Any live/attenuated vaccine (eg, varicella zoster; yellow fever; rotavirus; oral polio; and measles, 
mumps, rubella [MMR]) during treatment and until 100 days post last dose. Inactivated influenza 
vaccination will be permitted on study without restriction.
It is the local imaging facility’s responsibility to determine, based on subject attributes (eg, allergy 
history, diabetic history, and renal status), the appropriate imaging modality and contrast regimen 
for each subject. Imaging contraindications and contrast risks should be considered in this 
assessment. Subjects with renal insufficiency should be assessed as to whether or not they should 
receive contrast and, if so, what type and dose of contrast is appropriate. Specific to MRI, subjects 
with severe renal insufficiency (ie, estimated glomerular filtration rate < 30 mL/min/1.73 m2) are 
at increased risk of nephrogenic systemic fibrosis. Magnetic resonance imaging contrast should 
not be given to this subject population. In addition, subjects are excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc. 
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the Investigator, and the standard set by the local Ethics Committee.
3.4.3
Permitted Therapy
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Immunosuppressive agents and the use of 
systemic corticosteroids are permitted in the context of treating AEs, prophylaxis prior to a 
diagnostic procedure (eg, contrast MRI/CT scans), or as specified in Section 3.4.4. A brief course 
of corticosteroids for prophylaxis (eg, contrast dye allergy) is permitted after discussion with the 
BMS Medical Monitor. 
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Subjects may continue to receive HRT.
For subjects who need to undergo elective surgery (not tumor related) during the study, it is 
recommended to hold study drug(s) for at least 2 weeks before and 2 weeks after surgery or until 
the subject recovers from the procedure, whichever is longer. Prior to resuming study drug 
treatment, surgically related AEs should resolve to Grade 1 or baseline, and subjects must meet 
relevant eligibility criteria as determined by the BMS Medical Monitor in discussion with the 
Investigator. The BMS Medical Monitor must be consulted prior to reinitiating treatment in a 
subject with a dosing interruption lasting > 6 weeks after the last dose.
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-986016 in combination with nivolumab is unknown.
COVID-19 vaccines that are NOT live are allowed and should be handled in the same manner as 
other vaccines. Administration may occur during the study, including during the administration of 
the BMS study treatment and after the last administration of the BMS study treatment.
3.4.3.1
Palliative Radiotherapy
Palliative radiotherapy and supportive care for disease-related symptoms may be offered to all 
subjects on the trial; however, Investigators should consult with the BMS Medical Monitor prior 
to initiating palliative radiotherapy in subjects who have not yet completed the DLT evaluation 
interval (Parts A and B).
The potential for overlapping toxicities with radiotherapy and BMS-986016 nivolumab is 
currently not known. Therefore, palliative radiotherapy is not recommended while receiving any 
of these drugs, alone or in combination. If palliative radiotherapy in short courses and for isolated 
fields is required to control symptoms not clearly related to disease progression, then drug 
administration should be withheld, if possible, for at least 1 week before radiation and for at least 
1 week after its completion. Subjects should be closely monitored for any potential toxicity during 
and after receiving radiotherapy. Prior to resuming study drug treatment, radiotherapy-related AEs 
should resolve to Grade 1 or baseline and subjects must meet relevant eligibility criteria as 
determined by the BMS Medical Monitor in discussion with the Investigator. The BMS Medical 
Monitor must be consulted prior to reinitiating treatment in a subject with a dosing interruption 
lasting > 6 weeks after the last dose.
Details of palliative radiotherapy should be documented in the source records and electronic case 
report form (eCRF). Details in the source records should include dates of treatment, anatomical 
site, dose administered, fractionation schedule, and AEs. Symptoms requiring palliative 
radiotherapy should be evaluated for objective evidence of disease progression. Subjects receiving 
palliative radiation of target lesions will have the evaluation of ORR just prior to radiotherapy, but 
such subjects will no longer be evaluable for determination of response subsequent to the date 
palliative radiotherapy occurs.
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3.4.4
Treatment of BMS-986016, Nivolumab-related Infusion Reactions
Since all study treatments contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 
3 or 4 infusion reactions should be reported within 24 hours to the BMS Medical Monitor and 
reported as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI 
CTCAE v4.0 guidelines.
If a subject has an infusion reaction with nivolumab, the BMS-986016 infusion can be given 
(without prophylactic medications) if the infusion reaction resolves within 3 hours. For scheduling 
purposes after a nivolumab infusion reaction, the BMS-986016 infusion may be given within the 
next 2 days. Prophylactic preinfusion medications should be given prior to all subsequent 
nivolumab infusions.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated):
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 
and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before additional study 
drug administrations.
For Grade 2 symptoms (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, nonsteroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours):
Stop the infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg; 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid and/or 
bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, then 
restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor subject closely. If symptoms recur, then no further study drug will be administered 
at that visit.
For future infusions, the following prophylactic premedications are recommended:
Diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before study drug infusions. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
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For Grade 3 or 4 symptoms (severe reaction, Grade 3: prolonged [ie, not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal 
impairment, pulmonary infiltrates]; life-threatening, Grade 4: pressor or ventilatory 
support indicated):
Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and treat 
the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 solution 
for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed. Subject should be monitored until the Investigator is comfortable that the 
symptoms will not recur. All study drug(s) will be permanently discontinued. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
Please refer to Appendix 4 for a complete list of the AE management algorithms.
3.5
Discontinuation of Subjects From Treatment
Subjects MUST discontinue investigational product (and noninvestigational product at the 
discretion of the Investigator) for any of the following reasons:
Subject’s request to stop study treatment
Pregnancy
Termination of the study by BMS
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration for 
treatment of either a psychiatric or physical (eg, infectious disease) illness
Inability to comply with protocol requirements

Progressive disease (see also Section 4.3.4 for details regarding continuing treatment beyond 
initial assessment of PD per RECIST)
Clinical deterioration as assessed by the Investigator
Adverse event meeting discontinuation criteria (Section 4.3.5)
All subjects who discontinue investigational product should comply with protocol-specified 
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a 
subject withdraws consent for all study procedures, including post-treatment study follow-up, or 
loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
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If study treatment is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Treatment Study Follow-up
In this study, OS is an exploratory endpoint of the study. Post-treatment study follow-up is of 
critical importance and is essential to preserving subject safety and the integrity of the study. 
Subjects who discontinue study treatment must continue to be followed  for collection of outcome 
and/or survival follow-up data as required and in line with Section 5 until death or the conclusion 
of the study.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the Investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the Investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post-treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject 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.
3.6.2
Lost to Follow-up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of 3 documented phone calls, faxes, 
or emails, as well as lack of response by subject to 1 registered mail letter. All attempts should be 
documented in the subject’s medical records. If it is determined that the subject has died, the site 
will use permissible local methods to obtain the date and cause of death.
If Investigator’s use of a third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s ICF, then the Investigator may use a Sponsor-retained third-
party representative to assist site staff with obtaining the subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If, after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the Investigator should be 
reported and documented in the subject’s medical records.
4
TREATMENTS
All protocol-specified investigational and noninvestigational products are considered study drug.
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4.1
Study Treatments
Product description and storage information is described in Table 4.1-1. Preparation and 
administration instructions will be provided separately via site training materials.
For study drugs not provided by BMS and obtained commercially by the site, storage should be in 
accordance with the package insert, SmPC, or similar documentation.
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Table 4.1-1:
Product Description and Dosage Form
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/Label Type
Secondary Packaging
(Qty)/Label Type
Appearance
Storage Conditions
(per Label)
BMS-986016-01a
Relatlimab Injection, 
100 mg/vial or 80 
mg/vial
10 mg/mL
10 mL vial/open label 
or 8 mL vial/open label
4 vials/carton/open 
label
A clear to slightly 
opalescent, colorless to 
pale yellow liquid. May 
contain particles
Store refrigerated, 
2-8°C (36-46 °F)
Protect from light
Protect from freezing
BMS-936558-01b
Nivolumab
Injection, 100 mg/vial 
(10 mg/mL)
10 mg/mL
10 mL vial/open label
4 or 5 vials/carton/open 
label
Clear to opalescent, 
colorless to pale yellow 
liquid. May contain 
particles
Store refrigerated, 
2-8°C (36-46°F)
Protect from light
Protect from freezing
BMS-986213c
(Relatlimab 80 mg/
Nivolumab 240 mg vial)
(16 mg/mL)
16 mg/mL
20 mL vial/open label
2 vials/carton
Colorless to pale 
yellow liquid, clear to 
slightly opalescent, 
light (few) particulates 
(consistent in 
appearance to protein 
particulates) may be 
present.
Refer to the label on 
container and/or 
pharmacy manual
a Designated as BMS-986016 in the protocol.
b Nivolumab; designated as BMS-936558 in the protocol.
c Designated as BMS-986213 in the protocol.
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product 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 than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the Investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational products are BMS-986016, BMS-936558 (nivolumab), and 
BMS-986213 (relatlimab/nivolumab). BMS-986213 is a FDC drug product and contains 
relatlimab and nivolumab at a protein-mass ratio of 1:3 in a single vial. 
4.1.2
Noninvestigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
noninvestigational products. 
In this protocol, noninvestigational product(s) is/are: not applicable for this study. 
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration, and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
For noninvestigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, SmPC, or similar.
In Part B Q2W dose escalation, nivolumab will be administered first over approximately 
60 minutes, followed by approximately 60 minutes infusion of BMS-986016 within 15 to 
30 minutes after completion of the nivolumab infusion. In Part B, for doses of BMS-986016 960 
mg + 480 mg nivolumab Q4W and higher doses, BMS-986016 infusion should be administered 
no sooner than 30 minutes following completion of nivolumab infusion. The nivolumab infusion 
will be administered over approximately 30 minutes in Part B Q4W and all Part C cohorts. In Part 
D, BMS-986016 and nivolumab will be coadministered in a single IV bag over approximately 
60 minutes and BMS-986213 (FDC) will be administered over approximately 60 minutes. In 
Part E, BMS-986016 and nivolumab will be coadministered in a single IV bag over approximately 
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60 minutes Q4W. Further details regarding preparation and administration will be provided 
separately in site/pharmacy training materials.
4.2
Method of Assigning Subject Identification
This is an open-label study. All subjects must be assigned a subject number upon providing signed 
written informed consent. The investigative site will call into the enrollment option of the IVRS 
designated by BMS for assignment of a -digit subject number that will be unique across all sites. 
Enrolled subjects, including those not dosed, will be assigned sequential subject numbers starting 
with
 The patient identification number (PID) will ultimately 
comprise the site number and subject number. For example, if the first subject is enrolled at site 3, 
they will have a PID of 
. Specific instructions for using IVRS will be provided to the 
investigational sites in a separate document.
Once it is determined that the subject meets the eligibility criteria, the investigative site will call 
the IVRS within 3 days prior to first study drug administration for the subject to be either:
Assigned to a part (Parts A and B) and dose cohort in the dose escalation portion of the study
Assigned to an expansion cohort in the cohort expansion portion (Parts A1 and C) of the study 
Assigned to Part D1 or Part D2 based on eligibility criteria.

Part D1: randomized to either Arm 1, 2, or 3
Assigned to Part E based on eligibility criteria, including status of prior anti-PD-1 therapy 
(melanoma participants who experienced disease progression on prior anti-PD-1 therapy and 
melanoma participants who have not received prior systemic anticancer therapy for unresectable 
or metastatic melanoma). Melanoma participants who experienced disease progression on prior 
anti-PD-1 therapy will be allocated to a single treatment arm, and melanoma participants who have 
not received prior systemic anticancer therapy for unresectable or metastatic melanoma will be 
randomized to 1 of 2 treatment cohorts.
During dose escalation, all subjects will be assigned to Part A until the decision is made to escalate 
to the third dose cohort. Subsequently, treatment in Part B will be initiated, and escalation in the 
2 parts will occur in parallel. Treatment assignments for subjects eligible for both Part A and Part 
B will alternate between the 2 parts, with consecutively treated subjects assigned to different parts 
through IVRS whenever possible. If there are no openings available in the part to which the subject 
would be assigned by this algorithm, then the subject will be assigned to the next open part/cohort.
During dose escalation (Parts A and B), subjects who are not evaluable for DLT determination 
may be replaced. Replacement subjects will be assigned to the same part (Part A or Part B) and 
dose but will be assigned a new subject number.
Treatment assignments for subjects eligible for both Part A1 and Part C will alternate between the 
2 parts, with consecutively treated subjects assigned to different parts through IVRS whenever 
possible. If there are no openings available in the part to which the subject would be assigned by 
this algorithm, then the subject will be assigned to the next open part/cohort.
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Prior to Revised Protocol 09, Part D1 subjects are being enrolled only into single arm BMS-986016 
80 mg + nivolumab 240 mg Q2W. Subsequent to activation of this amendment, and until the 
enrollment to Part D1 arm BMS-986016 80 mg + nivolumab 240 mg Q2W is completed, subjects 
in Part D1 will be randomized 1:1:1 across the 3 arms: Part D1 BMS-986016 80 mg + nivolumab 
240 mg Q2W (Arm 1), Part D1 BMS-986016 160 mg + nivolumab 480 mg Q4W coadministration 
(Arm 2), Part D1 BMS-986016 160 mg/nivolumab 480 mg Q4W FDC (Arm 3). Once enrollment 
to Part D1 arm BMS-986016 80 mg + nivolumab 240 mg Q2W is completed, subjects will be 
randomized 1:1 to the 2 remaining arms. If enrollment to Q4W arms is completed prior to arm 
BMS-986016 80 mg + nivolumab 240 mg Q2W, then enrollment to arm BMS-986016 80 mg + 
nivolumab 240 mg Q2W will be completed as a single arm. 
4.3
Selection and Timing of Dose for Each Subject
4.3.1
Guidelines for Dose Modification
4.3.1.1
Intrasubject Dose Escalation
Intrasubject dose escalation of BMS-986016, BMS-986213, or nivolumab (BMS-936558) is not 
permitted in this study.
4.3.1.2
Dose Reductions
With the possible exception of subjects being treated at a dose level that is subsequently deemed 
to exceed the MTD, intrasubject dose reduction of BMS-986016, BMS-986213, or nivolumab 
(BMS-936558) is not permitted.
4.3.2
Dose Delay Criteria
In some cases, the natural history of select AEs associated with immunotherapy can differ from 
and be more severe than AEs caused by other therapeutic classes. Early recognition and 
management may mitigate severe toxicity. 
Guidance for Investigators is provided in the current BMS-986016 and BMS-936558 (nivolumab) 
IBs.11,29 Additionally, management algorithms have been developed to assist Investigators with 
select toxicities and can be found in the current BMS-936558 (nivolumab) IB; toxicities for which 
management algorithms have been developed include:
Pulmonary 
Gastrointestinal
Hepatic
Endocrine
Renal
Dermatologic
Neurologic (see Table 5.1-2 “Neurological Exam” for criteria for protocol-required neurologic 
exams)
Cardiac
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Subjects who experience the following must have all study drug(s) held:
Potential DLTs (per definition, are related to study drug) until DLT relatedness is defined
Select drug-related AEs and drug-related laboratory abnormalities: 

Grade 1 pneumonitis

Grade 1 myocarditis (see Appendix 4)

All troponin T or I elevations require a dose delay to allow for prompt cardiac and safety 
evaluation.

Single grade increase shift from baseline (at least to Grade 2) of AST, ALT, and/or total 
bilirubin

Grade 2 creatinine

Grade 2 diarrhea or colitis

Grade 2 neurological AE 

Grade 4 amylase and/or lipase abnormalities regardless of symptoms or clinical 
manifestations
AE, laboratory abnormality, or concurrent illness that, in the judgment of the Investigator, warrants 
delaying the dose of study drug.
Subjects may be dosed no less than 12 days in Q2W regimen and 25 days in Q4W from the 
previous dose and no more than 3 days from scheduled dose. If an infusion cannot be administered 
at a scheduled visit, it should be administered as soon as possible. Subsequent dosing visits will 
follow every 2 weeks or every 4 weeks after the delayed dose. A dose given more than 3 days after 
the intended dose date will be considered a delay. A maximum delay of 6 weeks between doses is 
allowed. Longer delays may be allowed following discussion with the Medical Monitor. Subjects 
who meet criteria listed in Section 4.3.5 are required to permanently discontinue all study drug(s). 
All other subjects will be permitted to resume therapy with study drug(s) at the same dose level(s) 
following resolution of the AE as described in Section 4.3.3.
4.3.3
Criteria to Resume Treatment After Dose Delay
Subjects will be permitted to resume therapy at the same dose level(s) following resolution of the 
AE to Grade 1 or to baseline within 6 weeks after last dose, with the exception of subjects who 
meet criteria for permanent discontinuation as specified in Section 4.3.5. Subjects who meet 
criteria for permanent discontinuation should receive no further study therapy. The following 
exceptions apply:
If the toxicity resolves to Grade 1 or baseline > 6 weeks after last dose but the subject does not 
otherwise meet the criteria for permanent discontinuation (see Section 4.3.5) and the Investigator 
believes that the subject is deriving clinical benefit, then the subject may be eligible to resume the 
study drug(s) following the approval of the BMS Medical Monitor.
Subjects with a Grade 4 drug-related amylase and/or lipase increase that is not associated with 
symptoms or clinical manifestations of pancreatitis can be restarted on therapy once the levels 
have recovered to Grade 3 or less, and after consultation with the BMS Medical Monitor.
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Subjects with baseline Grade 1 AST, ALT, or total bilirubin who require dose delays for reasons 
other than a drug-related hepatic event may resume treatment in the presence of Grade 2 AST, 
ALT, or total bilirubin.
Subjects who require dose delays for drug-related elevations in AST, ALT, or total bilirubin may 
resume treatment when these values have returned to their baseline CTCAE Grade or normal, 
provided the criteria for permanent discontinuation are not met.
Subjects may resume treatment in the presence of Grade 2 fatigue.
Drug-related endocrinopathies adequately controlled with only physiologic HRT may resume 
treatment.
Troponin T or I elevations will require the participant to undergo a cardiac and safety evaluation. 
Following this evaluation, determination of further treatment will be based on the discussion with 
the BMS Medical Monitor or designee.
4.3.4
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. 
Participants treated with nivolumab and BMS-986016 or BMS-986213 will be permitted to 
continue treatment beyond initial RECIST v1.1–defined PD, assessed by the Investigator, as long 
as they meet the following criteria:
Investigator-assessed clinical benefit
Tolerance of study treatment
Stable performance status
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
Subjects provides written informed consent prior to receiving additional study treatment. All other 
elements of the main consent including description of reasonably foreseeable risks or discomforts 
or other alternative treatment options will still apply.
A follow-up scan should be performed at the next scheduled imaging evaluation 8 weeks later (but 
no sooner than 4 weeks) to determine whether there has been a decrease in the tumor size or 
continued PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the participant is clinically deteriorating and unlikely to receive any benefit from 
continued treatment with nivolumab and BMS-986016 or BMS-986213.
If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment beyond progression, the subject should remain on the trial and continue to receive 
monitoring according to the Schedule of Activities (Table 5.1-2).
For the subjects who continue study therapy beyond progression, further progression is 
defined as an additional 10% increase in tumor burden with a minimum 5 mm absolute 
increase from time of initial PD. This includes an increase in the sum of diameters of all 
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target lesions and/or the diameters of new measurable lesions compared to the time of initial 
PD. Study treatment should be discontinued permanently upon documentation of further 
progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes that must have a short axis of at least 
15 mm). Any new lesion considered nonmeasureable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes that must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions that become measurable, these new lesions must demonstrate an absolute increase of 
at least 5 mm.
4.3.5
Guidelines for Permanent Discontinuation
Subjects meeting any of the following criteria will be required to permanently discontinue all study 
drug(s) (BMS-986016 in Part A and Part A1; BMS-986016 and nivolumab [BMS-936558] or 
BMS-986213 in Parts B, C, D, and E):
Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the retreatment period OR requires 
systemic treatment 
Any Grade 3 nonskin, drug-related AE lasting > 7 days or recurs, with the following exceptions 
for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reactions, infusion reactions, and endocrinopathies
Any Grade 3 drug-related myocarditis, uveitis, pneumonitis, bronchospasm, or hypersensitivity 
reaction of any duration requires discontinuation.
Any Grade 3 infusion reaction that does not return to Grade 1 in 6 hours or less requires
discontinuation.
Any Grade 3 drug-related endocrinopathies adequately controlled with only physiologic HRT
do not require discontinuation.
Any Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:

Any Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation.

AST, ALT, or bilirubin abnormalities that meet DLT criteria (Section 3.1.2.6) (In most 
cases of AST or ALT elevation meeting DLT criteria, study drugs will be permanently 
discontinued. If the Investigator determines a possible favorable benefit-risk ratio that 
warrants continuation of study drugs, a discussion between the Investigator and the BMS 
Medical Monitor/designee must occur.)

Elevated troponin that meets DLT criteria (Section 3.1.2.6)
Any Grade 4 drug-related AE or laboratory abnormality (including, but not limited to, creatinine, 
AST, ALT, or total bilirubin), except for the following events, which do not require 
discontinuation:
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
Grade 4 neutropenia 7 days

Grade 4 lymphopenia or leukopenia

Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset

Grade 
4 
drug-related 
endocrinopathy 
AEs, 
such 
as 
adrenal 
insufficiency, 
adrenocorticotropic hormone deficiency, hyper- or hypothyroidism, or glucose intolerance, 
which resolve or are adequately controlled with physiologic HRT (corticosteroids, thyroid 
hormones) or glucose-controlling agents, respectively, may not require discontinuation 
after discussion with and approval from the BMS Medical Monitor.
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to reinitiating treatment in a subject with a dosing delay lasting > 6 weeks 
from the previous dose, the BMS Medical Monitor must be consulted. Tumor assessments 
should continue as per protocol even if dosing is delayed. Periodic study visits to assess 
safety and laboratory studies should also continue every 6 weeks or more frequently if 
clinically indicated during such dosing delays.

Dosing delays lasting > 6 weeks from the previous dose that occur for nondrug-related 
reasons may be allowed if approved by the BMS Medical Monitor. Prior to reinitiating 
treatment in a subject with a dosing delay lasting > 6 weeks, the BMS Medical Monitor 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue 
every 6 weeks or more frequently if clinically indicated during such dosing delays.
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, 
presents a substantial clinical risk to the subject with continued nivolumab dosing.
The consideration to reinitiate study therapy in selected cases at any time point after 
discontinuation could be made on a case-by-case basis after considering the overall benefit-risk 
profile and in consultation between the Investigator and the study Sponsor. The selected subjects 
will need to meet eligibility criteria. The original dose and schedule and protocol rules would apply 
accordingly (Section 3.1.2.5). 
4.4
Blinding/Unblinding
Data emerging from this exploratory study may be necessary to inform timely decisions for 
adjusting procedures in subsequent portions of the study, including early termination of the study. 
Additionally, treatment assignments may facilitate optimization of the bioanalytical analysis of 
samples. 
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Designated staff of the Sponsor can access Interactive Response Technology (IRT) treatment 
codes prior to the formal locking of the study database. This access to the treatment codes will not 
impact the data integrity of the study.
4.5
Treatment Compliance
Study drug will be administered in the clinical facility by trained medical personnel. Treatment 
compliance will be monitored by drug accountability, as well as by recording BMS-986016, 
BMS-986213, and nivolumab (BMS-936558) administration in subjects’ medical records and 
CRFs.
4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the Investigator) such as partially 
used study drug containers, vials, and syringes may be destroyed on site. 
Any unused study drugs may only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are 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, 
quantity disposed, and identification of the person disposing the containers. The method of 
disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor, must be 
documented.
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met, the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures and provided that appropriate records of disposal are 
kept.
4.6.2
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to a BMS designated site for 
destruction. The return of study drug will be arranged by the responsible BMS Study Monitor. 
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It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures and provided that appropriate records of disposal are 
kept. 
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Study assessments and procedures are presented in Table 5.1-1, Table 5.1-2, and Table 5.1-3.
Additional measures, including nonstudy required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on-site/local 
labs until all study drug-related toxicities resolve, return to baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure.
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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Table 5.1-1:
Screening Procedural Outline (CA224020)
Procedure
Screening
Visit (Day -28 
to -1)
Day -14 
to -1
Visit
Day -3 
to -1 
Visit
Notes
Eligibility Assessments
Informed consent
X
See Notes
A subject is considered enrolled only when an IRB/IEC-approved ICF is signed and 
dated. Obtain subject number from IVRS.
Inclusion/exclusion 
criteria
X
Medical history
X
May include more detailed medical history of risk factors for potential events such as 
pulmonary-related events. Include any toxicities or allergy related to previous 
treatments. Include any prior PD-L1 results available. 
Submission of 
pretreatment tumor tissue
X
See Notes and 
Table 5.7-5
For all subjects:  
See Laboratory Manual for delivery and processing indications. Tumor tissue to be 
sent to central lab after performing specified tests locally within approximately 1 
week of C1D1  (see “Laboratory tests” in this table below).
During the screening period, all participants must have tumor tissue submitted, 
 
 
. If a screening biopsy is required, 
participants must have a lesion that can be biopsied at an acceptable clinical risk as 
judged by the investigator. Tissue may be from a core, punch, or excisional biopsy or 
surgical specimen. Sufficient quantities must be available: a block or a minimum of 
20 slides is required.
Safety Assessments
Physical examination 
(PE)
X
If the screening PE is performed within 1 day of dosing on Cycle 1 Day 1, then a 
single exam may count as both the screening and predose evaluation.
Performance status
X
ECOG PS/KPS for RCC subjects ONLY/Lansky for minors ONLY (Appendix 3)
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Table 5.1-1:
Screening Procedural Outline (CA224020)
Procedure
Screening
Visit (Day -28 
to -1)
Day -14 
to -1
Visit
Day -3 
to -1 
Visit
Notes
Physical measurements
X
Includes height, weight
Vital signs
X
See Notes
Includes body temperature, seated blood pressure, and heart rate. Blood pressure and 
heart rate should be measured after the subject has been seated quietly for at least 5 
minutes.
Oxygen saturation
X
See Notes
Collected at rest and after mild exertion via pulse oximetry to establish baseline. 
If subject has oxygen saturation 90%, consult BMS Medical Monitor prior to 
enrollment.
Electrocardiogram (ECG)
X
12-lead ECG
Chest radiograph
X
Posterior-anterior and lateral chest x-ray to establish baseline (preferred)
Echocardiogram
X
See Note
LVEF assessment with documented LVEF 50% by either TTE or MUGA (TTE 
preferred test) within 6 months from first study drug administration
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Table 5.1-1:
Screening Procedural Outline (CA224020)
Procedure
Screening
Visit (Day -28 
to -1)
Day -14 
to -1
Visit
Day -3 
to -1 
Visit
Notes
Laboratory tests
X
See Notes
Blood and Urine Tests:  To include hematology, serum chemistry, endocrine panel, 
serology, urinalysis, 
 See Section 
5.3.1 for panel requirements. (Subjects with controlled hyperthyroidism must be 
negative for thyroglobulin and thyroid peroxidase antibodies and thyroid-stimulating 
immunoglobulin.) (Subjects with type 2 diabetes must have HbA1c to establish 
baseline.)
If tests are performed within 3 days of dosing on C1D1, then C1D1 laboratories are not 
required. 
Tests on Tumor Tissue (see Section 5.3.1):  

For all subjects in Parts A, B, C, D, and E: Subjects with applicable tumor types 
must provide results of previous gene mutation testing. For colorectal cancer, 
EGFR, K-RAS, and microsatellite instability (MSI) mutation status; for gastric 
cancer, presence of EBV and human epidermal growth factor receptor 2 (HER-
2); for melanoma, BRAF mutation status; and for NSCLC, ALK, K-RAS and 
EGFR mutation status; otherwise, these tests will be performed locally. Test(s) 
will be requested at baseline, but subjects can proceed to treatment prior to 
receipt of results. 

Subjects in Part C with head and neck tumors:  Subjects must be tested for HPV 
status by p16 IHC and/or HPV in situ hybridization (ISH). If testing has not been 
previously performed, testing must be performed locally to confirm HPV status. 

Not required for subjects in cohorts for crossover and rechallenge. As of Protocol 
Amendment 14, rechallenge is not permitted.
Pregnancy test (WOCBP)
X
See 
Notes
Pregnancy test should be performed in all WOCBP prior to first study drug 
administration.
Serum or urine pregnancy test (minimum sensitivity of urine pregnancy test of 25 IU/L 
of either total hCG or the beta fraction). If performed within 24 hours of dosing on 
C1D1, then C1D1 pregnancy test is not required.
Follicle-stimulating 
hormone (FSH)
X
See Notes
If needed to document postmenopausal status as defined in Section 3.3.3
Not required at crossover or rechallenge. As of Protocol Amendment 14, rechallenge 
is not permitted.
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Table 5.1-1:
Screening Procedural Outline (CA224020)
Procedure
Screening
Visit (Day -28 
to -1)
Day -14 
to -1
Visit
Day -3 
to -1 
Visit
Notes
Concomitant medications
X
Collected during the 2-week period prior to Cycle 1 Day 1
Assessment of signs and 
symptoms
X
Collected during the 2-week period prior to Cycle 1 Day 1
Adverse Event Reporting
Monitor for serious 
adverse events
X
All SAEs must be collected from the date of subject’s written consent.
Efficacy Assessments
Diagnostic Imaging
X
See Notes
CT with contrast is the preferred modality (CT chest without contrast or MRI if CT is 
not feasible or appropriate given location of the disease). Assessment should include 
the chest/abdomen/pelvis at a minimum and should include other anatomic regions as 
indicated based on the subject’s tumor type and/or disease history. Imaging scans must 
be de-identified and archived in their native Digital Imaging and Communications in 
Medicine (DICOM) format as part of the subject study file.
Prior Diagnostic Imaging
X
See Notes
For Part D and Part E melanoma: All available scans on the most recent prior anti-
PD-1–containing regimen, including the baseline scan (prior to starting anti-PD-1) and 
scans after the last dose of anti-PD-1 but before the start of any intervening therapy, 
will be collected and submitted to a central imaging vendor. 
At minimum the following time points are to be submitted: 1) pretreatment scan; 2) 
nadir scan (if applicable); 3) scan documenting progression (does not need to be 
submitted if it has already been submitted as the baseline scan for the trial); 4) scan 
confirming progression (if applicable, it must be at least 4 weeks after the scan 
documenting progression and without intervening therapy and does not need to be 
submitted if it has already been submitted as the baseline scan for the trial); 
5) Treatment beyond progression scan (if applicable, as this is the last scan on treatment 
if the subject was treated beyond a progression confirmation scan and does not need to 
be submitted if it has already been submitted as the baseline scan for the trial).
Protocol Amendment No. 15
Date: 16-Feb-2024
131
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-1:
Screening Procedural Outline (CA224020)
Procedure
Screening
Visit (Day -28 
to -1)
Day -14 
to -1
Visit
Day -3 
to -1 
Visit
Notes
Brain imaging
X
See Notes
Applicable Subjects:  Brain imaging (MRI) for subjects with history or symptoms of 
brain metastases who have not had brain imaging within 30 days of anticipated first 
study drug administration. MRI of the brain should have been be done for all subjects 
treated on study as first-line NSCLC or first-line melanoma as part of their initial 
evaluation of advanced disease, and if not, it should be done during screening.
Bone Scan
X
See Notes
As clinically indicated (ie, subjects with history or symptoms of bone metastases), but 
bone scans will not be considered a modality for assessment for measurable disease.
Protocol Amendment No. 15
Date: 16-Feb-2024
132
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
IVRS Assignment
IVRS assignment
X
See 
Notes
Cycle 1 only
Once subject eligibility has been confirmed, IVRS 
assignment can be performed within 3 days prior to first 
study drug administration. (Discuss with Sponsor if 
institutional policies and procedures require additional 
lead time.)
For all subsequent treatment visits, IVRS assignment can 
be performed within applicable visit window.
Safety Assessments
All assessments are to be performed/results are to be reviewed PRIOR to study drug dosing 
unless otherwise specified.
Note: For Part D, D1, D2, and participants in Part E receiving doses of relatlimab/nivolumab 160mg/480mg Q4W: Study 
visits will occur Q2W (Day 1, 15, 29, 43) to assess safety for the first cycle of treatment, and thereafter visits will only be on 
Day 1 and Day 29 of each subsequent cycle.
Clinical Observation
See notes 
All participants should be clinically evaluated for any 
immune-mediated events. Evaluations should occur every 
week (± 1 day) up to and including Week 8. Participants 
with any clinical symptoms, in particular fatigue, should 
immediately be evaluated.
Physical examination (PE)b
X
See 
Notes
X
See 
Notes
X
See 
Notes
X
See 
Notes
Perform PE within 2 days of dosing for each cycle. On 
subsequent treatment visits in each cycle, perform a 
symptom-directed PE.
Protocol Amendment No. 15
Date: 16-Feb-2024
133
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
Neurological exam (NE)
See Notes
Subjects in Part B, Part C, Part D, and Part E:  Obtain 
neurological exam (performed by a neurologist) in 
subjects who experience a study drug related Grade 2 
neurological AE.
Performance status
X
X
X
X
ECOG PS/KPS for RCC subjects ONLY/Lansky for 
minors ONLY (Appendix 3).
Weight
X
X
X
X
Protocol Amendment No. 15
Date: 16-Feb-2024
134
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
Vital signs
X
See 
Notes
X
See 
Notes
X
See 
Notes
X
See 
Notes
Includes temperature, seated blood pressure, and heart 
rate. Blood pressure and heart rate should be measured 
after the subject has been seated quietly for at least 5 
minutes.
On Cycle 1 Day 1, vital signs will be obtained before the 
infusion and then every 15 minutes (5 minutes) until 60 
minutes (120 minutes for subjects in the first dose cohort 
of Part B) after the completion of the infusion(s).
Vital signs on subsequent treatment visits will be 
collected before the infusion and then every 30 minutes 
(10 minutes until 60 minutes following completion of 
the infusion(s). 
If any vital sign is abnormal (based upon clinician 
assessment) at the final check, the subject must be 
observed further for a period of time, as clinically 
indicated.
12-lead electrocardiogram 
(ECG)
X
See 
Notes
X
See 
Notes
X
See 
Notes
X
See 
Notes
Subjects enrolled in Parts A and B:  

Cycle 1 Day 1 and Cycle 3 Day 1: 12-lead ECG 
collected per Holter monitor. Monitoring to begin 
prior to dosing and to continue through the collection 
of the 4-hour postdose BMS-986016 PK sample.

12-lead ECG to be performed within 2 days of dosing 
for ALL cycles using site’s own ECG machine; 
results to be assessed prior to dosing. For Cycle 1 
Protocol Amendment No. 15
Date: 16-Feb-2024
135
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
only, 12-lead ECG is also to be performed predose 
on Day 15, Day 29, and Day 43.
Subjects enrolled in Part A1, Part C, Part D, and Part E:  

12-lead ECG to be performed within 2 days of Day 1 
dose for all cycles using site’s own ECG machine; 
results to be assessed prior to dosing. For Cycle 1 
only, 12-lead ECG is also to be performed predose 
on Day 15, Day 29, and Day 43.
Subjects enrolled in cohorts for rechallenge or crossover:  

12-lead ECG to be performed within 2 days of dosing 
on Day 1 of all cycles using site’s own ECG 
machine; results to be assessed prior to dosing.

As of Protocol Amendment 14, rechallenge is not 
permitted.
Chest radiograph
As clinically indicated
Oxygen saturation 
X
See 
Notes
X
See 
Notes
X
See 
Notes
X
See 
Notes
Collected at rest and after mild to moderate exertion via 
pulse oximetry. Oxygen levels will be used in 
combination with clinical signs and symptoms and 
radiographic images to evaluate pulmonary/respiratory 
status. Changes in O2 levels will not be used in isolation 
to document or diagnose pulmonary toxicity.
Laboratory tests
X
See 
Notes
X
See 
Notes
X
See 
Notes
X
See 
Notes
Labs are performed locally and may be collected within 3 
days prior to dosing. To include serum chemistry, 
hematology, urinalysis, 
; see 
Section 5.3.1 for panel requirements. All laboratory results 
should be checked prior to dosing.
Protocol Amendment No. 15
Date: 16-Feb-2024
136
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
In asymptomatic participants, these laboratory tests can 
be performed locally, but treating investigator must be 
notified on the same day.
Endocrine panel
X
See 
Notes
Labs are performed locally and may be collected within 3 
days prior to dosing. See Section 5.3.1 for panel 
requirements.
Results must be reviewed by the Investigator or 
appropriate designee within 2 days following dose 
administration.
See 
Notes
C2 Day 
1 ONLY 
X
See 
Notes
X
See 
Notes
X
See 
Notes
Labs are performed locally only for Cycle 1 Day 15, 29, 
and 43 and Cycle 2 Day 1 and may be collected within 3 
days prior to dosing. 
Section 5.3.1 for requirements.
Serologic tumor markers
X
See 
Notes
Labs performed locally for subjects with colorectal, 
gastric, germ cell, HCC, ovarian, or prostate cancer. See 
Section 5.3.1.
Pregnancy test (WOCBP)
X
X
A pregnancy test must be performed within 24 hours prior 
to administration of study drug.
Protocol Amendment No. 15
Date: 16-Feb-2024
137
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
See 
Notes
See 
Notes
Serum or urine pregnancy test may be performed (urine 
pregnancy test: minimum sensitivity 25 IU/L or equivalent 
units of hCG).
If results are positive, hold all study drug and perform 
confirmatory testing. If pregnancy is confirmed, 
permanently discontinue all study drug and immediately 
notify Sponsor per Section 6.4.
Assess adequate contraceptive 
use
X
See 
Notes
X
See 
Notes
For WOCBP: Assess for continued use of acceptable 
methods of contraception; see Appendix 1.
As of Protocol Amendment 14, no contraception 
requirements for relatlimab and nivolumab are necessary 
for male participants.
Adverse Event and ConMed 
Assessment
Monitor for nonserious 
adverse events
X
X
X
X
Monitor for serious adverse 
events
X
X
X
X
ConMed assessment
X
X
X
X
Sample Collection
Pharmacokinetic (PK) 
assessments
See Section 5.5 and Table 5.5.1-1 and Table 5.5.1-2 for Q2W 
dosing
See Table 5.5.1-3 for Q4W dosing Part B and Part C (Bladder 
Cohort), Table 5.5.1-4/Table 5.5.1-5 for Part D and Part E 
Performed in all subjects
Protocol Amendment No. 15
Date: 16-Feb-2024
138
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
Immunogenicity assessments 
See Section 5.5 and Table 5.5.1-1 and Table 5.5.1-2
See Table 5.5.1-3 for Q4W dosing Part B and Part C (Bladder 
Cohort), Table 5.5.1-4/Table 5.5.1-5 for Part D and Part E
Performed in all subjects
Biomarker assessments
See Section 5.7 and Table 5.7-1, Table 5.7-2, Table 5.7-3, and 
Table 5.7-4
See Notes
Subjects in Part A and B:  Performed in all subjects 
enrolled at each dose level. See Laboratory Manual for 
delivery and processing indications.
Subjects in Part C:  
 
 
 
 
. See Laboratory Manual for 
delivery and processing indications. 
Subjects in Part A1:  Mandatory in all subjects of each 
cohort for US IION sites. See Laboratory Manual for 
delivery and processing indications.
Subjects in Part D and E: Biomarker collections are 
required for all subjects. Refer to footnotes for Table 5.7-
3 and Table 5.7-4 for details.
Protocol Amendment No. 15
Date: 16-Feb-2024
139
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
On-treatment tumor biopsy
X
See 
Notes 
and 
Table 
5.7-5
OPTIONAL Postprogression 
(PD) tumor biopsy
See Notes
See Table 5.7-5
OPTIONAL tumor biopsy for any subject; obtained upon 
confirmation of PD. See Laboratory Manual for delivery 
and processing indications.
Efficacy Assessments
Diagnostic imaging
X
See Notes
Every 8 weeks by methods used at baseline, until disease 
progression or discontinuation of study treatment. 
Imaging scans must be de-identified and archived in their 
native DICOM format as part of the subject study file.
Brain imaging
X
See Notes
Subjects with known CNS disease must have imaging 
assessments at least every 12 weeks.
Bone scan
X
See Notes
As clinically indicated 
Response assessment
X
See Notes
Assessed by RECIST v1.1; see Appendix 2. Assessment 
must be performed prior to initiating the next cycle of 
treatment.
Protocol Amendment No. 15
Date: 16-Feb-2024
140
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
Study Drug Administration
Details regarding preparation and administration are provided in site training materials.c
Parts A, A1, B, and C:
BMS-986016 administration
X
X
X
X
Use vials assigned per IVRS: approximately 60-minute 
infusion.
Parts B and C Q2W:  
Nivolumab (BMS-936558) 
administration
X
See 
Notes
X
See 
Notes
X
See 
Notes
X
See 
Notes
Use vials assigned per IVRS. Nivolumab is administered 
ONLY for those subjects enrolled in Part B and Part C. 
Combination therapy with nivolumab and BMS-986016 
will be administered as sequential infusions (Parts B and 
C). In Part C, nivolumab infusion will be administered 
over approximately 30 minutes. 
Parts B and C Q4W:  
Nivolumab BMS-936558 and 
BMS-986016 administration 
X
See 
Notes
X
See 
Notes
Combination therapy with nivolumab and BMS-986016 
will be administered as sequential infusions. The 
nivolumab 
infusion 
will 
be 
administered 
over 
approximately 30 minutes and BMS-986016 over 
approximately 60 minutes. Study visits will occur Q2W 
(Day 1, 15, 29, 43) to assess safety for the first 3 cycles of 
treatment, and thereafter visits will only be on Day 1 and 
Day 29 of each subsequent cycle for Part B subjects. For 
Part C, study visits will occur Q2W (Day 1, 15, 29, 43) to 
assess safety for the first cycle of treatment, and 
thereafter visits will only be on Day 1 and Day 29 of each 
subsequent cycle.
Part D1 Q2W: Nivolumab 
BMS-936558 and BMS-
986016 coadministration
X 
See 
Notes
X
See 
Notes
X
See 
Notes
X
See 
Notes
Combination therapy with nivolumab and BMS-986016 
will be coadministered in a single IV bag over 
approximately 60 minutes.
Protocol Amendment No. 15
Date: 16-Feb-2024
141
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-2:
On-treatment Procedural Outline for Q2W and Q4W BMS-986016/Nivolumab Treatment Regimens 
Parts A Through E
Procedure
Treatment Cycles
Notes
Day 1 
Day 15 
Day 29 
Day 43 
Day 50-56a
Visit Window for Q2W
2 days
2 days
2 days
2 days
Visit Window for Q4W
3 days
3 days
3 days
3 days
Parts D1 and D2 Q4W:
Nivolumab BMS-936558 and 
BMS-986016 coadministration
X 
See 
Notes
X 
See 
Notes
Combination therapy with nivolumab and BMS-986016 
will be coadministered in a single IV bag over 
approximately 60 minutes. Study visits will occur Q2W 
(Day 1, 15, 29, 43) to assess safety for the first cycle of 
treatment, and thereafter visits will only be on Day 1 and 
Day 29 of each subsequent cycle.
Part D1 Q4W:
BMS-986213 FDC
X 
See 
Notes
X 
See 
Notes
FDC treatment will be administered over approximately 60 
minutes. Study visits will occur Q2W (Day 1, 15, 29, 43) 
to assess safety for the first cycle of treatment, and 
thereafter visits will only be on Day 1 and Day 29 of each 
subsequent cycle.
Part E Q4W: Nivolumab 
(BMS-936558) and 
BMS-986016 coadministration
X 
See 
Notes
X 
See 
Notes
Combination therapy with nivolumab and BMS-986016 
will be coadministered in a single IV bag over 
approximately 60 minutes. 
Study visits will occur Q2W (Day 1, 15, 29, 43) to assess 
safety for the first cycle of treatment, and thereafter visits 
will only be on Day 1 and Day 29 of each subsequent 
cycle.
a This visit is not a clinic visit. The purpose of this visit is for diagnostic imaging and subsequent evaluation of results by the Investigator (response assessment).
Diagnostic imaging should occur during Day 50-56, and response assessment must be completed prior to initiating the next cycle of treatment.
b
 
c Study drug may continue to be administered for applicable patients past 5 years from first dose. The original dose, schedule, and protocol rules would apply.
Protocol Amendment No. 15
Date: 16-Feb-2024
142
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-3:
Follow-up Procedural Outline Parts A Through E
Procedure
Clinical Follow-up
Survival Follow-up
Notes
FU 1 
30 daysa
(5 days)
FU 2
60 daysa
(5 days)
FU 3
135 daysa
(5 days)
Begins After Completion of 
Clinical Follow-up
Every 12 wks
(2 wks) up to 5 yrs after 
FIRST dose of study drug
Safety Assessments
Physical examination (PE)
X
X
X
Performance status
X
X
X
ECOG PS/KPS for RCC subjects 
ONLY/Lansky for minors ONLY 
(Appendix 3)
Weight
X
X
X
Vital signs
X
See Notes
X
See Notes
X
See Notes
Includes body temperature, seated blood 
pressure, and heart rate. Blood pressure 
and heart rate should be measured after 
the subject has been seated quietly for at 
least 5 minutes.
12-lead electrocardiogram 
(ECG)
X
See Notes
Subjects enrolled in Parts A and B:

12-lead ECG collected per Holter 
monitor, as well as an additional 12-
lead ECG using site’s own ECG 
machine
Subjects enrolled in Parts C, D, and E:  

12-lead ECG using site’s own ECG 
machine
Protocol Amendment No. 15
Date: 16-Feb-2024
143
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-3:
Follow-up Procedural Outline Parts A Through E
Procedure
Clinical Follow-up
Survival Follow-up
Notes
FU 1 
30 daysa
(5 days)
FU 2
60 daysa
(5 days)
FU 3
135 daysa
(5 days)
Begins After Completion of 
Clinical Follow-up
Every 12 wks
(2 wks) up to 5 yrs after 
FIRST dose of study drug
Oxygen saturation
X
See Notes
X
See Notes
X
See Notes
Collected at rest and after mild to 
moderate exertion via pulse oximetry. 
Oxygen levels will be used in 
combination with clinical signs and 
symptoms and radiographic images to 
evaluate pulmonary/respiratory status. 
Changes in O2 levels will not be used in 
isolation to document or diagnose 
pulmonary toxicity.
Laboratory tests
X
See Notes
X
See Notes
To include serum chemistry, hematology, 
endocrine panel, and urinalysis; see 
Section 5.3.1 for panel requirements.
Serologic tumor markers
X
See Notes
Labs performed locally for subjects with 
colorectal, gastric, germ cell, HCC, 
ovarian, or prostate cancer. See 
Section 5.3.1.
Pregnancy test (WOCBP)
X
See Notes
X
See Notes
X
See Notes
Serum or urine pregnancy test may be 
performed (clinic urine pregnancy test: 
minimum sensitivity 25 IU/L or 
equivalent units of hCG). 
Home pregnancy testing required on FU 
Days 90, 120, 150, and 165. 
If positive, perform confirmatory testing. 
If pregnancy is confirmed, immediately 
notify Sponsor per Section 6.4.
Protocol Amendment No. 15
Date: 16-Feb-2024
144
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-3:
Follow-up Procedural Outline Parts A Through E
Procedure
Clinical Follow-up
Survival Follow-up
Notes
FU 1 
30 daysa
(5 days)
FU 2
60 daysa
(5 days)
FU 3
135 daysa
(5 days)
Begins After Completion of 
Clinical Follow-up
Every 12 wks
(2 wks) up to 5 yrs after 
FIRST dose of study drug
Assess adequate contraceptive 
use
X
See Notes
X
See Notes
X
See Notes
For WOCBP: Assess for continued use of 
acceptable methods of contraception; see 
Appendix 1.
Adverse Event and 
Concomitant Medications 
Assessment
Monitor for nonserious adverse 
events
X
See Notes
X
See Notes
X
See Notes
Nonserious AEs will be collected starting 
with the first dose of study medication 
and through 135 days after 
discontinuation of dosing.
Monitor for serious adverse 
events
X
See Notes
X
See Notes
X
See Notes
All SAEs must be collected starting at the 
time a subject signs an ICF and through 
135 days after discontinuation of dosing.
Concomitant Medications 
assessment
X
X
X
Sample Collection
Pharmacokinetic (PK) 
assessments
X
See Notes
See Table 5.5.1-1 and Table 5.5.1-2 for 
Q2W.
See Table 5.5.1-3 for Q4W; see Table 
5.5.1-4/Table 5.5.1-5 for Part D and Part 
E.
Protocol Amendment No. 15
Date: 16-Feb-2024
145
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Table 5.1-3:
Follow-up Procedural Outline Parts A Through E
Procedure
Clinical Follow-up
Survival Follow-up
Notes
FU 1 
30 daysa
(5 days)
FU 2
60 daysa
(5 days)
FU 3
135 daysa
(5 days)
Begins After Completion of 
Clinical Follow-up
Every 12 wks
(2 wks) up to 5 yrs after 
FIRST dose of study drug
Immunogenicity (ADA) 
assessments
X
See Notes
See Table 5.5.1-1 and Table 5.5.1-2 for 
Q2W.
See Table 5.5.1-3 for Q4W; see Table 
5.5.1-4/Table 5.5.1-5 for Part D and Part 
E. 
Efficacy Assessments
Diagnostic imaging
X
See Notes
X
See Notes
Diagnostic imaging required by method 
used at baseline; an unconfirmed PR, 
unconfirmed CR, or unconfirmed PD 
must be confirmed 4 weeks after initial 
assessment.
Q12W diagnostic imaging must be 
performed in subjects who discontinue 
study treatment, at Investigator’s 
discretion, with CR, PR, or SD by 
RECIST v1.1, until disease progression. 
Images will be acquired until withdrawal 
of consent, death, or initiation of another 
anticancer treatment.
Response assessment
X
See Notes
Assessed by RECIST v1.1; see Appendix 
2.
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Table 5.1-3:
Follow-up Procedural Outline Parts A Through E
Procedure
Clinical Follow-up
Survival Follow-up
Notes
FU 1 
30 daysa
(5 days)
FU 2
60 daysa
(5 days)
FU 3
135 daysa
(5 days)
Begins After Completion of 
Clinical Follow-up
Every 12 wks
(2 wks) up to 5 yrs after 
FIRST dose of study drug
Survival Status
Assessment of subject survival 
status
X
See Notes
Subject status will be assessed by either a 
clinic visit or telephone contact. The 
nature and start dates of any new 
anticancer therapies during this period 
will be recorded.
a After last dose of study drug.
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5.2
Study Materials
The following materials will be provided at study start:
NCI CTCAE v4.0
BMS-986016, BMS-986213, and BMS-936558 IBs
Pharmacy binder
Laboratory manuals for collection and handling of blood (including PK, immunogenicity, and 
biomarkers) and tissue specimens
Holter monitor, associated supplies, and manual
IVRS manual
Enrollment worksheets
Serious Adverse Event forms
Pregnancy Surveillance forms
5.3
Safety Assessments
Adverse events will be assessed continuously during the study and for 135 days after the last 
treatment. Adverse events will be evaluated according to the NCI CTCAE v4.0 and should be 
followed per requirements in Sections 6.1.1 and 6.2.1. Adverse events will be coded using the 
most current version of MedDRA and reviewed for potential significance and importance. 
Protocol-specified assessments are described in Table 5.1-1 (Screening Procedural Outline), Table 
5.1-2 (On-treatment Procedural Outline), and Table 5.1-3 (Follow-up Procedural Outline).
5.3.1
Laboratory Test Assessments
A local laboratory will perform the analyses and will provide reference ranges for these tests. 
Investigators must document their review of each laboratory safety report.
Clinical laboratories will be assessed at the time points indicated in Table 5.1-1 (Screening 
Procedural Outline), Table 5.1-2 (On-treatment Procedural Outline), and Table 5.1-3 (Follow-up 
Procedural Outline). 
At screening, sites should collect samples during the timeframe indicated in Table 5.1-1 and ensure 
that results required for eligibility are verified prior to registration. During treatment, unless 
otherwise indicated in Table 5.1-2, results of clinical laboratory tests must be reviewed prior to 
dosing.
The following clinical laboratory tests will be performed:
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
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Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Creatinine clearancea (screening only)
Blood urea nitrogen (BUN)
Glucose
Amylase
HbA1c (obtain during screening to establish 
baseline in subjects with type 2 diabetes, then as 
clinically indicated)
a Cockcroft-Gault formula
Lipase
C-reactive protein (CRP)
Albumin
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Magnesium
Phosphorus
Endocrine Panel
Thyroid-stimulating hormone (TSH) with reflex to free triiodothyronine (T3) and free 
thyroxine (T4) as applicable
Subjects with controlled hyperthyroidism must be negative for thyroglobulin and thyroid 
peroxidase antibodies and thyroid stimulating (receptor) immunoglobulin (screening only).
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase/leukocyte count
Microscopic examination of the sediment if blood, protein, or leukocyte esterase are positive 
on the dipstick
Serology (screening only)
Hepatitis B surface antigen (HBsAg, Australia antigen) and/or hepatitis B core antigen
Hepatitis D antibody (for hepatitis B infected HCC subjects only)
Test for quantitative hepatitis B viral load (by polymerase chain reaction [PCR]) (for HCC 
subjects only)
Test for quantitative hepatitis C viral load (by PCR) 
HIV-1, -2 antibody
For those subjects receiving on-going treatment with BMS-986016 and nivolumab, 
 elevations will require the subject to undergo a cardiac evaluation. Following 
this evaluation, determination of further treatment will be based on the discussion with the 
BMS Medical Monitor or designee.
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Reproductive Analyses
Pregnancy test:  serum or urine (minimum sensitivity of urine pregnancy test of 25 IU/L of 
either total human chorionic gonadotropin (hCG) or the beta fraction)
Home pregnancy test kits
Follicle-stimulating hormone (FSH; if needed to document postmenopausal status as defined 
in Section 3.3.3)
Other Analyses
Various serologic tumor markers, gene mutation status, and additional analyses are required 
dependent upon the subject’s tumor type as listed in Table 5.3.1-1. With the exception of the 
serologic tumor markers, the assessments do not need to be performed if the lab results from 
previous testing are available to be submitted to the Sponsor.
Table 5.3.1-1:
Biomarkers by Tumor Type: All Cohorts Except for Subjects 
Crossing Over or Rechallenged 
Tumor Type
Matrix
Lab Test
Assessment
Time point
Colorectal
Blood
Serologic Tumor 
Marker
CEAa
Multiple
Tumor Tissue
Gene Mutation 
Status
EGFRb
K-RAS
MSIc
Screening
Gastric
Blood
Serologic Tumor 
Marker
CEAa
Multiple
Tumor Tissue
Gene Amplification 
Status
HER-2d
Screening
Tumor Tissue
Real Time qPCRe
and/or EBER ISHi
(ICH also allowed 
but not preferred)
EBVf
Screening
Germ Cell
Blood
Serologic Tumor 
Marker
βhCGg
AFPh
Multiple
HNC
Tumor Tissue
p16 IHC and/or HPV 
ISHi
HPVj
Screening 
HCC
Blood
Quantitative PCR 
(qPCR)
HBV or HCV 
viral loadn
Multiple 
Blood
Serologic Tumor 
Marker 
AFPh
Multiple 
Melanoma
Tumor Tissue
Gene Mutation 
Status
BRAF
Screening
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Table 5.3.1-1:
Biomarkers by Tumor Type: All Cohorts Except for Subjects 
Crossing Over or Rechallenged 
Tumor Type
Matrix
Lab Test
Assessment
Time point
NSCLC
Tumor Tissue
Gene Mutation 
Status
ALKk
K-RAS
EGFRb
Screening
Ovarian
Blood
Serologic Tumor 
Marker
CA125l
Multiple
Prostate
Blood
Serologic Tumor 
Marker
PSAm
Multiple
a CEA:  carcinoembryonic antigen.
b EGFR:  epidermal growth factor receptor.
c MSI:  microsatellite instability.
d HER-2:  human epidermal growth factor receptor 2 amplification status via IHC and/or ISH.
e Real-time qPCR:  real-time quantitative polymerase chain reaction for BamH1-A Reading Frame-1 (BARF1) gene.
f EBV:  Epstein-Barr virus.
g βhCG:  beta-human chorionic gonadotropin.
h AFP:  alpha-fetoprotein.
i
ISH:  in situ hybridization.
j
HPV:  human papilloma virus.
k ALK:  anaplastic lymphoma kinase.
l
CA125:  cancer antigen 125.
m PSA:  prostate-specific antigen.
n HBV/HCV:  Hepatitis B virus or hepatitis C virus load, depending on the underlying infection, if any.
Note: As of Protocol Amendment 14, rechallenge is not permitted.
Additional measures including nonstudy-required laboratory tests should be performed as 
clinically indicated.
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism as agreed upon between the 
Investigator and BMS (eg, provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the Investigator must be recorded on the 
appropriate AE page of the CRF (see Section 6.3).
5.4
Efficacy Assessments
5.4.1
Imaging Assessment for the Study
As described in Section 5.1, images will be collected during study treatment and acquired until 
withdrawal of consent, death, or initiation of another anticancer treatment. 
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Images will be submitted to an imaging central lab. Sites should be trained prior to scanning the 
first study participant. Image acquisition guidelines and submission process will be outlined in the 
protocol. Imaging manual will be provided by the core lab. 
Contrast-enhanced CT scans acquired on dedicated CT equipment is preferred for this study. CT 
scans with contrast of the chest, abdomen, and pelvis is to be performed for tumor assessments. 
CT scans should be acquired with 5-mm slices with no intervening gap (contiguous). Should a 
subject have a contraindication for CT IV contrast, a noncontrast CT of the chest and a contrast-
enhanced MRI of the abdomen and pelvis may be obtained. MRIs should be acquired with slice 
thickness of 5 mm with no gap (contiguous). Every attempt should be made to image each subject 
using an identical acquisition protocol on the same scanner for all imaging time points.
MRI of brain is required at screening only for subjects with a history of brain metastasis or as 
clinically indicated. MRI brain scans at least every 12 weeks during on-study treatment and follow-
up periods are required only if there is a prior history of lesions or if there are new signs and 
symptoms that suggest CNS involvement, if applicable 
Bone scans can be used to evaluate metastatic disease, if applicable.
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 Investigator as per standard 
medical/clinical judgment.
Tumor assessments at other time points may be performed, if clinically indicated, and should be 
submitted to the central imaging vendor as soon as possible. Unscheduled CT/MRI should be 
submitted to central imaging vendor. X-rays and bone scans that clearly demonstrate interval 
progression of disease, eg, most commonly as unequivocal lesions that are unmistakably new since 
the prior CT/MRI, should be submitted to central imaging vendor. Otherwise, they do not need to 
be submitted centrally.
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled time points and/or at an outside institution) should be collected for 
RECIST v1.1 tumor assessment and submitted to the BICR.
5.4.2
Efficacy Assessment for the Study
Efficacy will be evaluated in Parts A and B (dose escalation) as well as in Parts A1, C, and D 
(cohort expansion) and Part E. Changes in tumor measurements and tumor response at the time of 
each assessment will be determined by the Investigator based on RECIST v1.1 (see Appendix 2).55
In addition, the longest diameter of any new measureable lesions will be captured at each time 
point. 
In Part C melanoma prior IO and NSCLC prior IO, and Part D and Part E subjects, all available 
scans on the most recent prior anti-PD-1-containing regimen, including the baseline scan (prior to 
starting anti-PD-1) and scans after the last dose of anti-PD-1 but before the start of any intervening 
therapy, will be collected and submitted to a central imaging vendor. At minimum, the following 
time points are to be submitted:  1) pretreatment scan; 2) nadir scan (if applicable); 3) scan 
documenting progression (does not need to be submitted if it has already been submitted as the 
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baseline scan for the trial); 4) scan confirming progression (if applicable, it must be at least 4 weeks 
after the scan documenting progression and without intervening therapy and does not need to be 
submitted if it has already been submitted as the baseline scan for the trial); and 5) treatment 
beyond progression scan (if applicable, as this is the last scan on treatment if the subject was treated 
beyond a progression confirmation scan and does not need to be submitted if it has already been 
submitted as the baseline scan for the trial).
The baseline assessment during the screening period requires chest CT and CT or MRI scans of 
the abdomen, pelvis, and other anatomic regions as indicated by individual subject’s tumor type 
and/or disease history. Subsequent time points require scans of the chest, abdomen, and pelvis, as 
well as other anatomic regions that were scanned at baseline based on the individual subject’s 
tumor type and/or disease history. Scans of the brain are otherwise required as clinically indicated. 
Individual subject’s best overall response (BOR) will be determined as appropriate. 
Tumor status will be assessed at baseline during treatment (every 8 weeks regardless of dose 
delays) during the Treatment period. Tumor assessments will continue every 12 weeks during the 
Clinical Follow-up and Survival periods until disease progression in subjects who discontinue 
study treatment, at the Investigator’s discretion, with CR, PR, or SD by RECIST v1.1. CT and 
MRI scans will be read and assessed locally per RECIST v1.1. All imaging scans must be 
de-identified and archived in their native DICOM format as part of the subject’s study file. At the 
Sponsor’s discretion, scans may be collected centrally to be reviewed by independent radiologists. 
Efficacy assessment of subjects who have been rechallenged after achieving a response or SD will 
be conducted in a separate analysis. Scans for participants who are rechallenged should be 
performed as per the on-treatment schedule in Table 5.1-2 and submitted to the central imaging 
vendor for collection. However, the BOR in the first treatment may be considered in the study 
analysis. Subjects who cross over from BMS-986016 monotherapy (Part A1) to combination 
therapy are not to be included in the analysis of any expansion cohorts with combination therapy. 
As of Protocol Amendment 14, rechallenge is not permitted.
5.4.3
Primary Efficacy Assessment
The BOR based on BICR assessment using RECIST v1.1 will be the primary assessment, where 
applicable, in selected cohorts in Parts C, D, and E.
5.4.4
Secondary Efficacy Assessments
The BOR will be assessed by investigator using RECIST v1.1. OS in Part D1 will also be assessed 
as a secondary efficacy measure.
5.4.5
Exploratory Efficacy Assessments
OS will be assessed as an exploratory efficacy measure in parts other than Part D1. 
5.5
Pharmacokinetic Assessments
Serum samples for BMS-986016 and nivolumab (BMS-936558) PK and ADA assessments will 
be collected for all subjects. 
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5.5.1
Pharmacokinetics: Collection and Processing
A detailed schedule of PK and ADA evaluations is provided in Table 5.5.1-1 and Table 5.5.1-2 for 
Q2W dosing and in Table 5.5.1-3, Table 5.5.1-4, and Table 5.5.1-5 for Parts B and C (bladder 
cohort) for Q4W dosing and for Part D and Rechallenge (As of Protocol Amendment 14, 
rechallenge is not permitted) and Part E. All time points are relative to the start of BMS-986016 
study drug administration except for Part D, which is from the start of the coadministration of 
nivolumab and BMS-986016 or BMS-986213 infusion. Predose samples should be taken within 
30 minutes before the start of dose administration. End-of-infusion samples should be taken just 
prior to the end of infusion (preferably within 2 minutes). Further details of sample collection, 
processing, and shipment will be provided in the laboratory procedures manual. On-treatment PK 
samples are intended to be drawn relative to actual dosing days; if a dose occurs on a different day 
within the cycle due to delays or minor schedule adjustments, PK samples should be adjusted 
accordingly. As per Protocol Amendment 14: PK sample collection upon the occurrence of a ≥ 
Grade 3 AE is not required.
Table 5.5.1-1:
PK and ADA Sampling Schedule for BMS-986016 and Nivolumab 
for Dose Escalation Parts A and B Q2W Dosing and Expansion 
Parts A1 and C (Approximately the First 6 Subjects in Each Cohort 
Only)
Study Day of 
Sample 
Collection
Event
(Relative 
to BMS-
986016)
Time 
(Relative to 
Start of 
BMS-986016 
Infusion) 
Hour:Min
BMS-986016 
PK Sample
(All 
Subjects)
Nivolumab 
PK Sample
(All Subjects 
Except Part 
A and A1)
BMS-
986016 
ADA 
Sample (All 
Subjects)
Nivolumab 
ADA Sample 
(All Subjects 
Except Part 
A and A1)
Cycle 1
1
Predosea
00:00
X
X
X
X
1
EOI b
01:00 b
X
X
1
04:00
X
2
24:00
X
5c
96:00
X
8d
168:00
X
15
Predosea
00:00
X
X
X
X
29
Predosea
00:00
X
X
X
X
43
Predosea
00:00
X
X
X
X
Cycle 2
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00 b
X
X
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Table 5.5.1-1:
PK and ADA Sampling Schedule for BMS-986016 and Nivolumab 
for Dose Escalation Parts A and B Q2W Dosing and Expansion 
Parts A1 and C (Approximately the First 6 Subjects in Each Cohort 
Only)
Study Day of 
Sample 
Collection
Event
(Relative 
to BMS-
986016)
Time 
(Relative to 
Start of 
BMS-986016 
Infusion) 
Hour:Min
BMS-986016 
PK Sample
(All 
Subjects)
Nivolumab 
PK Sample
(All Subjects 
Except Part 
A and A1)
BMS-
986016 
ADA 
Sample (All 
Subjects)
Nivolumab 
ADA Sample 
(All Subjects 
Except Part 
A and A1)
15
Predosea
00:00
X
X
Cycle 3
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00 b
X
X
1
04:00
X
2
24:00
X
5 c
96:00
X
8 d
168:00
X
15
Predosea
00:00
X
X
Alternate Treatment Cycles (Starting from Cycle 5 to treatment discontinuation or maximum of 24 months 
of treatment, whichever comes first)
1
Predosea
00:00
X
X
X
X
End of Treatment and Follow-up Period
135 Day FUe
X
X
X
X
a Predose: All predose samples for nivolumab and BMS-986016 should be taken prior to the start of nivolumab 
infusion.
b EOI: End of Infusion. EOI samples for both nivolumab and BMS-986016 should be collected after the end of the 
BMS-986016 infusion. This sample should be taken immediately prior to stopping the infusion (preferably within 
2 minutes prior to EOI). If the EOI is delayed to beyond the nominal infusion duration, the collection of this sample 
should also be delayed accordingly. 
c Day 5 sample may be taken during Days 3-5 of a cycle.
d Day 8 sample may be taken during Days 7-9 of a cycle.
e  FU: Follow-up.
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Table 5.5.1-2:
PK and ADA Sampling Schedule for BMS-986016 and Nivolumab 
for Dose Expansion Part C Q2W Dosing (After First 6 Subjects) 
and for Cohort with Crossover or Rechallenge 
Study Day of 
Sample 
Collection
Event
(Relative 
to BMS-
986016)
Time 
(Relative to 
Start of 
BMS-986016 
Infusion) 
Hour:Min
BMS-986016 
PK Sample
(All 
Subjects)
Nivolumab 
PK Sample
(All Subjects 
Except Part 
A1)
BMS-
986016 
ADA 
Sample 
(All 
Subjects)
Nivolumab 
ADA Sample 
(All Subjects 
Except Part 
A1)
Cycle 1
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00 b
X
X
15
Predosea
00:00
X
X
X
X
29
Predosea
00:00
X
X
X
X
43
Predosea
00:00
X
X
Cycle 2
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00 b
X
X
Cycle 3
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00b
X
X
Alternate Treatment Cycles (Starting From Cycle 5 to treatment discontinuation or maximum of 24 
months of treatment, whichever comes first)
1
Predosea
00:00
X
X
X
X
End of Treatment and Follow-up Period
135 Day FUc
X
X
X
X
a Predose: All predose samples for nivolumab and BMS-986016 should be taken prior to the start of nivolumab 
infusion.
b EOI: End of Infusion. EOI samples for both nivolumab and BMS-986016 should be collected after the end of the 
BMS-986016 infusion. This sample should be taken immediately prior to stopping the infusion (preferably within 
2 minutes prior to EOI). If the EOI is delayed to beyond the nominal infusion duration, the collection of this sample 
should also be delayed accordingly. 
c   FU: Follow-up.
Note: As of Protocol Amendment 14, rechallenge is not permitted.
.
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Table 5.5.1-3:
PK and ADA Sampling Schedule for BMS-986016 and Nivolumab 
for Dose Escalation Parts B and C (Bladder Cohort Approximately 
First 6 Subjects) with Q4W Regimen
Study Day of 
Sample 
Collection
Event
(Relative 
to BMS-
986016)
Time 
(Relative to 
Start of 
BMS-986016 
Infusion) 
Hour:Min
BMS-986016 
PK Sample
Nivolumab 
PK Sample
BMS-
986016 
ADA 
Sample 
Nivolumab 
ADA Sample 
Cycle 1
1
Predosea
00:00
X
X
X
X
1
EOI b
01:00 b
X
X
1
04:00
X
2
24:00
X
5 c
96:00
X
8 d
168:00
X
15
336:00
X
29
Predosea
00:00
X
X
X
X
Cycle 2
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00 b
X
X
29
Predosea
00:00
X
X
Cycle 3
1
Predosea
00:00
X
X
X
X
1
EOI b
01:00 b
X
X
1
04:00
X
2
24:00
X
5 c
96:00
X
8 d
168:00
X
15 e
336:00
X
29
Predosea
00:00
X
X
Alternate Treatment Cycles (Starting From Cycle 5 to treatment discontinuation or maximum of 24 
months of treatment, whichever comes first)
1
Predosea
00:00
X
X
X
X
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Table 5.5.1-3:
PK and ADA Sampling Schedule for BMS-986016 and Nivolumab 
for Dose Escalation Parts B and C (Bladder Cohort Approximately 
First 6 Subjects) with Q4W Regimen
Study Day of 
Sample 
Collection
Event
(Relative 
to BMS-
986016)
Time 
(Relative to 
Start of 
BMS-986016 
Infusion) 
Hour:Min
BMS-986016 
PK Sample
Nivolumab 
PK Sample
BMS-
986016 
ADA 
Sample 
Nivolumab 
ADA Sample 
End of Treatment and Follow-up Period
135 Day FUf
X
X
X
X
a Predose: All predose samples for nivolumab and BMS-986016 should be taken prior to the start of nivolumab 
infusion.
b EOI: End of Infusion. EOI samples for both nivolumab and BMS-986016 should be collected after the end of the 
BMS-986016 infusion. This sample should be taken immediately prior to stopping the infusion (preferably within 
2 minutes prior to EOI). If the EOI is delayed to beyond the nominal infusion duration, the collection of this sample 
should also be delayed accordingly. 
c Day 5 sample may be taken during Days 3-5 of a cycle.
d Day 8 sample may be taken during Days 7-9 of a cycle.
e Day 15 sample may be taken during Days 14-16 of a cycle.
f   FU: Follow-up.
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Table 5.5.1-4:
PK and ADA Sampling Schedule for BMS-986016 and Nivolumab 
for Dose Expansion Part C Bladder Cohort (After Approximately 
First 6 Subjects), Part D1 Arm 1, Part D1 (Arm 2 and Arm 3, After 
First 12 Subjects), Part D2, Part E, and Rechallenge
Study Day of 
Sample 
Collection
Event
(Relative 
to BMS-
986016)
Time 
(Relative to Start 
of 
BMS-986016 
+Nivolumab 
Coadministration)
OR BMS-986213 
Infusion
Hour:Min
BMS-
986016 PK 
Sample
Nivolumab 
PK Sample
BMS-
986016 
ADA 
Sample 
Nivolumab 
ADA Sample 
Cycle 1
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00b
X
X
29
Predosea
00:00
X
X
X
X
Cycle 2
1
Predosea
00:00
X
X
X
X
Cycle 3
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00b
X
X
Alternate Treatment Cycles (Starting From Cycle 5 to treatment discontinuation or maximum of 24 
months of treatment, whichever comes first)
1
Predosea
00:00
X
X
X
X
End of Treatment and Follow-up Period
135 Day FUc
X
X
X
X
a Predose: All predose samples for nivolumab and BMS-986016 should be taken prior to the start of the 
coadministration of nivolumab and BMS-986016 infusion.
b EOI: end of infusion. EOI samples for both nivolumab and BMS-986016 should be collected after the end of the 
coadministration or BMS-986213 infusion. This sample should be taken immediately prior to stopping the infusion 
(preferably within 2 minutes prior to EOI). If the EOI is delayed to beyond the nominal infusion duration, the 
collection of this sample should also be delayed accordingly. 
c   FU: Follow-up.
Note: As of Protocol Amendment 14, rechallenge is not permitted.
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Table 5.5.1-5:
PK and ADA Sampling Schedule for BMS-986016 and Nivolumab 
for Part D1 (Arm 2 and 3, First 12 Subjects) 
Study Day of 
Sample 
Collection
Event
(Relative 
to BMS-
986016)
Time 
(Relative to Start 
of BMS-986016 +
Nivolumab 
Coadministration
OR BMS-986213 
Infusion)  
Hour:Min
BMS-
986016 PK 
Sample
Nivolumab 
PK Sample
BMS-
986016 
ADA 
Sample 
Nivolumab 
ADA Sample 
Cycle 1
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00b
X
X
1
04:00
X
8c
168:00
X
15d
336:00
X
29
Predosea
00:00
X
X
X
X
Cycle 2
1
Predosea
00:00
X
X
X
X
Cycle 3
1
Predosea
00:00
X
X
X
X
1
EOIb
01:00b
X
X
Alternate Treatment Cycles (Starting From Cycle 5 to treatment discontinuation or maximum of 24 
months of treatment, whichever comes first)
1
Predosea
00:00
X
X
X
X
End of Treatment and Follow-up Period
135 Day FUe
X
X
X
X
a Predose: All predose samples for nivolumab and BMS-986016 should be taken prior to the start of the 
coadministration of nivolumab and BMS-986016 infusion.
b EOI: End of Infusion. EOI samples for both nivolumab and BMS-986016 should be collected after the end of the 
coadministration or BMS-986213 infusion. This sample should be taken immediately prior to stopping the infusion 
(preferably within 2 minutes prior to EOI). If the EOI is delayed to beyond the nominal infusion duration, the 
collection of this sample should also be delayed accordingly. 
c Day 8 sample may be taken during Days 7-9 of a cycle.
d Day 15 samples may be taken during Days 14-16 of a cycle.
e FU: Follow-up.
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5.5.2
Pharmacokinetic Sample Analyses
The serum samples will be analyzed for BMS-986016 and nivolumab by a validated immunoassay. 
In addition, selected serum samples may be analyzed by an exploratory orthogonal method (eg, 
liquid chromatographymass spectrometry [LC-MS]/MS) that measures total BMS-986016 and/or 
nivolumab, but the generated data will not be reported. Only results generated from the validated 
immunoassay method will be reported. Potential results generated from any orthogonal method 
are intended as informational for technology exploration purposes and will not be reported.
5.6
Biomarker Assessments
Not applicable.
5.7
Exploratory Biomarker Assessments
 
 
 
 Detailed schedules of pharmacodynamic evaluations are 
provided in Table 5.7-1 and Table 5.7-2. For Parts D and E, sample collection will be per Table 
5.7-3 and Table 5.7-4, respectively. Details regarding the tumor tissues requirements for subjects 
in all parts of the study are provided in Table 5.7-5. Details regarding the biomarkers to be analyzed 
are provided in the sections that follow.
Further details of blood collection and processing will be provided to the site in the procedure 
manual.
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Table 5.7-1:
Part A and B (Dose Escalation): Biomarker Sampling Schedule (for All Subjects in Each Dose Level 
Either Q2W or Q4W Dosing)
Collection 
Timing
Serum
Tumor
Study Day
Soluble 
Biomarkers
Serum 
Biomarkers
Fresh 
Tumor 
Biopsyb
Screening
Xb
Day 1 
X
Day 5c
X
Day 8d
X
Day 15e
X
Day 29
X
X b
Day 43e
X
Cycle 2
Day 1
X
Upon Progression
Upon progressionf
X
X
Upon Drug-related AE
Upon occurrence 
of Grade 3 drug-
related AE 
X
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b During the screening period, all participants must have tumor tissue submitted,
 
. An on-treatment (predose Days 23-31) 
biopsy is optional but encouraged.
c Day 5 visit can occur on Day 3 or Day 4.
d Day 8 visit can occur on Day 7 or Day 9.
e For Q4W dosing, Day 15 and Day 43 samples are not predose.
f Optional: to be collected upon confirmation of PD.
Note: All samples are to be drawn predose.
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Table 5.7-2:
Parts A1 and C (Cohort Expansion) and Cohorts for Crossover or Rechallenge: Biomarker Sampling
Collection Timing
Serum
Tumor
Study Day
Soluble Biomarkers
(Serum 
Biomarkers)b
“Fresh” 
Tumor
Biopsyd
Screening
X d
Cycle 1
Day 1 
X
Day 5e
X
Day 8f
X
Day 15
X
Day 29
X
Xd
Cycles 2, 3, 5, 7, 9, and 11
Day 1
X
Upon Progression
Upon progressiong
X
X
Upon Drug-related AE 
Upon occurrence of 
Grade 3 drug-
related AE 
X
.
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d During the screening period, all participants must have tumor tissue submitted,
 
. 
 
. For other sites, on-treatment biopsy is optional but encouraged.
e Day 5 visit can occur on Day 3 or Day 4.
f Day 8 visit can occur on Day 7 or Day 9.
g Optional: to be collected upon confirmation of PD.
NOTE:  All samples are to be drawn predose. As of Protocol Amendment 14, rechallenge is not permitted.
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Table 5.7-3:
Biomarker Sampling for Part D Melanoma Prior IO Extended Expansion and Rechallenge 
Collection 
Timing
Serum
Tumorb
Study Day
Soluble 
Biomarkers
(Serum 
Biomarkers)
Fresh 
Tumor 
Biopsy
Screening
X b
Cycle 1
Day 1 
X
Day 15
X
Day 29
X
X b
Day 43
X
Cycle 2 and Alternate Treatment Cycles (Starting From Cycle 3 to treatment discontinuation or maximum of 24 months of treatment)
Day 1
X
Upon Progression
Upon 
progressiond
X
Upon Drug-related AE 
Upon occurrence 
of Grade 3 
drug-related AE
X
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b During the screening period, all participants must have tumor tissue submitted,
 
. Tumor tissue should be sent to central 
laboratory within 1 week from Cycle 1 Day 1 (see Table 5.7-5 for details). On-treatment (predose Days 23-31) biopsy is optional.
d Optional: to be collected upon confirmation of PD.
NOTE: All samples to be drawn predose. As of Protocol Amendment 14, rechallenge is not permitted.
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Table 5.7-4:
Biomarker Sampling for Part E Exposure/Response Expansion Q4W Dosing and Rechallenge
Collection
Serum
Tumorb
Study Day
Soluble 
Biomarkers
(Serum 
Biomarkers)
Fresh Tumor 
Biopsy
Screening
X (fresh or 
archived)
Cycle 1
Day 1
X
Day 15
X
Day 29
X
X
Day 43
X
Cycle 2 and Alternate Treatment Cycles (Starting From Cycle 3 to treatment discontinuation or maximum of 24 months of treatment)
Day 1
X
Upon Progression
Upon 
progressiond
X
Upon Drug-related AE 
Upon 
occurrence of 
Grade 3 
drug-related 
AE
X
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b During the screening period, all participants must have tumor tissue submitted,
 
. On-treatment (predose Days 23-31) 
biopsy is encouraged but optional.
d Optional: to be collected upon confirmation of PD.
Note: As of Protocol Amendment 14, rechallenge is not permitted. 
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Table 5.7-5:
Tumor Tissue Requirements
Study Part
Parts A and B
(Dose Escalation)
Parts A1 and C (Cohort Expansion) and D and E
Subjects
ALL Subjects
Type of Specimen
Baseline
During the screening period, all participants must have tumor tissue submitted, 
 
 
 
.
 
 
 
On-treatment 
Optional “fresh” biopsy 
predose at Day 23-31 of 
first cycle
MANDATORY 
 
 
 
Upon Progression
Optional “fresh” biopsy upon confirmation of PD
5.7.1
Soluble Biomarkers (Serum Biomarkers)
Pretreatment and on-treatment serum levels of chemokines, cytokines, and tumor-associated 
soluble proteins will be assessed by techniques that may include, but are not limited to, ELISA or 
multiplex assays. Analyses may include markers of inflammation, immune activation, host tumor 
growth factors, and tumor-derived proteins, including sLAG-3.
5.7.2
Antitumor Antibodies (Serum Biomarkers)
Treatment with BMS-986016 and nivolumab may result in the generation of novel, or an increase 
in existing, antibodies to tumor-associated antigens. An assessment of antibodies to a panel of 
> 8000 proteins will be performed using pretreatment and on-treatment serum in multiplex and
ELISA. These data will be used in a subset of subjects to explore whether antitumor antibodies are 
associated with clinical response and safety parameters, as well as to inform pharmacodynamics 
of drug administration.
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5.7.9
Tumor Biopsy Analysis
Tumor biopsy specimens will be obtained from consenting participants prior to treatment to 
characterize immune cell populations and expression of selected tumor markers. 
 
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 must be available for submission prior to randomization. Tumor 
tissue will be collected from all subjects. Immunohistochemistry will be used to assess the number 
and composition of immune infiltrates in order to define the immune cell subsets present within 
tumor tissue before and potentially after exposure to BMS-986016 and nivolumab. 
 
 
 
5.7.10
Tumor-based Biomarker Measures
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The Investigator, in consultation with the radiology staff, must determine the degree of risk 
associated with the procedure and find it acceptable. Biopsies may be done with local anesthesia 
or conscious sedation. Institutional guidelines for the safe performance of biopsies should be 
followed. Excisional biopsies may be performed to obtain tumor biopsy samples. Invasive 
procedures that require general anesthesia should not be performed to obtain a biopsy specimen. 
However, if a surgical procedure is performed for a clinical indication, excess tumor tissue may 
be used for research purposes with the consent of the subject.
5.7.11
Additional Research Collection 
This protocol will include residual sample storage for additional research.
For All US Sites:
Additional research participation is required for all investigational sites in the US.
For Non-US Sites:
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational research and 
development capability at BMS and will support as yet undefined research aims that will advance 
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our understanding of disease and options for treatment. It may also be used to support health 
authority requests for analysis and advancement of pharmacodiagnostic development to better 
target drugs to the right patients. This may also include genetic/genomic exploration aimed at 
exploring disease pathways, progression and response to treatment, etc. 
Sample Collection and Storage
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study Sponsor’s senior leaders in Research and Development (or Designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
Residual samples from tumor biopsies and biomarker collections (Table 5.7.11-1) will also be 
retained for additional research purposes.
Samples kept for future research will be stored at the BMS Biorepository in 
 or 
an independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than 15 years after 
the end of the study or the maximum allowed by applicable law.
Transfers of samples by research Sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Table 5.7.11-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Time Points for Which Residual Samples Will Be Retained
Tumor biopsy 
All
Biomarker blood collections
All
5.8
Outcomes Research Assessments
Not applicable.
5.9
Other Assessments 
5.9.1
Immunogenicity Assessments
Serum samples collected at time points identified in Table 5.5.1-1 and Table 5.5.1-2 for Q2W 
dosing, Table 5.5.1-3 for Q4W dosing, and Table 5.5.1-4 and Table 5.5.1-5 for Part D and Part E 
will be analyzed by a validated immunogenicity assay. Selected serum samples may be analyzed 
by an exploratory orthogonal method that measures anti-BMS-986016 or anti-nivolumab. 
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Potential results generated from any orthogonal method are intended as informational for 
technology exploration purposes and will not be reported.
In addition, ad hoc serum samples designated for PK or biomarker assessments may also be used 
for immunogenicity analysis if required (eg, insufficient volume for complete immunogenicity 
assessment or to follow up on suspected immunogenicity-related AE).
5.10
Results of Central Assessments
The effect of BMS-986016 on QTc interval when administered alone or in combination with 
nivolumab will be evaluated by a central reader using ECG data collected via Holter monitors 
supplied by a core laboratory; these results will be summarized at the end of the study. For the 
purposes of monitoring subject safety, Investigators will review 12-lead ECGs per the 
protocol-specified schedule (see Table 5.1-2) using their site’s standard ECG machines. 
6
ADVERSE EVENTS
An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical 
condition in a clinical investigation subject administered an investigational (medicinal) product 
and that does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of investigational product, whether or not considered 
related to the investigational product.
Events Meeting the AE Definition:
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or results from 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific judgment 
of the investigator. Note that abnormal lab tests or other safety assessments should only be reported 
as AEs if the final diagnosis is not available. Once the final diagnosis is known, the reported term 
should be updated to be the diagnosis.
Exacerbation of a chronic or intermittent preexisting condition including either an increase in 
frequency and/or intensity of the condition.
New conditions detected or diagnosed after study intervention administration, even though it may 
have been present before the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose, as a verbatim term (as reported by the Investigator), should 
not be reported as an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae and should specify 
"intentional overdose" as the verbatim term.
Events NOT Meeting the AE Definition:
Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to the 
procedure is the AE.
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Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
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 IB and/or product information for marketed products in 
his/her assessment.
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial transmission 
of the SAE data to the Sponsor.
The Investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. 
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.
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.
6.1
Serious Adverse Events
A SAE is any untoward medical occurrence that at any dose: 
Results in death
Is life-threatening (defined as an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more 
severe)
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Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect 
Is an important medical event (defined as a medical event[s] that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require intervention [eg, medical, surgical] to prevent 
one of the other serious outcomes listed in the definition above). Examples of such events include, 
but are not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization. Potential DILI 
is also considered an important medical event (see Section 6.6 for the definition of potential DILI).
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, cancer, and potential DILI are not always serious by regulatory definition, 
these events must be handled as SAEs (see Section 6.1.1 for reporting pregnancies.)
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint; if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as a SAE (see Section 6.1.1 for reporting details).
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies: 

A visit to the emergency room or other hospital department < 24 hours that does not result 
in admission (unless considered an important medical or life-threatening event)

Elective surgery, planned prior to signing consent

Admissions as per protocol for a planned medical/surgical procedure

Routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)

Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases.

Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason)
Immune-mediated AEs (IMAEs) are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which noninflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology that were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the subject’s case report form.
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6.1.1
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate in the study, all SAEs, whether related or not
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within 
135 days of discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). 
The Investigator should report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
A SAE Report Form should be completed for any event where doubt exists regarding its 
seriousness. 
If the Investigator believes that an SAE is not related to study drug but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) immediately within 24 hours. SAEs must be recorded on the SAE Report Form; 
pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The required method 
of SAE data reporting collection is through the eCRF. The paper SAE/Pregnancy Surveillance 
Forms are only intended as a back-up option when the eCRF system is unavailable/not functioning. 
In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, the 
original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term[s] initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious AE is an AE not classified as serious.
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6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug and continue 
for 135 days after discontinuation of dosing. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
Any laboratory test result that is clinically significant or meets the definition of an SAE 
Any laboratory test result abnormality that required the subject to have study drug discontinued or 
interrupted
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that, wherever possible, the clinical rather than laboratory term would be used by the 
reporting Investigator (eg, anemia vs low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives plus 30 days after product administration, the Investigator 
must immediately notify the BMS Medical Monitor/Designee of this event and complete and 
forward a Pregnancy Surveillance Form to BMS Designee within 24 hours and in accordance with 
SAE reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). If the Investigator determines a possible favorable benefit-
risk ratio that warrants continuation of study treatment or reinitiation of study treatment, a 
discussion between the Investigator and the BMS Medical Monitor/designee must occur. If, for 
whatever reason, pregnancy has ended, confirmed by negative serum pregnancy test, treatment 
may be resumed (at least 3 weeks and not greater than 6 weeks after the pregnancy has ended), 
following approvals of participant/Sponsor/IRB/IEC, as applicable.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy
follow-up procedures should be considered if indicated.
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The Investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
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.
6.5
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. See Section 6 for reporting of overdose.
6.6
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs meeting 
the defined criteria must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential DILI is defined as: 
1. Aminotransaminase (AT) (ALT or AST) elevation > 3 times ULN
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, tumor progression; acute viral hepatitis; cholestasis; preexisting 
hepatic disease; or the administration of other drug(s), herbal medications, and substances 
known to be hepatotoxic. 
Given the organ-specific nature of HCC, the definition of potential DILI is defined 
differently specifically for HCC subjects. The rationale for HCC-specific DILI language as 
follows: 1) standardization of the DILI definition so that a unified approach is taken across the 
BMS HCC program; 2) concern that the previous language may not be sensitive to capture all 
potential cases given the lack of a requirement for a concomitant elevation in transaminases and 
bilirubin and the significant increase in total bilirubin regardless of baseline value; and 3) 
alignment with the daclatasvir direct-acting antiviral agent (DAA) program, which has criteria that 
have been developed after consultation with Health Authorities for subjects with chronic HCV 
infection with underlying liver disease and therefore consistent with the patient population in this 
study.
Therefore, potential DILI for HCC subjects is defined as: 
1.
AT (ALT or AST) elevation > 10 times ULN
AND 
2. Total bilirubin > 2 times ULN or baseline value (if elevated bilirubin at study entry)
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AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, tumor progression; acute viral hepatitis; cholestasis; preexisting 
hepatic disease; or the administration of other drug(s), herbal medications, and substances 
known to be hepatotoxic. 
This change in potential DILI definition is not anticipated to pose any risk for subjects since 
management of hepatic events will follow pre-established algorithms that are not impacted by the 
DILI definition and include dose delay and/or discontinuation as well as intervention with 
immunosuppressants.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, radiologic 
exams, or any other potential safety assessment required or not required by protocol should also 
be recorded as a nonserious or SAE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
7.1
Data Monitoring Committee
A data monitoring committee (DMC) will be established to provide oversight of safety and to 
provide advice to the sponsor regarding actions the committee deems necessary for the continuing 
protection of participants. The DMC will be charged with assessing such actions in light of an 
acceptable benefit-risk profile for BMS-986016. The DMC will act in an advisory capacity to BMS 
and will monitor participant safety and evaluate the available efficacy data for the study. The 
oncology therapeutic area of BMS has primary responsibility for design and conduct of the study. 
The DMC will meet as outlined in the DMC charter or as needed on an ad hoc basis. Information 
regarding DMC membership, responsibilities, and procedures are detailed in the DMC charter. 
The DMC will be informed should a safety signal emerge and may convene an ad hoc meeting on 
its own initiative. When required, adjudicated events will be submitted to the DMC and Health 
Authorities for review. The DMC will review all available data (safety and efficacy) at each 
meeting. At the conclusion of each DMC meeting, the committee will provide the Sponsor with a 
recommendation to continue, modify, or terminate the study protocol based upon their review. 
Ultimately, decisions regarding the study protocol will be made by the Sponsor in conjunction 
with feedback from Investigators and the DMC.
7.2
Blinded Independent Central Review Committee
A BICR committee may be used in selected disease cohorts in Part C, Part D, and Part E. 
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8
STATISTICAL CONSIDERATIONS 
8.1
Sample Size Determination
8.1.1
Dose Escalation (Parts A and B )
Sample size at each dose depends on observed toxicity and cannot be precisely determined. Parts 
A and B will have 3 to 9 (15 in BLRM-Copula in Part B) subjects in each cohort.
In the Part B dose escalation using BLRM-Copula, the sample size at each dose depends on 
observed toxicity and posterior inference. Initially, approximately 3 subjects will be treated at the 
starting dose level (using the new BLRM-Copula design) of BMS-986016 in combination with 
nivolumab. Due to the potential for early discontinuation, an additional subject(s) may be enrolled 
to ensure approximately 3 evaluable subjects at each dose level.
Cohort tolerability assessment and subsequent dose recommendation will occur when 2 evaluable 
subjects within a set have completed the DLT evaluation period. If the potential DLT occurring in 
any third evaluable subject regarding the specific dose level does not influence the dose 
recommendation by BLRM-Copula, the BLRM-Copula recommended next dose level may 
proceed without waiting for the third subject to complete the corresponding DLT observation 
period, after discussion and agreement between Sponsor and Investigators. Continuous 
reassessment of dose recommendation by BLRM-Copula in the combination phase will be carried 
out at each dose level.
During dose escalation, BLRM could recommend escalating to the next dose or skipping an entire 
dose level altogether. In that case, a new cohort of approximately 3 subjects will be treated at the 
recommended new dose. BLRM could also recommend staying at the same dose level, in which 
case an additional increments of approximately 3 subjects will be treated at that dose. At least 6 
DLT-evaluable subjects will be treated in the selected dose cohort(s) chosen for expansion. Up to 
15 subjects may be treated at any dose level for further evaluation of safety and 
pharmacodynamic/PK parameters as required.
8.1.2
Cohort Expansion Monotherapy (Part A1)
A sample size of 6 subjects per cohort allows for estimation of the proportion of subjects with 
objective response (ie, BOR of CR + PR) within a cohort such that the maximum distance between 
the estimated rate and either limit of the exact 2-sided 95% Clopper-Pearson confidence interval 
(CI) is 47.5%. 
A sample size of 12 subjects per cohort allows for estimation of the proportion of subjects with 
objective response (ie, BOR of CR + PR) within a cohort such that the maximum distance between 
the estimated rate and either limit of the exact 2-sided 95% Clopper-Pearson CI is 32.2%
8.1.3
Cohort Expansion (Part C)
The objective of this expansion in combination with nivolumab is to support further clinical testing 
by demonstrating adequate safety and tolerability as well as favorable benefit-risk by assessing 
preliminary efficacy measured by ORR and other clinically relevant efficacy measures such as 
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DOR and DCR. However, the sample size is strictly based on efficacy, specifically based on the 
target ORR relative to historic ORR.
Disease- and prior IO therapy–restricted cohorts will be investigated in the Part C cohort 
expansion: NSCLC progressed on IO therapy; melanoma progressed on anti-PD-1/anti-PD-L1; 
RCC naive to IO therapy; NSCLC naive to IO therapy; melanoma first line; SCCHN naive to IO 
therapy; bladder naive to IO therapy; gastric cancer naive to IO therapy; and HCC naive to IO 
therapy. The NSCLC progressing on IO therapy cohort will be analyzed as a whole and as 2 
separate subgroups, refractory and relapsed, as defined in Section 3.3.1. All disease cohorts will 
be handled independently, and there will be no multiplicity adjustment.
A multistage design will be used as a guide for each expansion cohort in order to decide whether 
the treatment of BMS-986016 in combination with nivolumab warrants more extensive 
development. At first, a 2-stage design57,58 with a reasonable false positive rate (eg, < 10%) and 
false negative rate (eg, < 10%) will be used for decision making based on assumptions of true 
(target) and historic/standard-of-care response rate for each cohort. The assumed historic and target 
response rates may change over time and may need to be adjusted by the time of response data 
from this study are available. Using a 2-stage design provides an option to stop early for futility as 
well as a signal of preliminary antitumor activity for strong-go early on. Enrollment may continue 
into stage 2 while the planned number of subjects for Stage 1 are followed for efficacy evaluable 
tumor assessments. There will be no stopping of a disease cohort for efficacy, although early plan 
for the next stage of clinical development may be initiated.
The ORRs considered to be of clinical value for further expansion of selected populations, sample 
size, and operational characteristics of using a 2-stage design, as an example, are provided in Table 
8.1.3-1, although this is not used for statistical hypothesis testing.
Table 8.1.3-1:
Example of a 2-stage Design Characteristics
Cohort
Historic/
Target 
Rate (%)
Stage
Cum.
Sample 
Size
Conclude 
Futility if 
Ra
Conclude 
Efficacy if
R
PETb or 
Futility 
(%)
PEEc or 
Efficacy 
(%)
Gastric
IO naive 
10/30
1
2
15
26
1
5
4
6
55
70
HCC 
IO naive 
Melanoma progressed on 
anti-PD-1/PD-L1
RCC 
IO naive
25/50
1
2
11
26
2
9
6
10
46
50
NSCLC IO refractory
5/20
1
2
12
37
0
3
3
4
54
44
NSCLC IO relapsed
NSCLC 
20/45
1
14
3
7
70
45
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Table 8.1.3-1:
Example of a 2-stage Design Characteristics
Cohort
Historic/
Target 
Rate (%)
Stage
Cum.
Sample 
Size
Conclude 
Futility if 
Ra
Conclude 
Efficacy if
R
PETb or 
Futility 
(%)
PEEc or 
Efficacy 
(%)
1/2L, IO naive
2
25
7
8
Melanoma 
1L 
40/65
1
2
13
28
5
14
10
15
57
28
SCCHN
IO naive
20/40
1
2
20
36
4
10
8
11
63
58
Bladder
IO naive
a R is the cumulative number of responses at the end of stage.
b PET: probability of early termination.
c PEE: probability of early expansion.
Once there is preliminary evidence of the treatment effect that may represent substantial 
improvement over available therapies, sufficient additional subjects will be treated to demonstrate 
a substantial and clinically meaningful effect in ORR that is supported by duration of the effect. 
The total sample size at this stage will be determined based on the ability to produce a CI, which 
would exclude an ORR of the historic response, and to provide sufficient information for a reliable 
understanding of the safety profile. With 90 to 120 subjects in total, this design yields a less than 
5% 2-sided type I error rate and at least 80% power depending on tumor type with specified 
historic/standard of care and target rates. Table 8.1.3-2 summarizes the 95% exact CI for various 
observed ORRs with sample sizes of 90, 100, and 120.
Guided by Table 8.1.3-1 initially, approximately 11 RCC subjects, for example, will be treated in 
Stage 1. Assuming the true response rate is 50% when treated with BMS-986016 in combination 
with nivolumab, if there are 6 or more responses in 11 subjects, it may be decided to expand further 
up to approximately 90 subjects in total after careful evaluation of all available data, including 
DOR and safety profile. The probability of early decision to expand further for efficacy is 
approximately 50% if, in fact, the treatment is efficacious. If there are 2 or fewer responses in 11 
treated subjects, the cohort may be stopped for futility. The probability of early stopping for futility 
is approximately 46% if, in fact, the treatment is inefficacious, eg, 25%. If there are 3 to 5 
responses, an additional 15 subjects may be treated to collect more data. At the end of Stage 2, if 
there are 10 or more responses, an additional 64 subjects may be treated up to a total of 90 subjects. 
Table 8.1.3-2 shows that at observed ORR 36%, the lower bound of the 95% CI excludes 25% 
with a sample size of 90.
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Table 8.1.3-2:
Observed ORR with Exact 95% CI
Sample Size
Number of Responses
ORR
95% Exact CI
90
18
27
32
37
46
20%
30%
36%
41%
51%
[12.3%, 29.8%]
[20.8%, 40.6%]
[25.7%, 46.4%]
[30.8%, 52.0%]
[40.4%, 61.8%]
100
20
30
35
40
50
20%
30%
35%
40%
50%
[12.7%, 29.2%]
[21.2%, 40.0%]
[25.7%, 45.2%]
[30.3%, 50.3%]
[39.8%, 60.2%]
120
24
36
42
48
60
20%
30%
35%
40%
50%
[13.3%, 28.3%]
[22.0%, 39.0%]
[26.5%, 44.2%]
[31.2%, 49.3%]
[40.7%, 59.3%]
8.1.4
Melanoma Prior IO Extended Expansion (Part D)
The objective of this expansion in melanoma subjects whose disease is progressing while receiving 
anti-PD-1 (anti-PD-L1 allowed in Part D2) antibody therapies is to assess safety and tolerability 
of more convenient dosing regimen (ie, coadministration and Q4W dosing interval) and 
demonstrate preliminary clinical evidence of the treatment effect measured by ORR, as determined 
by BICR, that may represent substantial improvement over available therapies in subjects with 
LAG-3 expression (Part D1). 
8.1.4.1
Melanoma Prior IO Extended Expansion (Part D1-Q2W)
Data from Part C melanoma subjects who progressed while receiving anti-PD-1 antibody therapies 
demonstrated a preliminary evidence that subjects with LAG-3 expression are more likely to 
respond to treatment of BMS-986016 in combination with nivolumab. The marker prevalence 
using the initial 1% cut (ie, LAG-3 expression 1%) is estimated to be approximately 60% in this 
patient population.
In order to establish safety and tolerability of a more convenient dosing regimen and further 
characterize an enriched responder population, approximately a total of 150 subjects who meet the 
eligibility criteria for Part D1 will be treated with BMS-986016 80 mg + nivolumab 240 mg Q2W 
coadministered. A sample size of 150 is expected to provide approximately 90 subjects with LAG-
3 expression using the initial cutoff of 1% and provide reasonable precision to examine the 
enrichment of patient population with LAG-3 expression.
Since the optimal marker cutpoint is not well known prior to the study, several different cutoffs 
may be explored, and, depending on the prevalence of the marker-positive using these cutoffs, the 
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initial total sample size may be modified in order to have an adequate precision for demonstrating 
preliminary clinical evidence of the treatment effect in the marker-positive population (ie, 
approximately 90 subjects). Although evaluation of the cutpoint will be based on the ORR, the 
decision of the cutpoint will be based on the totality of the efficacy data, including DOR and DCR.
Additionally, in an effort to explore an enriched patient population in advanced melanoma subjects 
who progressed while on anti-PD-1 antibody therapies in Part D1, other potential predictive 
markers such as BRAF mutation status may be explored. Approximately 60 subjects among the 
90 subjects with LAG-3 expression in Part D1 are expected to be BRAF wild-type.
For the purpose of demonstrating preliminary clinical evidence of the treatment effect, the primary 
efficacy population will be subjects with LAG-3 expression who progressed while on anti-PD-1 
antibody therapies and receive BMS-986016 80 mg + nivolumab 240 mg Q2W in Part D1. A 
portion of subjects in Part C who meet the eligibility criteria of Part D1 will be included in a 
sensitivity analysis to further strengthen the evidence. 
The sample size of 90 subjects with LAG-3 expression was determined based on the ability to 
produce a CI, which would exclude an ORR of the historic response, and to provide sufficient 
information for a reliable understanding of the safety profile. 
There is no standard of care for advanced melanoma patients who have progressed during prior 
anti-PD-1 therapy; thus, the demonstration of effective and tolerable therapy in these patients 
remains a large unmet need. The only published or reported studies in this clinical setting employ 
anti-CTLA-4 therapy, namely ipilimumab, and they are small retrospective or exploratory ad hoc 
analyses. The patient population characteristics and results of ipilimumab monotherapy in these 
studies are listed in Table 8.1.4.1-1 below. There have been no prospective studies defining the 
benefit of anti-CTLA-4 therapy after progression during anti-PD1 therapy.  
Table 8.1.4.1-1:
Ipilimumab After Prior Anti-PD-1 Therapy
Study Population
ORR/CI/DOR
Toxicity
Source
Retrospective: Sequential 
treatment of anti-PD-1 (all 
progressed on clinical trials) then 
ipilimumab. 10% BRAF mutant. 
42% with PD as BOR to prior 
anti-PD-1. 10% prior ipilimumab 
(response not reported).
10% (4/40 PRs)
No CI reported
DOR not reported
55% received all 4 doses 
of ipilimumab
35% had Grade 3 to 5 
irAE;1 drug-related 
death due to pneumonitis
Bowyer et al
10.1038/bjc.2016.10
7
Retrospective: Documented 
progression on prior anti-PD-1 as 
per RECIST v1.1 (details not 
provided). 15% BRAF mutant. 
51% with PD as BOR to prior 
anti-PD-1. 26% prior ipilimumab 
(response not reported).
16% (7/43 PRs)
No CI reported
DOR not reported
Median DoDC 7 months 
95% CI (2.8-22.8) 
months
53% received all 4 doses 
of ipilimumab (33% did 
not due to toxicity) 
Rates of irAEs were not 
reported
Zimmer et al
10.1016/j.ejca.2017.01
.009
Exploratory post-hoc analysis of 
patients who received ipilimumab 
sequentially after pembrolizumab 
13% (3 CRs and 10 PRs 
out of 97 patients)
No CI reported
Not reported
Long et al
KEYNOTE-006 
presentation at 
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Table 8.1.4.1-1:
Ipilimumab After Prior Anti-PD-1 Therapy
Study Population
ORR/CI/DOR
Toxicity
Source
(91% with documented 
progression). Data from 
subsequent therapies case report 
forms. 16% BRAF mutant. 62% 
with PD as BOR to prior anti-
PD1. 
DOR not reported
Society for 
Melanoma Research 
November 6-9, 2016
All treated subjects - nivolumab 
crossover to ipilimumab (the 
subjects randomized to nivolumab 
who received ipilimumab as 
subsequent therapy). 56% with 
PD as BOR to prior anti-PD-1.
10% (7/68 PRs)
95% CI (4.2%, 20.1%)
DOR not reported
Not reported
CA209066 study
Unpublished 
analysis
Combined analyses employing a standard response evaluable population definition across the 
multiple small studies of ipilimumab monotherapy in the setting of prior anti-PD-1 therapy reveal 
an approximate 12% ORR. Durability of these responses are poorly documented.  
In heavily pretreated patients where clinical benefit is observed in only a subset of the population, 
safety is a significant concern. The reported rates of Grade 3 (or greater) TRAEs of approximately 
35% from single-agent ipilimumab after anti-PD-1 therapy limits the overall utility of this 
approach.59
The majority of our patient population (approximately 60%) have also been previously treated 
with anti-CTLA-4 therapy. There are no reported effective therapies in this setting. In addition, 
antitumor responses with continued anti-PD-1 therapy after initial progression on anti-PD-1 
therapy is relatively rare, with estimates of incidence of approximately 5%.60 Thus, given a 
population in which all have progressed during prior anti-PD-1 therapy, and the majority have 
received prior anti-CTLA-4 therapy as well, it is reasonable to target an ORR that excludes 10% 
as a lower bound within a 95% CI.  
Table 8.1.4.1-2:
Observed ORR with Exact 95% CI for Cohort D
Sample Size
Number of Responses
ORR
95% Exact CI
60
12
15
18
20%
25%
30%
[10.8%, 32.3%]
[14.7%, 37.9%]
[18.9%, 43.2%]
90
16
18
20
18%
20%
22%
[10.5%, 27.3%]
[12.3%, 29.8%]
[14.1%, 32.2%]
120
20
24
27
17%
20%
23%
[10.5%, 24.6%]
[13.3%, 28.3%]
[15.4%, 31.0%]
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Table 8.1.4.1-2:
Observed ORR with Exact 95% CI for Cohort D
Sample Size
Number of Responses
ORR
95% Exact CI
150
24
27
30
16%
18%
20%
[10.5%, 22.9%]
[12.2%, 25.1%]
[13.9%, 27.3%]
220
26
29
32
12%
13%
15%
[7.9%, 16.8%]
[9.0%, 18.4%]
[10.2%, 19.9%]
8.1.4.2
Melanoma Prior IO Focused Eligibility Expansion (Part D1-Q4W)
The coprimary objective in Part D1-Q4W is to evaluate the difference in safety between 
coadministration relative to FDC as measured by the incidence of AEs in the Broad Scope 
MedDRA Anaphylactic Reaction SMQ occurring within 2 days after dosing during the 
combination and to confirm with Q4W dosing of BMS-986016 160 mg in combination with 
nivolumab 480 mg the safety of the BMS-986016 80 mg in combination with nivolumab 240 mg 
Q2W in advanced melanoma subjects who progressed while on anti-PD-1 antibody therapies (see 
Appendix 5).
Prior to Revised Protocol 09, subjects are being enrolled into a single arm: Part D1 BMS-986016 
80 mg + nivolumab 240 mg Q2W. Subsequent to this amendment, and until the enrollment to Part 
D1 BMS-986016 80 mg + nivolumab 240 mg Q2W is completed, subjects in Part D1 will be 
randomized 1:1:1 to Part D1 BMS-986016 80 mg + nivolumab 240 mg Q2W, Part D1 
BMS-986016 160 mg + nivolumab 480 mg Q4W coadministration, and Part D1 BMS-986213 
(relatlimab 160 mg/nivolumab 480 mg) Q4W arms. Once enrollment to Part D1 BMS-986016 80 
mg + nivolumab 240 mg Q2W is completed, subjects will be randomized 1:1 to Part D1 BMS-
986016 160 mg + nivolumab 480 mg Q4W coadministration and Part D1 BMS-986213 (relatlimab 
160 mg/nivolumab 480 mg) Q4W arms. If enrollment to Q4W arms is completed prior to arm 
BMS-986016 80 mg + nivolumab 240 mg Q2W, then enrollment to arm BMS-986016 80 mg + 
nivolumab 240 mg Q2W will be completed as a single arm.
Approximately 150 subjects will be randomized to the 2 treatment arms Part D1 BMS-986016 160 
mg + nivolumab 480 mg Q4W coadministration and Part D1 BMS-986213 (relatlimab 160 
mg/nivolumab 480 mg) Q4W. This number of treated subjects was chosen to achieve a sufficient 
level of precision for a descriptive analysis to estimate the difference in rates of AEs in the Broad 
Scope MedDRA Anaphylactic Reaction SMQ between the 2 treatment arms. Seventy-five (75) 
treated subjects per arm will allow estimation of the rate difference within 95% confidence limits 
of 15% or less and will be supplemented by a qualitative clinical assessment of the type and 
severity of events to evaluate benefit-risk (see Appendix 5).
From the Q2W expansion cohorts in Part C of the current study, AEs in the Broad Scope MedDRA 
Anaphylactic Reaction SMQ with onset within 2 days after sequential dosing of nivolumab 240 mg 
combined with BMS-986016 80 mg were reported in 14% of treated subjects. In Part D1-Q4W, if 
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the observed rate of these events is equal to 14% among 75 treated subjects in each arm, then the 
95% CI for the difference in rates between arms will be (-11.1%, 11.1%) (see Appendix 5).
Table 8.1.4.2-1 shows the precision that the sample size of 75 treated subjects per arm in Part D1-
Q4W and 150 treated subjects each in Part D1-Q2W and Part D1-Q4W dosing will provide for 
estimating rates and rate differences between the treatment arms under different assumed observed 
rates. Enrollment and randomization across treatment arms Part D1 BMS-986016 160 mg + 
nivolumab 480 mg Q4W coadministration and Part D1 BMS-986016 160 mg + nivolumab 480 mg 
Q4W FDC may continue until the following criteria are met: 90 efficacy-evaluable LAG-3-
positive subjects have been treated, 60 efficacy-evaluable LAG-3-positive and BRAF wild-type 
subjects have been treated, and 60 efficacy-evaluable LAG-3–positive and ipilimumab pretreated 
subjects have been treated. 
Table 8.1.4.2-1:
95% CI for Rate Differences When Observed in 75 Subjects per 
Arm and 150 Subjects per Dosing Regimen
75 Subjects per Arm
Coadministration Arm
Fixed Dose Combination Arm
Rate Difference (95% CI)
  14% 
14%
0% (-11.1%, 11.1%)
14%
12%
2% (-8.8%, 12.8%)
16%
14%
2% (-9.4%, 13.4%)
18%
16%
2% (-10%, 14%)
20%
18%
2% (-10.6%, 14.6%)
150 Subjects Each in Part D1-Q4W and Part D1-Q2W 
Q2W
Q4W
Rate Difference (95% CI)
14% 
14%
0% (-7.9%, 7.9%)
14%
12%
2% (-5.6%, 9.6%)
16%
14%
2% (-6.1%, 10.1%)
18%
16%
2% (-6.5%, 10.5%)
20%
18%
2% (-6.9%, 10.9%)
Also, with 75 subjects per arm, there is a 99% probability that the 95% CI for the geometric mean 
ratio of Cmax of FDC to coadministration is wholly contained within [0.8, 1.25]. log(Cmax) is 
assumed to follow a normal distribution and, with intrasubject coefficients of variation, is assumed 
to be no greater than 30%.
8.1.4.3
Melanoma Prior IO Expanded Eligibility Expansion (Part D2)
Part D2 will have an expanded eligibility criteria with 2 cohorts in sequence: 160 mg BMS-986016 
with 480 mg nivolumab Q4W and 240 mg BMS-986016 with 480 mg nivolumab Q4W. Subjects 
in Part D2 on average will have a worse performance status and be more heavily treated. 
Approximately 30 subjects will be initially treated with 160 mg BMS-986016 with 480 mg 
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nivolumab Q4W. Once this dose level is deemed safe, approximately up to 220 additional subjects 
will be treated with either 160 mg BMS-986016 with 480 mg or 240 mg BMS-986016 with 480 mg 
nivolumab Q4W to establish safety and efficacy in this broader group of melanoma patients. With 
30 subjects, there is approximately 96% chance to observe at least 1 occurrence of any AE that 
would occur with a 10% incidence in the population from which the sample is drawn. With 250 
subjects, there is approximately 92% chance to observe at least 1 occurrence of any AE that would 
occur with a 1% incidence in the population from which the sample is drawn. Safety and efficacy 
data will be collected as in the other cohorts, and the data will be used as supportive evidence of 
safety and efficacy of the combination therapy. 
8.1.5
Exposure/Response Expansion Q4W Dosing (Part E)
In Part E, 2 disease cohorts will be investigated: melanoma participants who experienced disease 
progression on prior anti-PD-1 therapy in the advanced, unresectable, or metastatic setting and 
melanoma participants who have not received prior systemic anticancer therapy for unresectable 
or metastatic melanoma. The objective of this expansion is to support further clinical testing at 
higher dose of relatlimab in combination with nivolumab by demonstrating adequate safety and 
tolerability as well as favorable benefit-risk by assessing preliminary efficacy measured by ORR 
and other clinically relevant efficacy measures such as DOR and DCR. However, the sample size 
is based on efficacy, specifically on the target ORR relative to the ORR observed at the lower dose 
of relatlimab in combination with nivolumab. Both disease cohorts will be handled independently, 
and there will be no multiplicity adjustment. The sample size of the melanoma cohort of 
participants who experienced disease progression on prior anti-PD-1 therapy is based on the 
comparison of the ORR of subjects who receive 480 mg BMS-986016 + 480 mg nivolumab Q4W 
vs the benchmark (ie, historical control) observed ORR of subjects who received 80 mg BMS-
986016 + 240 mg nivolumab Q2W in this study. A sample size of 75 subjects who experienced 
disease progression on prior anti-PD-1 therapy will provide approximately 85% power for testing 
the ORR difference with a 2-sided alpha of 0.1, assuming ORR of 25% and 10% in the 480 mg 
BMS-986016 + 480 mg nivolumab Q4W arm and in the historical control arm, respectively.
The sample size of the cohort of participants who have not received prior systemic anticancer 
therapy for advanced, unresectable, or metastatic melanoma is based on the comparison of the 
ORR of subjects who receive 480 mg BMS-986016 + 480 mg nivolumab Q4W vs the ORR of 
subjects who receive 160 mg BMS-986016 + 480 mg nivolumab Q4W. A sample size of 150 
subjects who have not received prior systemic anticancer therapy for unresectable or metastatic 
melanoma randomized in a 1:1 ratio in 2 arms will provide approximately 81% power for testing 
the ORR difference with a 2-sided alpha of 0.1, assuming ORR of 67% and 47% in the 480 mg 
BMS-986016 + 480 mg nivolumab Q4W arm and in the 160 mg BMS-986016 + 480 mg 
nivolumab Q4W arm, respectively.
8.2
Populations for Analyses
All Enrolled Subjects Analysis Set: This analysis set contains all subjects (including screen 
failures) who signed an ICF for the study.
All Treated Subjects Analysis set: This analysis set includes all subjects who receive either drug.
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Response-evaluable Subjects: This analysis set includes all subjects who receive either study 
drug, have a baseline tumor assessment with measurable disease, and 1 of the following: 1) at least 
1 evaluable on-treatment tumor assessment, 2) clinical progression, or 3) death prior to the first 
on-treatment tumor evaluation.
Enriched Subjects: This analysis set includes all treated subjects with LAG-3 expression.
BMS-986016 Pharmacokinetic Analysis Set: This analysis set includes all subjects who receive 
BMS-986016 and have at least 1 valid PK parameter to be included in statistical analyses of BMS-
986016 PK data.
BMS-986016 Immunogenicity Analysis Set: This analysis set includes all subjects who receive 
BMS-986016 and have baseline and at least 1 postbaseline preinfusion BMS-986016 
immunogenicity assessment.
Nivolumab Immunogenicity Analysis Set: This analysis set includes all subjects who receive 
nivolumab and have baseline and at least 1 postbaseline preinfusion nivolumab immunogenicity 
assessment.
Pharmacodynamic Analysis Set: This analysis set includes all treated subjects for whom 
pharmacodynamic measurements are available at baseline and at least 1 other time point.
8.3
Endpoints
8.3.1
Primary Endpoints
The primary endpoint of this Phase 1/2a study is safety as measured by the rate of AEs, SAEs, 
AEs leading to discontinuation of treatment, deaths, and laboratory abnormalities assessed during 
treatment and for up to 135 days of follow-up. All subjects who receive at least 1 dose of BMS-
986016 or nivolumab will be analyzed for safety.
The coprimary endpoints in Part C are ORR, DCR, and DOR based on BICR assessments using 
RECIST v1.1, where applicable, in selected disease cohorts.
The coprimary endpoint in Part D1-Q2W is ORR, as determined by BICR using RECIST v1.1, in 
advanced melanoma subjects with LAG-3 expression who progressed while on anti-PD-1 antibody 
therapies.

ORR is defined as the total number of subjects whose BOR is either CR or PR divided by the 
total number of treated subjects in the population of interest.
Best overall response per RECIST v1.1 is defined as the best response designation recorded 
between the date of first dose and the date of first objectively documented progression per 
RECIST v1.1 or the date of subsequent therapy, whichever occurs first. CR or PR 
determinations included in the BOR assessment must be confirmed by a second scan no less 
than 4 weeks after the criteria for response are first met. For subjects who continue treatment
beyond progression per RECIST v1.1 or begin subsequent therapy, the BOR should be 
determined based on response designations recorded up to the time of the initial progression 
or subsequent therapy, whichever occurs first. For subjects without documented progression 
or subsequent therapy, all available response designations should contribute to the BOR 
assessment.
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
DCR is defined as the total number of subjects whose BOR is either CR, PR, or SD for at least 
12 weeks divided by the total number of treated subjects in the population of interest.
DOR computed only for subjects with a BOR of CR or PR is defined as the number of days 
between the date of first response and the date of first objectively documented disease progression 
based on the criteria (RECIST v1.1) or death, whichever occurs first. For those subjects who 
neither progress nor die, the duration of objective response will be censored at the same time they 
will be censored for the primary definition of PFS (see Section 8.3.2.2).
The primary endpoint in Part D1-Q4W of the study is the incidence of AEs in the Broad Scope 
MedDRA Anaphylactic Reaction SMQ occurring within 2 days after dosing. This incidence rate 
is defined as number of subjects who experienced at least 1 AE in the Broad Scope MedDRA 
Anaphylactic Reaction SMQ with onset on the day of or within 2 days after any study therapy 
infusion divided by number of treated subjects. The terms included in the MedDRA Anaphylactic 
Reaction SMQ based on the most current MedDRA version will be listed in the statistical analysis 
plan (see Appendix 5).
8.3.2
Secondary Endpoints
8.3.2.1
Pharmacokinetics
The PK of BMS-986016 administered both alone and in combination with nivolumab will be 
assessed as a secondary objective using the following endpoints derived from serum concentration 
vs time data in Cycle 1 and Cycle 3:
Cmax
Maximum observed serum concentration
Tmax
Time of maximum observed serum concentration
Ctrough
Trough observed serum concentration
Ctau
Concentration at the end of a dosing interval (eg, concentration at 336 
hours)
Css,avg
Average concentration over a dosing interval ([AUC(TAU)/tau]
AUC(TAU)
Area under the concentration-time curve in 1 dosing interval
CLT
Total body clearance
T-HALFeff_AUC
Effective elimination half-life that explains the degree of AUC 
accumulation observed
T-HALFeff_Cmax
Effective elimination half-life that explains the degree of Cmax 
accumulation observed
AI_AUC
Accumulation index; ration of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax accumulation index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau accumulation index; ratio of Ctau at steady state to Ctau after the 
first dose
DF
Degree of fluctuation or fluctuation index ([Cmax - Ctau]/Css,avg)
Individual subject PK parameter values will be derived by noncompartmental methods by a 
validated PK analysis program. Actual times will be used for the analyses.
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In Part D1-Q4W, PK of nivolumab and BMS-986016 coadministered will be assessed and 
compared to that of FDC of BMS-986016 and nivolumab. PK will be measured using serum 
concentration-time data. PK of nivolumab and BMS-986016 in Part D1-Q4W and Part D1-Q2W 
will also be assessed.
8.3.2.2
Efficacy
The BOR, ORR, DCR, DOR, and PFS rates at prespecified time points (eg, 24 weeks) based on 
Investigator assessment using RECIST v1.1 will be the secondary efficacy endpoints. The efficacy 
endpoints based on BICR assessment, where applicable (ie, not designated as the primary), will 
also be the secondary efficacy endpoints.
BOR, ORR, DCR, and DOR were defined under the primary endpoints. Progression Free Survival
is defined as the time from first dose to the date of first objectively documented progression, per 
RECIST v1.1, or death due to any cause, whichever occurs first. Clinical deterioration in the 
absence of objectively documented progression per RECIST v1.1 is not considered progression 
for the purpose of determining PFS. Subjects who die without a reported progression will be 
considered to have progressed on the date of their death. Subjects who did not progress or die will 
be censored on the date of their last evaluable tumor assessment. Subjects who did not have any 
on study tumor assessments and did not die will be censored on the date of first dose. Subjects 
who started any subsequent anticancer therapy, including tumor-directed radiotherapy and tumor-
directed surgery, without a prior reported progression will be censored at the last evaluable tumor 
assessment prior to initiation of the subsequent anticancer therapy. The PFS rate at time T is 
defined as the probability that a subject has not progressed and is alive at time T following first 
dose.
Landmark 1-year and 2-year OS rates will be assessed as secondary efficacy endpoints in Part D.
8.3.2.3
Immunogenicity
Incidence of ADA to either BMS-986016 or nivolumab will be assessed during treatment and for 
up to 135 days after their last treatment in post-treatment follow-up or for a maximum of up to 24 
months of treatment, whichever comes first. A baseline ADA-positive subject is defined as a 
subject with positive seroconversion detected in the last sample before initiation of treatment. An 
ADA-positive subject is a subject with at least 1 ADA-positive sample relative to baseline after 
initiation of the treatment.
8.3.2.4
Centrally Read ECGs (Parts A and B)
In Part A and Part B, QTc will be assessed by a central reader at follow-up Visit 1, and on Day 
1 of Cycle 1 and Cycle 3 (predose and 4-hour postdose time points). These assessments will be 
used to address the secondary objective of assessing the effect of BMS-986016 administered alone 
and in combination with nivolumab on QTc.
ECGs assessed locally by the Investigator are also collected at the start of each cycle. QTc will be 
calculated by the Sponsor for these ECGs. However, results will be summarized separately and 
are not considered part of the secondary objective. 
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8.3.2.5
Safety 
8.3.2.5.1
Part D1-Q4W
The secondary endpoint in Part D1-Q4W is the incidence of AEs in the Narrow Scope MedDRA 
Anaphylactic Reaction SMQ occurring within 2 days after any study therapy infusion. This 
incidence rate will be defined similarly to the primary safety endpoint for this part of the study 
except that the event rate will be based on terms within the Narrow Scope SMQ rather than the 
Broad Scope.
The second secondary endpoint in Part D1-Q4W is the incidence of events within the 
hypersensitivity/infusion reaction select AE category occurring within 2 days after any study 
therapy infusion. The select AEs consist of a list of preferred terms (PTs) defined by the Sponsor 
and represent AEs with a potential immune-mediated etiology. The MedDRA PTs to be included 
in the hypersensitivity/infusion reaction select AE category will be updated with each new version 
of MedDRA prior to database lock. The list that is the most current at the time of analysis will be 
used. The incidence rate of hypersensitivity/infusion reaction select AEs will be defined similarly 
to the primary endpoint except that the event rate will be based on terms from the 
hypersensitivity/infusion reaction select AE category rather than the Broad Scope MedDRA 
Anaphylactic Reaction SMQ.
The drug-related and all-causality Grade 3 - 5 AE rate is defined as number of subjects who 
experienced at least 1 AE of Grade 3 or higher, or at least 1 AE of Grade 3 or higher judged to be 
related to study drug by the Investigator, and with onset on or after the first dose of study treatment 
and within 30 days of the last dose of study treatment divided by number of treated subjects.
8.3.3
Exploratory Endpoints 
8.3.3.1
Biomarkers
Biomarker endpoints from peripheral blood will generally be measured at multiple time points and 
evaluated as both predictive and pharmacodynamic markers in the context of the exploratory 
biomarker objectives. These may include measures such as levels and change from baseline in 
levels of the following at each scheduled time point: 

Serum soluble factors 
Biomarker endpoints from tumor biopsies will be explored predominantly in an effort to identify 
baseline markers predictive of efficacy since they are only measured at baseline for most subjects. 
For the subset of subjects who have both pretreatment and on-treatment biopsies, 
pharmacodynamic associations may be explored. Endpoints may include measures such as 
pretreatment levels and change in levels observed on-treatment of: 
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Appropriate functional transformation of these exploratory measures will be applied as necessary. 
Measures not available at the time of the clinical study report may be summarized in a separate 
report.
8.3.3.2
Pharmacokinetics
Nivolumab concentration-time data at scheduled trough (Ctrough) and end-of-infusion time points 
will be evaluated as an exploratory endpoint. Measurements will be collected on treatment (up to 
12 cycles) and for up to 135 days during the post-treatment follow-up or for a maximum of up to 
24 months of treatment, whichever comes first.
8.3.3.3
Efficacy
The BOR, ORR, DCR, DOR, and PFS rates at prespecified time points will be explored by 
iRECIST assessments based on BICR. Landmark 1-year and 2-year OS rates will be assessed as 
exploratory efficacy endpoints in the study (except for Part D).
8.4
Analyses
Unless otherwise specified, data from Part A (monotherapy dose escalation) and Part A1 
(monotherapy dose expansion) will be presented separately from data collected in Part B, Part C 
(sequential combination therapy), and Part D (coadministration). Safety data from dose escalation 
phases will be summarized by dose, dosing regimen, and across all doses and dosing regimens. 
Safety data from dose expansion phases will be summarized for each disease cohort, overall by 
dose and dosing regimen, and across doses and dosing regimens, as appropriate. Efficacy data 
from dose expansion phases will be summarized for each disease cohort by dose and across doses. 
Efficacy data from dose escalation phases will be summarized by dose and listed by tumor type.
Descriptive statistics will include the number of observations and percentage in each category for 
categorical variables. For continuous variables, the number of observations, mean, median, 
standard deviation, minimum, and maximum will be presented unless otherwise specified. All 
available data will be included in-subject listings. 
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender, race, ethnicity, and other categorical baseline characteristics 
will be tabulated. Baseline body mass index (BMI) will be derived from measurements of baseline 
body weight and height. Summary statistics for age, body weight, height, and BMI will be 
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tabulated. Baseline disease characteristics will be summarized for expansion cohorts for different 
disease cohorts separately, as appropriate.
8.4.2
Efficacy Analyses
Individual BOR, DOR, and PFS will be determined based on RECIST v1.1 criteria for the primary 
and secondary analyses. iRECIST will be used as an exploratory analysis in Parts C and D. BOR 
outcomes will be summarized using frequency tables together with 2-sided 95% CIs. Time to event 
distribution (eg, PFS and DOR) will be estimated using the Kaplan-Meier method. When 
appropriate, the median along with 95% CI will be provided using Brookmeyer and Crowley 
methodology (using log-log transformation for constructing the CIs). Rates at fixed time points 
(eg, PFS rate 24 weeks) will be derived from the Kaplan-Meier estimate, and corresponding CI 
will be derived based on Greenwood formula. CIs for binomial proportions will be derived using 
the Clopper-Pearson method. OS data will be analysed similarly to PFS data analysis.
For the purpose of demonstrating preliminary clinical evidence of the treatment effect in advanced 
melanoma subjects who progressed while on receiving anti-PD-1 antibody therapies, the primary 
efficacy population will be subjects with LAG-3 expression who progressed while on anti-PD-1 
antibody therapies in Part D1-Q2W. A portion of subjects in Part C who meet the eligibility criteria 
of Part D1 will be included in the sensitivity analysis to further strengthen the evidence. Efficacy 
analysis will also be performed for subjects with a lack of LAG-3 expression, and also for all 
treated subjects regardless of LAG-3 expression to support the treatment effect of the combination 
therapy.
Initial cutpoint for the purpose of exploring an enriched population is LAG-3 expression 1%. 
However, as the optimal marker cutpoint is not well known prior to the study, several different 
cutoffs may be explored other than the initial cutpoint of 1% by examining receiver operating 
characteristics curves using the ORR, although the decision of the cutpoint will be based on the 
totality of the efficacy data, including DOR and DCR. Details of methodology will be described 
in the statistical analysis plan prior to any data exploration in Part D.
In an effort to explore an enriched patient population in advanced melanoma subjects who 
progressed while on anti-PD-1 antibody therapies in Part D1, other potential predictive markers 
such as BRAF mutation status may be explored.
Subsequently, efficacy analysis for Part D1-Q4W will be done similarly to that for Part D1-Q2W. 
If the outcome of BOR in the Part D1-Q4W is deemed similar to that of the Part D1-Q2W, data 
from both Part D1-Q2W and Part D1-Q4W may be combined to strengthen the evidence.
Efficacy analysis for Part D2 will be done similarly to that for Part D1.
8.4.3
Safety Analyses
All subjects who receive study drug therapy will be evaluated for safety endpoints. All recorded 
AEs will be coded according to the most current version of MedDRA and will be graded using the 
NCI CTCAE v4.0. AEs will be listed and subjects with AEs will be summarized based on the 
event with worst CTCAE grade by system organ class (SOC) and PT, counting once at the PT term 
level and once at the SOC level, for each dose, dosing regimen, and overall. The incidence of AEs 
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in the Broad and Narrow Scope MedDRA Anaphylactic Reaction SMQ and select AEs in 
hypersensitivity/infusion reaction category occurring within 2 days after dosing by treatment arm, 
the difference in rates between arms, and the corresponding 95% CIs will be reported descriptively. 
The CIs for the rate estimates will be based on the Clopper-Pearson method. Vital signs and clinical 
laboratory test results will be listed and summarized by treatment. In addition, the worst grade of 
a laboratory measure observed on-study by the baseline grade (per CTCAE v4.0) will also be 
generated for selected laboratory tests. Any significant physical examination findings and results 
of clinical laboratory tests will be listed. ECG results will be evaluated by the Investigator, and 
abnormalities, if present, will be listed. In Parts A and B, ECG will be assessed by a central reader 
at specific time points. All ECG data analyses, including summaries of each ECG parameter, 
frequency distributions of subjects’ maximum values/changes, and scatter plots, will be performed 
following the current practice of ECG data analysis. Concentration-response analysis may be 
performed using mixed-effect model, if appropriate. The details of ECG data analysis will be 
provided in the statistical analysis plan. 
8.4.4
Pharmacokinetic Analyses
Pharmacokinetic parameters for BMS-986016 will be calculated using noncompartmental 
analyses. Summary statistics will be tabulated for the PK parameters of BMS-986016 by dose and 
study day/cycle. To describe the association of these parameters with dose of BMS-986016, scatter 
plots of Cmax and AUC(TAU) vs dose may be provided for each day/cycle measured. Dose 
proportionality of BMS-986016 when administered alone or coadministered with nivolumab may 
also be assessed based on a power model. Trough concentrations of BMS-986016 will be plotted 
vs study day and cycle. Nivolumab end-of-infusion and trough (Ctrough) concentrations will be 
tabulated using summary statistics. These data may also be pooled with other datasets for 
population PK analysis, which will be presented in a separate report. In Part D1-Q4W, PK 
comparisons will be summarized using descriptive summary statistics, and the point estimate and 
CI of geometric mean ratios of Cmax and AUC(TAU) will be presented to compare nivolumab 
and BMS-986016 administered as FDC to that of coadministered nivolumab and BMS-986016. 
PK parameters will also be summarized using descriptive summary statistics for nivolumab and 
BMS-986016 administered in Part D1-Q2W and Part D1-Q4W dosing.
8.4.5
Biomarker Analyses
Not applicable. 
8.4.6
Exploratory Biomarker Analyses
Pharmacodynamic effect in subjects who undergo biopsy will be assessed using summary statistics 
and plots. 
 
 
 
 
 
 
 
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8.4.7
Outcomes Research Analyses
Not applicable.
8.4.8
Other Analyses 
8.4.8.1
Immunogenicity Analyses
A listing will be provided for all available immunogenicity data. A baseline ADA-positive subject 
is defined as a subject with positive seroconversion detected in the last sample before initiation of 
treatment. An ADA-positive subject is a subject with at least 1 ADA-positive sample relative to 
baseline after initiation of the treatment. For each drug, frequency distribution of baseline ADA-
positive subjects and ADA-positive subjects after initiation of the treatment will be summarized. 
To examine the potential relationship between immunogenicity and safety, a table summarizing 
the frequency and type of AEs of special interest may be explored by immunogenicity status. In 
addition, potential relationships between immunogenicity and efficacy and/or PK may also be 
explored.
8.5
Interim Analyses
Data emerging from this study may be needed for timely decisions about adjustments to procedures 
in subsequent parts of the study. Therefore, data may be reviewed prior to the final lock of the 
study database. Additional interim analyses may also be performed for administrative purposes or 
publications. No formal inferences requiring adjustment to the statistical significance level will be 
performed.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The Investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:
IRB/IEC for review and approval/favorable opinion
BMS
Regulatory Authority(ies), if required by local regulations
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Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; 2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and 3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, Investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
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. 
In addition, the study may be evaluated by BMS 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 BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include, but are not limited to, GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The Investigator 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, whichever is longer. The Investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the Investigator 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, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the Investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug(s) are inventoried and dispensed. Records or logs must comply with applicable regulations 
and guidelines and should include:
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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 subject, including unique subject identifiers
Amount transferred to another area/site for dispensing or storage
Nonstudy disposition (eg, lost, wasted) 
Amount destroyed at study site, if applicable
Amount returned to BMS
Retain samples for bioavailability/bioequivalence, if applicable 
Dates and initials of person responsible for investigational product dispensing/accountability, as 
per the Delegation of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS EDC tool, electronic CRFs will be prepared for all data collection fields 
except for fields specific to SAEs and pregnancy, which will be reported on the paper or electronic 
SAE Report Form and Pregnancy Surveillance Form, respectively. Spaces may be left blank only 
in those circumstances permitted by study-specific CRF completion guidelines provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The Investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the Investigator or qualified physician who is a subinvestigator and 
who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review and 
approval/signature is completed electronically through the BMS EDC tool. The Investigator must 
retain a copy of the CRFs, including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS EDC tool using the unique user account provided by BMS. User 
accounts are not to be shared or reassigned to other individuals.
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9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:
Subject recruitment (eg, among the top quartile of enrollers)
Involvement in trial design
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation and 
must adhere to BMS’s publication requirements as set forth in the approved Clinical Trial 
Agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information contained 
in any proposed presentation or abstract and may delay publication for up to 60 days for purposes 
of filing a patent application.
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GLOSSARY OF TERMS
Term
Definition
Adverse reaction
An AE that is considered by either the Investigator or BMS 
as related to the investigational product
Unexpected adverse reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, IB for 
an unapproved investigational product)
Serious adverse event
Any untoward medical occurrence that, at any dose, results in 
death; is life threatening (defined as an event in which the 
subject was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused 
death if it were more severe); requires inpatient 
hospitalization or causes prolongation of existing 
hospitalization; results in persistent or significant 
disability/incapacity; is a congenital anomaly/birth defect; or 
is an important medical event (defined as a medical event[s] 
that may not be immediately life threatening or result in 
death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of 
the other serious outcomes listed in the definition above). 
Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias, or convulsions that 
do not result in hospitalization.. For reporting purposes only, 
BMS also considers the occurrence of pregnancy (regardless 
of association with an AE) and cancer as important medical 
events.
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LIST OF ABBREVIATIONS
Term
Definition
ADA
antidrug antibody
AE
adverse event
AFP
alpha-fetoprotein
AI
accumulation index
AI_AUC
AUC accumulation index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax accumulation index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau accumulation index; ratio of Ctau at steady state to Ctau after the 
first dose
AJCC
American Joint Committee on Cancer 
ALK
anaplastic lymphoma kinase
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransaminase
AUC
area under the concentration-time curve
AUC(TAU)
area under the concentration-time curve in 1 dosing interval
hCG
beta-human chorionic gonadotrophin
CR
Blinded Independent Central Review
BLRM
Bayesian Logistic Regression Model
BMI
body mass index
BMS
Bristol-Myers Squibb
BOR
best overall response
BTLA
B and T lymphocyte attenuator
BUN
blood urea nitrogen
CEA
carcinoembryonic antigen
CI
confidence interval
CLT
total body clearance
CLTp
systemic clearance
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Term
Definition
Cmax
maximum observed concentration
CNS
central nervous system
COVID-19
coronavirus disease 2019
 
CR
complete response
CRF
case report form
Css,avg
average concentration over a dosing interval ([AUC(TAU)/tau]
CT
computed tomography
CTA
Clinical Trial Agreement
Ctau
concentration at the end of a dosing interval (eg, concentration at 24 
hours, concentration at 12 hours, etc.)
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyte–associated antigen 4
Ctrough
trough observed serum concentration
DCR
disease control rate
DF
degree of fluctuation or fluctuation index ([Cmax - Ctau]/Css,avg)
DICOM
Digital Imaging and Communications in Medicine
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
data monitoring committee
DOR
duration of response
EBV
Epstein-Barr virus
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EOI
end of infusion
EOT
end of treatment
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Term
Definition
EU CTR
EU Clinical Trial Regulation
FDC
fixed-dose combination
FFPE
formalin-fixed paraffin-embedded
FSH
follicle-stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma 
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HED
human equivalent dose
HER-2
human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HNC
head and neck cancer
HPV
human papilloma virus
HRT
hormone replacement therapy
IB
Investigator Brochure
ICF 
informed consent form
ICH
International Council for Harmonisation 
ICOS
inducible T cell costimulator
IEC
Independent Ethics Committee
IFN
interferon
IFN-
interferon gamma
IHC
immunohistochemistry
IION
International Immuno-Oncology Network
IL
interleukin
IMAE
immune-mediated adverse event
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Term
Definition
IMP
investigational medicinal product
IO
immuno-oncology
irAE
immune-related adverse event
IRB
Institutional Review Board
irRECIST
immune-related Response Evaluation Criteria in Solid Tumors
IRT
Interactive Response Technology
ISH
in situ hybridization
IV
intravenous
IVRS
interactive voice response system
KPS
Karnofsky Performance Score
LAG-3
lymphocyte activation gene 3
LC
liquid chromatography
LDH
lactate dehydrogenase
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MAD
maximum administered dose
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRI
magnetic resonance imaging
MS
mass spectrometry
MSI
microsatellite instability
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
NCI
National Cancer Institute
NK
natural killer
NOAEL
no-observed-adverse-effect level
NSCLC
non-small cell lung cancer
ORR
objective response rate
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Term
Definition
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death protein ligand 1
PD-L2
programmed cell death protein ligand 2
PE
physical examination
PEE
probability of early expansion
PET
probability of early termination
PFS
progression-free survival
PID
patient identification number
PK
pharmacokinetic(s)
PR
partial response
PSA
prostate-specific antigen
PT
preferred term
Q2W
every 2 weeks
Q4W
every 4 weeks
qPCR
qualitative polymerase chain reaction
RCC
renal cell carcinoma 
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SCCHN
squamous cell carcinoma of the head and neck 
SD
stable disease
SmPC
Summary of Product Characteristics
SMQ
Standardized MedDRA Query
SOC
system organ class
STD10
severely toxic dose in 10% of the animals
T3
triiodothyronine
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Term
Definition
T4
thyroxine
TCIP
T cell–inflamed phenotype
TGI
tumor growth inhibition
T-HALF
terminal half-life
T-HALFeff_AUC
effective elimination half-life that explains the degree of AUC 
accumulation observed
T-HALFeff_Cmax
effective elimination half-life that explains the degree of Cmax 
accumulation observed)
TIL
tumor-infiltrating lymphocyte
TKI
tyrosine kinase inhibitor
Tmax
time of maximum observed concentration
Treg
regulatory T cell
TSH
thyroid-stimulating hormone
TTE
transthoracic echocardiogram
ULN
upper limit of normal
US IION sites
 
WOCBP
women of childbearing potential
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59 Bowyer S, Prithviraj P, Larkin J, et al. Efficacy and toxicity of treatment with the anti-CTLA-
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60 Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 
2 Phase 3 Clinical Trials.Long GV, Weber JS, Larkin J, Atkinson V, Grob JJ, Schadendorf D, 
Dummer R, Robert C, Márquez-Rodas I, McNeil C, Schmidt H, Briscoe K, Baurain JF, Hodi 
FS, 
Wolchok 
JD.JAMA 
Oncol. 
2017 
Nov 
1;3(11):1511-1519. 
doi: 
10.1001/jamaoncol.2017.1588. PMID: 28662232
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APPENDIX 1
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 1 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 
participants, refer to Section 3.3.1: Inclusion Criteria of the protocol. Only the contraception 
methods as described in Section 3.3.1: Inclusion Criteria of the protocol are acceptable for this 
study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
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Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the 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 for a total of 5 months post treatment completion.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months post-treatment completion. 
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 (These methods of contraception can only be
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol)b 

oral (birth control pills)

intravaginal (rings)

transdermal 

Combined (estrogen- and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy.

Progestogen-only hormonal contraception associated with inhibition of ovulation (This
method of contraception can only be used by WOCBP participants in studies 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
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
Intrauterine device (IUD)c

Intrauterine hormone-releasing 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

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

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 3.3.3. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants 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 those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized.
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide
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
Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited).
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, 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 6.4 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 2
RECIST 1.1
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable tumor lesion. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable lesions
Measurable lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of the measurement to be recorded) with a minimum size of:

10 mm by CT/MRI scan (CT/MRI scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)

20 mm by chest x-ray

Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.2
Non-measurable lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with 10 to < 15 mm short axis), as well as truly non-measurable lesions.  

Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that in not 
measurable by reproducible imaging techniques.  
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions

Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
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
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.

Blastic bone lesions are non-measurable.
1.3.2
Cystic lesions

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 

‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions.
1.3.3
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. 
1.4
Specifications by methods of measurements
1.4.1
Measurement of lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should 
be performed as close as possible to the treatment start and never more than 30 days before the 
beginning of the treatment.
1.4.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
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1.4.2.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung.
1.4.2.3
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
1.4.2.4
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response.  
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
2.1
Target lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted below, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
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2.1.1
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed.
2.2
Non-target lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION 
3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions,
taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
3.1.1
Special notes on the assessment of target lesions
3.1.1.1
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed.
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3.1.1.2
Target lesions that become ‘too small to measure’  
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:

if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 

if the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (note: in case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).   
3.1.1.3
Target lesions that split or coalesce on treatment

When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should 
be added together to calculate the target lesion sum. 

As lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the ‘coalesced lesion’.
3.2
Evaluation of non-target lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR):
Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (<10 mm short axis).
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s).
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).
3.2.1
Special notes on assessment of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the subject also has measurable disease

To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 
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
A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
quality for unequivocal progression status. 
3.2.1.2
When the subject has only non-measurable disease

To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. 

A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. 

Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are non-measurable) a useful test that can be applied when assessing subjects for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. 

If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD 
at that point. 
3.2.1.3
Tumor markers
Tumor markers alone cannot be used to assess objective tumor responses.
3.3
New lesions  
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: i.e. not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the subject’s baseline lesions show partial or complete response. For 
example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, 
which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain scan
ordered which reveals metastases. The subject’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan.
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4
RESPONSE CRITERIA
4.1
Timepoint response
A response assessment should occur at each time point specified in the protocol.
For subjects who have measurable disease at baseline, Table 1 provides a summary of the 
overall response status calculation at each time point.
Table 1:
Timepoint Response - Subjects with Target (+/- Non-Target) Disease
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any 
PD
Yes or No
PD
Any
Any 
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE =not evaluable.
4.1.1
Missing assessments and not evaluable designation
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, the case is also considered NE at that time point, unless a convincing argument can 
be made that the contribution of the individual missing lesion(s) would not have changed the 
assigned time point response.
4.1.2
Confirmation Scans

Verification of Response: Confirmation of PR and CR is required within 4 weeks to ensure 
responses identified are not the result of measurement error. To be assigned a status of CR or 
PR, changes in tumor measurements must be confirmed by consecutive repeat assessments 
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that should be performed no less than 28 days after the criteria for response are first met. For 
this study, the next scheduled tumor assessment can meet this requirement.

Verification of Progression:  Progression of disease should be verified in cases where 
progression is equivocal. If repeat scans confirm PD, then progression should be declared 
using the date of the initial scan. If repeat scans do not confirm PD, then the subject is 
considered to not have progressive disease. Additionally, see protocol section 4.3.4 
“Treatment beyond Disease Progression” for information regarding verification of 
progression in select subjects treated beyond initial PD.  Evaluation of further PD is required 
for subjects with treatment beyond progression.
4.2
Best overall response: All timepoints
The best overall response is determined once all the data for the subject are known. It is the best 
response recorded from the start of the study treatment until the end of treatment taking into 
account any requirement for confirmation. The subject’s best overall response assignment will 
depend on the findings of both target and non-target disease and will also take into consideration 
the appearance of new lesions. Tumor assessments performed after subsequent antitumor therapy 
is initiated will not be considered in the best overall response assessment.
Best response is defined as the best response across all timepoints with subsequent confirmation. 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent timepoint as specified in the protocol (4 weeks later). 
In this circumstance, the best overall response can be interpreted as specified in Table 2. When 
SD is believed to be best response, measurements must have met the SD criteria at least once no 
less than 6 weeks after study entry.
Table 2:
Best overall response (confirmation of CR and PR required)
Overall Response First 
Timepoint
Overall Response Subsequent 
Timepoint
BEST overall response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration 
met, otherwise, PD
CR
PD
SD provided minimum criteria for SD duration 
met, otherwise, PD
CR
NE
SD provided minimum criteria for SD duration 
met, otherwise NE
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Table 2:
Best overall response (confirmation of CR and PR required)
Overall Response First 
Timepoint
Overall Response Subsequent 
Timepoint
BEST overall response
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration 
met, otherwise, PD
PR
NE
SD provided minimum criteria for SD duration 
met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not evaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met (i.e., 6 weeks from baseline 
assessment). However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely 
still present and in fact the subject had PR, not CR at the first time point. Under these circumstances, the original 
CR should be changed to PR and the best response is PR.
4.3
Duration of response
4.3.1
Duration of overall response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented.
4.3.2
Duration of stable disease  
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
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APPENDIX 3
ECOG, KARNOFSKY, AND LANSKY PERFORMANCE STATUS
PERFORMANCE STATUS CRITERIA: ECOG Score 
ECOG (Zubrod) 
Score 
Description
0
Fully active; able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of alight or 
sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self care but unable to carry out any work activities; up and about more 
than 50% of waking hours.
3
Capable of only limited self care; confined to bed or chair more than 50% of waking hours.
4
Completely disabled; cannot carry on any self care; totally confined to bed or chair.
PERFORMANCE STATUS CRITERIA: Karnofsky and Lansky
Score
Karnofsky Description
Lansky Description
100
Normal; no complaints; no evidence of disease
Fully active, normal
90
Able to carry on normal activity; minor signs or 
symptoms of disease.
Minor restrictions in physically strenuous 
activity
80
Normal activity with effort; some signs or symptoms of 
disease.
Active, but tires more quickly
70
Cares for self; unable to carry on normal activity or to 
do active work.
Substantial restriction of, and less time 
spent, in play activity
60
Requires occasional assistance, but is able to care for 
most of their personal needs.
Out of bed, but minimal active play; keeps 
busy with quiet activities
50
Requires considerable assistance and frequent medical 
care.
Gets dressed, but inactive much of day; no 
active play, able to participate in quiet play
40
Disabled; requires special care and assistance.
Mostly in bed; participates in some quiet 
activities
30
Severely disabled; hospital admission is indicated 
although death not imminent.
In bed; needs assistance even for quiet play
20
Very sick; hospital admission necessary; active 
supportive treatment necessary.
Often sleeping; play limited to passive 
activities
10
Moribund; fatal processes progressing rapidly.
No play; does not get out of bed
0
Dead
Unresponsive
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APPENDIX 4
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 5
MEDDRA ANAPHYLACTIC REACTIONS
Preferred Terms Included in the MedDRA Anaphylactic Reaction SMQ - Broad and 
Narrow Scopes
Preferred Term
Term Scopea
Acute respiratory failure
Broad Scope
Allergic oedema
Broad Scope
Anaphylactic reaction
Narrow Scope
Anaphylactic shock
Narrow Scope
Anaphylactic transfusion reaction
Narrow Scope
Anaphylactoid reaction
Narrow Scope
Anaphylactoid shock
Narrow Scope
Angioedema
Broad Scope
Asthma
Broad Scope
Blood pressure decreased
Broad Scope
Blood pressure diastolic decreased
Broad Scope
Blood pressure systolic decreased
Broad Scope
Bronchial oedema
Broad Scope
Bronchospasm
Broad Scope
Cardiac arrest
Broad Scope
Cardio-respiratory arrest
Broad Scope
Cardio-respiratory distress
Broad Scope
Cardiovascular insufficiency
Broad Scope
Chest discomfort
Broad Scope
Choking
Broad Scope
Choking sensation
Broad Scope
Circulatory collapse
Narrow Scope
Circumoral oedema
Broad Scope
Cough
Broad Scope
Cyanosis
Broad Scope
Diastolic hypotension
Broad Scope
Dyspnoea
Broad Scope
Erythema
Broad Scope
Eye oedema
Broad Scope
Eye pruritus
Broad Scope
Eye swelling
Broad Scope
Eyelid oedema
Broad Scope
Face oedema
Broad Scope
First use syndrome
Narrow Scope
Flushing
Broad Scope
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Preferred Terms Included in the MedDRA Anaphylactic Reaction SMQ - Broad and 
Narrow Scopes
Preferred Term
Term Scopea
Generalised erythema
Broad Scope
Hyperventilation
Broad Scope
Hypotension
Broad Scope
Injection site urticaria
Broad Scope
Kounis syndrome
Narrow Scope
Laryngeal dyspnoea
Broad Scope
Laryngeal oedema
Broad Scope
Laryngospasm
Broad Scope
Laryngotracheal oedema
Broad Scope
Lip oedema
Broad Scope
Lip swelling
Broad Scope
Mouth swelling
Broad Scope
Nasal obstruction
Broad Scope
Ocular hyperaemia
Broad Scope
Oedema
Broad Scope
Oedema mouth
Broad Scope
Oropharyngeal spasm
Broad Scope
Oropharyngeal swelling
Broad Scope
Periorbital oedema
Broad Scope
Pruritus
Broad Scope
Pruritus allergic
Broad Scope
Pruritus generalised
Broad Scope
Rash
Broad Scope
Rash erythematous
Broad Scope
Rash generalised
Broad Scope
Rash pruritic
Broad Scope
Respiratory arrest
Broad Scope
Respiratory distress
Broad Scope
Respiratory failure
Broad Scope
Reversible airways obstruction
Broad Scope
Sensation of foreign body
Broad Scope
Shock
Narrow Scope
Skin swelling
Broad Scope
Sneezing
Broad Scope
Stridor
Broad Scope
Swelling
Broad Scope
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Preferred Terms Included in the MedDRA Anaphylactic Reaction SMQ - Broad and 
Narrow Scopes
Preferred Term
Term Scopea
Swelling face
Broad Scope
Swollen tongue
Broad Scope
Tachypnoea
Broad Scope
Throat tightness
Broad Scope
Tongue oedema
Broad Scope
Tracheal obstruction
Broad Scope
Tracheal oedema
Broad Scope
Type I hypersensitivity
Narrow Scope
Upper airway obstruction
Broad Scope
Urticaria
Broad Scope
Urticaria papular
Broad Scope
Wheezing
Broad Scope
a All Narrow Scope PTs are also included in the Broad Scope.
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APPENDIX 6
STATISTICAL METHODOLOGY
STATISTICAL DETAILS FOR BAYESIAN LOGISTIC REGRESSION MODEL (BLRM 
AND BLRM-COPULA) AND PRIORS FOR DOSE ESCALATION
1
MODEL SETUP FOR BMS-986016 IN COMBINATION WITH NIVOLUMAB   
1.1
Methodology Description for Combination Therapy
Toxicity profiles of BMS-986016 and nivolumab monotherapies will be incorporated to develop 
the BMS-986016 and nivolumab combination therapy model framework. A copula-type model 
will be utilized to cover all general combination cases, including subadditive, additive, and 
synergistic effects. The combination of the 2 treatments will be explored using a Bayesian 
hierarchical model by utilizing the toxicity profiles of each monotherapy as prior marginal 
profiles for the combination. The following copula-type model1 will be used to describe the 
probability 
of toxicity when dose level 
of treatment A and dose level 
of treatment B are 
administered in combination:
Where 
is the pre-specified best guess toxicity probability for treatment A and 
is the 
pre-specified best guess toxicity probability for treatment B. Here
and 
characterize the 
individual drug effect and characterizes drug-drug interactive effect.
The joint toxicity framework models the toxicity rates of all 2 treatments as well as their 
interaction effects in a multi-parameter hierarchical model, where each of the monotherapy dose-
toxicity relationships will be characterized by a 2-parameter BLRM model.2,3
For example, the dose-toxicity relationship for BMS-986016 alone is assumed to follow a 
logistic model:
where 
is the probability of toxicity at dose level
. Note that the 
parameters are 
assumed positive, and 
is the reference dose for BMS-986016 (
and 
are defined in 
Section 1.2.1).
There are 3 additional parameters for the copula-type model, 1 for each treatment (
) as 
well as 1 for the interaction term ( ). A dose-toxicity surface will be characterized for different 
dose combinations of these 2 treatments. 
As there are currently no historical data or prior knowledge to indicate how much information to 
be borrowed for each of the single treatments, parameters m and n are all set to be 1, meaning 
borrowing 100% of the information from all 3 treatments. The above formula is then simplified 
into a 5-parameter model as follows:
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Posteriors for the corresponding 5 parameters (2 logistic regression parameters [
] for 
BMS-986016, 2 logistic regression parameters for nivolumab [
], and 1 interaction 
parameter for the copula-type model
, see details in Section 1.2]) will be fit into the in-house 
developed model, which implements the above described theoretical setup.
1.2
Priors Specification for BMS-986016 and Nivolumab Combination 
Therapy
1.2.1
Marginal Prior for BMS-986016
The Bayesian approach requires the specification of prior distributions for model parameters,
which include parameters (
) for BMS-986016. At the beginning, a weakly informative 
prior will be used for parameters (
) for BMS-986016 to allow for considerable prior 
uncertainty.
Further details are provided below.
Weakly Informative Prior

The median DLT rate at the reference dose (BMS-986016 at 1600 mg Q4W) was assumed to 
be 30%, that is, mean (log(
)) = -0.847.

A doubling in dose was assumed to double the odds of DLT, that is, mean(log(
)) = 0.
The standard deviation of log(
) was set to 1.53 using the following steps:

If the toxicity probability range was set to be [1%, 99%], then the toxicity interval would be 
logit (0.99)-logit (0.01) = 9.19.

To cover 99.7% of the variance, the toxicity interval will cover 6*sd (log(
)).
Correspondingly, the standard deviation of log(
) was set to 2, which allows for considerable 
larger prior uncertainty for the dose toxicity.
1) The correlation between log(
) and log(
) was set to 0.
2) Log(
) and log(
) follow a bivariate normal distribution.
Table 1:
Prior Distribution for Model Parameters for BMS-986016
Parameter
Means
Standard Deviations
Correlation
log(
), log(1)
(-0.847, 0)
(1.53, 2)
0
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1.2.2
Marginal Prior for Nivolumab Parameters (log(2), log(2))
Similar to BMS-986016 monotherapy, the logistic model for nivolumab is as follows:
, 
where 
is the probability of toxicity at dose level
. Note that the
parameters are 
assumed positive, and 
is the reference dose for nivolumab.
The toxicity profile of nivolumab has been studied in several studies. A bivariate normal prior 
for the nivolumab model parameters (log(2), log(2)) was obtained by extracting a posterior of 
nivolumab using incidence of treatment-related Grade 3 to 4 AEs from a Phase 1 dose-escalation 
study and several Phase 3 nivolumab studies, which are used later as the MAP prior for 
nivolumab. These include a Phase 1 dose-escalation study of nivolumab (Study CA209003, 
N=306 in doses of 0.1, 0.3, 1, 3, and 10 mg/kg across multiple tumor types), a randomized Phase 
3 study in advanced melanoma subjects progressing post anti-CTLA-4 therapy (Study 
CA209037, N=268 in a dose of 3 mg/kg), a Phase 3 study in previously treated subjects with 
squamous cell NSCLC (Study CA209017, N=131 in a dose of 3 mg/kg), a Phase 3 study in 
previously treated subjects with non-squamous cell NSCLC (Study CA209057, N=287 in a dose 
of 3 mg/kg), and a Phase 3 study in previously treated subjects with clear-cell RCC (Study 
CA209025, N=406 in a dose of 3 mg/kg). The results from the simulation of nivolumab flat dose 
exposures, the corresponding exposure-response analyses, and review of nivolumab safety 
support nivolumab flat dose and the overall distributions of nivolumab exposures are comparable 
after treatment with either 3 mg/kg Q2W or 240 mg Q2W nivolumab. In addition, dose 
proportionality of nivolumab exposures supports nivolumab 240 mg Q2W being comparable to 
480 mg Q4W.
The MAP prior for the model parameters (log(2), log(2)) was obtained in the following steps.

First, a prior distribution for nivolumab was developed:

The median toxicity rate at the nivolumab reference dose (3 mg/kg every 2 weeks) was 
assumed to be 10%, that is, mean (log(2)) = logit(0.10) = log(0.1/0.9) = -2.197.

A doubling in dose was assumed to double odds of toxicity, ie, mean(log(2)) = 0.

The standard deviation of log(2) was set to 2, and the standard deviation of log(2) was 
set to 1, which allows for considerable prior uncertainty for the dose-toxicity profile.

The correlation between log(2) and log(2) was assumed to be 0 (assuming 
independence of log(2) and log(2)).

In addition, heterogeneity between the historical studies and the current study was 
incorporated using a MAP by defining between-trial standard deviations 1 and 2 for 
log(2) and log(2), respectively. The between-trial variability is assumed to be 
moderate, therefore, 1 and 2 were set to follow a log-normal distribution, with mean 
log(0.25) and log(0.125), respectively, with a common standard deviation log(2)/1.96.
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
With this prior, the clinical trial data below (Table 2) were used to generate the posterior for 
nivolumab, which is then used as the MAP prior for this study (Table 3).
Table 2:
Data from Nivolumab Studies
Nivolumab Flat Dose (mg), Q4W
Dose of Nivolumab (mg/kg), Q2W
Toxicitya
0.1
29% (5/17)
0.3
17% (3/18)
160
1
14% (12/86)
480
3
13% (150/1146)
10
16% (21/131)
a % of subjects with treatment-related Grade 3 or higher AEs
Abbreviation: Q2W = every 2 weeks.
Table 3:
Marginal Prior Distribution for Model Parameters for Nivolumab (ie, 
Posterior from MAP Method)
Parameter
Means
Standard Deviations
Correlation
log(2), log(2)
(-1.856, -2.131)
(0.404, 0.546)
-0.009
1.2.3
Prior for Interaction Parameters for Joint Toxicity of BMS-986016 and 
Nivolumab Combination Therapy
A gamma prior distribution for the interaction parameter is derived to reflect the current 
uncertainty about the toxicity profile of the combination of BMS-986016 and nivolumab. 
Although no pharmacokinetic (PK) drug-drug interaction is expected, the possibility of a 
significant positive interaction between BMS-986016 and nivolumab cannot be totally excluded. 
The interaction parameter was chosen accordingly but with a degree of uncertainty to allow for 
the possibility that the interaction may be positive or negative. Therefore, the following 
assumptions are made for the interaction parameter:

follows a gamma distribution with a mean centered at 1.2, which means the combination of 
2 agents is likely to have only a small synergistic effect.

The standard deviation of is 0.5 such that there is a 61% prior probability that is larger 
than 1.
This model assigns the highest probability to there being small synergistic interaction and also 
allows for the potential of larger synergism of the toxic profiles. It also does not completely 
ignore the possibility of antagonism because there is a 39% prior probability that is less than 1.
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The final prior information to be used in the model will be continuously updated when additional 
toxicity information from different monotherapy or doublet combinations are available. Safety 
information for BMS-986016 from CA224020 study will be used to update the prior distribution 
before being used for dose escalation.
2
DECISION RULE FOR DOSE ESCALATION
2.1
Parameters for Dose escalation
BLRM-copula model will be utilized for dose recommendations after DLT information becomes 
available for each safety cohort. Final dose selection for expansion will be based on BLRM-
copula dose recommendations with the totality of data available on all dosed subjects, after 
discussion and agreement between investigators and the BMS Medical Monitor.
The Bayesian Logistic Regression Method (BLRM)-copula with an overdose control principle 
(escalation with overdose control [EWOC])4 was selected as an appropriate design for the dose 
escalation part B of this study. BLRM -Copula is similar to the rule-based method (ie, 3 + 3 
design) in that the cohort size is approximately 3 subjects for each subject cohort and the toxicity 
boundaries are set at a minimum 16% (~ 1 in 6) dose-limiting toxicity (DLT) rate and a 
maximum 33% (~ 1 in 3) DLT rate. These boundaries were chosen in order to target a dose that 
has meaningful activity but not unacceptably high toxicity. A minimum 16% DLT rate ensures 
that the model does not guide to use of too low a dose and sacrifice opportunity for benefit 
without meaningful improvement in safety. The 33% maximum is chosen as this would be the 
maximum DLT rate where a positive benefit/risk ratio is likely to be demonstrated.
Compared with the rule-based method, BLRM-copula offers more accuracy and efficiency in 
determining the safety by incorporating historical data and all previous on-study safety/DLT 
data. The model also quantifies the benefit and risk during the dose level decision making 
process. When DLT data are incorporated into the model, the distribution of predicted DLT rates 
(based on posterior estimation) for a specific dose level will be updated accordingly. The 
predicted DLT rates will be categorized according to the following 3 categories: 

“Under-dosing” defined as a predicted DLT rate between 0% and up to 16%.

“Target dosing” defined as a predicted DLT rate between over 16% and up to 33%.

“Overdosing” defined as a predicted DLT rate between over 33% and 100%.
Following the principle of EWOC, after DLT information is obtained from each cohort, a dose 
cohort will be declared safe if the the dose level has less than 35% chance of excessive toxicity 
for combination therapies. For dose expansion, the final recommended maximum tolerated dose 
(MTD)/recommended Phase 2 dose (RP2D) of BMS-986016 in combination with nivolumab 
will be based on the recommendation from the BLRM (-copula) model and a synthesis of all the 
data available on all dosed subjects, including clinical and laboratory safety assessments, PK and 
pharmacodynamic data, and efficacy data from all treated subjects. BLRM-copula model with 
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prior information will also be used to help with dose de-escalation on finding intermediate doses 
if needed.
During dose escalation for BMS-986016 in combination with nivolumab, initially a cohort of 
approximately 3 subjects will be treated at the selected dose level. The DLT data collected will 
be used in the BLRM-copula method to obtain the posterior joint toxicity probability profile for 
that combination dose. BLRM-copula dose recommendation will be used to evaluate the safety 
of the selected dose. If the current dose is deemed safe, approximately 3 subjects will be treated 
at the next higher dose level based on the model recommendation. If the current dose is not 
deemed safe, a lower dose cohort may be explored. A minimum of 6 DLT-evaluable subjects 
will be treated at a specific dose before using that dose for expansion. Up to 15 subjects may be 
treated per dose level for the dose escalation.
3
REFERENCES
1
Yin G, Yuan Y. Bayesian dose escalation in oncology for drug combinations by copula 
regression. J R Stat Soc Ser C Appl Stat 2009;58(2):211-24.
2
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
Phase I cancer trials. Stat Meed 2008;27:2420-39.
3
Neuenschwander B, Capkun-Niggli G, Branson M, et al. Summarizing historical information 
on controls in clinical trials. Clin Trials 2010;7:5-18.
4
Babb J, Rogatko A, Zacks S. Cancer Phase I clinical trials: efficient dose escalation with 
overdose control. Stat Med 1998;17:1103-20.
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APPENDIX 7
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 14, 28-Oct-2022
The CA224020 study started with the first patient enrolled on 01-Nov-2013 and is closed to 
enrollment as of 30-Jul-2021 with the last patient enrolled on 30-Jul-2021. 
The purpose of this protocol amendment is to clarify the study duration for patients remaining on 
treatment beyond 5 years, remove the rechallenge period among patients currently on the study, 
align the protocol with the current coronavirus disease 2019 (COVID-19) guidance, and update 
the contraceptive guidance. 
Currently, study duration is defined as approximately 5 years from the first dose of study drug 
including 5 years of follow-up for survival and will remain as such except for those patients who 
remain on treatment beyond 5 years and are still deriving clinical benefit. Patients who 
discontinue treatment before 5 years will complete a 135-day clinical follow-up period and a 
survival follow-up period for up to 5 years after the first dose. Patients who continue study 
treatment for longer than 5 years will complete a 135-day clinical follow-up period once the 
criteria for treatment discontinuation are met, but will not participate in a survival follow-up 
period. The study will end when all patients have completed their respective follow-up periods.
 
 
 
 Current literature is not sufficient to give clear recommendations on the clinical utility of 
immunotherapy rechallenge. Furthermore, data concerning rechallenge utilizing combination 
treatments from randomized cohorts with similar clinical characteristics is limited or missing. 
Given the lack of rechallenge data from randomized clinical trials, no standardized approach 
exists; however, the current practice is to switch therapies upon progression. Given this limited 
data and 
, the decision was 
made to suspend future participation in the rechallenge period. All subjects who discontinue 
primary study treatment following implementation of this amendment will not be eligible for 
rechallenge. Subjects currently receiving rechallenge treatment will be allowed to continue, and
subjects currently in the rechallenge-eligible Survival Follow-up as of this Protocol Amendment 
remain eligible for rechallenge. 
Summary of Key Changes for Protocol Amendment 14
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Incorporates changes below as 
applicable.
Updated to reflect study 
changes.
Section 1.5: Overall Benefit-risk 
Assessment
Added language on benefit-risk of 
COVID-19 vaccine use in this trial. 
Added to align with language 
from COVID-19 guidance  
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Summary of Key Changes for Protocol Amendment 14
Section Number & Title
Description of Change
Brief Rationale
Section 3.1: Study Design and 
Duration

As of Protocol Amendment 14,
rechallenge is not permitted. 
Clarified that rechallenge-eligible 
Survival Follow-up may continue 
for up to 5 years from the first dose.

Added clarification that study 
duration may be extended for those 
subjects who are remaining on 
treatment beyond 5 years and still 
deriving clinical benefit.

Given the limited data on 
rechallenge 
 
 
 
, no new treatment 
rechallenges among 
patients currently on study
will be allowed. For 
patients currently in 
rechallenge-eligible 
Survival Follow-up, 
clarified the duration of 
the follow-up period to be 
consistent with the 
survival follow-up period 
for all other parts of the 
study. 

Provided clarification that 
study treatment may be 
continued beyond 5 years 
as several patients have 
approached the 5-year 
treatment mark and are 
still deriving clinical 
benefit on this study. 
Figure 3.1-4: Detailed Study 
Schematic
As of Protocol Amendment 14,
rechallenge is not permitted.

Given the limited data on 
rechallenge 
 
 
 
 no new treatment 
rechallenges among 
patients currently on study 
will be allowed.

For patients currently in 
rechallenge-eligible 
Survival Follow-up, 
clarified the duration of 
the follow-up period to be 
consistent with the 
survival follow-up period 
for all other parts of the 
study.
Section 3.1.2.4: Rechallenge in 
Dose Escalation (Parts A and B) 
and Cohort Expansion Parts (A1, C, 
D and E) 
As of Protocol Amendment 14,
rechallenge is not permitted. Clarified 
that Survival Follow-up may continue 
for up to 5 years from the first dose for 
rechallenge-eligible patients.
Section 3.3.1: Inclusion Criteria 
Updated women of childbearing 
potential contraceptive duration and 
modified contraceptive requirements for 
male participants.  
Changes were made to reflect 
the latest nivolumab and 
relatlimab contraceptive 
guidance.  
Section 3.4.3: Permitted Therapy 
Added language on COVID-19 
vaccination. 
Added to align with language 
from COVID-19 guidance.  
Protocol Amendment No. 15
Date: 16-Feb-2024
247
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of Key Changes for Protocol Amendment 14
Section Number & Title
Description of Change
Brief Rationale
Table 5.1-1: Screening Procedural 
Outline
As of Protocol Amendment 14,
rechallenge is not permitted.
Given the limited data on 
rechallenge 
 
 
 no new treatment 
rechallenges among patients 
currently on study will be 
allowed.
Table 5.1-2: On-treatment 
Procedural Outline for Q2W and 
Q4W BMS-986016/Nivolumab 
Treatment Regimens Parts A 
through E 

As of Protocol Amendment 14,
rechallenge is not permitted.

Removed male contraceptive 
language. 

Added a footnote on treatment 
beyond 5 years. 

Given the limited data on 
rechallenge 
 
 
 
 no new treatment 
rechallenges among 
patients currently on study 
will be allowed. 

Aligned with latest 
relatlimab/nivolumab 
contraceptive guidance.

Clarified that patients may 
continue to be treated past 
the 5-year mark if they are 
still deriving clinical 
benefit.  
Table 5.1-3: Follow-up Procedural 
Outline Parts A Through E 

Removed male contraceptive 
language.

Removed diagnostic imaging 
duplicate row and added survival 
follow-up imaging to existing row. 

Added a footnote on treatment 
beyond 5 years.

Aligned with latest 
relatlimab/nivolumab 
contraceptive guidance.

Removed repetitive 
language. 

Clarified that patients may 
continue to be treated past 
the 5-year mark if they are 
still deriving clinical 
benefit.  
Protocol Amendment No. 15
Date: 16-Feb-2024
248
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of Key Changes for Protocol Amendment 14
Section Number & Title
Description of Change
Brief Rationale
Table 5.3.1-1: Biomarkers by
Tumor Type: All Cohorts Except 
for Subjects Crossing Over or 
Rechallenged
Table 5.5.1-2: PK and ADA 
Sampling Schedule for BMS-
986016 and Nivolumab for Dose 
Expansion Part C Q2W Dosing 
(After First 6 Subjects) and for 
Cohort with Crossover or 
Rechallenge
Table 5.5.1-4: PK and ADA 
Sampling Schedule for BMS-
986016 and Nivolumab for Dose 
Expansion Part C Bladder Cohort 
(After Approximately First 6 
Subjects), Part D1 Arm 1, Part D1 
(Arm 2 and Arm 3, After First 12 
Subjects), Part D2, Part E and 
Rechallenge
Table 5.7-2: Parts A1 and C 
(Cohort Expansion) and Cohorts for 
Crossover or Rechallenge: 
Biomarker Sampling
Table 5.7-3: Biomarker Sampling 
for Part D Melanoma Prior IO 
Extended Expansion and 
Rechallenge
Table 5.7-4: Biomarker Sampling 
for Part E Exposure/Response 
Expansion Q4W Dosing and 
Rechallenge
Section 5.4.2: Efficacy Assessment 
for the Study 

As of Protocol Amendment 14,
rechallenge is not permitted.

Given the limited data on 
rechallenge 
 
 
 
 no new treatment 
rechallenges among 
patients currently on study 
will be allowed. 
Protocol Amendment No. 15
Date: 16-Feb-2024
249
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of Key Changes for Protocol Amendment 14
Section Number & Title
Description of Change
Brief Rationale
Table 5.5.1-1: PK and ADA 
Sampling Schedule for BMS-
986016 and Nivolumab for Dose 
Escalation Parts A and B Q2W
Dosing and Expansion Parts A1 and 
C (Approximately the First 6 
Subjects in Each Cohort Only)
Table 5.5.1-2: PK and ADA 
Sampling Schedule for BMS-
986016 and Nivolumab for Dose 
Expansion Part C Q2W Dosing 
(After First 6 Subjects) and for 
Cohort with Crossover or 
Rechallenge
Table 5.5.1-3: PK and ADA 
Sampling Schedule for BMS-
986016 and Nivolumab for Dose 
Escalation Parts B and C (Bladder 
Cohort Approximately First 6 
Subjects) with Q4W Regimen
Table 5.5.1-4: PK and ADA 
Sampling Schedule for BMS-
986016 and Nivolumab for Dose 
Expansion Part C Bladder Cohort 
(After Approximately First 6 
Subjects), Part D1 Arm 1, Part D1 
(Arm 2 and Arm 3, After First 12 
Subjects), Part D2, Part E and 
Rechallenge
Table 5.5.1-5: PK and ADA 
Sampling Schedule for BMS-
986016 and Nivolumab for Part D1 
(Arm 2 and 3, First 12 Subjects)
Table 5.7-3: Biomarker Sampling 
for Part D Melanoma Prior IO 
Extended Expansion and 
Rechallenge
Table 5.7-4: Biomarker Sampling 
for Part E Exposure/Response 
Expansion Q4W Dosing and 
Rechallenge
Section 8.3.2.3: Immunogenicity

Updated PK and ADA sampling 
schedule.

Updated biomarker sampling 
schedule.

Nivolumab+relatlimab 
has shown low 
immunogenic potential 
over 24 months of 
treatment period and is 
considered to be not 
clinically relevant. Hence, 
additional PK and 
immunogenicity beyond 
24 months or after the 
treatment discontinuation 
is not required.

Nivolumab and relatlimab 
exposure after the first 
dose is established as a 
meaningful exposure 
metric in characterizing 
the exposure-response for 
the safety events of 
≥Grade 3 TRAEs and 
≥Grade 2 IMAEs. 
Nivolumab+relatlimab 
has shown a low 
immunogenicity rate, and 
presence of ADA was not 
associated with safety. 
Hence, PK and 
immunogenicity 
collection upon the 
occurrence of ≥ Grade 3 
AEs is not required.
Section 8.3.2.3: Immunogenicity 
Updated text on timing of ADA 
assessment.
Changes were made to 
maintain consistency with 
other immunogenicity text in 
the protocol. 
Protocol Amendment No. 15
Date: 16-Feb-2024
250
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of Key Changes for Protocol Amendment 14
Section Number & Title
Description of Change
Brief Rationale
Appendix 1: Women of 
Childbearing Potential Definitions 
and Methods of Contraception 
Updated women of childbearing 
potential contraceptive duration and 
removed contraceptive requirements for 
male participants. Added text on “End of 
Relevant Systemic Exposure.”
Changes were made to reflect 
the latest nivolumab and 
relatlimab contraceptive 
guidance.  
Appendix 8: Country Specific 
requirements/difference 
Added France and Italy to list of 
countries. 
Clarified country/site specific 
requirements/differences. 
Overall Rationale for the Revised Protocol 13, 29-Jul-2021
 
 
.
Revisions are applicable to future participants in the study, and where applicable, to all 
participants currently enrolled.
Summary of key changes for Protocol Amendment 13
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated clinical scientist and medical 
monitor contact information.
Changes have been made to 
reflect the correct study team 
information.
Synopsis
Incorporates changes below as 
applicable.
Updated to reflect study 
changes.
Section 1.4.1.2: Toxicity
Updated text to refer to current 
Investigator’s Brochure (IB) of 
relatlimab.
Provided flexibility for any 
updates to the relatlimab IB in 
the future.
Protocol Amendment No. 15
Date: 16-Feb-2024
251
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Protocol Amendment 13
Section Number & Title
Description of Change
Brief Rationale
Protocol Amendment No. 15
Date: 16-Feb-2024
252
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Protocol Amendment 13
Section Number & Title
Description of Change
Brief Rationale
Section 7.1 Data Monitoring 
Committee
Updated the frequency which the data 
monitoring committee (DMC) meets to 
reflect frequency as outlined in the DMC 
charter.
To align with DMC charter. 
Overall Rationale for the Revised Protocol 12, 05-Feb-2020
This revision reflects changes made at the request of the 
. As a 
result, duration of response was added as a secondary objective for Part E and PK and Biomarker 
tables were updated to add sample collection upon occurrence of Grade 3 adverse events.
Summary of key changes for Revised Protocol 12
Section Number 
& Title
Description of Change
Brief Rationale
Protocol Amendment No. 15
Date: 16-Feb-2024
253
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 12
Section Number 
& Title
Description of Change
Brief Rationale
Global
Typographical and grammatical errors were corrected, and 
edits were made for consistency and clarity.
Editorial
1.3.2, Secondary 
Objectives
Added the following secondary objective: To evaluate the 
clinical benefit of the 480 mg BMS-986016 + 480 mg 
nivolumab Q4W dosing regimen using DOR in melanoma 
participants who have not received prior systemic anticancer 
therapy for unresectable or metastatic melanoma and for 
melanoma participants who experienced disease progression 
on prior anti-PD-1 therapy.
3.1, Study Design 
and Duration
Added the following sentence: Survival follow-up visits will 
be scheduled based on the last clinical follow up visit.
Clarify when visits will 
be scheduled
3.1, Study Design 
and Duration
Figure 3.1-4: 
Detailed Study 
Schematic
For subjects who discontinue at the investigator’s discretion 
with CR, PR, or SD, imaging must be performed every 12 
weeks until disease progression
Clarified that imaging 
is until disease 
progression.
3.3.2, Exclusion 
Criteria
Added the following to criterion h) under 2) Medical History 
and Concurrent Diseases:  NOTE: Testing for HIV must be 
performed at sites where mandated locally.
Added criterion b) under 3) Allergies and Adverse Drug 
Reactions: History of allergy or hypersensitivity to study drug 
components
To bring in line with 
current program 
standards.
5.1, Flow Chart/Time 
and Events Schedule
Added the following paragraphs:
Additional measures, including nonstudy required laboratory 
tests, should be performed as clinically indicated or to comply 
with local regulations. Laboratory toxicities (eg, suspected 
drug induced liver enzyme evaluations) will be monitored 
during the follow-up phase via on-site/local labs until all 
study drug-related toxicities resolve, return to baseline, or are 
deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, 
fever) or symptoms (eg. dyspnea, cough, fever) consistent 
with possible pulmonary adverse events, the participant 
should be immediately evaluated to rule out pulmonary 
toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) 
Investigator Brochure.
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.
To bring in line with 
current program 
standards.
Protocol Amendment No. 15
Date: 16-Feb-2024
254
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 12
Section Number 
& Title
Description of Change
Brief Rationale
Table 5.1-2: On-
Treatment Procedural 
Outline for Q2W and 
Q4W BMS-
986016/Nivolumab 
Treatment Regimens 
Parts A through E
In the notes for Efficacy Assessments, Diagnostic imaging, 
the timing of imaging was defined as every 8 weeks until 
disease progression or discontinuation of study treatment.
Clarified timing of 
imaging.
Table 5.1-3: Follow-
Up Procedural 
Outline Parts A 
through E
In the notes for Efficacy Assessments, Diagnostic imaging 
and Survival Status, Diagnostic imaging, the timing of 
imaging was defined as every 12 weeks until disease 
progression.
Clarified that imaging 
is until disease 
progression.
5.3.1, Laboratory 
Test Assessments
Added the following sentence to first paragraph:  
Investigators must document their review of each laboratory 
safety report.
To bring in line with 
current template 
language.
5.4.1, Imaging 
Assessment for the 
Study
Added the following sentence to the second paragraph:  Sites 
should be trained prior to scanning the first study participant.
Added paragraph to end of section: Any additional imaging 
that may demonstrate tumor response or progression 
(including scans performed at unscheduled time points and/or 
at an outside institution) should be collected for RECIST v1.1 
tumor assessment and submitted to the BICR.
To bring in line with 
current template 
language and program 
standards.
5.5.1, 
Pharmacokinetics:  
Collection and 
Processing
Added the following sentence: Effective with Revised 
Protocol 12, PK samples should be taken coincident with the 
occurrence of a study drug-related Grade 3 AE.
Table 5.5.1-1, Table 
5.5.1-2, Table 5.5.1-
3, Table 5.7-1, Table 
5.7-2, Table 5.7-3, 
and Table 5.7-4
In the PK and Biomarker Sampling Schedule tables under the 
heading Upon drug-related AE the category was changed 
from:
Upon occurrence of 2 drug-related pneumonitis or 
neurological AE 
to:
Upon occurrence of Grade 3 drug-related AE
Table 5.5.1-1 to 
Table 5.5.1-5
In the PK Sampling Schedule Tables, redefined stopping 
point of alternate treatment cycles from Cycle 11 to End of 
Treatment
Clarify timing of 
sample collection.
Table 5.5.1-4 and 
Table 5.5.1-5
In the PK Sampling Schedule tables the following header and 
category was added to table:
Header: Upon drug-related AE
Category: Upon occurrence of Grade 3 drug-related AE
Protocol Amendment No. 15
Date: 16-Feb-2024
255
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 12
Section Number 
& Title
Description of Change
Brief Rationale
Table 5.7-3 and 
Table 5.7-4
In the Biomarker Sampling Schedule tables for Part D and 
Part E, timing of samples for Cycle 2 to end of treatment was 
clarified and header was changed to: Cycle 2 and Alternate 
Treatment Cycles (Starting from Cycle 3 to End of 
Treatment)
Clarify timing of 
sample collection.
Overall Rationale for the Revised Protocol 11, 11-Oct-2019
Changes reflect the update from the February 2019 evaluation of the BMS-986016 480 mg + 
nivolumab 480 mg Q4W dosing regimen. Inclusion criteria for adjuvant/neoadjuvant subjects 
were updated to exclude anti-PD-1 or anti-PD-L1 therapy with the exception of the Expanded 
Eligibility Cohort under certain conditions.
Summary of key changes for Revised Protocol 11
Section Number & Title
Description of Change
Brief Rationale
Global
Typographical and grammatical errors 
were corrected, and edits were made for 
consistency and clarity.
Minor; therefore have not be 
summarized
1.1.7, Rationale for Part E 
(Melanoma Expansion)
1.1.9.7, Part E: Co-administration 
of BMS-986016 and Nivolumab
1.4.1.4.2, Clinical Safety
3.1, Study Design and Duration
3.1.2.6, Part E Exposure Response 
Evaluation (Co-administration)
Updated information about the safety of 
BMS-986016 480/960/1440 mg + 
nivolumab 480 mg Q4W dosing regimen
Regimen was being evaluated 
in Part B (Dose Escalation 
with DLT criteria) of this 
study in Feb 2019. That 
evaluation is complete and text 
was updated accordingly.
1.1.9.8, Dose Rationale for 
Adolescents
3.1, Study Design and Duration
Removed reference to 3 mg/kg BMS-
986016 and 6 mg/kg of nivolumab Q4W
The weight based dose of 6 
mg/kg BMS-986016 and 6 
mg/kg of nivolumab Q4W will 
correspond to fixed dose of 
480/480 Q4W.
1.4.1.4.3, Clinical Efficacy-
Monotherapy (Part A) versus 
Combination Therapy (Part B): 
CA224020 Study
Updated number of subjects treated with 
BMS-986016 and nivolumab in Part B 
and Part C
Reflects subjects treated as of 
most recent cutoff.
Protocol Amendment No. 15
Date: 16-Feb-2024
256
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 11
Section Number & Title
Description of Change
Brief Rationale
3.1, Study Design and Duration
Figure 3.1-1 CA224020 Study 
Schematic, Footnotes
Figure 3.1-4, Detailed Study 
Schematic, Footnotes
4.1.3, Handling and Dispensing
Added timing of infusion for 960 mg 
(and higher) doses of relatlimab 
following 480 mg nivolumab
Updated to reflect the changes 
based on the completion of the 
dose regimen evaluation in 
part B.
Figure 3.1-3 Part E
Removed statement from figure 
indicating that LAG3 status is 
determined prior to randomization.
To add clarification
3.1, Study Design and Duration
Figure 3.1-4, Detailed Study 
Schematic
3.1.2.4, Re-challenge in Dose 
Escalation (Parts A and B) and 
Cohort Expansion Parts (A1, C, D, 
and E)
Table 5.1-2 On-Treatment 
Procedural Outline for Q2W and 
Q4W BMS-986016/Nivolumab 
Treatment Regimens Parts A 
through E
5.4.2, Efficacy Assessment for the 
Study
Removed from Treatment period 
references to up to twelve 8-week 
treatment cycles.
Removed the treatment limit.
3.1, Study Design and Duration
Figure 3.1-4, Detailed Study 
Schematic
Table 5.1-3 Follow-Up Procedural 
Outline Parts A through E
Changed Survival Follow-up period to 
say length is up to 5 years following the 
first dose of study drug.
To add clarification
3.1, Study Design and Duration
Figure 3.1-4, Detailed Study 
Schematic
3.5 Discontinuation of Subjects 
from Treatment
Removed confirmed complete response 
and completion of the maximum number 
of twelve 8 week cycles from 
discontinuation criteria
Patients will not be treated 
until disease progression, 
clinical deterioration, or 
meeting other discontinuation 
criteria.
Removed the treatment limit.
3.1, Study Design and Duration
Figure 3.1-4, Detailed Study 
Schematic, footnote
Table 5.1-3 Follow-Up Procedural 
Outline Parts A through E
5.4.2, Efficacy Assessment for the 
Study
Changed timing of diagnostic imaging to 
every 8 weeks until disease progression 
and every 12 weeks for subjects who 
discontinue due CR, PR, or SD at 
investigators discretion.
To add clarification
Protocol Amendment No. 15
Date: 16-Feb-2024
257
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 11
Section Number & Title
Description of Change
Brief Rationale
3.1, Study Design and Duration
Figure 3.1-4, Detailed Study 
Schematic
3.1.2.4, Re-challenge in Dose 
Escalation (Parts A and B) and 
Cohort Expansion Parts (A1, C, D, 
and E)
Removed from re-challenge period that 
subjects could receive therapy for up to 6 
additional eight-week cycles
Removed the treatment limit.
3.3.1, Inclusion Criteria; 1) Signed 
Written Informed Consent, b) 
Consent for tumor biopsy samples, 
i) and ii)
Table 5.1-1 Screening Procedural 
Outline (CA224020)
Table 5.7-1 to Table 5.7-4, footnote
Table 5.7-5 Tumor Tissue 
Requirements
Updated sample language, so that 
participants must have tumor tissue 
submitted, 
 
 
On-treatment biopsies for all sites, with 
the exception of US IION sites are 
optional.
Updated Screening Procedural Outline 
(CA224020) table, Biomarker Sampling 
tables, and Tumor Tissue Requirements 
table to reflect these changes.
To add clarification
3.3.1, Inclusion Criteria; 2) Target 
Population, v) Part D1 Melanoma 
Prior IO Extended Expansion: 
Focused Eligibility Cohort
Changed criteria for 
Adjuvant/Neoadjuvant therapy: 
Adjuvant (or neo-adjuvant) anti-PD-1 or 
anti-PD-L1 therapy is not allowed. Other 
adjuvant (or neoadjuvant) melanoma 
therapies, including anti-CTLA-4, are 
allowed.
Change made to make 
consistent with current 
program standards
3.3.1, Inclusion Criteria; 2) Target 
Population, vi) Part D2 Melanoma 
Prior IO Extended Expansion: 
Expanded Eligibility Cohort
Changed criteria for 
Adjuvant/Neoadjuvant therapy: Patients 
with prior adjuvant or neo-adjuvant anti-
PD-1 therapy are allowed as long as one 
of the two conditions are met, 1) 
progression occurred during or within 6 
months of the last dose of adjuvant anti-
PD-1 therapy, or 2) there has been 
subsequent progression on additional 
anti-PD-1 therapy in the metastatic 
setting
Change made to make 
consistent with current 
program standards
3.3.1, Inclusion Criteria; 2) Target 
Population, vii) Part E: Exposure 
Response Evaluation in Melanoma 
Participants, (1) Melanoma 
participants who experienced 
disease progression on prior anti 
PD 1 therapy
Changed criteria for 
Adjuvant/Neoadjuvant therapy: 
Adjuvant (or neo-adjuvant) anti-PD-1 or 
anti-PD-L1 therapy is not allowed. Other 
adjuvant (or neoadjuvant) melanoma 
therapies, including anti-CTLA 4, are 
allowed.
Change made to make 
consistent with current 
program standards
Protocol Amendment No. 15
Date: 16-Feb-2024
258
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 11
Section Number & Title
Description of Change
Brief Rationale
3.3.1, Inclusion Criteria; 2) Target 
Population, vii) Part E: Exposure 
Response Evaluation in Melanoma 
Participants, (2) Melanoma 
participants who have not received 
prior systemic anticancer therapy 
for unresectable or metastatic 
melanoma
Added the following criterion: Uveal 
melanoma subjects are NOT eligible
To bring in line with other 
melanoma treatment groups in 
the study.
3.4.1, Prohibited and/or Restricted 
Treatments
Updated second bulled about concurrent 
administration of anticancer therapies so 
that the bullet now reads:  Concurrent 
administration of any anticancer 
therapies (investigational or approved) in 
the Treatment Period, with the exception 
of subjects in Clinical Follow-up period 
as well as the Survival period of the 
study
To add clarification
Table 5.1-1 Screening Procedural 
Outline (CA224020)
Removed Archived tumor tissue sample 
row
Made redundant based on 
changes to reflect new 
guidance on submission of 
pre-treatment tumor tissue.
5.4.1, Imaging Assessment for the 
Study
The following paragraph was added: 
Tumor assessments at other time points 
may be performed, if clinically indicated, 
and should be submitted to the central 
imaging vendor as soon as possible. 
Unscheduled CT/MRI should be 
submitted to central imaging vendor. X-
rays and bone scans that clearly 
demonstrate interval progression of 
disease, for example most commonly as 
unequivocal lesions that are 
unmistakably new since the prior 
CT/MRI, should be submitted to central 
imaging vendor. Otherwise, they do not 
need to be submitted centrally.
Outlines procedures for tumor 
assessments done outside of 
scheduled assessments, if 
clinically indicated.
Overall Rationale for the Revised Protocol 10, 15-Feb-2019
The purpose of revised protocol 10 is to 1) add four additional Part B combination dosing 
cohorts: 480 mg, 960 mg , 1440 mg, and 1600 mg BMS-986016 (relatlimab) + 480 mg 
nivolumab, every four weeks (Q4W), 2) change the dose escalation statistical methodology from 
3+3+3 to an adaptive Bayesian Logistic Regression Model (BLRM) Copula design for Part B, 
which will more precisely predict the safety profile, 3) change the dose-limiting toxicity period 
from 8 weeks to 6 weeks 4) add Part E exposure-response evaluation cohorts (melanoma 
participants who experienced disease progression on prior anti-PD-1 therapy and melanoma 
participants who have not received prior systemic anticancer therapy for unresectable or 
Protocol Amendment No. 15
Date: 16-Feb-2024
259
19.0
Approved
930071758
18.0
v
Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
metastatic melanoma), and. Additionally, details of clinical safety and pharmacokinetic sections 
were reduced as the information is available in the Investigator Brochure(s) and Opdivo 
(nivolumab) package insert.
Sections in the synopsis have been updated to align with the protocol section changes listed 
below.
Summary of key changes for Revised Protocol 10
Section Number & 
Title
Description of Change
Brief Rationale
1) PART B CHANGES:
Section 3.1, Figure 3.1-1, 
3.1-4, Table 3.1.1.2-1 
Added 480 mg, 960 mg, 1440 mg and 
1600 mg doses of BMS-986016 plus 480 
mg nivolumab, Q4W to the Part B 
dosing cohorts.
To complete the stated primary 
objective of the dose escalation portion 
of the protocol.
Section 1.1.9.3 Part B 
BMS-986016 Dose 
Escalation (Applies to 
only a sub-set of sites 1-6)
To provide clarity on 
participation in Part B of 
the study.
Clarified that Part B (Dose Escalation) is 
limited to a sub-set of sites.
Updated the section title and provided 
updated safety information for BMS-
986016 from Phase 1/2 studies.
To provide clarity on participation in 
Part B of the study.
To provide the most up-to-date safety 
information for BMS-986016 and 
include the risk/benefit assessment for 
Part E.
2) STATISTICAL METHODOLOGY CHANGES:
Section 3.1 Investigational 
Plan, Figure 3.1-1; Table 
3.1.1.2-1 “Dose Escalation 
Schedule for Part B 
BMS-986016 in 
Combination with 
Nivolumab every 4 week 
dosing”;
Section 8.1.1 Dose 
Escalation (Parts A and B)
Include the BLRM (Bayesian Logistic 
Regression Model)-Copula design (for 
part B only), Figure 3.1-1 study 
schematic was updated to include 
additional doses for Part B, Table 
3.1.1.2-1 was updated to include 
additional doses for Part B
Described the BLRM design for Part B.
Statistical methodology was changed 
from 3+3+3 to an adaptive BLRM to 
more precisely predict the safety profile. 
3) PART E CHANGES
Section 1.1.7 Rationale for 
Part E (Melanoma 
Exposure-Response 
Evaluation ), Section 
1.1.9.7 Part E: Co-
administration of 
BMS-986016 and 
Nivolumab; 
Section 1.2 Research 
Hypothesis; Section 1.3 
Primary Objectives; 
Section 3.1.2.6 Part E 
Exposure-Response 
Evaluation (Co-
Added the rationale for adding new Part 
E (Melanoma Exposure Response 
Evaluation) into the protocol.
Added Part E to the research hypothesis 
and primary objectives.
Added Part E to the cohort expansion 
section
Part E was added to the study to more 
fully elucidate the exposure-response 
curve in melanoma participants.
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 10
Section Number & 
Title
Description of Change
Brief Rationale
administration)
Figure 3.1-3, Figure 3.1-4
Section 3.3.1 Inclusion 
Criteria 2) Target 
Population (6); vii) Part E: 
Exposure Response 
Evaluation in Melanoma 
Participants Table 5.1-1 
Screening Procedural 
Outline; Table 5.1-2 On-
Treatment procedural 
Outline
Section 4.2 Method of 
Assigning Subject 
Identification
Table 5.5.1-4 
Pharmacokinetic 
Sampling Schedule
Table 5.7-4 Part E 
Biomarker Sampling 
Schedule;
8.1.5 Sample size 
Exposure/Response 
Expansion Q4W Dosing 
(Part E)
Figure 3.1-3 Part E was added and 
Figure 3.1-4 was updated to include Part 
E
Added inclusion criteria for Part E 
participants
Added tumor tissue requirements for 
Part E participants, and Part E 
participants need to be screened for 
BRAF mutation, added part E dosing 
Added assignment criteria for Part E 
participants
Added time points for Part E
New Table 5.7-4 was added for Part E 
biomarker testing schedule
Added the rationale for Part E sample 
size
Added rationale for sample size for new 
Part E
4) DLT CHANGES:
Section 3.1.3 Dose-
Limiting Toxicities; 
3.1.3.1 Rationale for 6-
week DLT period in Part 
B
Dose-Limiting Toxicities (DLT) period 
was changed from 56 days (8 weeks) to 
42 days (6 weeks); new rationale section 
added for the reduced DLT period in 
Part B.
Dose Limiting Toxicity (DLT) 
observation period reduced from 8 
weeks to 6 weeks as (1) we now have 
acquired safety data, with  relatlimab in 
combination with nivolumab, from over 
800 patients since the initiation of the 
program and (2) need to reduce the 
incidence of patients developing 
progressive disease, and becoming 
unevaluable, during the DLT period.
ADDITIONAL MISC 
CHANGES:
Section 1.4.1.2 Toxicity
Added results of BMS-986016 3-month 
IV toxicity study in cynomolgus 
monkeys 
Updated IB version number 
To align this section of the protocol 
with the most recent version of the IB 
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 10
Section Number & 
Title
Description of Change
Brief Rationale
Section 1.4.1.4.1 Clinical 
Pharmacology 
Updated to include the results of the 
relatlimab Population PK model, 
 
 
, and relatlimab 
immunogenicity results. 
To reflect the most up-to-date clinical 
pharmacology data for BMS-986016
Section 1.4.1.4.2 Clinical 
Safety
Updated using clinical cut-off date of 
18-Jun-2018
To reflect the most up-to-date safety 
information for BMS-986016
Section 1.5 Overall 
Risk/Benefit Assessment
Updated using clinical cut-off date of 
18-Jun-2018
To reflect the most up-to-date safety 
information for BMS-986016
Section 2.1 Good Clinical 
Practice
Section was updated to align with 
current BMS language describing Good 
Clinical Practice  
To align with the latest BMS standards.
Section 3.3 Study 
Population
Language added allowing retesting of 
laboratory parameters and/or other 
assessments within any single Screening 
or Lead-in period 
To clarify that retest is allowed during 
screening
Section 3.3.1 Inclusion 
Criteria 2) Target 
Population (6); 3) Age and 
Reproductive Status; 
Appendix 4
Added :”Weight 40 kg” as an 
inclusion criterion for all participants;
Added inclusion criteria for Part E; 
allow certain adjuvant and neo-adjuvant 
therapies
Updated criteria 3) e) related to male 
contraceptive requirements for all males 
(even azoospermic males).
Weight requirement was added to 
ensure that all dosing was in accord 
with ICH guidance on impurities for 
pharmaceutical products.
Guidance added for azoospermic males 
regarding exposure of partners to 
seminal fluid from study participant and 
contraception methods were updated to 
align with latest BMS policy.
Section 3.3.1 Exclusion 
Criteria 2) Medical 
History and Concurrent 
Diseases; Exclusion 2) o)
Troponin criteria was clarified and 
simplified as follows: Troponin T (TnT) 
or I (TnI) > 2 × institutional ULN. 
Between > 1 to 2 x ULN will be 
permitted if a repeat assessment remains 
2 x ULN and subject undergoes a 
cardiac evaluation
To clarify the criteria for exclusion 
regarding Troponin T (TnT) or I (TnI) 
test result.
Section 3.4.2
Language added prohibiting live or 
attenuated vaccines during treatment and 
until 100 days post last dose
To align with the latest BMS standards 
for subjects who may be treated with 
nivolumab
Section 3.4.3 Permitted 
Therapy
Language added as guidance for subjects 
who need to undergo elective surgery 
(not tumor-related) during the study
Provide guidance for subjects who need 
to undergo elective surgery.
Section 4.4 
Blinding/Unblinding
Updated the text to clarify that 
designated staff of the Sponsor can 
access IRT treatment codes prior to the 
formal locking of the study database.
To facilitate the access to treatment 
codes for interim data analyses.
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 10
Section Number & 
Title
Description of Change
Brief Rationale
Section 4.1 Study 
treatments, Table 4.1-1
Added relatimab Injection 80 mg/vial to 
product description and dosage form
To reflect current packaging of 
relatimab 
Table 5.1-2
Changed visit window for Q4W to 3 
days
Visit window of 3 days is appropriate 
for a 4-week interval
Section 6 Adverse Events
Entire section was updated to align with 
the updated BMS standards for defining 
adverse events, assessment of causality, 
pregnancy and overdose language.
To align with the latest BMS standards.
Inclusion/Exclusion 
Criteria
Clarification that prior disease 
progression on anti-PD-1 antibodies is 
limited to only nivolumab and 
pembrolizumab  anti-PD-1 antibodies
Only nivolumab and pembrolizumab 
have a documented, verifiable clinical 
safety and efficacy safety profile.
Appendix 1 Women of 
Childbearing Potential 
Definitions and Methods 
of Contraception
Highly Effective Methods of 
Contraception, Less Than Highly 
Effective Contraceptive Methods That 
Are User Dependent were updated to 
align with BMS policy.
CONTRACEPTION GUIDANCE FOR 
MALE PARTICIPANTS WITH 
PARTNER(S) OF CHILD BEARING 
POTENTIAL- added requirement for 
use of a condom by male participants 
during any sexual activity while on 
study plus 5 half-lives of study 
treatments plus 90 days
To align with the latest BMS standards
Appendix 4 Management 
Algorithms
Updated Appendix 4 
Management Algorithms to the 
most recent version 
To align with the latest BMS standards
Appendix 6 Myocarditis 
Adverse Event 
Management Algorithm
Added Appendix 6 Adverse Event 
Management Algorithm
Adding myocarditis algorithm to reflect 
evolving safety information for 
relatlimab
All
Minor formatting and typographical 
corrections
Made corrections for clarity and 
consistency within the document.
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Overall Rationale for the Revised Protocol 09, 31-Jan-2018
The purpose of this amendment is to incorporate testing of the relatlimab/nivolumab fix dose 
combination (FDC) drug product BMS-986213 into Part D1. The primary objective will be to 
compare the safety of the FDC drug product with co-administration of relatlimab and nivolumab. 
Additional analyses are added and clarified to assess PK of the FDC drug product as well as 
confirm the efficacy and safety of the every four-week dosing schedule.
Additionally this revised protocol reflects the changes that were mentioned in approved 
administrative letters 05 and 06 and are not included in the summary of key changes listed 
below. 
Revisions apply to future participants enrolled in the study and where applicable to all 
participants currently enrolled.
Summary of key changes for Revised Protocol 09
Section Number & 
Title
Description of Change
Brief Rationale
Section 1.1.6 Rationale for 
Part D Expansion; 
Clarification added as per new data
Clarification and definition of FDC drug 
product use.
Section 1.1.8 Rationale for 
Dose Selection
Clarification text has been added for 
BMS-986016 and Nivolumab 
administered for subjects in Parts A, A1, 
B, C and D.
Dosage clarification based on revised 
study design for Part D.
Section 1.1.8.4
Parts B, 
C -Nivolumab and 
Combination Dosing -
Sequential infusion
Clarification about infusion time has
been added for Part B. 
To clarify that only for Part B 
nivolumab infusion are approximately 
60 minutes, vs. Part C where the 
infusion is 30 minutes. 
Section 1.1.8.5
Rationale for 30 minute 
Nivolumab Infusion
New section added
Section has been added as nivolumab is 
infused over 30 minutes in Part C.
Section 1.1.8.6 Part D: 
Co-administration) or 
Fixed Dose Combination 
(FDC); Section 3.1.2.5 
Part D Melanoma Prior IO 
Extended Expansion (Co-
administration or 
treatment with 
FDC(BMS-986213))
Clarification text added about fixed dose 
combination
Treatment clarifications based on 
revised study design for Part D.
Synopsis, Study Design, 
Section 1.1.8.7 Dose 
Rationale for Adolescents
The text has been modified as the fixed 
dose combination is added to Part D1 in
this amendment.
Changing dosing for adolescents to flat 
dosing for those at least 40 kg and 
weight based dosing for those below 40 
kg.
Synopsis; Section 1.2 
Research Hypothesis
Additional text about Part D1 treatment 
with fixed dose combination has been 
added. 
Hypothesis statement regarding FDC 
drug product.
Synopsis; Section 1.3.1 
Clarification text for Part D1-Q4W and 
Objectives for testing of the FDC 
Protocol Amendment No. 15
Date: 16-Feb-2024
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1.0
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 09
Section Number & 
Title
Description of Change
Brief Rationale
Primary Objectives; 
Section 1.3.2 Secondary 
Objectives
Part D1-Q2Whas been added
product have been added
Synopsis; Section 1.3.3 
Exploratory Objectives
Additional objective has been added to 
characterize PK and Immunogenicity 
when administered in combination with 
BMS-986016
Objectives for testing of the FDC 
product have been added
Section 1.4.1.4.2 Clinical 
Safety- Monotherapy (Part 
A) versus Combination 
Therapy (Part B) in 
CA224020; Section 
1.4.1.4.3 Clinical 
Efficacy- Monotherapy 
(Part A) versus 
Combination Therapy 
(Part B): CA224020 Study
Sections has been updated and modified 
as new clinical data is available
Update of efficacy data from the Part C 
melanoma prior anti-PD-1 cohort.
Section 1.4.3 BMS-
986213 (Fixed Dose 
Combination Product) 
New section added
New information of the FDC product 
have been added
Section 1.5 Overall 
Risk/Benefit Assessment
Minor safety updates 
To provide the latest safety information, 
however overall Risk/benefit 
assessment did not change. 
Synopsis; Section 3.1 
Study Design and 
Duration
Schema design has been updated to 
show three treatment arms for Part D1
Study design for Part D1 was revised to 
include a FDC treatment arm 
Clarification about fixed dose 
combination product has been added for 
Part D. 
Also modified the text for adolescents 
weight based dosing. 
Information of the FDC product has 
been added.
Clarification text added for the 
adolescents weighing less than 40 kg. 
Section 3.1 Study Design; 
Table 5.1-3 Follow-Up 
Procedural Outline; 
Section 5.4.1 Imaging 
Assessment for the Study
Statement about imaging to be acquired 
until withdrawal of consent death, or 
initiation of another anti-cancer 
treatment was added.
Clarification text about acquiring 
imaging has been added. 
Synopsis; Section 3.1.2.5 
Part D Melanoma Prior IO 
Extended Expansion (Co-
administration or 
treatment with 
FDC(BMS-986213))
Part D1 Safety lead-in language has 
been added
Given the theoretical risk of infusion 
reactions with the FDC drug product an 
acute safety lead-in is being employed.
Protocol Amendment No. 15
Date: 16-Feb-2024
265
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1.0
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 09
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.1.3 Dose-
Limiting Toxicities
Clarification about dose escalation in 
Part B has been added
Given the change in schedule to once 
every four week dosing needed to state 
how many doses are needed within the 
DLT period to define DLT evaluable.
Section 4.3.2. Dose Delay 
Criteria; Section 4.3.3. 
Criteria to Resume 
Treatment After Dose 
Delay; Section 4.3.5 
Guidelines for Permanent 
Discontinuation
Clarification text for troponin elevations 
and myocarditis was added
Clarifications of rules for treatment 
delay and discontinuation based upon 
troponin elevations and myocarditis 
adverse events to align with the current 
relatlimab program language.
Section 3.3.1 Inclusion 
Criteria
Explicit statement that for Part D2 
eligibility subjects must not qualify for 
Part D1
Clarified that subjects need to be 
evaluated for Part D1 first, before being 
evaluated for Part D2
Section 3.3.2 Exclusion 
Criteria
Criteria 1b) has been removed after 
implementation of this revised protocol
No longer needed
Criteria 2h) has been modified to not 
include HCC subjects
Fixing omission from prior amendment.
Criteria 2e) iii) has been updated to add 
“poorly controlled atrial fibrillation” 
Clarification on eligibility for potential 
subjects with atrial fibrillation. 
Criteria 2e) v) has been modified to be 
read as “poorly controlled venous 
thrombosis” instead of “deep venous 
thrombosis”
Clarification in defining an example of 
a clinically significant DVT.
Criteria 2q) has been removed after 
implementation of this revised protocol
There is no more weight exclusion and 
no longer needed.
Criteria 2m) ii) has been modified to 
remove “investigational” for cytotoxic 
drug.
Clarification as “investigational” is not 
required in the definition. 
Section 4.1 Study 
Treatments; Section 4.1.1 
Investigational Product
Information about investigational 
product BMS-986213 
(relatlimab/nivolumab) has been added
Description of FDC drug product.
Under Table 4.1-1 - removed 
information about BMS-986016 
injection vial of 11 mg/mL
No longer applicable
Section 4.1.3 Handling 
and Dispensing
The text has been modified to include 
the infusion time for nivolumab and 
BMS-986016.
Clarification of infusion time 
Section 4.2 Method of 
Assigning Subject 
Identification
Clarification text has been added for the 
subjects enrolled in Part D1 
randomization treatment arms.
Definition of treatment arms for the D1 
randomization and rules governing 
assignment of treatment.
Synopsis; Section 3.1.3 
Dose-Limiting Toxicities; 
Clarification text has been added that -
subjects may be dosed no less than 12 
Clarification of dose delay for the Q4W 
regimen. 
Protocol Amendment No. 15
Date: 16-Feb-2024
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Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 09
Section Number & 
Title
Description of Change
Brief Rationale
Section 4.3.2 Dose Delay 
Criteria
days in Q2W regimen and 25 days in 
Q4W from the previous dose.
Also clarified that dosing visits will 
follow either every 2 weeks or every 4 
weeks after the delayed dose.
Section 4.3.4 Treatment 
beyond Disease 
Progression
Section updated to align with the 
Nivolumab program guidelines for 
Treatment beyond progression. 
Improves efficiency of study conduct. 
The protocol contains detailed criteria 
for Investigators to determine clinical 
judgement of the risk/benefit of 
continuing treatment beyond 
progression.  This change also results in 
alignment with the Nivolumab program 
standards. 
Section 4.3.5 Guidelines 
for Permanent 
Discontinuation
Added additional discontinuation criteria 
“Grade 3 infusion reaction that does not 
return to Grade 1 in 6 hours or less 
requires discontinuation. 
Given the emerging and evolving 
understanding on optimal duration of 
immunotherapies this allows the 
investigator to apply up to date clinical 
judgement in deciding if an individual 
patient should continue or stop study 
treatment in the setting of confirmed 
complete response.
Table 5.1-1: Screening 
Procedural Outline 
(CA224020)
Added more information in Notes 
section about minimum time points to be 
submitted for prior to diagnostic imaging 
procedure 
To provide guidance to clinical sites of 
the suggested pre-study diagnostic 
imaging timepoints to be submitted to 
BICR.
Table 5.1-2: On-
Treatment Procedural 
Outline for Q2W and 
Q4W Treatment 
Regimens
Added “FDC” in vital signs procedure
Also separated Part D study drug 
administration into Part D1 and Part D2
Incorporation of FDC in procedures 
tables.
Removed notes from Weight procedure
There is no more weight exclusion and 
so no longer needed.
For “Laboratory tests” procedure 
statement in notes about Serology tumor 
markers to be performed on Day 1 of 
each cycle was removed.
Clerical change of duplication. 
For “OPTIONAL Post-progression (PD) 
tumor biopsy” comments in Notes 
section was modified to remove the 
tumor tissue to be sent to central lab.
Deletion of incorrect information 
Additional information for subjects 
enrolled in Part C at Q4W was added. 
To clarify there is a cohort in Part C 
which will treat subjects with a Q4W 
regimen 
Section 5.3.1 Laboratory 
Test Assessments
Added “Leukocyte count” under 
Endocrine Panel.
Added Leukocyte count to provide 
flexibility in reporting for certain 
Protocol Amendment No. 15
Date: 16-Feb-2024
267
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930071758
18.0
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Approved
1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 09
Section Number & 
Title
Description of Change
Brief Rationale
Added “Australia antigen” for Hepatitis 
B surface antigen and removed Hepatitis 
A antibody from Serology (screening 
only). 
countries. 
Added description for Hepatitis B 
surface antigen.
Hepatitis A is not a specific eligibility 
criteria lab, it’s not a standard 
requirement in nivolumab protocols. 
Section 5.4.2 Efficacy 
Assessment for the Study
Added more information in about 
minimum time points to be submitted. 
Clarification text - “regardless of dose 
delays” has been added for tumor status 
assessment statement
To provide guidance to clinical sites of 
the suggested pre-study diagnostic 
imaging timepoints to be submitted to 
BICR.
Section 5.5.1 
Pharmacokinetics: 
Collection and Processing
References to Table 5.5.1-4 and Table 
5.5.1-5 has been added
To align PK collections with new study 
design for Part D.
Table 5.5.1-5: PK and 
ADA Sampling Schedule 
for BMS-986016 and 
Nivolumab for - Part D1 
(Arm 2 and 3, first 12 
subjects)
New table has been added to show the 
sampling schedule for the subjects 
enrolled in Part D1 Arm 2 and Arm 3
PK collections for Part D1 FDC drug 
product.
Table 5.7-4 Tumor Tissue 
Requirement
Added a note in Type of Speciment 
Baseline: 
“Note: In lieu of a biopsy during 
screening, acceptable MANDATORY 
pre-treatment biopsies include samples 
obtained 
 
 
 
 
 
 
 
.
This text was added to clarify language 
regarding the mandatory tissue 
collection requirements for clinical trial 
participation. It will clarify what is an 
acceptable MANDATORY pre-
treatment biopsy.
Synopsis; Section 8.1.4.1 
Clarification text has been added
To align with new study design for Part 
Protocol Amendment No. 15
Date: 16-Feb-2024
268
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1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Summary of key changes for Revised Protocol 09
Section Number & 
Title
Description of Change
Brief Rationale
Melanoma Prior IO 
Extended Expansion (Part 
D1-Q2W)
D
Synopsis; Section 8.1.4.2 
Melanoma Prior IO 
Focused Eligibility 
Expansion (Part D1-Q4W)
Clarification text has been added
To align with new study design for Part 
D
Synopsis; Section 8.1.4.3 
Melanoma Prior IO 
Expanded Eligibility 
Expansion (Part D2)
Clarification text has been added
To align with new study design for Part 
D
Synopsis; Section 8.3.1 
Primary Endpoints; 
Section 8.4.3 Safety 
Analyses
Clarification text about AE in the 
MedDRA Anaphylactic Reaction broad 
scope SMQ for Part D1-Q4W has been 
added
Improved description of how to assign 
and enter IMAEs and description of 
Anaphylactic Reaction SMQ which will 
be used for acute toxicity assessments.
Section 8.3.2.5 Safety 
(Part D1 Q4W)
New section for Part D1 Q4W has been 
added
Description of statistical analyses 
surrounding FDC drug product 
endpoints.
Synopsis; Section 8.3.2.1 
Pharmacokinetics; Section 
8.4.4 Pharmacokinetic 
Analyses
Clarification text for PK comparison in 
Part D1-Q4W and Part D1-Q2W has 
been added
To align with new study design for Part 
D. 
Appendix 5 MedDRA 
Anaphylactic Reactions
New appendix has been added
Anaphylactic Reactions PT listings
Protocol Amendment No. 15
Date: 16-Feb-2024
269
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1.0
v

Clinical Protocol
CA224020
BMS-986016
relatlimab
Overall Rationale for the Revised Protocol 08, 13-Jul-2017
There are 4 main changes to the protocol: Revised Protocol 08 adds 1) a bladder cancer cohort to 
Part C of the study. 2) Data from Part C of the study, specifically subjects with advanced 
melanoma and whose tumor associated immune cells express more LAG-3, showed an improved 
response rate. Therefore, Part D (melanoma expansion) is being added to the study to further 
evaluate efficacy. 3) Due to the increasing incidence of melanoma in childhood and adolescent 
populations, (Part C melanoma only) and Part D will allow adolescents. 4) BMS-986016 and 
nivolumab will be co-administered in Part D.  See below for further details.
3) Adding bladder (urothelial) cancer cohort to Part C
Bladder cancers have been shown to be responsive to immunotherapy (anti-PD-(L)1 therapy) 
but the large majority of subjects do not obtain significant benefit.  The study combination 
will thus be tested in immunotherapy naive subject to assess potential for increased rates and 
duration of response.
4) Addition of Part D: Melanoma prior IO Extended Expansion
As of cut-off date of April 7, 2017, preliminary proof of concept efficacy has been revealed 
in the Part C combination treatment expansion cohort of advanced melanoma with prior 
treatment with anti-PD1/PDL1. All subjects were treated with BMS-986016 80 mg + 
nivolumab 240 mg every two weeks. The overall objective response rate (ORR) was 12.5% 
(n=48 response evaluable) with a disease control rate of 54%. Biomarker analyses showed 
that patients whose tumor expressed more LAG-3 had a higher response rate, with a nearly a 
three-fold increase in ORR observed in patients with evidence of LAG-3 expression in at 
least one percent (n=25) of nucleated cells within and including the tumor margin, compared 
to less than 1 percent LAG-3 expression (n=14) (20 percent and 7.1 percent, respectively). 
Overall Anti-LAG-3 (BMS 986016) in combination with nivolumab demonstrated 
encouraging initial efficacy with a safety profile similar to nivolumab monotherapy
Therefore, based on initial efficacy signal in advanced melanoma subjects who progressed on 
anti-PD1/PDL1 therapy, additional subjects in this subset population for further clinical 
testing is justified.  Assessment in this population will be extended in two sub-parts, Part D1 
and D2.  D1 will test the combination in a focused eligibility population while D2 will allow 
assessment in a broader population under expanded eligibility criteria. Given the improved 
response rate in subjects whose tumor associated immune cells express more LAG-3, 
efficacy analysis in Part D1 will be the primary focus.  Subjects whose tumors are LAG 3 
negative will also be evaluated to determine the role of LAG-3 expression on the anti-tumor 
activity of BMS 986016. Part D2 will explore safety and efficacy in a broader patient 
population including those with ECOG up to 2 and among those with a more diverse set of 
prior therapies.
5) Allowing adolescents to participate
Adding eligibility to adolescents (ages 12-17) in Part C (melanoma only) and in Part D.  
Melanoma can afflict adolescents and adolescents are vastly underrepresented in clinical 
trials.  This addition will allow access and testing in this underserved population of patients 
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with high unmet need.  Dosing in adolescents will be weight based (and capped at the adult 
flat doses) and individual countries and sites have the option of opting out of adolescent 
eligibility.
6) Co-administration of study drug
Co-administration of both study medications in Part D.  For Part D only, both BMS 
986016.and nivolumab will be co-administered through the same IV bag.  This will decrease 
the treatment burden on study subjects and medical staff.  The rest of the study will remain 
consistent with current sequential administration
Additionally, the revised protocol incorporates Administrative Letter 04 which clarified the 
collection of biopsies and clarified inclusion criteria for Part C, Non-small cell lung cancer 
(NSCLC).
Revisions apply to future participants enrolled in the study, and where applicable to all 
participants currently enrolled.
Summary of key changes of Revised Protocol 08
Section Number 
& Title
Description of Change
Brief Rationale
Synopsis
Updated the number of subjects and 
Parts C & D of the study will enroll 
adolescent subjects. 
Parts C and D will enroll additional subjects to 
the study due the increasing incidence of 
melanoma in childhood and adolescent 
populations.
Section 1.1 Study 
Rationale
Sections updated or added as 
appropriate for the addition of bladder 
cancer cohort to Part C, adolescents in 
Parts C (melanoma only) and Part D, 
(Melanoma Prior IO Extended 
Expansion), co-administration of 
nivolumab and BMS-986016  
Updated based on recent data received
Section 1.2 Research 
Hypothesis, 
Synopsis
Added Part D1 
To align the hypothesis with the addition of Part 
D of the study.
Section 1.3 
Objectives, Synopsis
Added Part D1 to the objectives. 
To align the study objectives with the additional 
parts of the study.
Section 1.4.1.4.2 
Clinical Safety 
Monotherapy (Part 
A) versus 
Combination 
Therapy (Part B) in 
CA224020
Safety data updated
To provide updated safety data as of 07-Apr-
2017.
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Summary of key changes of Revised Protocol 08
Section Number 
& Title
Description of Change
Brief Rationale
Section 1.4.1.4.3 
Clinical Efficacy-
Monotherapy (Part 
A) versus 
Combination 
Therapy (Part B): 
CA224020 Study
Data updated 
To provide updated efficacy data based on 
results from this study as of 07-Apr-2017.
Section 1.4.2.4 
Clinical Safety
Added an overview of safety results 
from subjects treated with nivolumab 
480 mg Q4W.
To summarize safety data for nivolumab 480 
mg Q4W dosing regimen.
Section 1.4.2.6 
Clinical Activity
Updated various indications such as 
urothelial carcinoma, esophageal 
cancer SCLC, Merkel Cell carcinoma, 
and combined malignant tumors.
To align with the current Nivolumab IB
Section 1.5 Overall 
Risk Benefit 
Assessment
Safety and efficacy results updated 
To provide updated risk:benefit profile as of 
07-Apr-2017.
Section 2.3 Informed 
Consent
Added informed consent requirements 
for minors 
Updated to incorporate language to allow 
minors to participate according to ICH 
Guidelines. 
Section 3.1 Study 
Design and 
Duration, Synopsis,
Schematics and descriptions updated 
for Part C (bladder cohort), Part D 
(Melanoma Prior IO Extended 
Expansion).
To describe Part C addition of bladder cohort 
and Part D of the study (including co-
administration). 
Section 3.3.1 
Inclusion Criteria
Target Population was revised for 
NSCLC and Head and Neck Cancer 
 
(j) Added bladder carcinoma to Part C 
of the study
iv) Part A1 Cohort Expansion-
Monotherapy
Where applicable, the requirement of 
scans to be collected and submitted to 
BICR.
v) Part D1 Focused Eligibility Cohort
(vi) Part D2 Expanded Eligibility 
Cohort
Added Lansky for pediatrics to the 
Karnofsky and ECOG Performance 
status 
xi) 
 moved to 
exclusion criteria
Target population revised as 
Updated for addition of Part C (bladder cohort) 
and Part D of the study.
Revised inclusion criteria to allow prior 
exposure to other IOs.
Lansky Performance Status added for the 
addition of adolescents to the study
Revised for the addition of adolescents to the 
study.
For clarification of requirements
Revised for the addition of adolescents to the 
study
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Summary of key changes of Revised Protocol 08
Section Number 
& Title
Description of Change
Brief Rationale
Age and Reproductive Status was 
revised to allow adolescents 12 
years of age into the study for Parts C 
(melanoma only) and Part D where 
allowed.
Section 3.3.2 
Exclusion Criteria, 
Section 5.3.1 
Laboratory Test 
Assessments
Exclusion criteria h i), ii), iii), was 
revised to clarify hepatitis exclusion 
criteria. 
 was moved 
from inclusion criteria to exclusion 
criteria. Added prior treatment with 
LAG-3 targeted agents added 
adolescent body weight requirement of 
at least 30 kg.
Hepatitis exclusion criteria was updated to be 
less restrictive. 
 was moved 
for clarification of requirements.
Weight requirement added for combination 
dose drug concentration stability reasons.  
Section 4.1.3 
Handling and 
Dispensing
In Part D BMS-986016 and nivolumab 
will be co-administered in a single IV 
bag Adolescents  will be dosed based 
on weight 
For Part D to allow co-administration using a 
single IV bag and update the timing and weight 
based dosing regimen. 
Table 5.1-2 On-
Treatment 
Procedural Outline 
for Q2W and Q4W 
Treatment 
Regimens, Section 
5.4.1 Imaging 
Assessment for the 
Study
On-Treatment Procedural Outline has 
been updated 
Brain imaging- subjects with known 
CNS disease updated requirements for 
imaging assessments
Updated throughout to add Part D and 
co-administration.
Brain imaging: Subjects with known 
CNS disease must have imaging 
assessments at least every 12 weeks.
Part D dosing schedules and procedures added 
to the tables to specify procedures to be 
conducted in Part D
For consideration of subject safety
Table 5.1-3 Follow-
Up Procedural 
Outline
Updated throughout to add Part D 
To align with the addition of Part D to the 
study.
Section 5.4 Efficacy 
Assessments, 
Synopsis
Updated to include Part D 
To align with the addition of Part D to the study
Section 5.5.1 
Pharmacokinetics 
Collection and 
Processing, Table 
5.5.1-2, Table 5.5.1-
3, 5.5.1-4
Table 5.5.1-2, 5.5.1-3, and 5.5.1-4 
have been updated:
Pharmacokinetic collection schedules revised 
for the addition of Part D of the study.
Section 5.7
Exploratory 
Table 5.7-1: Revised the title to 
specify Q2W or Q4W regimen and 
Biomarker table revised for the addition of Part 
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Summary of key changes of Revised Protocol 08
Section Number 
& Title
Description of Change
Brief Rationale
Biomarker 
Assessments Table 
5.7-1
table has been updated.
D of the study.
Section 5.7.11 
Additional Research 
Collection
Added details regarding banking of 
residual samples.
To define which samples will be banked for 
further testing in the future if needed.
Section 7.1 Data 
Monitoring 
Committee
Updated text 
To further expand the DMC to expansion 
cohorts of the study (Parts C & D).
Section 8 Statistical 
Considerations, 
Synopsis
All applicable sections updated to 
include all new and revised parts of 
the study.
To align with the addition of Part D to the study 
and co-administration.
All
Minor formatting and typographical 
corrections
Minor, therefore have not been summarized
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APPENDIX 8
COUNTRY SPECIFIC REQUIREMENTS/DIFFERENCES
Country/Location 
Requirement
Section Number
Country-specific Language or Differences
France (per 
country-specific 
amendment; 
29-Jul-2019)
Synopsis, Dose 
Escalation-Sequential 
Infusion (Part B):
Add the following statement to the end of this section: 
“Note: subjects are excluded from Part B.” 
Synopsis, Part E 
Exposure Response 
Evaluation in 
Melanoma 
Participants
Add the following statement to the end of this section: 
“Melanoma patients with high tumor burden should have been 
offered targeted therapy.” 
Section 3.3.1, 
Inclusion Criteria, 2) 
Target Population, a) 
Subjects must have 
histologic or 
cytologic 
confirmation of an 
incurable solid 
malignancy that is 
advanced (metastatic 
and/or unresectable): 
ii) Part B: Dose 
Escalation: BMS-
986016 + nivolumab
The following criteria are not applicable. 
Criterion (3), NSCLC subjects progressing while on or after 
therapy with anti-PD-1 or anti-PD-L1 antibody (for Part B this 
does not need to be the most recent therapy).
Criterion (3), (b) Cannot have had therapy discontinued due to 
serious and/or life-threatening anti-PD-1 or anti-PD-L1 antibody-
related toxicity (e.g., dose-limiting toxicity in prior study) per 
Investigator’s assessment in consultation with the BMS Medical 
Monitor. 
Criterion (3), (e) Subjects with targetable EGFR or ALK genetic 
aberrations must have previously received prior targeted therapy. 
Criterion 5 (a), For first line NSCLC subjects: The drug regimen 
with the highest likelihood of benefit with toxicity deemed 
acceptable to both the physician and the patient should be given 
as initial therapy for advanced lung cancer. Subjects should be 
offered chemotherapy if appropriate and available. Patients may 
refuse these standard treatments. The reason for why a subject 
does not receive standard first line metastatic therapy must be 
documented. Subjects with targetable EGFR or ALK genetic 
aberrations must have previously received prior targeted therapy.
Criterion 5 (c), For first line NSCLC subjects: Prior adjuvant or 
neoadjuvant chemotherapy, or definitive chemo/radiation, is 
permitted as long as the last administration of the prior regimen 
occurred at least 6 months prior to enrollment; while prior IO 
therapies are not allowed. 
Section 3.3.1, 
Inclusion Criteria, 2) 
Target Population, a) 
Subjects must have 
histologic or 
cytologic 
confirmation of an 
incurable solid 
malignancy that is 
advanced (metastatic 
and/or unresectable): 
ii) Part B: Dose 
Escalation:
Replace: “(5) Subjects must have received, and then progressed 
or been intolerant to, at least one standard treatment regimen or 
refused standard therapy in the advanced or metastatic setting, if 
such a therapy exists; except for NSCLC and melanoma, where 
treatment as 1st line therapy is allowed.” 
With: “(5) Subjects must have exhausted all approved treatment 
options for their respective tumor type.” 
Removed NSCLC Cohort
Replace: (7) Selected tumor types (and all subtypes) include
melanoma, RCC, NSCLC, head and neck (any histology), gastric 
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BMS-986016 + 
nivolumab
(includes gastro-esophageal junction) cancer, hepatocellular, 
cervical, ovarian, colorectal and bladder cancers. 
With: (7) Selected tumor types (and all subtypes) include 
melanoma, RCC, head and neck (any histology), gastric (includes 
gastro-esophageal junction) cancer, hepatocellular, cervical, 
ovarian, colorectal and bladder cancers.
Section 3.3.1, 
Inclusion Criteria, 2) 
Target Population, a) 
Subjects must have 
histologic or 
cytologic 
confirmation of an 
incurable solid 
malignancy that is 
advanced (metastatic 
and/or unresectable): 
vii) Part E: Exposure 
Response Evaluation 
in Melanoma 
Participants, (2) 
Melanoma 
participants who 
have not received 
prior systemic 
anticancer therapy 
for unresectable or 
metastatic 
melanoma:
Add a note to criterion (c): 
Replace: (c) Participants must not have had prior systemic 
anticancer therapy for unresectable or metastatic melanoma.
With: 
(c) Participants must not have had prior systemic anticancer 
therapy for unresectable or metastatic melanoma* 
(i) *except for BRAF mutated patient with high-tumor burden and 
life-threatening progression (who should have been offered a 
targeted therapy).
Italy (per site 
13-specific 
amendment; 
03-Oct-2016) 
5.7 Exploratory 
Biomarker 
Assessments
Add the following text:
Table 5.7.2a details the biomarker sub-study collection for site 
013. 
Collection 
Timing
Serum
Tumor
Study Day
Soluble 
Biomarkers
(Serum 
Biomarkers)
“Fresh” 
Tumor 
Biopsy
Screening
X
Cycle 1
Day 1
X
Day 15
X
Day 29
X
X c
Upon Progression
Upon 
Progression
X
X
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NOTE:  All samples are to be drawn pre-dose
5.7.1 Soluble 
Biomarkers (Serum 
Biomarkers)
Add the following statement: 
Samples collected will be analyzed for circulating PDL1 and LAG-
3 levels with ELISA, and Cytokinome (27+21 multiplex) in whole 
blood samples.
Italy (per site 
14-specific 
amendment; 
17-Oct-2016)  
5.7 Exploratory
Biomarker 
Assessments
Add the following text:
Table 5.7.2a details the biomarker sub-study collection for site 
014. 
Collection 
Timing
Tumor
Study Day
“Fresh” 
Tumor Biopsy
Screening
X
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c
 
 
NOTE:  All samples are to be drawn pre-dose
Cycle 1
Day 1
Day 5
Day 8
Day 15
Day 29
X c
Cycle 2, 3, 5, 7, 9 and 11
Day 1
Upon Progression
Upon 
Progression
X
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