A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (Relatlimab, BMS-986016) Administered Alone and in Combination With Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Relapsed or Refractory B-Cell Malignancies
Phase: PHASE1
Conditions: Hematologic Neoplasms
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 (Relatlimab, BMS-986016) Administered Alone 
and in Combination with Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in 
Relapsed or Refractory B-Cell Malignancies 
 
NCT Number: NCT02061761 
Document Date (Date in which document was last revised): November 17, 2020 

Page:
1
Protocol Number:
CA224022
IND Number:
119,758
EUDRACT Number
2017-001780-20
Date:
28-Oct-2013
Revised Date:
17-Nov-2020
CLINICAL PROTOCOL CA224022
A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and 
Efficacy of Anti-LAG-3 Monoclonal Antibody (Relatlimab, BMS-986016) Administered Alone 
and in Combination with Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in 
Relapsed or Refractory B-Cell Malignancies
Short Title:
Safety Study of Anti-LAG-3 in Relapsed or Refractory Hematologic Malignancies
Revised Protocol Number: 09
Medical Monitoring Contact Information
Bristol Myers Squibb Company
Bristol Myers Squibb Company
3401 Princeton Pike
3401 Princeton Pike
Lawrence Township, NJ 08648
Lawrence Township, NJ 08648
Phone:
Phone:
Email: 
Email: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Company
Route 206 & Province Line Road
Lawrenceville, NJ 08543
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
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this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 09
17-Nov-2020
Revised protocol 09 focuses on clarifying the response evaluation 
scale utilized for primary endpoint evaluation of response for 
Cohort D. This is a result of the ongoing study duration and several 
criterions being introduced in the clinical setting.
Revised Protocol 08
11-Oct-2019
Revised protocol 08 incorporates Administrative Letters 06 and 07 
and changes described in the table of Summary of Key Changes.
Administrative Letter 07
27-Nov-2018
Changes the Medical Monitor contact.
Administrative Letter 06
11-Jun-2018
Removes the PK and immunogenicity assessments scheduled on 
follow-up visit 1 in Table 5.1-3, Follow-Up Procedural Outline 
(CA224022), and to align with the PK and ADA sampling schedules 
for relatlimab and nivolumab in Tables 5.5.1-1 and 5.5.1-2.
Revised Protocol 07
28-Mar-2018
Revised protocol 07 incorporates Administrative Letters 03, 04 and 05
and the following changes: require pre-and on-treatment biopsies for 
all subjects in Part D, adds Survival Follow-up, clarifies eligibility
criteria, and updates safety, clinical pharmacology information, and 
criteria for dose delay and permanent discontinuation. Also includes 
grammatical revisions and references.
Administrative Letter 05
05-Jan-2018
Administrative Letter 05 change in Study Director and Medical 
Monitor.
Administrative Letter 04
03-Feb-2017
Administrative Letter 04 change in Study Director and Medical 
Monitor.
Administrative Letter 03
09-Dec-2016
Administrative Letter 03 defined the intermediate dose used for Part C 
dose escalation.
Revised Protocol 06
07-Nov-2016
Incorporates Amendment 06.
Amendment 06
07-Nov-2016
Amendment 06 consists of changes in response to a related adverse 
event of meningitis.  Additional neurological eligibility criteria are 
included to further exclude patients that have a confirmed history of 
encephalitis, meningitis, or uncontrolled seizures. Also, a neurological 
exam was added for subjects who experience a study drug related 
Grade 2 neurological adverse event. Safety algorithms in 
Appendix 4 have been updated. Language regarding re-challenge has 
been added.  Laboratory collections have been updated. 
Administrative changes were also included.
Revised Protocol 05
25-May-2016
Incorporates Amendment 05.
Amendment 05
25-May-2016
Amendment 05 consists of changes in response to a related event of 
life-threatening grade 4 myocarditis which occurred in a subject 
receiving combination BMS-986016 and nivolumab on study 
CA224020. Additional cardiovascular eligibility criteria are included 
to further exclude patients that are less likely to tolerate and recover 
from a potential myocarditis event. Screening procedures have been 
added in support of these new criteria. In addition, more robust and 
frequent cardiovascular safety monitoring has been incorporated into 
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Document
Date of Issue
Summary of Change
the first 8 weeks of study therapy, which is the time period during 
which immune-related myocarditis is most likely to occur.
This amendment should therefore be implemented urgently, and it 
prospectively applies to all currently on going subjects and future 
subjects enrolled. 
Revised Protocol 04
28-Mar-2016
Incorporates Amendment 04.
Amendment 04
28-Mar-2016
The protocol amendment allows for administration of BMS-986016 in 
combination with nivolumab in Part C (dose escalation) and in Part D 
(cohort expansion). The DLT period for Part C has been updated as 
well as the tumor indications in Part C and D. The statistical sections 
was updated to align with revised study design. Administrative 
changes and correction of typographical errors were also included.
Revised Protocol 03
06-May-2015
Incorporates Amendment 03, and Administrative Letter 02
Amendment 03
06-May-2015
The protocol amendment allows for the inclusion of an extended 
biomarker plan during both, escalation and expansion phases. It also 
introduces an expansion cohort at 
 mg (Part B) in four selected 
tumor types as well as a conditional expansion cohort at 
 mg 
(Part C) in two selected tumor types.  It also includes administrative 
changes and correction of typographical errors.
Revised Protocol 02
30-Jul-2014
Incorporates Amendment 02, and Administrative Letter 01
Amendment 02
30-Jul-2014
The protocol amendment allows enrollment of subjects with multiple 
myeloma in Part A and Part B.  The number of subjects enrolled will 
be increased by 12 subjects in Part B. Glucose laboratory assessment 
may be fasting or non-fasting. Additional changes to inclusion and 
exclusion criteria are described in the amendment.
Revised Protocol 01
06-Dec-2013
Incorporates Amendment 01
Amendment 01
06-Dec-2013
The following changes were made based on FDA review and 
feedback: (1) remove language regarding possible addition of 4th 
subject to first cohort of 3 subjects during dose escalation; (2) modify 
eligibility criteria related to prior therapy, transplantation or life-
prolonging treatments, minimum neutrophil count, and duration of 
time prior to first dose whereby growth factors and transfusions are 
prohibited; (3) revise exceptions to non-hematologic DLT criteria; (4) 
revise hematologic DLT criteria to include Grade 4 anemia in all 
subjects and Grade 3 anemia in subjects with Grade 1 anemia at 
baseline; (5) increase DLT evaluation interval from 6 weeks to 8 
weeks; and (6) specify that all subjects who receive at least 1 dose of 
study drug will be evaluable for DLT.
Original Protocol
28-Oct-2013
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OVERALL RATIONALE FOR REVISED PROTOCOL 09:
This amendment focuses on clarifying the response evaluation scale utilized for primary endpoint 
evaluation of response for Cohort D. This is a result of the ongoing study duration and several 
criteria being introduced in the clinical setting.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 09
Section 
Number & 
Title
Description of Change
Brief Rationale
Synopsis
As noted below.
The synopsis has been updated to reflect 
all changes made in the sections listed 
below.
Section 1.3.1: 
Primary 
Objectives
The co-primary objective was 
modified to clarify that tumor 
response will be evaluated 
according to the revised 
International Working Group 
criteria for Malignant Lymphoma.
Several evaluation scales have been 
introduced to assess response in HL 
since the start of the study (ie, Lugano, 
LYRIC), prompting the need to specify 
the response criteria utilized for the 
primary objective.
Section 1.3.3: 
Exploratory 
Objectives
Clarified that preliminary efficacy 
will be assessed in Part D NHL 
and HL subjects.
Clarified that 
 
will be assessed in DLBCL 
patients in addition to HL patients 
in Part D. Clarified that 
 will 
be assessed based on IWG (2007) 
and Lugano (2014) criteria.
Added an exploratory objective to 
evaluate
 
 
 
 in Part D.
Lugano 2014 incorporates additional 
dimensions (metabolic response) in 
evaluation of HL patients. Clinically, it 
is of interest to see response 
comparisons between IWG 2007 and 
Lugano 2014.
Section 5.4: 
Efficacy 
Assessments
Added that Lugano 2014 response 
criteria will be used as an 
exploratory analysis to evaluate 
NHL or HL participants for 
metabolic response.
Clarified response types for the 
PET scan assessments.
As noted above.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 09
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 
8.3.2.3: 
Efficacy
Clarified that all efficacy analyses 
will be based on the all treated 
analysis population except 
otherwise stated.
Added the exploratory endpoints 
of objective response rate and 
duration of objective response 
based on the Lugano 2014 
response criteria in the NHL and 
HL subjects in Part D.
Clarified the complete response 
rate is based on IWG criteria for 
NHL and HL subjects.
As noted above.
Section 
8.3.3.3: Other 
Efficacy 
Endpoints
Section added to define 
progression free survival and 
complete metabolic response rate 
based on Lugano (2014) criteria.
As noted above.
Section 8.4.2: 
Efficacy 
Analysis
Added complete metabolic 
response, partial metabolic 
response, and duration of 
complete metabolic response.
Clarified the analyses will be 
assessed based on IWG and 
Lugano criteria.
As noted above.
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SYNOPSIS
Clinical Protocol CA224022
Protocol Title: A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy 
of Anti-LAG-3 Monoclonal Antibody (Relatlimab, BMS-986016) Administered Alone and in Combination with Anti-
PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Relapsed or Refractory B-Cell Malignancies
Short Title: Safety Study of Anti-LAG-3 in Relapsed or Refractory Hematologic Malignancies
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Relatlimab (BMS-986016, antiLAG-3 antibody) is supplied as a sterile 
 mg/mL or 
mg/mL 
formulation to be administered as an intravenous (IV) infusion. Nivolumab (BMS-936558) is available as a sterile 
mg/mL formulation to be administered as an IV infusion.
In Part A (dose escalation monotherapy), relatlimab will be administered at doses of 
 mg once 
every 2 weeks (Q2W), in 8-week cycles, for up to 12 cycles of study therapy.
Part B, cohort expansion, monotherapy, will be carried out at
 mg. The dose selected has not exceeded the 
maximum tolerated dose [MTD], or maximum administered dose [MAD] (if an MTD is not established) identified in 
Part A, monotherapy escalation. Study therapy will be administered once every 2 weeks, in 8-week cycles, for up to 
12 cycles.
In Part C (dose escalation, combination therapy), relatlimab will be administered starting at 
 mg dose in combination 
with a fixed dose of nivolumab at 
 mg once every 2 weeks, in 8-week cycles, for up to 12 cycles of study therapy. 
The intermediate dose of relatlimab (anti-LAG-3) 
 mg and nivolumab ( BMS-936558) 
 mg was also tested 
under MTD and shown to be well-tolerated.
Part D is a cohort expansion, combination therapy. The doses selected for Part D will not exceed the MTD (or MAD 
if no MTD is determined) in Part C, but may incorporate assessment of other data including toxicities and PK and 
pharmacodynamic data from Parts A, B and C and data from the CA224020 study. Doses to be considered may include 
doses intermediate to those evaluated in Part C if recommended by the Investigators and the Sponsor. Modeling may 
be used to help inform the selection of the combination dose level to carry forward in Part D if a dose below the MTD 
is chosen. Study therapy will be administered once every 2 weeks, in 8-week cycles, for up to 12 cycles. The 
combination of anti-LAG-3 
mg and nivolumab 
 mg was selected for expansion in Part D after showing the 
tolerability in Part C.
Study Phase: Phase 1/2a
Research Hypothesis: It is anticipated that antiLAG-3 antibody (relatlimab), administered as monotherapy or in 
combination with nivolumab, will demonstrate adequate safety and tolerability, as well as a favorable risk/benefit 
profile, to support further clinical testing. No prospective hypotheses are being formally evaluated.
Objectives:
Primary Objective:

The primary objective is to characterize the safety, tolerability, dose-limiting toxicities (DLTs), and maximum 
tolerated dose (MTD) of relatlimab administered alone or in combination with nivolumab to subjects with 
relapsed or refractory B-cell malignancies.

The co-primary objective in combination therapy expansion Part D is to investigate the preliminary efficacy of 
relatlimab in combination with nivolumab in subjects with relapsed or refractory Hodgkin lymphoma (HL), and 
relapsed or refractory Diffused Large B Cell lymphoma (DLBCL). Tumor response will be evaluated according 
to the revised International Working Group (IWG) criteria for Malignant Lymphoma (2007 IWG criteria); see 
Appendix 1.
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Secondary Objectives:
The secondary objectives are:

To characterize the pharmacokinetics (PK) of relatlimab administered as monotherapy or in combination with 
nivolumab 

To characterize the immunogenicity of relatlimab administered as monotherapy or in combination with nivolumab
Exploratory Objectives:


To characterize pharmacokinetics and immunogenicity of nivolumab in combination with relatlimab.

To evaluate the pharmacodynamic activity of relatlimab in the peripheral blood and tumor tissue as measured by, 
but not limited to, flow cytometry, immunohistochemistry, soluble factor analysis, and gene expression (eg, 
microarray technology and/or quantitative reverse transcription polymerase chain reaction [RT-PCR] and/or 
ribonucleic acid sequencing [RNAseq]).

To investigate the association between biomarkers in the peripheral blood and tumor tissue, such as 
 
expression, lymphocyte infiltration, neoantigen status, inflammatory gene signatures, with safety and efficacy 
following treatment with relatlimab administered as monotherapy and in combination with nivolumab.

To determine the receptor occupancy of 
 in the peripheral blood and bone marrow.

To explore the preliminary antitumor activity of relatlimab administered as monotherapy in subjects with relapsed 
or refractory B-cell malignancies. 

To characterize T-cell function in response to relatlimab administered as monotherapy or in combination with 
nivolumab.

To explore exposure-response relationships in subjects treated with relatlimab as monotherapy and in combination 
with nivolumab.

To assess the overall survival (OS) rates and progression-free survival (PFS) rates at various time points in HL
and DLBCL patients in Part D. PFS will be assessed based on IWG (2007) criteria and the Lugano (2014) criteria.

To evaluate tumor metabolic response per Lugano 2014 criteria using Deauville scoring (Appendix 7) in NHL 
and HL patients in Part D.
Study Design: This is a Phase 1/2a, open-label study of relatlimab administered as monotherapy or in combination 
with nivolumab to subjects with relapsed or refractory B-cell malignancies. The study will be conducted in 4 parts. 
Part A consists of a 3 + 3 + 3 dose escalation design in subjects with relapsed or refractory Chronic Lymphocytic 
Leukemia (CLL), HL, NHL, and multiple myeloma (MM) with relatlimab administered as monotherapy. Part B 
consists of cohort expansion in disease-restricted populations of 
to  subjects each with relatlimab administered 
as monotherapy Part C consists of a 3+3+3 dose escalation design in subjects with advanced HL and DLBCL with 
relatlimab administered in combination with nivolumab. Part D consists of cohort expansion in three disease restricted 
populations of 
to 
subjects each with relatlimab administered in combination with nivolumab (Figure 1).
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Figure 1:
Study Design Schematic
* In Part A, and selected cohort in Part D (ie, Hodgkin Lymphoma PD-1/PD-L1 naive cohort), subjects will be naive 
to immune cell-modulating antibody regimens (ICMARs), such as but not limited to anti PD-1, anti PD-L1, anti 
PD-L2, anti CTLA-4, anti-KIR, and/or anti-OX40 antibodies. Prior anti-CD20, alemtuzumab, and/or anti-CD30 
antibody therapy are allowed.
**In Part B, Part C, and selected cohorts in Part D (ie, Hodgkin Lymphoma anti-PD-1/PD-L1 resistant/failure cohort 
and Diffuse Large B-Cell Lymphoma cohort),subjects will be naive to immune cell-modulating antibody regimens 
(ICMARs), such as, but not limited to anti CTLA-4, anti PD-L2, anti-KIR, and/or anti-OX40 antibodies. Prior 
anti-PD-1, anti-PD-L1, anti CD137, anti-CD20, alemtuzumab, and/or anti-CD30 antibody therapy are allowed. 
Subjects will complete up to 4 periods of the study: Screening (up to 28 days), Treatment (up to a maximum of 
 
-week cycles of study therapy), Clinical Follow-up (135 days following the last dose of study drug) and Survival 
Follow-up (up to 
years following the first dose of study drug). Women of childbearing potential (WOCBP) will 
have additional follow-up assessments through Day 165 for home pregnancy tests. An independent period, Re-
challenge, may be conducted in selected cases at progression.
The Treatment Period consists of up to twelve 8-week treatment cycles. Each treatment cycle comprises  doses of 
relatlimab administered on Days 
. Subjects will be allowed to continue study therapy until the first 
occurrence of either: (1) meeting criteria for discontinuation as described in Section 4.3.5, (2) completion of the 
maximum number of twelve 8-week cycles, (3) confirmed progressive disease (PD), or (4) clinical deterioration. 
Subjects who discontinue treatment will enter a 135-day Clinical Follow-up period. After completion of the Clinical 
Follow-up period, HL patients in Parts C and D 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. For participants who discontinue 
study treatment prior to disease progression, diagnostic imaging will be obtained every 6 months after the first clinical 
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follow-up in year 1 and in year 2, and annually thereafter for a total of 5 years maximum (since the first dose of the 
study drug) until disease progression. Re-challenge may be conducted in selected cases at progression.
If subjects progress during the Clinical Follow-Up period or the Survival Follow-Up period, they could further receive 
therapy with relatlimab alone or in combination with nivolumab (Re-challenge period) as long as the risk:benefit ratio 
is considered favorable by the Investigator and the Medical Monitor and eligibility criteria is met (Section 3.3). The 
original dose and schedule and protocol rules would apply accordingly. Thus, subjects could receive therapy for up to 
12 additional eight-week cycles. Subjects will not be re-challenged a second time. Collection of archival tissue 
(baseline) and tumor biopsies (baseline and on-treatment) will be optional for subjects enrolled for re-challenge. PK 
and biomarker monitoring will be limited (Sections 5.5 and 5.7).
A study schematic is shown in Figure 2.
Figure 2:
Study Schematic for Parts A,1 B, C, and D
1 Part A DLT period: 8 weeks.
2 Treatment beyond progression may be considered in selected subjects as described in Protocol Section 4.3.4.
3 WOCBP will have additional follow-up assessments through Day 165 for home pregnancy tests.
4 For participants who discontinue study treatment prior to disease progression, diagnostic imaging will be obtained 
every 6 months after the first clinical follow-up in year 1 and in year 2, and annually thereafter for a total of 5 years 
maximum (from the first dose of the study drug) until disease progression.
5 Survival follow up is for HL patients recruited in Parts C and D only.
Dose Escalation (Part A): In Part A, a 3 + 3 + 3 design will be used to assess the safety of relatlimab. The dose levels 
evaluated during dose escalation are provided in Figure 1. Dose escalation rules are outlined below.
 subjects 
will initially be treated in each dose cohort; in Dose Cohort 1, the first  subjects 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 will be based on the number of DLTs experienced during the DLT evaluation interval as determined 
by the Medical Monitor and Investigators. The DLT evaluation interval begins on the first day of treatment and 
continues for 8 weeks, ie, through Day 
of the first cycle.
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Dose escalation in Part A (Table 1) will proceed as follows:

If none of the first  evaluable subjects in a dose cohort experiences a DLT within the DLT evaluation interval, 
then the next  subjects will be treated at the next higher dose cohort. 

If  of the first  evaluable subjects in a cohort experiences a DLT within the DLT evaluation interval, then 
additional subjects will be treated in that dose cohort. 

If no more than  of the first  evaluable subjects experiences a DLT during the DLT evaluation interval, 
then the next  subjects will be enrolled at the next higher dose cohort. 

If  of the first  evaluable subjects in a cohort experience a DLT, that cohort will be expanded to evaluable 
subjects.

If
of the first  evaluable subjects,
 of the first  evaluable subjects, or
of the first  evaluable subjects 
in a cohort experience a DLT within the DLT evaluation interval, that dose level will have exceeded the MTD 
and dose escalation will be terminated.
Table 1:
Relatlimab Dose Escalation Schedule for Part A - Relatlimab Monotherapy
Dose Cohort Number
Relatlimab Dose
(IV; mg)
Total Subjects
1
n = approximately 
2
n = approximately 
3
n = approximately 
4
n = approximately 
Total
N = approximately 
In consultation with Investigators, the Sponsor may investigate dose levels intermediate to those defined in the 
protocol. 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 the additional cohorts. A maximum of  subjects will be enrolled in any additional 
dose cohorts.
Cohort Expansion (Part B): The purpose of this cohort expansion is to gather additional safety, tolerability, PK, and 
pharmacodynamic information regarding relatlimab dosed at 
 mg. The dose selected for Part B has not exceeded 
the MTD in Part A (the MTD was not reached at up to 
 mg relatlimab Q2W in monotherapy). 
In Part B, the four expansion cohorts will be restricted to the tumor types listed in Figure 1 and Table 2. Continuous
evaluation of toxicity events will be assessed throughout enrollment in the expansion cohorts. If, at any time, the 
aggregate rate of treatment-related toxicities meeting DLT criteria exceeds 
 across all subjects treated in the Part B 
cohort expansions, the findings will be discussed with the Medical Monitor and Investigators; further enrollment may 
be interrupted. Depending on the nature and grade of the toxicity and after assessing the risk:benefit ratio, the dose 
for all or for select cohorts may be reduced.
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Table 2:
Tumor Types Eligible For Part B - Cohort Expansion Relatlimab Monotherapy
Tumor Type
Total Subjects
Chronic Lymphocytic Leukemia (CLL)
approximately 
Diffuse Large B-Cell Lymphoma (DLBCL)
approximately 
Indolent non-Hodgkin lymphoma
approximately 
Hodgkin Lymphoma (HL)
approximately 
Total 
approximately 
All subjects in Part B will be naive to immune cell-modulating antibody regimens (ICMARs), such as, but not limited 
to anti-CTLA-4, anti PD-L2, anti-KIR, and/or anti-OX40 antibodies except for anti-PD-1, anti-PD-L1, anti-CD137, 
anti-CD20, alemtuzumab, or anti-CD30 antibody therapy.
Cohort Escalation Combination Therapy (Part C): As in Part A, a 3 + 3 + 3 design will also be used in Part C to 
assess the safety of relatlimab 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 subject is able to start the first day of dosing within approximately one week of the third 
subject in the same dose escalation cohort.
The dosages during dose escalation are provided in Figure 1 and Table 3. 
Treatment in Part C will be initiated after the decision is made to escalate to the fourth dose cohort (
 mg anti-LAG-3 
in combination with 
 mg anti-PD-1) in CA224020 study. At no point will the dose of relatlimab administered in 
combination with nivolumab (Part C) exceed doses of relatlimab that have been demonstrated previously to be safe 
on the monotherapy dose escalation arm (Part A). The escalation cohorts in Part C will be restricted to subjects with 
1) HL naive to anti-PD-1/PD-L1, 2) HL (naive to anti-PD-1/PD-L1 or whose disease progresses while-on or within 3 
months after treatment with anti-PD-1 or anti-PD-L1 antibody 3) DLBCL.
Dose escalation in Part C will proceed as described for Part A with the exception that the DLT period will be reduced 
from 8 weeks to 4 weeks (see Section 3.1.5). If no MTD is reached through Dose Cohort 3, then additional cohorts of 
relatlimab given in combination with nivolumab may be considered based on the aggregate safety experience during 
dose escalation. Enrollment of additional cohorts will be implemented upon consultation and agreement between 
Investigators and the Sponsor via a protocol amendment.
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  subjects will be enrolled 
in any additional or expanded dose cohorts.
After completion of the relatlimab (anti-LAG-3) 
 mg and nivolumab (BMS-936558) 
 mg cohort, the 
intermediate dose combination of anti-LAG-3 
 mg and nivolumab 
 mg was investigated in Part C. The dose 
combination (
mg anti-LAG-3/
mg nivolumab) was well-tolerated in Part C and therefore selected for Part D 
(expansion).
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.
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Table 3:
Dose Escalation Schedule for Part C - Relatlimab in Combination with 
Nivolumab
Dose Cohort 
Number
Total Subjects
Relatlimab Dose (IV; mg)
Nivolumab Dose (IV; mg)
1
n = approximately
2
n = approximately 
3
n = approximately 
Total
N = approximately 
Note: Part C will be limited to subjects with HL (naive to anti-PD-1/PD-L1 or whose disease progresses while-on or 
within 3 months after treatment with anti-PD-1 or anti-PD-L1 antibody) and DLBCL.
Cohort Expansion Combination Therapy (Part D): 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 relatlimab. The doses selected for Part D will not exceed the MTD (or 
MAD if no MTD is determined) in Part C, but may incorporate assessment of other data including toxicities and PK, 
pharmacodynamic data from Parts A, B and C and data from the CA224020 study. Doses to be considered may include 
doses intermediate to those evaluated in Part C if recommended by the Investigators and the Sponsor. The intermediate 
dose of relatlimab (anti-LAG-3) 
 mg and nivolumab 
 mg, tested below the MTD, and was well tolerated and 
was selected for extension. Modeling may be used to help inform the selection of the combination dose level to carry 
forward in Part D if a dose below the MTD is chosen. Three expansion cohorts will be restricted to the tumor types 
listed in Table 4. Continuous evaluation of toxicity events will be assessed throughout enrollment in the expansion 
cohorts. If, at any time, the aggregate rate of treatment-related toxicities meeting DLT criteria exceeds 
 across all 
subjects treated in the Part D cohort expansions, the findings will be discussed with the Medical Monitor and 
Investigators; further enrollment may be interrupted. Depending on the nature and grade of the toxicity and after 
assessing the risk:benefit ratio, the dose for all or for select cohorts may be reduced.
Table 4:
Tumor Types Eligible For Part D - Cohort Expansion Relatlimab in Combination 
with Nivolumab
Tumor Type
Total Subjects
Hodgkin Lymphoma - anti-PD-1 naive
n=approximately 
Hodgkin Lymphoma - anti-PD-1 progressed
n=approximately 
Diffuse Large B-Cell Lymphoma 
n=approximately 
Total 
n=approximately 
Re-challenge in Dose Escalation and Cohort Expansion
If subjects progress during the clinical follow-up period or the survival follow-up period, they could further receive
therapy with relatlimab alone or in combination with nivolumab (Re-challenge) as long as the risk:benefit ratio is 
considered favorable by the Investigator and the Medical Monitor and the following eligibility criteria is met: 
1) Subject has confirmed disease progression 2) Subject has not experienced relatlimab related adverse events leading 
to permanent discontinuation. The original dose and schedule of therapy and protocol rules will apply. Thus subjects 
could receive therapy for up to 6 additional eight-week cycles. 
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Subjects who are re-challenged and who subsequently have an objective response will not be included in the primary
analysis of efficacy. Responses to re-challenge will be evaluated in a separate analysis. Subjects will not be 
re-challenged a second time.
Dose-Limiting Toxicities:
For the purpose of guiding decisions regarding dose escalation in Part A, (DLT) will be determined based on the 
incidence, intensity, and duration of AEs that are related to study drug and that occur within 8 weeks of initiation of 
study drug (ie, the DLT evaluation interval which begins on the first day of treatment and ends on Day 56 of the first 
cycle).
For the purpose of guiding decision in combination dose escalation in Part C, (DLT) will be determined based on the 
incidence, intensity, and duration of AEs that are related to study drug and that occur within 4 weeks of initiation of 
study drug (ie, the DLT evaluation interval which begins on the first day of treatment and ends on Day 29 of the first 
cycle).
Adverse events will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0). For the purpose of subject management, any AE that meets DLT criteria, 
regardless of the cycle in which it occurs, will lead to dose interruption.
Dose escalation will be based on the number of DLTs experienced during the DLT evaluation interval as determined 
by the Medical Monitor and Investigators.
No intra subject dose escalation is allowed. In Part A, subjects who receive at least 1 dose of study drug during the 
8-week evaluation interval will be considered evaluable for DLT determination. In Part C, subjects who receive at 
least 2 doses of study drug during the 4-week evaluation interval will be considered evaluable for DLT determination. 
Subjects who withdraw from the study during the DLT evaluation interval for reasons other than a DLT and/or for 
whom safety data are unavailable for the entire DLT evaluation interval may be replaced at the same dose level. In 
the event that an infusion cannot be administered at a scheduled visit during the DLT evaluation interval, it must be 
administered as soon as possible. If the delay is between 1 and 7 days, the procedures at the originally scheduled visit 
should be performed and subjects will be considered evaluable for DLT determination. If the delay is more than 7 
days, the dose will be considered missed and will not be replaced. Subjects with a delay of more than 7 days will not 
be considered evaluable for DLT determination. Unevaluable subjects may be replaced at the same dose level. 
Duration of Study: Subjects will be allowed to continue on therapy for up to twelve 8-week cycles or confirmed PD
or until meeting criteria for discontinuation as described in Section 3.5. Treatment beyond progression may be 
considered in select subjects as described in Section 4.3.4. Subjects may be on study for a total of up to approximately 
5 years, including a 28-day screening period, up to twelve 8-week cycles of treatment, a 135-day clinical follow-up 
period, and up to 5 years of follow-up for survival (beginning from the first dose of study drug). The study will end 
once survival follow-up has concluded. For WOCBP, additional home pregnancy tests through Day 
. The total 
duration of the study is expected to be approximately 9-10 years from the time of the first visit of the first subject to 
the required survival follow-up of the last subject enrolled. If subjects progress during the clinical follow-up prior or 
the survival follow-up period, could further receive therapy with relatlimab alone or in combination with nivolumab 
(Re-challenge) as long as they meet eligibility criteria and the risk:benefit ratio is considered favorable by the 
Investigator and the Medical Monitor. The original dose and schedule and protocol rules would apply accordingly. 
Subjects will not be re-challenged a second time.
Number of Subjects: Approximately 
subjects may be dosed.
Study Population: Male and female subjects with histologic or cytologic confirmation of CLL, Hodgkin lymphoma, 
non-Hodgkin lymphoma, and multiple myeloma who have relapsed following prior treatment or been refractory to 
prior treatment and who meet all entry criteria will be eligible to participate
Dose Escalation (Part A): Adult subjects with relapsed or refractory non-Hodgkin lymphoma (NHL), Hodgkin 
lymphoma (HL), chronic lymphocytic leukemia (CLL), or multiple myelomas are eligible.
Cohort Expansion (Part B): Four disease-restricted groups will be permitted during cohort expansion per Table 2. 
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Cohort Escalation Combination Therapy (Part C): Adult subjects with relapsed or refractory Hodgkin lymphoma, 
and Diffuse Large B-Cell Lymphoma.
Cohort Expansion Combination Therapy (Part D): Three disease-restricted groups will be permitted per Table 4.
Parts A, B, C, and D: Neutrophil count must be > 750/L and platelet count > 50,000/L. Subjects with primary 
cutaneous lymphoma, lymphoproliferative diseases associated with primary immune deficiencies, and lymphomas 
associated with human immunodeficiency virus (HIV) infection are excluded. Subjects with solitary bone or solitary 
extramedullary plasmacytoma as the only evidence or plasma cell dyscrasia, subject with Monoclonal gammopathy 
of undetermined significance (MGUS), smoldering myeloma or Waldenstrom’s macroglobulinemia or active plasma 
cell leukemia are excluded. Subjects with autoimmune disorders are also excluded.
Women must not be nursing or pregnant. WOCBP must have a negative pregnancy test within 24 hours prior to 
receiving their first dose of study medication. WOCBP must agree to follow instructions for method(s) of 
contraception based on the information in Appendix 3 for a total of 24 weeks after their last dose of investigational 
drug (a period of 30 days plus the time required for the investigational drug to undergo 5 half-lives [ie, 165 days total 
or 24 weeks]).
Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception based on 
the information in Appendix 3 for a total of 33 weeks after their last dose of investigational drug (a period of 90 days 
plus the time required for the investigational drug to undergo 5 half-lives [ie, 225 days total or 33 weeks]).
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, pulse oximetry, 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 Medical Dictionary for Regulatory Activities (MedDRA) and 
reviewed for potential significance and importance. AEs and laboratory tests will be graded using the NCI 
CTCAE v4.0.

Efficacy measures: Tumor responses will be determined for subjects with adequate data as defined by the 
following efficacy criteria. 

NHL and HL subjects: Revised Response Criteria for Malignant Lymphoma (Appendix 1)

NHL or HL subjects who had FDG-PET scans performed in the pre-treatment period and during this study: 
retrospective assessment using Lugano 2014 Response Criteria (Appendix 7)

CLL subjects: Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia (Appendix 2)

MM subjects: Response Criteria Modified from IMWG for Multiple Myeloma (Appendix 6)

Pharmacokinetic measures: Serial serum samples will be collected from all subjects at specified time points to 
evaluate concentrations of relatlimab and/or nivolumab. PK parameters such as Cmax, Ctrough, Tmax, 
AUC(TAU), CLT, and AI will be derived from serum concentration versus time data.

Immunogenicity measures: Serum samples will be collected from all subjects at specified time points to evaluate 
development of anti-drug antibodies (ADA) to relatlimab and/or nivolumab.

Exploratory Biomarker measures: The sample collection and biomarker assessment strategy is designed to address 
mechanisms of action, pharmacodynamic changes associated with relatlimab administered as monotherapy or in 
combination with nivolumab, and potential identification of predictive safety and efficacy biomarkers associated 
with relatlimab, and to evaluate potential mechanisms of resistance to relatlimab. To address these key questions, 
peripheral blood, serum, and biopsy samples will be collected prior to and during study drug treatment in Parts A,
B, C, and D, of this study.
Statistical Considerations:
Sample Size:
Dose escalation (Part A and C): The sample size at each dose depends on observed toxicity and cannot be precisely 
determined. Part A will have  to  subjects in each cohort.
Cohort expansion (Part B): Approximately 
 subjects at 
 mg dose of relatlimab together with 
subjects 
from Part A 
 mg dose level (a total of 
 subjects) will provide better understanding of the safety profile at 
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mg dose level. If  of 
subjects or 
 of 
 subjects (ie,
) experience a toxicity there is at least 
 
confidence that the true toxicity rate is not greater than 
(based on Clopper-Pearson exact binomial 1-sided 
confidence interval). In addition, administration of relatlimab at the dose of 
 mg to 
 or 
 subjects provides 
 probability of observing at least one occurrence of any adverse event that would occur with 
or 
 incidence, 
respectively, in the population from which the sample was drawn.
Cohort Expansion for Combination Therapy (Part D): The objective of this expansion in combination with nivolumab 
is, in addition to demonstrating adequate safety and tolerability, to evaluate a favorable risk/benefit assessed by signal 
seeking for anti-PD-1/PD-L1 progressed nivolumab HL, improvement in complete response rate (CRR) for 
anti-PD 1/PD-L1 naive HL relative to PD-1 monotherapies, and improvement in objective response rate (ORR) for 
DLBCL relative to existing available therapies. 
A 2-stage design (Fleming’s), which allows to stop early for futility as well as for efficacy, will be used as a guidance 
for each disease cohort with reasonable false positive rate (eg, FPR 
) and false negative rate (eg, FNR 
) 
based on assumptions of true (target) and historic response rate for each cohort. Each disease cohort will be handled 
independently and there will be no multiplicity adjustment. The assumed historic and target response rates may change 
over time and may need to be adjusted by the time response data from this study are available. 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.
For anti-PD-1/PD-L1 progressed HL, the assumed target response rate will be 
% vs % of inefficacious rate; as 
there is no standard of care available in this patient population. For anti-PD-1/PD-L1 naive HL, the assumed target 
CRR will be 
% vs 
% observed with anti-PD 1 monotherapy. For DLBCL, the assumed target ORR will be 
 
vs 
%, which was obtained from Study CA209039 by averaging the observed rates of monotherapy 
 and 
a combination treatment with ipilimumab 
. The sample size and operational characteristics of using 
Fleming’s 2-stage design are provided, as an example, in Table 5, although not used for statistical hypothesis testing.
Guided by Table 5, approximately 
 subjects, for example, will be treated in Stage 1 for an initial evaluation of 
efficacy. This will inform potential early decisions and guide planning/operations, or early termination after taking 
into consideration of additional data such as time to and/or duration of response, and safety. For example, assuming 
the true response rate is 
 for anti-PD-1/PD-L1 progressed HL cohort when treated with relatlimab in combination 
with nivolumab, if there are  or more responses in 
 subjects, the cohort may be stopped for efficacy and consider 
larger scale comparative trials. The probability of early stopping for efficacy is approximately 
 if in fact the 
treatment is efficacious. If there is no response in 
 treated subjects, the cohort may be stopped for futility. The 
probability of early stopping for futility is approximately 
 if in fact the treatment is inefficacious, eg, 
. If there 
is just  response, an additional  subjects may be treated to collect more data. This design yields a FPR of
 when 
the true response rate is 
 and FNR of 
 when the true response rate is 
 rather than 
. For anti-PD-1/PD-L1
naive HL and DLBCL cohorts assuming the true response rate is 
 when treated with relatlimab in combination 
with nivolumab, if there are  or more responses in 
 subjects, the cohort may be stopped for efficacy. The probability 
of early stopping for efficacy is approximately 
 if in fact the treatment is efficacious. If there are  or fewer 
responses in 
 treated subjects, the cohort may be stopped for futility. The probability of early stopping for futility is 
approximately 
 if in fact there is no improvement with the combination treatment. If there are  or  responses in 
 treated subjects, additional  subjects may be treated to collect more data. This design yields a FPR of 
 when 
the true response rate is
 and FNR of 
 when the true response rate is 
.
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Table 5:
Example of a Two-stage Design Characteristics
Cohorta
Historic/Target
Rate (%)
Stage
Cumulative
Sample Size
Conclude
Futility
If Rb
Conclude
Efficacy
If R
PETc for
futility (%)
PET for
efficacy (%)
FPR/FNRd
(%)
HL anti-PD-1/PD-L1
progressed
1
2
HL anti-PD-1/PD-L1
naive and DLBCL
1
2
a DLBCL: diffuse large B cell lymphoma.
b R is the cumulative number of responses at the end of stage.
c Probability of early termination.
d False positive rate/false negative rate.
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Endpoints
Primary Endpoints
The primary endpoint of this Phase 1 study is safety as measured at the study level by the rate of AEs, SAEs, AEs 
leading to discontinuation, deaths, and laboratory abnormalities, assessed during treatment and for up to 135 days after 
the last treatment. All subjects who receive at least one dose of relatlimab alone or in combination with nivolumab 
will be analyzed for safety. Co-primary endpoint in Part D is objective response rate (ORR) and duration of response 
(DOR).
Secondary Endpoints
Pharmacokinetics Select PK parameters, such as Cmax, Ctrough, Tmax, AUC(TAU), CLT, and AI, will be assessed 
from concentration-time data at select time points throughout treatment with relatlimab administered alone or in 
combination with nivolumab 
Immunogenicity The proportion of subjects who are ADA-positive at baseline, the proportion of subjects who
become ADA-positive on study, and the proportion of subjects who remain ADA-negative to relatlimab will be 
measured during treatment and for up to 135 days after their last treatment in post-treatment follow-up.
Efficacy: All efficacy analyses will be based on the all treated analysis population except otherwise stated.
Co-primary, secondary and exploratory efficacy endpoints for Part D subjects are as follows:
Objective Response Rate (ORR)
ORR based on investigator assessment, according to the applicable criteria based on tumor type, will be a co-primary 
endpoint in Part D. For the NHL and HL subjects, the ORR will be based on the IWG (2007) response criteria. In 
addition to the primary ORR endpoint, an exploratory endpoint of ORR based on the Lugano (2014) response criteria 
in the NHL and HL subjects in Part D will be assessed. For the Lugano criteria, response is defined as complete 
metabolic response (CMR) and partial metabolic response (PMR).
Duration of Objective Response (DOR)
DOR is defined as the time between the date of first documented response (CR or PR) to the date of the first objectively 
documented progression as per criteria relevant to each disease type in Part D (Appendices 1, 2, and 6)], or death due 
to any cause, whichever occurs first. For subjects who neither progress nor die, DOR will be censored on the date of 
their last tumor assessment. Subjects who start subsequent therapy without a prior reported progression will be 
censored at the last tumor assessments prior to initiation of the subsequent anticancer therapy. This endpoint will only 
be evaluated in subjects with objective response of CR or PR. DOR will be evaluated based on investigator 
assessments. DOR is co primary endpoint in Part D. DOR based on the Lugano (2014) response criteria, response 
defined as CMR or PMR, will be assessed for the NHL/HL subjects in Part D as an exploratory endpoint.
Complete Response (CR) Rate and Duration
The CR rate is defined as the number of subjects with a best overall response (BOR) of CR according to the applicable 
criteria based on tumor type, based on IWG criteria for NHL and HL subjects, divided by the number of treated 
subjects. The duration of CR (DoCR) will only be evaluated in subjects with BOR of CR and is defined as the time 
from first documentation of CR (the date of first negative FDG-PET scan) to the date of initial objectively documented 
progression as determined using the applicable criteria based on tumor type or death due to any cause, whichever 
occurs first. Censoring will be applied as per DOR definition. CR rate and DoCR will be evaluated based on 
investigator assessments. CR rate is an exploratory endpoint in this study.
Progression Free Survival (PFS) Rate
PFS is defined as the time from first dose to the date of first objectively documented progression, per applicable 
criteria based on tumor type or death due to any cause, whichever occurs first. 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 
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assessments and did not die will be censored on the date of first dose. Subjects who started any subsequent anti-cancer 
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 anti-cancer 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.
PFSR will be assessed at Weeks 16, 24, 32, 40, and 100, and evaluated based on investigator assessments. PFS will 
be an exploratory endpoint in this study.
Overall Survival (OS) Rate
OS is defined as the time between the date of first dose and the date of death. For subjects without documentation of 
death, OS will be censored on the last date the subject was known to be alive. The overall survival rate at time T is 
defined as the probability that a subject is alive at time T following first dose OS will be assessed at various time 
points in HL patients in Part D.
Exploratory Endpoints:
Biomarkers Biomarkers endpoints from peripheral blood may include measures such as levels of soluble factors, as
well as activation and proliferation of subsets of immune cells including but not limited to subset of T cells
characterized by immunophenotyping, at each scheduled time point. Biomarker endpoints from tumor biopsies may
include, but will not be limited to, expression of immune activation genes, the architecture of immune cells in the
tumor and expression of LAG3, major histocompatibility complex (MHC) class II, programmed cell death 1 (PD-1),
and programmed cell death ligand 1 (PD-L1). Measures of receptor occupancy as characterized in peripheral blood,
bone marrow, and lymph node (if available) may also be provided.
Receptor Occupancy Measures of receptor occupancy as characterized in peripheral blood, bone marrow, and lymph 
node (if available) will be provided.
Other Efficacy Endpoints
PFS based on Lugano (2014) Criteria PFS for a subject is defined as the time from the first dosing date to the date of 
first progressive metabolic disease or death due to any cause (death occurring after retreatment will not be considered), 
whichever occurs first. Subjects who died without a reported prior progression will be considered to have progressed 
on the date of their death. The censoring rules applied to the PFS endpoint based on the IWG criteria will also be used 
for this endpoint.
Complete Metabolic Response Rate based on Lugano 2014 Criteria The CMR rate is defined as the number of subjects 
with a BOR of CMR based on the Lugano (2014) criteria divided by the number of treated subjects. The duration of 
CMR (DoCMR) will only be evaluated in subjects with BOR of CMR and is defined as the time from first 
documentation of CMR (the date of first negative FDG-PET scan) to the date of initial objectively documented 
progressive metabolic disease based on the Lugano (2014) criteria or death due to any cause, whichever occurs first. 
Censoring will be applied using the DOR definition. CMR rate and DoCMR will be evaluated based on investigator 
assessments.
Analyses:
Unless otherwise specified, safety data from Parts A-D will be summarized both (1) overall by dose level and across 
all dose levels and (2) by dose level and across all dose levels within each tumor type. Efficacy data will be summarized 
by dose level within each tumor type and patient population. 
Efficacy Individual ORR, CRR, DOR, CMR, PMR, and PFS (based on IWG and Lugano criteria) will be determined. 
BOR outcomes will be summarized using frequency tables together with 2-sided 95% confidence intervals. Time to 
event distribution (eg, PFS, DOR, and DoCMR) will be estimated using Kaplan-Meier (K-M) method. When 
appropriate, the median along with 95% CI will be provided using Brookmeyer and Crowley methodology (using log-
log transformation for constructing the confidence intervals). Rates at fixed time points (e.g. PFSR 24 weeks) will be 
derived from the K-M estimate and corresponding confidence interval will be derived based on Greenwood formula. 
Confidence intervals for binomial proportions will be derived using the Clopper-Pearson method. OS data will be 
analyzed similarly to PFS data analysis.
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Safety: 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 be graded using the NCI CTCAE version 4.0. AEs will 
be listed and subjects with AEs will be summarized based on the event with worst CTC 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. 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 v 4) 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.
Pharmacokinetics: PK parameters for relatlimab as monotherapy and in combination with nivolumab will be 
calculated using noncompartmental analyses. Summary statistics will be tabulated for the PK parameters of relatlimab
by treatment and study day/week. To describe the dependency on dose of relatlimab, scatter plots of Cmax and AUC 
(TAU) versus dose may be provided for each day measured. Dose proportionality of BMS 986016 will also be assessed 
based on a power model. Summary statistics of nivolumab exposure at trough and end of infusion will be tabulated 
separately.
Immunogenicity: A listing will be provided for all available immunogenicity data. The number and percent of subjects 
who meet specified endpoint definitions in the statistical analysis plan (SAP) will be summarized for each drug. 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, pharmacodynamic markers, and/or PK may also be explored.
Exploratory Biomarkers: The pharmacodynamic effect on TILs, MILs, and other key tumor markers in subjects who 
undergo biopsy will be summarized using summary statistics and plots. In addition, the correlation of 
 or
 
changes and tumor marker expression with measures of peripheral blood markers may be explored graphically, and 
using appropriate modeling approaches based on data availability. Associations of biomarker measures from
peripheral blood or tumor biopsy with clinical outcomes may also be explored graphically and further assessed as
needed by methods such as, but not limited to, logistic regression and characterized by appropriate statistics.
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR REVISED PROTOCOL 09: ..................................... 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 09 ......................... 
 
SYNOPSIS .................................................................................................................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
1.1 Study Rationale ................................................................................................. 
 
1.1.1 Relapsed Refractory Hematological Malignancies as Unmet Medical 
Needs ........................................................................................................... 
 
1.1.2 Rationale for Nivolumab Therapy ........................................................... 
 
1.1.3 LAG-3 and T Cell Exhaustion .................................................................. 
 
1.1.4 LAG-3 Expression in Hematological Malignancies ................................ 
 
1.1.5 Rationale for Anti-LAG-3 Antibody (Relatlimab, BMS-986016) Therapy
..................................................................................................................... 
 
1.1.6 Preclinical Studies Utilizing Murine Anti-PD-1 and Anti-LAG-3 
Antibodies ................................................................................................... 
 
1.1.7 Rationale for Combination of Anti-LAG-3 Antibody (Relatlimab) and 
Nivolumab ................................................................................................... 
 
1.1.8 Rationale for Dose Selection ................................................................... 
 
1.1.8.1 Rationale for Flat Dosing ............................................................... 
 
1.1.8.2 Rationale for 
minute Nivolumab Infusion ................................. 
 
1.1.8.3 Part A — Relatlimab Dose .............................................................. 
 
1.1.8.4 Part B — Relatlimab Dose .............................................................. 
 
1.1.8.5 Part C - Dose Escalation - Combination of Relatlimab and 
Nivolumab ............................................................................................. 
 
1.1.8.6 Part D - Dose Expansion - Combination of Relatlimab and 
Nivolumab ............................................................................................. 
 
1.2 Research Hypothesis ......................................................................................... 
 
1.3 Objectives(s) ..................................................................................................... 
 
1.3.1 Primary Objectives .................................................................................. 
 
1.3.2 Secondary Objectives ............................................................................... 
 
1.3.3 Exploratory Objectives ............................................................................ 
 
1.4 Product Development Background ................................................................... 
 
1.4.1 Relatlimab (BMS-986016, Anti-LAG-3 Antibody) ................................... 
 
1.4.1.1 Non-Clinical Pharmacology ........................................................... 
 
1.4.1.2 Toxicity ............................................................................................ 
 
1.4.1.3 Nonclinical Metabolism and Pharmacokinetics ............................. 
 
1.4.1.4 Clinical Pharmacology ................................................................... 
 
1.4.1.5 Clinical Safety-Monotherapy (Part A and Part B) and Combination 
Therapy (Part C and D) in CA224022 .................................................. 
 
1.4.1.6 Serious Adverse Events ................................................................... 
 
1.4.1.7 Infusion Reactions ........................................................................... 
 
1.4.1.8 Adverse Events Leading to Discontinuation ................................... 
 
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1.4.1.9 Deaths ............................................................................................. 
 
1.5 Clinical Safety - Monotherapy (Part A and A1) and Relatlimab in Combination 
with Nivolumab Therapy (Parts B, C, and D) in Solid Tumor Study CA224020
........................................................................................................................... 
1.5.1 Adverse Events ......................................................................................... 
 
1.5.2 Serious Adverse Events ............................................................................ 
 
1.5.3 Infusion Reactions .................................................................................... 
 
1.5.4 Adverse Events Leading to Discontinuation ............................................ 
 
1.5.5 Deaths ...................................................................................................... 
 
1.6 Clinical Efficacy - Studies CA224020 and CA224022 .................................... 
 
1.7 Nivolumab (BMS-936558, Anti-PD-1 Antibody) ............................................ 
 
1.7.1 Nonclinical Pharmacology ...................................................................... 
 
1.7.2 Toxicity ..................................................................................................... 
 
1.7.3 Nonclinical Metabolism and Pharmacokinetics ...................................... 
 
1.7.3.1 Clinical Pharmacology ................................................................... 
 
1.7.3.2 Clinical Safety and Activity ............................................................. 
 
1.8 Overall Risk/Benefit 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 Part A - Dose Escalation ......................................................................... 
 
3.1.2 Part B - 
 mg Cohort Expansion .......................................................... 
 
3.1.3 Part C - Dose Escalation Combination Therapy ..................................... 
 
3.1.4 Part D - Dose Expansion Combination Therapy ..................................... 
 
3.1.5 Re-challenge in Dose Escalation (Part C) and Cohort Expansion (Part 
D) ................................................................................................................
 
3.1.6 Dose-Limiting Toxicities .......................................................................... 
 
3.1.6.1 Rationale for 4-week DLT Period in Part C ................................... 
 
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 ......................................................... 
 
3.4.2.1 Vaccinations .................................................................................... 
 
3.4.2.2 Imaging Restrictions and Precautions ............................................ 
 
3.4.3 Permitted Therapy ................................................................................... 
 
3.4.4 Treatment of Relatlimab or Nivolumab-Related Infusion Reactions ....... 
 
3.5 Discontinuation of Subjects from Treatment .................................................... 
 
3.6 Post Treatment Study Follow-Up ..................................................................... 
 
3.6.1 Withdrawal of Consent ............................................................................ 
 
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3.6.2 Lost to Follow-Up .................................................................................... 
 
4 TREATMENTS ......................................................................................................... 
 
4.1 Study Treatments .............................................................................................. 
 
4.1.1 Investigational Product ............................................................................ 
 
4.1.2 Non-investigational 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 ............................................................ 
 
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 Imaging Assessment for the Study............................................................ 
 
5.3.2 Genomic Analysis ..................................................................................... 
 
5.3.3 Laboratory Test Assessments ................................................................... 
 
5.4 Efficacy Assessments ........................................................................................ 
 
5.5 Pharmacokinetic Assessments .......................................................................... 
 
5.5.1 Pharmacokinetics - Collection and Processing ....................................... 
 
5.5.2 Pharmacokinetic Sample Analyses .......................................................... 
 
5.5.3 Labeling and Shipping of Biological Samples ......................................... 
 
5.6 Biomarker Assessments .................................................................................... 
 
5.7 Exploratory Biomarker Assessments ................................................................ 
 
5.7.1 Soluble Biomarkers .................................................................................. 
 
5.7.2 Immunophenotyping of PBMC and Bone Marrow Aspirates .................. 
 
5.7.3 Ex Vivo Functional Assays ....................................................................... 
 
5.7.4 Peripheral Blood Gene Expression ......................................................... 
 
5.7.5 Relatlimab Receptor Occupancy .............................................................. 
 
5.7.7 Tumor-Based Biomarker Measures ......................................................... 
 
5.7.8 Additional Research Collection ............................................................... 
 
5.8 Outcomes Research Assessments ..................................................................... 
 
5.9 Other Assessments ............................................................................................ 
 
5.9.1 Immunogenicity Assessments ................................................................... 
 
5.10 Results of Central Assessments ...................................................................... 
 
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6 ADVERSE EVENTS ................................................................................................. 
 
6.1 Serious Adverse Events .................................................................................... 
 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
 
6.2 Non-serious Adverse Events ............................................................................. 
 
6.2.1 Non-serious Adverse Event Collection and Reporting ............................ 
 
6.3 Laboratory Test Result Abnormalities .............................................................. 
 
6.4 Pregnancy .......................................................................................................... 
 
6.5 Overdose ........................................................................................................... 
 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
 
6.7 Other Safety Considerations ............................................................................. 
 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
 
8 STATISTICAL CONSIDERATIONS....................................................................... 
 
8.1 Sample Size Determination ............................................................................... 
 
8.1.1 Parts A and C - Dose Escalation ............................................................. 
 
8.1.2 Part B Cohort Expansion for Monotherapy ............................................ 
 
8.1.3 Part D Cohort Expansion for Combination Therapy .............................. 
 
8.2 Populations for Analyses .................................................................................. 
 
8.3 Endpoints .......................................................................................................... 
 
8.3.1 Primary Endpoint(s) ................................................................................ 
 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.3.2.1 Pharmacokinetics ............................................................................ 
 
8.3.2.2 Immunogenicity ............................................................................... 
 
8.3.2.3 Efficacy ........................................................................................... 
 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
 
8.3.3.1 Biomarkers ...................................................................................... 
 
8.3.3.2 Receptor Occupancy ....................................................................... 
 
8.3.3.3 Other Efficacy Endpoints ................................................................ 
 
8.4 Analyses ............................................................................................................ 
 
8.4.1 Demographics and Baseline Characteristics........................................... 
 
8.4.2 Efficacy Analysis ...................................................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.5 Exploratory Biomarker Analyses ............................................................. 
 
8.4.6 Outcomes Research Analyses .................................................................. 
 
8.4.7 Other Analyses ......................................................................................... 
 
8.4.7.1 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 ................................................................................. 
 
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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 2007 INTERNATIONAL WORKING GROUP (IWG) RESPONSE 
CRITERIA FOR MALIGNANT LYMPHOMA .................................................... 
 
APPENDIX 2 2008 INTERNATIONAL WORKING GROUP (IWG) RESPONSE 
CRITERIA FOR CLL WITH MODIFICATIONS ................................................. 
 
APPENDIX 3 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 4 MANAGEMENT ALGORITHMS ....................................................... 
 
APPENDIX 5 ECOG, KARNOFSKY, AND LANSKY PERFORMANCE STATUS
................................................................................................................................. 
 
APPENDIX 6 RESPONSE CRITERIA MODIFIED FROM IMWG FOR MULTIPLE 
MYELOMA ............................................................................................................ 
 
APPENDIX 7 LUGANO 2014 RESPONSE CRITERIA ............................................ 
 
APPENDIX 8 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
 
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1
INTRODUCTION AND STUDY RATIONALE
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, enabling the endogenous immune system to reject tumors. The recent 
success of immune-modulating agents blocking checkpoint inhibitor molecules (eg, programmed 
cell death 1 [PD-1], programmed cell death protein ligand 1 [PD-L1], and cytotoxic 
T lymphocyte–associated antigen 4 [CTLA-4]) 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 overall survival when treated 
with the antiCTLA-4 antibody, ipilimumab.1 Moreover, the same patient population treated with 
the combination of ipilimumab and an antiPD-1 antibody (nivolumab, BMS-936558) achieved 
an unprecedented 53% response rate and prolonged responses.2 Recent preclinical data support the 
clinical testing of yet another checkpoint inhibitor molecule, lymphocyte activation gene 3 
(LAG-3), as a relevant therapeutic target in select hematological malignancies. Current concepts 
suggest that therapy with immune-modulating agents may achieve robust and prolonged responses 
and deserves to be further explored.
1.1
Study Rationale
1.1.1
Relapsed Refractory Hematological Malignancies as Unmet Medical 
Needs
Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative malignancies 
with distinct clinical outcomes and responses to treatment. There are an estimated 69,740 new 
cases to be diagnosed in the United States in 2013.3 The NHLs can be divided into 2 prognostic 
groups: the indolent lymphomas (eg, follicular) and the aggressive lymphomas (eg, diffuse large 
B-cell [DLBCL], mantle cell, Burkitt). Aggressive lymphomas have an overall survival of 
approximately 60% at 5 years. Despite the fact that half of the aggressive cases are cured, the vast 
majority of relapses occur in the first 2 years after therapy. The concerning issue is that not all 
patients tolerate standard treatment with high-dose therapy and stem cell rescue at relapse.4
Chronic lymphocytic leukemia (CLL) is the most commonly diagnosed leukemia among adults in 
the United States, with approximately 16,000 new cases estimated in the United States for 2013.3
The median age at diagnosis is 72 years, with approximately 70% of patients diagnosed at older 
than 65 years (and 40% diagnosed at age 75 years).5 Thus, CLL mainly affects elderly patients 
who cannot tolerate current myelosuppressive regimens used in younger and fitter patients.6
Hodgkin’s lymphoma (HL) is yet another malignancy of lymphoid tissue with an estimated 
9,290 new cases in the United States in 2013.3 HLs can be divided into 2 pathology groups: 
classical HL (CHL) and lymphocyte-predominant HL (LPHL). In Western countries, CHL 
accounts for 95% of HL cases. CHL is pathologically characterized by the presence of 
Hodgkin-Reed-Sternberg (HRS) cells in an inflammatory background. Combined chemotherapy 
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and radiotherapy result in durable response rates but at the expense of significant morbidity 
(eg, secondary malignancies, cardiac disease, and infertility). Unfortunately, around 30% of 
patients will become refractory to initial therapy or will relapse. The therapeutic options for 
refractory or relapsed patients are very limited and also carry a high morbidity rate.4
Multiple myeloma (MM) is an incurable malignancy arising from postgerminal mature B cells, 
characterized by an excess of monotypic plasma cells in the bone marrow, resulting in elevated 
levels of monoclonal immunoglobulins in the serum and/or urine. In the United States, the 
estimated annual diagnosed incidence is 16,000, with approximately 50,000 prevalent cases. 
Multiple myeloma accounts for 10% of all hematologic malignancies and 1% of all malignancies. 
Advances in therapy have improved outcomes but the disease remains essentially incurable and is 
associated with a high morbidity and mortality.
To address these unmet medical needs, compounds that have novel mechanisms of action with 
relevant single-agent activity and good safety profiles need to be evaluated in clinical studies with 
the goal of achieving a better therapeutic index when used in combination regimens.
1.1.2
Rationale for Nivolumab Therapy
Programmed cell death 1 (PD-1) is a cell surface signaling receptor that plays a critical role in the 
regulation of T cell activation and tolerance.7 It is a type I transmembrane protein and together 
with BTLA, CTLA-4, ICOS, and CD28, make up the CD28 family of T cell co stimulatory 
receptors. PD-1 is primarily expressed on activated T cells, B cells, and myeloid cells.8 It is also 
expressed on natural killer (NK) cells.9 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 
down-regulation 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.10 Evidence of this negative regulatory role comes from the finding 
that PD-1deficient mice develop lupus-like autoimmune diseases including arthritis and nephritis, 
along with cardiomyopathy.11,12 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, and its ligands are upregulated on the 
cell surface of many different tumors.13 Multiple murine cancer models have demonstrated that 
binding of ligand to PD-1 results in immune evasion. In addition, blockade of this interaction 
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 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-L2.14
Nivolumab does not bind other related family members, such as BTLA, CTLA-4, ICOS, or CD28. 
Nivolumab has demonstrated clinical activity as monotherapy in subjects with a variety of 
hematological advanced malignancies including diffuse large B-cell lymphoma, follicular 
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lymphoma, and Hodgkin’s lymphoma. Treatment with Nivolumab is indicated for patients with 
unresectable or metastatic melanoma as both a monotherapy and in combination with ipilimumab. 
Nivolumab is also approved for non-small cell lung cancer following failure on or after platinum 
based therapy, as well as for advanced renal cell carcinoma following treatment with an 
anti-angiogenic therapy (Section 1.7.3.2).
1.1.3
LAG-3 and T Cell Exhaustion
LAG-3 (CD223) is a type I transmembrane protein that is expressed on the cell surface of activated 
CD4+ and CD8+ T cells and subsets of natural killer (NK) and dendritic cells.15,16 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, major histocompatibility complex
(MHC) class II, 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 MHC class II 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.17 Both natural and induced 
Treg express increased LAG-3, which is required for their maximal suppressive function.18,19
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.19 Recent studies 
have also shown that high LAG-3 expression on exhausted lymphocytic choriomeningitis virus 
(LCMV)-specific CD8+ T cells contributes to their unresponsive state and limits CD8+ T-cell 
antitumor responses.20,21 In fact, LAG-3 maintained tolerance to self and tumor antigens via direct 
effects on CD8+ T cells in 2 murine models.21
Immune tolerance observed in the setting of tumor development and tumor recurrence, however, 
seems to be mediated by the co-expression of various T-cell negative regulatory receptors, not 
solely from LAG-3. Data from chronic viral infection models,20,21,22 knock-out mice,23,24,25 tumor 
recurrence models,26 and, to a more limited extent, human cancer patients,26 ,27,28 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 T cells and/or to increase Treg 
activity. However, the timing and sequence of expression of these molecules in the development 
and recurrence of each tumor type have not been fully characterized.
1.1.4
LAG-3 Expression in Hematological Malignancies
The expression of the checkpoint inhibitors PD-1 and PD-L1 in NHLs,29,30,31,32 CLL,33,34 HL,35,36
and MM37,38 has been associated with T cell exhaustion. Interestingly, the expression of these 
molecules may be driven by mutations leading to constitutive activity of their enhancers/promoters 
and/or by the infection of host T cells by Epstein Barr virus (EBV), among other factors.39
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Emerging data indicates that LAG-3 expression on tumor-infiltrating lymphocytes (TILs) and 
peripheral blood could also be mediating T cell exhaustion in hematological malignancies.
In primary CHL, for example, a small number of HRS cells are surrounded by a profuse 
inflammatory infiltrate. Yet, HRS cells fail to evoke an effective T cell response despite the 
expression of class II MHC on tumor cells. This effect, known as the “paradox effect,”40 could 
very well be mediated by T cell exhaustion. In this regard, Gandhi et al. have shown strong 
expression of LAG-3 on TILs in proximity to HRS cells, particularly in cases with EBV tissue 
positivity. In these HL subjects, circulating CD4+LAG-3hi cells were only elevated at diagnosis 
or at clinical relapse, but not during remission.28 Although FOXP3 positivity was neither linked to 
LAG-3 nor EBV tissue status, both Treg and LAG-3+ CD4+ T cells were shown to be involved in 
tumor immune evasion because the expression of FoxP3 and LAG-3, respectively, coincided with 
the impairment of tumor-specific T cell responses. These results, in addition to the known 
expression of PD-L1 and PD-L2 on tumor cells and PD-1 on infiltrating lymphocytes and 
peripheral T cells in HL,35 strongly suggest an ongoing “exhausted T cell phenotype” in HL 
subjects. In fact, an increased PD-1 expression on TILs has been determined as a stage-independent 
negative prognostic factor of overall survival as opposed to the number of FOXP3+ Tregs.41 The 
contribution of LAG-3 in this regard remains to be determined. 
Little is known about the expression and functions of LAG-3 in NHLs. LAG-3 expression has 
been documented in a subtype of DLBCL defined by gene expression profiling as “host response 
tumor”. These tumors have prominent T cell/dendritic cell infiltrates resembling those of smaller 
provisional (WHO) subtype of DLBCL, T cell/histiocyte-rich B-cell lymphoma (T/HRBCL).42
Since HR-DLBCL patients did not have the best outcomes following empiric chemotherapy in this 
study, the authors inferred that their immune responses were ineffective due to the expression of 
inhibitory receptors on CD8+ T cells43 or that tumors were inherently refractory to CHOP-based 
treatment. Interestingly, some aggressive B-cell and EBV-associated lymphomas also display 
ineffective T cell immune responses and express PD-L1 on tumor cells and infiltrating 
macrophages.39 Furthermore, the histology of EBV-positive DLBCL also resembles the changes 
found in HL, including HRS-like large cells admixed with abundant reactive small lymphocytes.44
The link between these findings and LAG-3 expression and function is yet to be established. 
It is also possible that LAG-3 expression may be a marker of uncontrolled clonal expansion in 
select leukemias. When B-cell CLL is associated with the expression of unmutated 
immunoglobulin heavy variable (IGHV) genes, it becomes a more aggressive form of CLL. By 
using gene co-expression network analysis, Zhang et al. found a gene set (ie, LAG-3, LPL, ZAP70) 
that is assigned to unmutated IGHV in CLL cells.45 Furthermore, Kotaskova et al. documented 
that high expression of LAG-3 on CLL cells correlates with unmutated IGHV status and reduced 
treatment-free survival.46 In addition, Dickinson et al. described a specific association of 11q22.3 
deletion with bulky lymphadenopathy and expression of ZAP-70 and LAG-3 in CLL. 47 In 
summary, these data suggest an association of LAG-3 expression with T cell exhaustion leading 
to bulky disease and poor prognosis. In contrast, the association between PD-1 expression and 
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clinical outcome is not clear. In one series, for example, only 5% of 66 CLL/SLL cases showed 
unequivocal PD-1 positivity of leukemic cells by IHC.30 The effects of both LAG-3 and PD-1 
expression and interaction on TILs, marrow-infiltrating lymphocytes (MILs), and peripheral blood 
from CLL patients remain to be elucidated. 
Multiple myeloma (MM) is a malignant proliferation of plasma cells that produces monoclonal 
immunoglobulins, usually IgG or IgA (60% and 20% of cases, respectively). MM is associated 
with T cell abnormalities including quantitative and functional defects of CD4+ T cells.48 In 
relation to the latter, T cells from MM subjects have been shown to overexpress PD-1while their 
malignant plasma cells express PD-L1.37 So, it is expected that other checkpoint inhibitor 
molecules, such as LAG-3, may be overexpressed in peripheral T cells and/or in marrow 
infiltrating-T-cells (ie, MILs) too. Furthermore, six tag SNPs in CD4 & LAG-3 genes (out of 
97 immune-genes tested in peripheral blood) have been significantly associated with MM risk48. 
So, it is hypothesized that genetic variations in the CD4/LAG-3 gene regions may be related to 
dysfunctional T-cell responses resulting in a loss of control over B-cell proliferation.
Epstein-Barr virus infection is yet another factor to consider in the potential induction of T cell 
exhaustion in hematological malignancies. It is known that EBV-associated CLL, Richter’s 
syndrome, and lymphoma cases are usually more aggressive than their EBV(-) 
counterparts.44,49,50,51,52 Interestingly, the expression of checkpoint inhibitors like PD-L1 has also 
been documented in EBV-associated malignancies.39,36 Thus, the chronic viral infection may be 
inducing the co-expression of other regulatory inhibitors as documented in chronic viral infection 
models. In the LCMV mouse model, for example, the co-expression of PD-1, LAG-3, and other 
inhibitory receptors correlated with greater T cell exhaustion and more severe infection. Blockade 
of PD-1 and/or LAG-3 with specific, targeted antibodies was able to improve T cell responses and 
reduce viral load infection.20
Altogether, these data suggest that T cell exhaustion induced by the aberrant expression of 
checkpoint inhibitor molecules (including LAG-3) and epigenetic factors (eg, EBV infection) may 
have an effect on the pathogenesis and outcomes of subjects with hematological malignancies.
1.1.5
Rationale for Anti-LAG-3 Antibody (Relatlimab, BMS-986016) Therapy
Relatlimab (BMS-986016) 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 
T cell killing. Relatlimab binds to a defined epitope on LAG-3 with high affinity (Kd, 
0.25-0.5 nM) and specificity and potently blocks the interaction of LAG-3 with its ligand, MHC 
class II (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, relatlimab 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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1.1.6
Preclinical Studies Utilizing Murine Anti-PD-1 and Anti-LAG-3 
Antibodies
The importance of LAG-3 as an immunotherapy target was initially validated in the A20 murine 
in vivo model using a surrogate antibody specific for mouse LAG-353 and anti-PD-1. One study 
evaluated tumor growth inhibition in a syngeneic tumor model (ie, A20 B-lymphocyte sarcoma). 
Mice were injected intravenously with the syngeneic A20 cell line and subsequently randomized 
to treatment with either control IgG, anti-LAG-3 (19C7), anti PD-1 (4H2), or the combination of 
anti-LAG-3/anti-PD-1. Survival was assessed as an endpoint of the study and the treatment 
regimen was considered active if it produced a statistically significant survival extension relative 
to animals treated with control IgG. The median survival of mice treated with control IgG was 
40.5 days and all animals were dead by Day 49. Anti-Lag-3 administration resulted in a statistically 
significant survival extension, with a median survival of mice in this group of 48 days and 20% of 
mice alive beyond Day 85. Administration of anti-PD-1 increased the median survival to 
48.5 days, with 10% of the mice alive at day 85. Anti-Lag-3 antibody administered in combination 
with anti-PD-1 antibody provided enhanced anti-tumor activity above the activity of either agent 
alone with a 60% of the mice alive beyond Day 85 (see Figure 1.1.6-1).
Figure 1.1.6-1:
Antitumor Activity of Anti-PD-1 and LAG-3 Antibody in the A20 
Model
Source: Adapted from Figure 1 of the Scientific Report of Study No. BDX-1408-263.53
1.1.7
Rationale for Combination of Anti-LAG-3 Antibody (Relatlimab) and 
Nivolumab
T-cell exhaustion induced by the expression of one or more checkpoint molecules on 
immune-modulating cells (or tumor cells) has been documented in different hematological 
malignancies during active disease. Some of these malignancies have underlying chronic viral 
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infections which may also contribute to maintain T cell exhaustion. EBV infection, for example, 
has been correlated with expression of checkpoint molecules in Hodgkin lymphoma and DLBCL. 
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. Thus, the combination of relatlimab and nivolumab (an 
antiPD-1 antibody) in hematological malignancies is expected to: 1) increase the number, type, 
and duration of responses 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). 
1.1.8
Rationale for Dose Selection
Study CA224022 currently consists of 4 parts, A to D. Part A consists of a 3 + 3 + 3 dose escalation 
design with relatlimab administered as monotherapy in subjects with advanced hematological 
malignancies while Part B consists of expansion cohorts of approximately 
to subjects each in 
disease-restricted populations, with relatlimab administered as monotherapy at 
 mg flat dose.
Amendment 3 to Study CA224022, introduces: 1) Part C, 3+3+3 dose escalation design with 
relatlimab administered in combination with nivolumab in disease-restricted populations 2) Part 
D dose expansion cohorts of approximately 
to 
 subjects each to assess relatlimab and 
nivolumab effects in selected tumor types.
1.1.8.1
Rationale for Flat Dosing
Therapeutic monoclonal antibodies 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 monoclonal 
antibodies have demonstrated that body weight-based dosing did not always offer advantages over 
flat dosing in reducing exposure variability.54,55 Since the magnitude of the impact of body weight 
on the human PK of relatlimab 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.
Flat doses for this study have been normalized for an average 80-kg adult cancer patient. A dataset 
from a recent internal preliminary population pharmacokinetics (PPK) analysis for another 
immuno-oncology monoclonal antibody 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 
2,519 adult patients with rheumatoid arthritis, breast cancer, colorectal cancer, non-small cell lung 
cancer, ovarian cancer, and non-Hodgkin’s lymphoma.55
Additionally, relatlimab flat dose of 
to 
 mg as monotherapy and up to 
mg in 
combination with nivolumab (both given every 2 weeks [Q2W]) has been studied in across the 
40 to 120 kg weight range in adults. Relatlimab flat dose 
 mg administered Q2W in 
combination with nivolumab is currently under evaluation in this trial.
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1.1.8.2
Rationale for 
-minute Nivolumab Infusion
Long infusion times place a burden on subjects and treatment centers. Establishing that nivolumab 
can be safely administered using shorter infusion times of 
 minutes duration in subjects will 
diminish the burden provided no change in safety profile. Previous clinical studies show that 
nivolumab has been administered safely over 
 minutes at doses ranging up to 
mg/kg over 
long treatment duration. In Study CA209010, (a Phase 2, randomized, double blinded, 
dose-ranging study of nivolumab in subjects with advanced/metastatic clear cell RCC) a dose 
association was observed for infusion site reactions and hypersensitivity reactions (
 at 
mg/kg, 
 at 
mg/kg and 
 at 
 mg/kg). All the events were Grade 1-2 and were 
manageable. An infusion duration of 
 minutes for 
 mg and 
 flat doses of nivolumab 
(~ 60% of the dose provided at 
 mg/kg) are not expected to present safety concerns compared 
to the prior experience at 
 mg/kg nivolumab dose infused over a 
 minute duration.
1.1.8.3
Part A — Relatlimab Dose
The dose selected for this study is based on all available nonclinical data. There was no observed 
abnormal phenotype in the LAG-3 knockout mice and no pathological changes associated with 
relatlimab monotherapy administered to mice (
 g twice weekly x 4 weeks, approximately 
mg/kg). In vitro studies suggest that relatlimab does not induce cytokine release. No adverse 
effects were observed in the repeat-dose Good Laboratory Practice (GLP) cynomolgus monkey 
toxicity study at the highest administered dose, 
 mg/kg/week, which was considered the 
no-observed-adverse-effect level (NOAEL) and highest non-severely toxic dose (HNSTD). 
Simple allometry was used to project human PK parameters and to calculate the human equivalent 
dose (HED) for this NOAEL. With an added 10-fold safety factor, the maximum recommended 
starting dose (MRSD) based on the cynomolgus toxicology study is 
mg/kg (intravenous [IV] 
infusion, Q2W) in humans. However, relatlimab showed different binding affinity between 
cynomolgus and human LAG-3 in in vitro studies and this must be taken into account for the 
selection of the starting dose. Studies in a LAG-3transfected Chinese hamster ovary (CHO) 
model indicated the binding affinity of relatlimab for cynomolgus LAG-3 is approximately 
-fold 
weaker than that for human LAG-3. Additional data generated from activated human and 
cynomolgus T cells have indicated that the affinity difference could be as high as 
-fold; the 
HED with an affinity correction targeted to achieve 
 (the most conservative safety factor) of 
the AUC at the NOAEL in monkey is 
 mg/kg. This approach of linear adjustment for the 
highest observed affinity difference is considered conservative, as it is based on an NOAEL, and 
does not take into account potential nonlinearity in drug exposure at the resulting low dose levels. 
This approach assumed linear PK for extrapolation to low dose levels (ie, 
 mg/kg). However, 
the 2 mouse tumor efficacy studies of mouse anti-LAG-3 surrogate antibody (19C7) showed more 
than dose proportional exposure increases between  and 
 mg/kg in monotherapy and between 
 and mg/kg when 19C7 was co-administered with anti-PD-1, whereas the exposure of 19C7 
was dose-proportional at doses higher than 
 mg/kg. This nonlinear PK, presumably due to the 
target-mediated binding and/or disposition (TMDD), could be possible for relatlimab at lower 
doses in cancer patients. This would result in lower exposures than projected in the lowest dose 
cohorts.
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An antitumor study with the 19C7 anti-LAG-3 antibody (a surrogate antibody with similar binding 
affinity for murine LAG-3 as relatlimab to human LAG-3) in a Sa1N model (the most sensitive 
mouse model tested) showed dose-dependent efficacy. Modeling and simulations based on these 
data project that a human dose of 
 mg/kg has the potential to produce tumor growth inhibition 
(TGI) of 
 to 
 and a 
mg/kg dose has the potential to result in 
 to 
 TGI, 
depending on different tumor growth kinetics and tumor killing potency translation from mouse 
tumor model to the clinic. A 
 TGI in preclinical models at clinically relevant exposures has 
generally been shown to correlate with clinical efficacy.56
To balance the potential for pharmacologic activity and reasonable safety in this cancer patient 
population, a dose of 
 mg (
 mg/kg) was selected as the starting dose for Part A. This dose 
is less than 
 of the human equivalent of the NOAEL (
 mg; 
mg/kg) and is below the 
HED after a linear adjustment of the NOAEL target exposure for the highest affinity difference 
estimate of 
-fold (
 mg; 
 mg/kg). 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 
-mg (
 mg/kg) dose is 
-fold 
based on the NOAEL of 
 mg/kg/week in the 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 3.1.2. The top dose of 
 mg (
mg/kg) is projected to 
have the potential for 
 to 
 TGI from the most sensitive model in mouse. 
1.1.8.4
Part B — Relatlimab Dose
The 
 mg dose selected for this expansion phase is based on recent safety, PK and PD data 
obtained from subjects treated with relatlimab monotherapy in the CA224020 and CA224022 
studies in solid tumors and hematological malignancies, respectively. 
The treatment with relatlimab at doses between 
 and 
mg has been well tolerated and the
MTD has not yet been reached (see safety section in Section 1.4.1.4). The trough concentration at 
 hours after first dose of 
 mg relatlimab was ~ 
 g/mL, which is a concentration that 
induces 
 in the presence of 
 in vitro57. Furthermore, available 
data from subjects treated with
 and 
 mg relatlimab showed receptor occupancy of 
 and 
, respectively. Finally, tumor growth inhibition in the mouse 
tumor model was 
% 
and 
 at days 
, respectively, when animals were treated with a dose of an anti-LAG-3 
antibody equivalent to the 
 mg tested in humans (ie,
mg/kg). So, it is anticipated that a dose 
of 
 mg in expansion cohorts will be a well-tolerated dose achieving adequate receptor 
occupancy and active plasma concentrations.
1.1.8.5
Part C - Dose Escalation - Combination of Relatlimab and Nivolumab 
In Part C, dose escalation combination, three dose escalation cohorts will be evaluated, starting
with nivolumab administered at a dose of 
 mg followed by infusion of relatlimab at the dose 
of 
 mg. 
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The starting doses for Part C were selected based on all nonclinical data available from studies of 
the combination and relatlimab monotherapy and on emerging clinical safety and pharmacokinetic 
data from Study CA224020 where relatlimab was administered in combination with nivolumab in 
subjects with advanced solid tumors.
In the repeated dose GLP toxicology study, a dose of 
 mg/kg/week of relatlimab + 
mg/kg/week nivolumab was considered the severely toxic dose in 
 of the animals (STD
; 
refer to Section 1.4.1.2).
The preliminary PK of relatlimab is approximately dose proportional at dose range of 
 to 
mg. The PK of relatlimab and nivolumab do not appear to alter when given in combination 
(refer to Section 1.4.1.4). 
The combination of relatlimab and nivolumab is currently tested in patients with advanced solid 
tumors in the clinical Study CA224020. Preliminary data analysis was performed on 
patients 
treated in combination therapy, on CA224020 as of 
. 
 patients received 
mg 
relatlimab and 
 mg nivolumab,  patients were treated with 
 mg relatlimab and 
 mg 
nivolumab and 
 patients received 
 mg relatlimab and 
mg nivolumab. 
In cohort #1, 
subjects with advanced solid tumors were treated with 
 mg relatlimab and 
mg nivolumab. One patient with
 cancer experienced an AE of Grade 3 mucosal 
inflammation
 days after the first administration of the treatment, which was considered a DLT. 
As a result, the cohort was expanded to  subjects, and  additional subjects were enrolled. 
However, 
 additional subject with
 cancer discontinued study drug due to disease 
progression prior to completion of the DLT period, and it was necessary to replace her with an 
additional subject (  subjects total).
out of  evaluable patients treated with 
 mg relatlimab
and 
 mg nivolumab were able to complete the DLT period without any relevant AE. 
Nine patients were treated in cohort #2 (
 mg relatlimab/
 mg nivolumab). Study drug was 
discontinued in one subject with 
 cancer due to a DLT of Grade 4 ventricular fibrillation.
The cohort was subsequently expanded to 
subjects. However, study drug was discontinued in 
subjects (one with 
 cancer and the other with 
 tumor) due to 
disease progression prior to completion of the DLT period. 
out of 
evaluable patients 
treated with 
 mg relatlimab/
 mg nivolumab were able to complete the DLT period without 
any relevant AE.
Preliminary analysis from the 
 subjects dosed with the combination of 
 mg relatlimab and 
 mg nivolumab in cohort #3 is summarized. One subject with thyroid cancer developed an 
asymptomatic Grade 4 lipase elevation that was a protocol defined DLT (day + 29 post first dose) 
requiring the patient to discontinue treatment. The lipase level decreased to normal within 
hours 
and the patient remained asymptomatic. The cohort was thus expanded to 
subjects. Study drug 
was discontinued in  subjects (
 with 
 cancer and the other with
 
cancer) due to disease progression prior to completion of the DLT period, so these subjects were 
replaced.
 subjects have completed the DLT period and continued on treatment. No subject in 
this cohort has experienced a clinically significant Grade 3 or higher drug related adverse event.
Given that only  out of  DLT evaluable subjects experienced a protocol defined DLT the dose 
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of 
 mg relatlimab combined with 
 mg nivolumab is deemed safe and escalation to a dose of 
 mg relatlimab and 
 mg nivolumab is commencing.
As mentioned previously, a dose of 
 mg/kg/week of relatlimab + 
 mg/kg/week nivolumab 
was considered the 
. Known human nivolumab PK parameters were used to calculate the 
HED. The same approach to identifying human equivalent doses as described for monotherapy 
was used. With an added 
-fold safety factor, the MRSD based on the 
 is 
 mg/kg in 
humans. The starting nivolumab dose for subjects in Part B is 
 mg (
mg/kg), which is the 
flat dose equivalent of the dose selected for the global Phase 3 program (
 mg/kg) which has been 
well tolerated in monotherapy.14
Taken together, pre-clinical and the preliminary safety data suggest that 
 mg relatlimab in 
combination with 
 mg nivolumab is safe and well tolerated dose in patients with advanced 
malignancies. Therefore, the proposed starting dose for Part C is 
 mg (
 mg/kg) relatlimab in 
combination with 
 mg nivolumab (
 mg/kg) is not expected to be toxic. At no point will the 
dose of relatlimab administered in combination with nivolumab (Part C) exceed doses of relatlimab
that have been demonstrated previously to be safe on the monotherapy dose escalation/expansion
arms (Part A and B). 
In Part C, the sequential infusion of both drugs will start with nivolumab administration first 
followed by infusion of relatlimab. 
1.1.8.6
Part D - Dose Expansion - Combination of Relatlimab and Nivolumab 
In Part D, cohort expansion, relatlimab and nivolumab will be administered at the combination 
doses selected for Part C, and may represent the maximum tolerated dose (MTD), maximum 
administered dose (MAD), or an alternative dose selected from dose escalation Part C. The selected 
dose may not exceed the MTD/MAD established in Part C. Study therapy will be administered 
with infusion of nivolumab first followed by relatlimab administration.
1.2
Research Hypothesis
It is anticipated that antiLAG-3 antibody (relatlimab), administered as monotherapy or in 
combination with nivolumab, will demonstrate adequate safety and tolerability, as well as a 
favorable risk/benefit profile, to support further clinical testing. No prospective hypotheses are 
being formally evaluated.
1.3
Objectives(s)
1.3.1
Primary Objectives

The primary objective is to characterize the safety, tolerability, dose-limiting toxicities (DLTs),
and maximum tolerated dose (MTD) of relatlimab administered alone or in combination with 
nivolumab to subjects with relapsed or refractory B-cell malignancies.

The co-primary objective in combination therapy expansion Part D is to investigate the
preliminary efficacy of relatlimab in combination with nivolumab in subjects with relapsed or
refractory Hodgkin lymphoma (HL), and relapsed or refractory Diffused Large B Cell 
lymphoma (DLBCL). Tumor response will be evaluated according to the revised International 
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Working Group (IWG) criteria for Malignant Lymphoma (2007 IWG criteria); see 
Appendix 1.
1.3.2
Secondary Objectives
The secondary objectives are:

To characterize the pharmacokinetics (PK) of relatlimab administered as monotherapy or in 
combination with nivolumab.

To characterize the immunogenicity of relatlimab administered as monotherapy or in 
combination with nivolumab.
1.3.3
Exploratory Objectives
Exploratory objectives are:


To characterize pharmacokinetics and immunogenicity of nivolumab in combination with 
relatlimab.

To evaluate the pharmacodynamic activity of relatlimab in the peripheral blood and tumor 
tissue as measured by, but not limited to, flow cytometry, immunohistochemistry, soluble 
factor analysis, and gene expression (eg, microarray technology and/or quantitative reverse 
transcription polymerase chain reaction [RT-PCR] and/or ribonucleic acid sequencing
[RNAseq]).

To investigate the association between biomarkers in the peripheral blood and tumor tissue, 
such as 
 expression, lymphocyte infiltration, neoantigen status, inflammatory gene 
signatures, with safety and efficacy following treatment with relatlimab administered as 
monotherapy and in combination with nivolumab.

To determine the receptor occupancy of 
 in the peripheral blood and bone marrow.

To explore the preliminary antitumor activity of relatlimab administered as monotherapy in 
subjects with relapsed or refractory B-cell malignancies.

To characterize T-cell function in response to relatlimab administered as monotherapy or in 
combination with nivolumab.

To explore exposure-response relationships in subjects treated with relatlimab as monotherapy 
and in combination with nivolumab.

To assess the overall survival (OS) rates and progression-free survival (PFS) rates at various 
time points in HL and DLBCL patients in Part D. PFS will be assessed based on IWG (2007) 
criteria and the Lugano (2014) criteria.

To evaluate tumor metabolic response per Lugano 2014 criteria using Deauville scoring
(Appendix 7) in NHL and HL patients in Part D.
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1.4
Product Development Background
Information for nivolumab (BMS-936558, anti-PD-1 antibody) and relatlimab (BMS-986016, 
anti-LAG-3 antibody) is provided in the sections below; additional details are provided in 
respective Investigator Brochures (IBs).14,58
1.4.1
Relatlimab (BMS-986016, Anti-LAG-3 Antibody)
1.4.1.1
Non-Clinical Pharmacology
The ability of relatlimab 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. Relatlimab binds to human LAG-3 with high affinity (Kd, 
 nM), and 
inhibits the binding of LAG-3 to cells expressing its ligand, MHC class II (IC50, 
 nM). 
Relatlimab binds to cynomolgus LAG-3 on transfected CHO cells and on activated cynomolgus 
T cells with a lower affinity (EC50, 
nM) than to activated human T cells. A high 
concentration of relatlimab, in the absence of secondary co-stimulation, 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 T cells. Relatlimab
promotes the activation of an antigen-specific mouse T-cell hybridoma expressing human LAG-3 
in co-culture with an MHC class II-positive antigen-presenting cell. In addition, relatlimab
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 relatlimab IB.58
1.4.1.2
Toxicity
The nonclinical toxicology package for relatlimab consists of the following studies: 
1) Four-Week Intermittent (QW) Intravenous Exploratory Combination Pharmacodynamic and 
Toxicity Study in Cynomolgus Monkeys with 
 Antibody (a precursor of the 
 antibody) and Nivolumab.
2) GLP-Compliant Four-Week Intravenous Combination Toxicity Study in Cynomolgus 
Monkeys with a 6-Week Recovery with Relatlimab and Nivolumab.
The key results were as follows:  

Single-agent relatlimab administered at up to 100 mg/kg/week did not result in adverse 
changes. 

Combined administration of relatlimab and nivolumab (
/kg/week, 
respectively) resulted in morbidity of  male out of  monkeys on study Day 
 From 
Days 
 to 
 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 
days of veterinary care and antibiotic treatment, this animal did not show any 
improvement and was euthanized on Day
 for poor clinical condition. There were no 
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remarkable gross necropsy findings. Histopathological findings in this monkey included: 
slight lymphoplasmacytic inflammation of the choroid plexus; minimal to moderate 
lymphohistocytic inflammation of the vasculature of the brain parenchyma, meninges, 
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 relatlimab and 
nivolumab (
 mg/kg/week, respectively) were limited to minimal to slight 
non-reversible lymphoplasmacytic inflammation of the choroid plexus in the brain in  of 
 remaining monkeys, and minimal lymphohistiocytic inflammation of the vasculature of 
the brain parenchyma in  of  remaining monkeys, whose reversibility could not be 
assessed.

NOAEL for single-agent relatlimab was considered to be 
 mg/kg/week (mean 
AUC[0-168h] = 
 gh/mL); NOAEL for single-agent nivolumab was considered 
to be 
mg/kg/week (mean AUC[0-168h] = 
 gh/mL); NOAEL for combination 
of relatlimab and nivolumab was not determined. 

However, the combination therapy was generally well tolerated and clinical signs of 
toxicity were observed in only 
 of 
 monkeys (approximately 
). Therefore, 
mg/kg/week 
relatlimab/nivolumab 
(mean 
relatlimab
AUC[0-168h] =
μgh/mL; mean nivolumab AUC[0-168h] = 
 μgh/mL) 
was considered the 
.

The doses administered (
 mg/kg relatlimab and 
 mg/kg nivolumab) are 
times 
higher than the maximum doses proposed for the current study.
3) GLP-Compliant Tissue Cross Reactivity Study in Human and Select Cynomolgus Monkey 
Tissues with Relatlimab. 

Positive staining with relatlimab-FITC was observed in the plasma membrane or plasma 
membrane granules of mononuclear leukocytes of most human tissues, including lymphoid 
tissues and hematopoetic cells of the bone marrow. In addition, staining with relatlimab-
FITC was observed in the cytoplasm of the human pituitary endocrine cell epithelium. 
Although relatlimab 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. 

In Vitro Cytokine Release and Lymphocyte Activation Assessment with Relatlimab using 
Human Peripheral Blood Mononuclear Cells. 

Relatlimab did not induce cytokine release when presented to human PBMCs 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 
 or were generally 
overlapping with cytokine levels from PBMCs incubated with negative controls (
 
). 

Consistent with the lack of cytokine release, there was no evidence that relatlimab induced 
 activation, as measured by surface expression of 
 and 
. Expression 
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levels of these markers on 
 cells following stimulation with relatlimab were 
similar to those observed upon stimulation with negative controls. 

Overall, these data indicate that relatlimab does not possess agonistic potential to induce 
either 
 cellular activation or cytokine release.
Refer to the relatlimab IB,58 for additional information regarding the nonclinical toxicity of 
relatlimab.
1.4.1.3
Nonclinical Metabolism and Pharmacokinetics
In accordance with regulatory guidelines for biotechnology-derived pharmaceuticals, 59 no 
metabolism studies with relatlimab have been conducted in animals. The expected in vivo 
degradation of monoclonal antibodies (mAbs) is to small peptides and amino acids via biochemical 
pathways that are independent of cytochrome P450 enzymes.
Relatlimab demonstrated favorable PK properties in cynomolgus monkeys. From both single-dose 
and repeat-dose IV PK studies, relatlimab decayed bi-exponentially and the exposure was 
approximately dose-proportional. The systemic clearance (CLTp) ranges from 
to 
mL/h/kg and a terminal half-life (T-HALF) 
 to 
 hours. The volume of distribution at 
steady state (Vss) was 
 to 
 mL/kg, suggesting limited distribution outside the plasma. 
Antirelatlimab antibodies were detected in some monkeys but the presence of antirelatlimab
antibodies appeared to have no impact on relatlimab exposure.
1.4.1.4
Clinical Pharmacology
An interim determination of relatlimab multiple dose PK was carried out using all available serum 
concentration data from Studies CA224020 and CA224022. Noncompartmental analysis was 
performed using concentration time data after the first dose (Cycle 1) and ninth dose (Cycle 3). In 
general, the Cmax and AUC(TAU) values over the first dosing interval increased approximately 
proportional to the increment in the relatlimab dose. Relatlimab accumulation from the first to 
ninth doses was around 
to 
fold for AUC(TAU) and 
to 
fold for Cmax. Relatlimab
effective half-life was estimated to be approximately
 to 
 days. The PK of relatlimab and 
nivolumab was not altered when given in combination.
Relatlimab population PK was best described by a 2-compartment model with parallel linear and 
non-linear CL. The linear portion represents the FcRn-mediated CL, and non-linear component 
represents target-mediated CL. The linear CL was 
 L/day, and the volume of distribution in 
the central compartment (VC) was 
 L. The Vmax was 
 mg/day, and the concentration that 
achieved 
 of Vmax (Km) was 
 g/mL.
Currently available data suggest that relatlimab monotherapy exhibits a low level of 
immunogenicity, with  out of 
 subjects having at least 1 post-baseline positive ADA samples. 
There are limited data available in combination cohort to make inference on immunogenicity rate.
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1.4.1.5
Clinical Safety-Monotherapy (Part A and Part B) and Combination 
Therapy (Part C and D) in CA224022
A total of 
 subjects have been evaluated in Study CA224022 as of the clinical data cutoff date
of 
 (
 subjects received relatlimab as monotherapy, and
 subjects received 
relatlimab in combination with nivolumab). In Part A, monotherapy dose escalation, 
 subjects 
with hematological malignancies were treated with relatlimab at 
 mg Q2W (  subjects), 
 mg 
Q2W (  subjects), 
 mg Q2W (  subjects), and 
 mg Q2W (6 subjects). 
 subjects were 
treated in Part B monotherapy dose expansion with 
 mg relatlimab Q2W.58
Of the 
 subjects treated with relatlimab monotherapy, 
 subjects experienced at least 
1 AE. The most commonly reported AEs (
of subjects) were fatigue (
 subjects); 
back pain (
 subjects); constipation and diarrhea (
 subjects each); nausea 
(
 subjects); malignant neoplasm progression (
 subjects); abdominal pain, 
cough, decreased appetite, headache, pain in extremity, upper respiratory tract infection, infusion-
related reaction and urinary tract infection (5
 subjects each); and acute kidney injury, 
anemia, dyspnea, myalgia, night sweats, peripheral edema, oropharyngeal pain, productive cough, 
rash, and weight decreased (
 subjects each).58
Drug-related AEs were reported in 
 subjects, with the most commonly reported (
 
of subjects) being fatigue (
subjects); headache and rash (
subjects each); and 
infusion-related reaction (
subjects). Most drug-related AEs were Grade 1 or 2. Grade 3 
to 4 drug-related AEs were anemia, amylase increased, lipase increased, and aseptic meningitis 
(
 each).58
The MTD for monotherapy was not reached at the tested doses up to a flat dose of 
 mg 
relatlimab Q2W.58
Of the 
 subjects treated with relatlimab and nivolumab Q2W (Part C, 
 mg relatlimab/
 mg 
nivolumab Q2W [  subjects], Part C 
 mg relatlimab/
 mg nivolumab Q2W [  subjects], 
Part C 
 mg relatlimab/
 nivolumab Q2W [  subject], and Part D, 
 mg relatlimab/
 mg 
nivolumab Q2W [
 subjects]), 
 subjects experienced at least 1 event. The most 
commonly reported AEs (
 of subjects) was fatigue (
 subjects). The reported AEs 
in at least 
 of subjects during combination therapy in Study CA224022 are summarized in the 
IB.58
Drug-related AEs were reported in 
 subjects, with the most commonly reported (
 
of subjects) being fatigue (
 subjects). Grade 3 or 4 drug-related AEs were increased 
ALT, increased AST, oesophageal spasm, generalized rash, lipase increased, transaminases 
increased, 
hypoalbuminaemia, 
adrenal 
insufficiency, 
neutropenia, 
lymphopenia, 
thrombocytopenia, autoimmune encephalitis, autoimmune hepatitis, hepatotoxicity, autoimmune 
disorder, headache and pneumonitis (
 each).58
Please refer to relatlimab IB for further details.58
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1.4.1.6
Serious Adverse Events
At least  SAE, regardless of causality, has been reported in 
 of the 
 subjects treated 
with relatlimab monotherapy in Study CA224022. The most commonly reported SAEs (
 of 
subjects) were malignant neoplasm progression (
 subjects), acute kidney injury (
 
subjects), and dehydration (
 subjects). 
 Grade 3 drug-related SAE of aseptic 
meningitis was reported.58
At least  SAE, regardless of causality, has been reported in 
subjects treated 
with relatlimab and nivolumab. The reported SAEs occurring in  or more subjects were malignant 
neoplasm progression (
 subjects); dyspnoea (
 subjects); and hypoxia, muscular 
weakness,adrenal insufficiency, neutropenia, and thrombocytopenia (
 subjects each).58
Drug-related SAEs were reported in  of the 
 subjects treated with relatlimab and 
nivolumab. These included Grade 3 to 4 events of esophageal spasm, neutropenia, pneumonitis, 
thrombocytopenia, adrenal insufficiency, autoimmune hepatitis, autoimmune encephalitis and 
transaminases increased (
 each).58
One of the drug-related SAEs (pancreatitis) led to discontinuation during the Part C dose escalation 
 Q2W. The remaining drug-related SAEs were Grade 3 adrenal insufficiency and Grade 3 
autoimmune hepatitis (
 Q2W) in Part D dose expansion phase.58
1.4.1.7
Infusion Reactions
In Study CA224022,  subjects were reported with infusion-related reactions during relatlimab 
monotherapy. 
 Grade 1 or Grade 2 infusion-related reactions were reported following 
administration of relatlimab. 
 subject experienced an infusion reaction after administration of 
rituximab, 
 days after the last infusion of relatlimab. Another subject experienced an infusion 
reaction after administration of daratumumab, 
 days after the last infusion of relatlimab.58
 infusion-related reactions, all Grade 3 or less were reported during combination therapy and 
were considered related to study drug.58
1.4.1.8
Adverse Events Leading to Discontinuation
In Study CA224022, there were no AEs leading to study drug discontinuation during relatlimab 
monotherapy.58
As of 
,  AEs leading to discontinuation were reported during combination therapy. 
 AEs were considered by the investigator to be related to study drug. These were Grade 3 
autoimmune hepatitis, Grade 3 adrenal insufficiency, Grade 2 immune-mediated enterocolitis and 
a Grade 2 pancreatitis.58
1.4.1.9
Deaths
 of 
 subjects treated with relatlimab monotherapy died. 
 death was reported 
within 
 days of last dose of study drug. All deaths in subjects treated with relatlimab 
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monotherapy in Study CA224022 were considered to be due to disease progression and were 
considered by the investigators to be not related to the study drug.58
Of the 
 subjects treated with relatlimab and nivolumab in combination therapy, 
 
subjects died (  deaths were reported within 
 days of last dose of study drug). All deaths were 
considered to be due to disease progression and were not considered by the investigator to be 
related to study drug.58
1.5
Clinical Safety - Monotherapy (Part A and A1) and Relatlimab in 
Combination with Nivolumab Therapy (Parts B, C, and D) in Solid
Tumor Study CA224020
1.5.1
Adverse Events
As of the clinical data cutoff date of 
, 
 subjects have been treated in Study 
CA224020 (
 in monotherapy and 
 in combination therapy). A total of 
 subjects in Part C 
and 
 subjects in Part D (which included 
 subjects in the fixed dose combination [FDC; 
relatlimab plus nivolumab at a 
 ratio] cohort) have been treated with the combination of 
relatlimab and nivolumab.58
Relatlimab monotherapy has had an acceptable safety profile at all tested doses in Parts A and A1 
(
and 
 mg, flat dose). Of the 
 subjects treated with relatlimab monotherapy, 
 subjects experienced at least  event. The most commonly reported AEs (
 of 
subjects) were malignant neoplasm progression 
; fatigue 
; decreased appetite and 
nausea (
 each); back pain 
; dizziness and pyrexia (
 each); and anemia, cough, 
and vomiting (
 each).58
Drug-related AEs were reported in 
 subjects, with the most commonly reported (
 
of subjects) being fatigue 
; decreased appetite 
; and arthralgia, cough, dry mouth, 
headache, lipase increased, maculo-papular rash, myalgia, nausea, pneumonitis, pruritus, and rash 
(
each). Most drug-related AEs were Grade 1 or 2. Grade 3 drug-related AEs were lipase 
increased 
, maculo-papular rash, pneumonitis, and drug hypersensitivity (
 each).58
The MTD for monotherapy was not reached at the tested doses up to a flat dose of 
 mg 
relatlimab Q2W.58
The all-combination group of study CA224020 includes 
 subjects treated with relatlimab and 
nivolumab. The all-combination group includes Parts B + C + D: Part B (
 subjects), Part C 
(
subjects) and Part D (
 subjects, including 
 in the FDC cohort). Based on an analysis of 
adverse events in the all-combination group, 
 subjects experienced at least  event. 
The most frequently reported AEs (
) were malignant neoplasm progression (
), fatigue 
(
), nausea (
), diarrhea (
), anaemia (
), decreased appetite (
), asthenia 
(
), constipation (
), pyrexia (
), arthralgia (
), pruritus (
), vomiting 
(
), cough (
), dysponea (
), back pain (
) and abdominal pain (
).58
Drug-related AEs were reported in 
 subjects, with the most commonly reported (
 
of subjects) being fatigue (
), pruritus (
), diarrhea (
), asthenia (
), rash (
), 
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nausea (
), arthralgia (
), and hypothyroidism (
). Grade 3 drug-related AEs were 
reported in 
 subjects, Grade 4 in 
 subjects, and Grade 5 in 
. 
Grade 3 to 4 drug-related AEs were reported in at least 
 subjects included increased 
lipase (
), colitis, increased amylase 
 each), increased ALT (
), pneumonitis (
), 
diarrhoea (
), increased AST (
), autoimmune hepatitis (
), myocarditis, type 1 
diabetes mellitus, gastritis, maculo-papular rash, hypophysitis, hepatitis, anaemia, asthenia, fatigue 
and mucosal inflammation (
each).58
Part D included all advanced melanoma subjects but different subgroups with different doses and 
schedules of administration. A separate analysis of the adverse events in Part D is reported in the 
relatlimab IB.58
1.5.2
Serious Adverse Events
At least 1 SAE, regardless of causality, has been reported in 
 subjects treated with 
relatlimab monotherapy. The most commonly reported SAEs (
 of subjects) were malignant 
neoplasm progression 
 and diarrhea, pneumonitis, and spinal cord 
compression (
 subjects each). There were  reported drug-related SAEs in monotherapy: 
pneumonitis, (Grade 2, Grade 3) and Grade 3 allergic reaction; all of which were reported in 
monotherapy dose cohort of 
 mg relatlimab Q2W. All events resolved.58
At least 1 SAE, regardless of causality, has been reported in 
 of the 
 subjects 
treated with relatlimab and nivolumab in Parts B, C, and D. The most frequently-reported SAE 
was malignant neoplasm progression 
. All other SAEs occurred at a 
frequency of 
.58
Drug-related SAEs were reported in 
 subjects treated with relatlimab and 
nivolumab in Parts B, C, and D. Grade 3 to 4 drug-related SAEs occurring in  or more subjects 
included pneumonitis, colitis, myocarditis, aspartate aminotransferase increase, autoimmune 
hepatitis, diarrhoea, gastritis, hypophysitis, lipase increased, and type 1 diabetes mellitus. All 
SAEs, (all at a dose level of 
 mg relatlimab/
 mg nivolumab Q2W), were reversible and 
manageable by withholding study drug administration providing standard medical care, and/or 
following immune-related AE algorithms.58
1.5.3
Infusion Reactions
In Part A, 1 Grade 2 infusion-related reaction has been reported in a subject with 
 cancer 
treated at 
 mg relatlimab Q2W. There was also 1 Grade 3 allergic reaction following 
administration of 
 mg relatlimab Q2W.All events were manageable per updated protocol 
guidelines without need for subsequent treatment discontinuation.58
In combination therapy (Parts B, C, and D), 
 Grade 1 and 
 Grade 2 infusion-related reactions 
were reported. There were 
 Grade 3 or higher infusion reactions reported. The overall frequency 
 observed in Study CA224020 is similar to nivolumab monotherapy. In patients receiving
nivolumab as a 
-minute intravenous infusion, infusion-related reactions occurred in 
 
 of patients. All events were manageable per updated protocol guidelines, and only 
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subjects required discontinuation, in each case due to recurrent Grade 2 infusion related 
reactions.58
1.5.4
Adverse Events Leading to Discontinuation
At least  AE leading to discontinuation has been reported in 
 subjects 
 treated with 
 (Parts A and A1). The AEs leading to discontinuation were Grade 5 malignant 
neoplasm progression (not drug related), Grade 3 allergic reaction (drug related), pneumonitis and 
wheezing (drug related), and Grade 1 abdominal pain and ascites (not drug related). At least 
1 drug-related AE leading to discontinuation has been reported in 
 subjects 
. The
other drug-related AEs leading to discontinuation were due to allergic reaction.58
At least  AE leading to discontinuation has been reported in 
 subjects treated 
with 
 therapy. At least  drug-related AE leading to discontinuation has been reported 
in 
 subjects. The drug-related AEs leading to discontinuation included colitis 
( subjects); myocarditis and diarrhoea (  subjects each); and gastritis, immune-mediated 
hepatitis, AST increased, and pneumonitis (  subjects each) and pancreatitis, mucosal 
inflammation, systemic inflammatory response syndrome, autoimmune hepatitis, ALT increased, 
lipase increased, rash maculo-papular, meningitis aseptic, infusion-related reaction ( subjects 
each).58
1.5.5
Deaths
Out of 
 subjects treated with relatlimab monotherapy in study CA224020, 
 subjects 
died. 
 death was reported within 
 days of last dose. Five deaths were reported after 
 days 
of last dose. Of the 
 subjects that died within 
 days of last dose, 
 deaths were because of 
disease progression, while for  subject the cause of death was unknown. All deaths were 
considered by the investigator to be not related to study drug. In the database,  malignant 
neoplasm progression events with an outcome of death had a CTC Grade 3 or 4.58
Out of 
 subjects treated with relatlimab and nivolumab in combination therapy, 
 
subjects had died. Of these deaths, 
 occurred within 
 days of last dose. Causes of death were 
reported as disease progression in 
 subjects, study drug toxicity (Grade 5 dyspnea, Grade 4 
myocarditis, and Grade 3 pneumonitis) in  subjects, unknown in 
 subject, and classified as 
“Other” in 
 subjects.58
1.6
Clinical Efficacy - Studies CA224020 and CA224022
As of the cutoff date of 
 for Study CA224020, in subjects treated with relatlimab
, partial, transient response was seen in 1 subject with 
 
. As of the cutoff date of 
 for Study CA224022, in subjects treated with 
relatlimab monotherapy, partial response was seen in 1 subject with 
 
; complete response was seen in 1 subject with 
; and stable 
disease was observed in  subjects with 
 and  subject with 
.58
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Relatlimab in combination with nivolumab has shown the capacity to induce responses in 
previously heavily treated advanced solid tumors, with the added ability to trigger responses in
tumors that have demonstrated resistance to nivolumab therapy. As of the cutoff date of
 for Part B of Study CA224020, in subjects treated with relatlimab and nivolumab
combination therapy, partial responses were seen in subjects with 
. In subjects treated with
relatlimab and nivolumab combination therapy in Part C of Study CA224020, the overall objective
response rate (ORR) was 
, response evaluable) with a disease control rate of 
. As
of the cutoff date of 
 for Study CA224022 in subjects treated with relatlimab and
nivolumab combination therapy, partial responses have been seen in
subjects with
 with stable disease observed in  subject for  months
(and treatment was continuing).58
1.7
Nivolumab (BMS-936558, Anti-PD-1 Antibody)
1.7.1
Nonclinical Pharmacology
Nivolumab is a fully human, IgG4 (kappa) isotype monoclonal antibody that binds to PD-1 with 
nanomolar affinity (Kd, 
nM) and a high degree of specificity, thus precluding binding to its 
. Nivolumab does not bind to other related family members, such as 
. Nonclinical testing of nivolumab demonstrated that binding to 
 results in enhanced 
 and release of 
 in 
vitro. Additional details are provided in the current version of the nivolumab IB.14
1.7.2
Toxicity
Toxicology studies in cynomolgus monkeys revealed that nivolumab was well tolerated at doses 
up to 
 mg/kg given twice weekly for 
 doses. Drug-related findings were limited to a reversible 
decrease in triiodothyronine (T3) by 
, without concomitant abnormalities in other markers of
thyroid function. Additional details are provided in the current version of the nivolumab IB.14
Preliminary new nonclinical safety findings of adverse pregnancy outcomes and infant losses in 
the absence of overt maternal toxicity have been reported.60 The findings of increased late-stage 
pregnancy loss and early infant deaths/euthanasia in nivolumab-exposed pregnant monkeys 
suggest a potential risk to human pregnancy if there is continued treatment with nivolumab during 
pregnancy.
1.7.3
Nonclinical Metabolism and Pharmacokinetics
Please see the nivolumab IB for current data.14
1.7.3.1
Clinical Pharmacology
Clinical Pharmacology Single dose pharmacokinetics (PK) of nivolumab was evaluated in subjects 
with multiple tumor types in CA209001, whereas multiple dose PK is being evaluated in subjects 
in CA209003. In addition, a preliminary population pharmacokinetic (PPK) model has been 
developed with data from 
 subjects from CA209001, CA209002, and CA209003.
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Single dose PK of nivolumab was evaluated in 
 subjects with multiple tumor types in Study 
CA209001 in the dose range of 
 mg/kg. The median Tmax across single doses ranged 
from 
 hours with individual values ranging from 
 hours. Geometric mean Cmax and 
AUC(INF) of nivolumab administered at dosages of 
 mg/kg,  mg/kg,  mg/kg, and
mg/kg 
demonstrated approximate dose proportionality. Geometric mean clearance (CL), after a single 
intravenous (IV) dose, ranged from 
 to 
 mL/h/kg, while mean volume of distribution 
during the terminal phase (Vz) varied between 
 to 
 mL/kg across doses. There was moderate 
variability in PK parameters among subjects, with coefficient of variation (CV) of 
 in 
Cmax, 
 in AUC(INF), 
 in clearance, and 
 in Vz. The mean 
terminal elimination half-life of nivolumab is 
 days, which is consistent with half-life of 
endogenous IgG4, indicating that the elimination mechanism or nivolumab may be similar to IgG4.  
Both elimination and distribution of nivolumab appear to be independent of dose in the dose range 
studied. Additional details are provided in the nivolumab IB.14
A preliminary PPK model was developed by nonlinear mixed effect modeling using data from 
subjects from CA209001, CA209002 and CA209003. Clearance (CL) of nivolumab is 
independent of dose in the dose range (
 mg/kg) and tumor types studied. The body weight 
normalized dosing produces approximately constant trough concentrations over a wide range of 
body weights, and hence is appropriate for future clinical trials of nivolumab.
1.7.3.2
Clinical Safety and Activity
Nivolumab has been studied in approximately 
subjects and is widely approved in multiple 
indications. Extensive details on the safety profile of nivolumab are available in the IB,14 and will 
not be repeated herein.
Overall, the safety profile of nivolumab monotherapy as well as combination therapy is 
manageable and generally consistent across completed and ongoing clinical trials with no MTD 
reached at any dose tested up to 
 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively 
few related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level.
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 4. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed 
in these algorithms. For additional material, see the nivolumab IB.14
The safety of nivolumab in combination with other therapeutics is being explored in several 
ongoing clinical trials. The most advanced combination under development is nivolumab and 
ipilimumab in subjects with 
 Thus far, the combination of both agents results in a safety 
profile with similar types of AEs as either agent alone, but in some cases, with a greater frequency 
and a higher rate of Grade 3 and 4 AEs than either ipilimumab or nivolumab alone. The safety 
profile of nivolumab + ipilimumab combination therapy was consistent with the mechanisms of 
action of nivolumab and ipilimumab. A dose of  mg/kg n
 mg/kg ipilimumab exceeded 
the MTD, and both  mg/kg 
 mg/kg ipilimumab and  mg/kg 
 mg/kg 
ipilimumab were identified as the MTD. For nivolumab monotherapy and combination therapy, 
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most high grade events were manageable with use of corticosteroids or hormone replacement 
therapy (endocrinopathies) as instructed in the management guidelines provided in this protocol
(Section 3.4.4 )
Nivolumab has demonstrated clinical activity as monotherapy in subjects with a variety of 
malignancies including 
 
 
.
Nivolumab is currently indicated for the treatment of patients with unresectable or metastatic 
melanoma as both monotherapy and in combination with ipilimumab. Nivolumab is also approved 
for non-small cell lung cancer following failure on or after platinum based therapy, as well as for 
advanced renal cell carcinoma following treatment with an anti-angiogenic therapy
Nivolumab has demonstrated clinical activity in a completed Phase 1 study in subjects with 
advanced Hodgkin’s lymphomas (n=23). The response rate was 87%, with complete responses 
documented in 4 patients (17%) and partial response observed in 16 patients (70%). The safety 
profile was consistent with prior clinical trials. Serious AEs were documented in 12 patients (53%). 
Drug related grade 3 AEs were reported in 5 patients (22%), and no grade 4 or 5 drug related 
adverse events have been observed61.
1.8
Overall Risk/Benefit Assessment
Subjects who have advanced hematological malignancies have poor prognosis and few curative 
options.
Administration of relatlimab in pre-clinical models, was able to significant improve anti-tumor 
responses and increase survival in aggressive lymphoma models (see Section 1.1.6). Thus 
administration of relatlimab is considered a promising strategy to improve anti-tumor activity in 
patients affected by advanced hematological malignancies.
Nivolumab has demonstrated clinical activity in subjects with advanced HL, NSCLC, RCC, 
melanoma, and other tumors. Treatment related adverse events (AEs) include those associated with 
autoimmune activation, such as pneumonitis, thyroiditis, hepatitis, nephrotoxicity, adrenal 
insufficiency, and less commonly neurotoxicity and myocarditis. Risk/benefit will be discussed in 
this section based on adverse events observed in both CA224022 and CA224020, a clinical trial 
evaluating the combination of relatlimab and nivolumab in subjects with solid tumors.
In the nonclinical GLP toxicology study, lymphoplasmacytic infiltration in the choroid plexus (and 
spinal cord) was reported at the highest doses of antiPD-1 antibody 
 animals) and the 
antiLAG-3 + antiPD-1 antibody combination (
). Importantly, these findings were not 
reported with anti-LAG-3 antibody alone (either the 
 mg/kg or 
 mg/kg [highest] dose). These 
include nonspecific histopathology changes, without clinical manifestations in all but one of the 
animals treated with combination therapy, which have been observed in other studies with 
antibodies and small molecules in monkeys. Three subjects across both clinical trials, have 
experienced treatment related and immune mediated aseptic meningitis that have responded to 
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immunosuppressive therapy. Vigilance regarding the communication and evaluation of potential 
neurologic toxicity remains an ongoing priority.
Therapy with relatlimab and nivolumab is investigational and it is possible that a higher incidence 
of immune mediated-adverse events may occur with the combination of 2 antibodies targeting 
T cells. The immune-related Grade 4 myocarditis event, observed in the CA224020 study, 
prompted closer monitoring of subjects with ECGs and troponins, as well as tighter eligibility 
criteria regarding baseline ejection fraction and history of cardiovascular disease. Unanticipated 
side effects events may also occur, like the Grade 4 VF that was also reported in combination 
therapy, Part B.in the CA224020 study. There were several confounding factors in this case but, 
in the absence of a clear etiology, the event was considered treatment-related. In the setting of 
troponin surveillance, three cases of Grade 1 myocarditis have been documented and managed 
without progression to subsequent cardiac dysfunction. Adverse events and SAEs will continue to 
be reviewed expeditiously by the Medical Monitor, investigators and the Pharmacovigilance group 
to monitor safety. Specific SAE narratives including the Grade 4 ventricular fibrillation event and 
the Grade 4 myocarditis event are included in the relatlimab IB.58
The types of treatment-related AEs, as well as the rates of treatment-related AEs, appeared 
comparable to historical nivolumab monotherapy rates. All treatment-related AEs, except for the 
Grade 4 myocarditis (
mg relatlimab
 mg nivolumab Q2W) and the Grade 4 potential drug 
induced liver injury (
 mg relatlimab/
 mg nivolumab Q2W), were reversible and manageable 
by withholding study treatment administration, providing standard medical care, and/or following 
immune-related AE algorithms.
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.  
 
 
The potential direct benefit to subjects who participate in the CA224022 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 duration of response 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) DLBCL, which is known 
to respond poorly to anti-PD-1 or anti-PD-L1 therapy; 2) HL that was refractory to or progressed 
after anti-PD-1 therapy. In fact, partial and complete responses as defined by the 2007 International 
Working Group (IWG) Response Criteria for Malignant Lymphoma62 (Appendix 1) have been 
observed with relatlimab monotherapy and in combination with nivolumab, both in the anti-PD-1
naive as well as in the anti-PD-1 resistant setting. Thus, the potential for direct benefit in subjects 
with few if any alternative treatment options warrants continued evaluation of the combination in 
the Phase 1/2a clinical setting, including evaluating potential response rates in specific tumor and 
prior anti-PD-1 defined expansion cohorts at combination doses shown to be tolerated.
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP 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 the 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. 
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 informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
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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 
non-technical and easily understood. 

Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.

Obtain an informed consent 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 informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.

If informed consent is initially given by a 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 informed consent 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. 
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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3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 1/2a, open-label study of relatlimab administered as monotherapy or in combination 
with nivolumab to subjects with advanced relapsed or refractory B-cell malignancies. The study 
will be conducted in 4 parts. Part A consists of a 3 + 3 + 3 dose escalation design in subjects with 
relapsed or refractory CLL, HL, NHL, and multiple myeloma with relatlimab administered as 
monotherapy. Part B consists of cohort expansion in 4 disease-restricted populations of 
to 
subjects each with relatlimab administered as monotherapy. Part C consists of a 3+3+3 dose 
escalation design in subjects with advanced HL and DLBCL with relatlimab administered in 
combination with nivolumab. Part D consists of cohort expansion in three disease-restricted 
populations of approximately 
to 
subjects each with relatlimab administered in combination 
with nivolumab (Figure 3.1-1).
Figure 3.1-1:
Study Design Schematic
* In Part A and selected cohort in Part D (ie, Hodgkin Lymphoma PD-1/PD-L1 naive cohort), subjects will be naive 
to immune cell-modulating antibody regimens (ICMARs), such as but not limited to anti PD-1, anti PD-L1, anti 
PD-L2, anti CTLA-4, anti-KIR, and/or anti-OX40 antibodies. Prior anti-CD20, alemtuzumab, and/or anti-CD30 
antibody therapy are allowed.
**In Part B, Part C, and selected cohorts in Part D (ie, Hodgkin Lymphoma anti-PD-1/PD-L1 resistant/failure cohort 
and Diffuse Large B-Cell Lymphoma cohort),subjects will be naive to immune cell-modulating antibody regimens 
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(ICMARs), such as, but not limited to anti CTLA-4, anti PD-L2, anti-KIR, and/or anti-OX40 antibodies. Prior
anti-PD-1, anti-PD-L1, anti-CD137, anti-CD20, alemtuzumab, and/or anti-CD30 antibody therapy are allowed. 
Subjects will complete up to 4 periods of the study: Screening (up to 28 days), Treatment (up to
a maximum of twelve 8-week cycles of study therapy), Clinical Follow-up (135 days following 
the last dose of study drug; and Survival Follow-up (up to 5 years following the first dose of study 
drug).WOCBP will have additional follow-up assessments through Day 165 for home pregnancy 
tests. Survival follow-up will be conducted for HL patients in Part C and D only, if appropriate.
The Treatment Period consists of up to twelve 8-week treatment cycles. Each treatment cycle 
comprises 4 doses of relatlimab administered on Days 
. Subjects will be allowed 
to continue study therapy until the first occurrence of either: (1) meeting criteria for 
discontinuation as described in Section 4.3.5, (2) completion of the maximum number of twelve 
 cycles, (3) confirmed progressive disease (PD), or (4) clinical deterioration. Subjects who 
discontinue treatment will enter a 135-day Clinical Follow-Up Period. After completion of the 
Clinical Follow-Up period, HL patients in Parts C and D will enter the Survival Follow-Up 
period. For participants who discontinue study treatment prior to disease progression, diagnostic 
imaging will be obtained every 6 months after the first clinical follow-up in year 1 and in year 2, 
and annually thereafter for a total of 5 years maximum (since the first dose of the study drug) until 
disease progression. Re-Challenge may be conducted in selected cases at progression.
If subjects progress during the clinical follow-up period or the survival follow-up period, they
could further receive therapy with relatlimab alone or in combination with nivolumab 
(Re-Challenge period) as long as the risk:benefit ratio is considered favorable by the Investigator 
and the Medical Monitor and eligibility criteria is met (Section 3.3). The original dose and schedule
and protocol rules would apply accordingly. Thus, subjects could receive therapy for up to 
additional eight-week cycles. Subjects will not be re-challenged a second time. Collection of 
archival tissue (baseline) and tumor biopsies (baseline and on-treatment) will be optional for 
subjects enrolled for re-challenge. PK and biomarker monitoring will be limited (Sections 5.5 and 
5.7).
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A study schematic is shown in Figure 3.1-2.
Figure 3.1-2:
Study Schematic for Parts A,1 B, C, and D
1 Part A DLT period: 8 weeks
2 Treatment beyond progression may be considered in selected subjects as described in Protocol Section 4.3.4
3 WOCBP will have additional follow-up assessments through Day 165 for home pregnancy tests
4 For participants who discontinue study treatment prior to disease progression, diagnostic imaging will be obtained 
every 6 months after the first clinical follow-up in year 1 and in year 2, and annually thereafter for a total of 5 years 
maximum (since the first dose of the study drug) until disease progression.
5 Survival follow up is for HL patients recruited in Parts C and D only
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), pulse 
oximetry, 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 will be 
collected following the start of study drug administration for pharmacokinetic (PK) analysis as 
described in Section 5.5. 
Subjects will be allowed to continue on therapy for up to twelve 8-week cycles, or, confirmed PD, 
or until meeting criteria for discontinuation as described in Section 4.3.5. Treatment beyond 
progression maybe considered in select subjects as described in Section 4.3.4. Subjects may be on 
study for a total of up to approximately 5 years, including a 28-day screening period, up to twelve 
8-week cycles of treatment, a 135-day clinical follow-up period and up to 5 years of follow-up for 
survival (beginning from the first dose of study drug). The study will end once survival follow-up 
has concluded. The total duration of the study is expected to be approximately 9 to 10 years from 
the time of the first visit of the first subject to the required survival follow-up of the last subject 
enrolled.
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3.1.1
Part A - Dose Escalation
In Part A, a 3 + 3 + 3 design will be used to assess the safety of relatlimab. The dose levels 
evaluated during dose escalation are provided in Table 3.1.1-1. Dose escalation rules are outlined 
below. Three subjects will initially be treated in each dose cohort; in Dose Cohort 1, the first 
3 subjects 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 will be based on the number of DLTs experienced during the DLT evaluation 
interval as determined by the Medical Monitor and Investigators (see Section 3.1.3 for DLT 
criteria). The DLT evaluation interval begins on the first day of treatment and continues for 
8 weeks, ie, through Day 
of the first cycle. Subjects who receive at least 1 dose of study drug 
during the 8-week evaluation interval will be considered evaluable for DLT determination. In 
consultation with Investigators, the Sponsor has the option to investigate dose levels intermediate 
to those defined in the protocol. 
Dose escalation in Part A (Table 3.1.1-1) will proceed as follows:

If none of the first  evaluable subjects in a dose cohort experiences a DLT within the DLT 
evaluation interval, then the next  subjects will be treated at the next higher dose cohort. 

If 1 of the first  evaluable subjects in a cohort experiences a DLT within the DLT evaluation 
interval, then  additional subjects will be treated in that dose cohort. 

If no more than  of the first  evaluable subjects experiences a DLT during the DLT 
evaluation interval, then the next  subjects will be enrolled at the next higher dose cohort. 

If  of the first  evaluable subjects in a cohort experience a DLT, that cohort will be 
expanded to  evaluable subjects. 

If  of the first  evaluable subjects,  of the first  evaluable subjects, or  of the first 
evaluable subjects in a cohort experience a DLT within the DLT evaluation interval, that 
dose level will have exceeded the MTD and dose escalation will be terminated.  
Table 3.1.1-1:
Dose Escalation Schedule for Part A - Relatlimab Monotherapy
Dose Cohort Number
Relatlimab Dose
(IV; mg)
Total Subjects
1
n = approximately
2
n = approximately 
3
n = approximately 
4
n = approximately 
Total
N = approximately 
In consultation with Investigators, the Sponsor may investigate dose levels intermediate to those 
defined in the protocol. Prior to declaring the MTD (or MAD), and in consultation with 
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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 the additional cohorts. A maximum of  subjects will be enrolled in any 
additional dose cohorts.
3.1.2
Part B -
 mg Cohort Expansion
The purpose of this cohort expansion is to gather additional safety, tolerability, PK, and 
pharmacodynamic information regarding relatlimab dosed at 
 mg. 
The dose selected for Part B has not exceeded the MTD in Part A (see rationale for dose selection 
in Section 1.1.8.4).
Four expansion cohorts will be restricted to the tumor types listed in Figure 3.1-1 and Table 3.1.2-
1. Continuous evaluation of toxicity events will be assessed throughout enrollment in the 
expansion cohorts. If, at any time, the aggregate rate of treatment-related toxicities meeting DLT 
criteria exceeds 
 across all subjects treated in Part B cohort expansions, the findings will be 
discussed with the Medical Monitor and Investigators; further enrollment may be interrupted. 
Depending on the nature and grade of the toxicity and after assessing the risk/benefit ratio, the 
dose for all or for select cohorts may be reduced.
Table 3.1.2-1:
Tumor Types Eligible For Part B - Cohort Expansion Relatlimab 
Monotherapy
Tumor Typea
Total Subjects
Chronic Lymphocytic Leukemia (CLL)
n=approximately 
Diffuse Large B-Cell Lymphoma (DLBCL)
n=approximately 
Indolent non-Hodgkin Lymphoma (i-NHL)
n=approximately 
Hodgkin Lymphoma (HL)
n=approximately 
Total 
n=approximately 
a All subjects in Part B will be naive to immune cell-modulating antibody regimens (ICMARs), such as, but not 
limited to anti-CTLA-4, anti PD-L2, anti-KIR, and/or anti-OX40 antibodies except for anti-PD-1, anti-PD-L1, anti-
CD137, anti-CD20, alemtuzumab, or anti-CD30 antibody therapy.
3.1.3
Part C - Dose Escalation Combination Therapy
As in Part A, a 3 + 3 + 3 design will also be used in Part C to assess the safety of relatlimab 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 subject is able to start the first day of dosing within approximately 
one week of the third subject in the same dose escalation cohort.
The dosages during dose escalation are provided in Table 3.1.3-1.
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Treatment in Part C will be initiated after the decision is made to escalate to the fourth dose cohort 
(
 mg anti-Lag-3 in combination with 
 mg anti-PD-1) in CA224020 study. At no point will 
the dose of relatlimab administered in combination with nivolumab (Part C) exceed doses of 
relatlimab that have been demonstrated previously to be safe on the monotherapy dose escalation 
arm (Part A). The escalation cohorts in Part C will be restricted to subjects with HL (naive to anti-
PD-1/PD-L1 or whose disease progresses while-on or within 3 months of treatment with anti-PD-
1 or anti-PD-L1 antibody) and DLBCL.
Dose escalation in Part C will proceed as described for Part A with the exception that the DLT 
observation period will be reduced from 8 weeks to 4 weeks. The rationale for the shorter 
observation period is presented in Section 3.1.6.1. If no MTD is reached through Dose Cohort 3, 
then additional cohorts of relatlimab given in combination with nivolumab may be considered 
based on the aggregate safety experience during dose escalation. Enrollment of additional cohorts 
will be implemented upon consultation and agreement between Investigators and the Sponsor via 
a protocol amendment.
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 subjects will be enrolled in any additional 
or expanded dose cohorts.
After completion of the relatlimab (anti-LAG-3) 
 mg and nivolumab  
 mg cohort, the 
intermediate dose combination of anti-LAG-3 
 mg and nivolumab 
 mg was investigated in 
Part C. The dose combination (
mg anti-LAG-3/
mg nivolumab) was well-tolerated in Part 
C and therefore selected for Part D (expansion).
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.
Table 3.1.3-1:
Dose Escalation Schedule for Part C - Relatlimab in Combination 
with Nivolumab
Dose Cohort Number
Total Subjects
Relatlimab Dose
(IV; mg)
Nivolumab Dose
(IV; mg)
1
n = approximately 
2
n = approximately 
3
n = approximately 
Total
N = approximately 
Note: Part C will be limited to subjects with HL (naive to anti-PD-1/PD-L1 or whose disease progresses while-on or 
within 3 months after treatment with anti-PD-1 or anti-PD-L1 antibody) and DLBCL.
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3.1.4
Part D - Dose Expansion Combination Therapy
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 relatlimab. The doses selected for Part D will not exceed the MTD 
(or MAD if no MTD is determined) in Part C, but may incorporate assessment of other data 
including toxicities, PK, and pharmacodynamic data from Parts A, B and C and from the 
CA224020 study. The dose selected can be chosen while additional Part C dose escalation cohorts 
continue to be explored. Doses to be considered may include doses intermediate to those evaluated 
in Part C if recommended by the Investigators and the Sponsor. The intermediate dose of relatlimab
(anti-lag-3) 
 mg and nivolumab 
 mg dose was well tolerated, and was thus selected for 
extension. Modeling may be used to help inform the selection of the combination dose level to 
carry forward in Part D if a dose below the MTD is chosen. Three expansion cohorts will be 
restricted to the tumor types listed in Table 3.1.4-1. Continuous evaluation of toxicity events will 
be assessed throughout enrollment in the expansion cohorts. If, at any time, the aggregate rate of 
treatment-related toxicities meeting DLT criteria exceeds 
 across all subjects treated in the 
Part D cohort expansions, the findings will be discussed with the Medical Monitor and 
Investigators; further enrollment may be interrupted. Depending on the nature and grade of the 
toxicity and after assessing the risk:benefit ratio, the dose for all or for select cohorts may be 
reduced. See Section 8.1.3.
Table 3.1.4-1:
Tumor Types Eligible For Part D - Cohort Expansion Relatlimab in 
Combination with Nivolumab
Tumor Type
Total Subjects
Hodgkin Lymphoma - anti-PD-1/PD-L1 naive
n=approximately 
Hodgkin Lymphoma - anti-PD-1/PD-L1 progressed
n=approximately 
Diffuse Large B-Cell Lymphoma 
n=approximately 
Total 
n=approximately 
3.1.5
Re-challenge in Dose Escalation (Part C) and Cohort Expansion (Part D)
If subjects progress during the clinical follow-up period or the survival follow-up period, they
could further receive therapy with relatlimab alone or in combination therapy (Re-challenge) as 
long as the risk:benefit ratio is considered favorable by the Investigator and the Medical Monitor 
and the following eligibility criteria are met: 1) Subject has confirmed disease progression; 2) 
Subject has not experienced relatlimab
related adverse events leading to permanent 
discontinuation. The original dose and schedule of therapy and protocol rules will apply. Thus 
subjects could receive therapy for up to
additional eight-week cycles. Subjects who are 
re-challenged and who subsequently have an objective response will not be included in the primary 
analysis of efficacy. Responses to re-challenge will be evaluated in a separate analysis. Subjects 
will not be re-challenged a second time.
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3.1.6
Dose-Limiting Toxicities
For the purpose of guiding decisions regarding dose escalation in Part A, dose-limiting toxicity 
(DLT) will be determined based on the incidence, intensity, and duration of AEs that are related 
to study drug and that occur within 8 weeks of initiation of study drug (ie, the DLT evaluation 
interval which begins on the first day of treatment and ends on Day 
 of the first cycle).
For the purpose of guiding decision in combination dose escalation in Part C, dose-limiting toxicity 
(DLT) will be determined based on the incidence, intensity, and duration of AEs that are related 
to study drug and that occur within 4 weeks of initiation of study drug (ie, the DLT evaluation 
interval which begins on the first day of treatment and ends on Day 
 of the first cycle).
The severity of AEs will be graded according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0.
For the purpose of subject management, DLTs that occur at any time, whether during dose 
escalation (Part A or C) or cohort expansion (Part B or D) will result in study drug being held 
pending evaluation of the event’s relatedness to study drug in accordance with Section 4.3.2. 
Subjects must meet criteria for re-treatment prior to re-initiation of study treatment (see 
Section 4.3.3).
3.1.6.1
Rationale for 4-week DLT Period in Part C
The identification of acute dose limiting toxicities that occur after administration of a study drug 
is crucial for the safety of the patients enrolled in a clinical trial. The length of the DLT is usually 
established based on the availability of pre-clinical data. When clinical data are available, the 
risk/benefit evaluation used to define the appropriate DLT period must be reassessed and should 
incorporate a critical analysis of all, clinical and pre-clinical data.
In Part C, the DLT period will be reduced from  weeks to  weeks in light of the availability of 
preliminary clinical data from the 2 ongoing clinical studies. This decision was made after 
reviewing the incidence of severe adverse event in monotherapy and in combination between 
Weeks 
to  and after Week  and the effect of a prolonged DLT on a population with advance 
cancers, as reported below.
Correlation between AEs and duration of treatment 
The safety profile of relatlimab as monotherapy is well manageable and generally consistent across 
the 2 ongoing clinical studies with no MTD reached at the  doses tested, up to 
 mg in dose 
escalation monotherapy. Only  subject experienced a related high-grade AE (asymptomatic Grade 
3 lipase increased), 
 days post the first administration of the study drug in CA224020. There 
were no related SAEs reported in the monotherapy in either study.
A preliminary analysis of the clinical data from the combination arm of Study CA224020 in which 
 subjects were treated with relatlimab in combination with nivolumab showed that there was no 
relationship between the incidence, severity, or causality of AEs and the dose level of study drugs. 
Seven subjects received 
 mg relatlimab/
 mg nivolumab, nine subjects were treated with 
 
mg relatlimab/
 mg nivolumab and eight subjects received 
 mg relatlimab/
mg nivolumab.
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Four acute treatment related AEs were observed (2 SAE and 2 AEs), three of them occurred during 
the first  weeks of treatment,
 event occurred at Week 6 and no treatment related AEs 
were documented after Week 
The treatment-emergent SAE reported at Week  (day 
 post 
first dose) was a Grade 4 ventricular fibrillation that occurred in a subject with 
 cancer that 
receive 
 mg relatlimab/
 mg nivolumab combination therapy. The event occurred 
spontaneously while the subject was shopping, and CPR was administered by paramedics for 
10 minutes. At the initial clinical assessment, the subject showed no evidence of coronary artery 
abnormality, myocardial infarction, myocarditis, or pulmonary embolism. A previous 
peri-infusional Holter electrocardiogram (ECG) recording on Cycle 1, Day 1 did not show an 
arrhythmia. The subject’s history of cannabinoid ingestion, tobacco smoking, hypertension, 
chlorphenamine and caffeine use, and a prior episode of loss of consciousness were considered 
potential contributing factors for the event and suggested pre-existing cardiac disease or an 
arrhythmia, but in the absence of a clearly identified etiology, contribution from relatlimab and 
nivolumab could not be excluded. Study drug was discontinued, and defibrillator was successfully 
implanted. Of note, despite to possible immuno-related mechanism, the patient never received 
steroids for the treatment of this AE. The subject has fully recovered with no sequelae and achieved 
a complete response after  doses of study drug. Due to the important role that the cannabinoids 
may have had is this event, the use of cannabinoids is now part of the exclusion criteria 
Effects of prolonged DLT period in a population with advanced cancer 
The target populations for phase 1/2a oncology studies are characterized by a high frequency of 
patients with advanced stage disease. As a consequence, a relevant group of patients will progress 
rapidly after initiation of study drug. Across the 2 ongoing studies with relatlimab, administered 
as monotherapy or in combination with nivolumab, 
 of the subjects enrolled in dose 
escalation cohorts experienced disease progression between Weeks 4 and 8 of the DLT period 
while only 
 of the subjects progressed between Weeks 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 adjudication and a new replacement subject must be enrolled at the same dose in order to 
complete the safety evaluation at that dose level. As a consequence, to date, nine additional patients 
have been exposed to safe but clinical suboptimal doses of relatlimab alone or in combination with 
nivolumab. 
In summary, the review of the safety data from the 2 ongoing studies strongly suggests that a 
4 weeks DLT period will provide an appropriate window to capture the acute, treatment related 
AEs and to ensure the safety of the patients enrolled in this clinical trial. Furthermore will limits 
the number of patients exposed to safe but suboptimal doses of the drugs due to progressive disease 
between Weeks 4 and 8.
Hepatic, non-hematologic, and hematologic DLTs are defined separately as outlined below. 
Hepatic DLT
Any of the following drug-related events will be considered a hepatic DLT:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 8 ULN, regardless 
of duration.
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
ALT or AST > 5 and 8 ULN, that fails to return to Grade 1 within 2 weeks despite 
medical intervention.

Total bilirubin > 5 ULN.

ALT or AST > 3 ULN and concurrent total bilirubin > 2 ULN.
Non-Hematologic DLT
Any of the following drug-related events will be considered a non-hematologic DLT:

Grade 2 immune related-eye pain or reduction in visual acuity that requires systemic treatment, 
or

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

Grade 3 non-hepatic or non-hematologic toxicity with the exceptions noted below.
The following Grade 3 or 4 non-hematologic 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 or lipase that is not associated with symptoms, clinical 
manifestations, or radiographic evidence 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 < 24 hours, does not result in hospitalization, and resolves to 
Grade 1 either spontaneously or with conventional medical intervention.

Grade 3 or 4 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.

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).
Hematologic DLT
Any of the following drug-related events will be considered a hematologic DLT:

Grade 4 anemia.
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
Grade 4 febrile neutropenia of any duration.

Grade 4 neutropenia that does not resolve to Grade 3 or less within 5 days of initiation of 
granulocyte colony stimulating factor (G-CSF).

Platelet transfusion or a platelet count < 10,000/L.

Grade 3 thrombocytopenia associated with clinically significant bleeding.

Grade 3 hemolysis.
In Part A, subjects who receive at least 1 dose of relatlimab during the 8-week evaluation interval
will be considered evaluable for DLT determination. In Part C, subjects who receive at least 2 
doses of relatlimab and nivolumab during the 4-week evaluation interval will be considered 
evaluable for DLT determination 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. If the delay 
is between 1 and 7 days, the procedures at the originally scheduled visit should be performed and 
subjects will be considered evaluable for DLT determination. If the delay is more than 7 days, the 
dose will be considered missed and will not be replaced. Subjects with a delay of more than 7 days 
will not be considered evaluable for DLT determination. Unevaluable subjects may be replaced at 
the same dose level. Subjects who miss a dose during the DLT evaluation period may continue on 
treatment if the subject does not otherwise meet the criteria for permanent discontinuation in 
Section 4.3.5.
3.2
Post Study Access to Therapy
At the end of the study, BMS will not continue to supply study drug to subjects/investigators unless 
BMS chooses to extend the study. The investigator should ensure that the subject receives 
appropriate standard of care to treat the condition under study.
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.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The subject must sign and date the IRB/IEC-approved written informed consent form prior 
to the performance of any study-related procedures that are not considered part of standard 
of care.
b) Consent for biopsy samples in subjects with Lymphoma.
i)
Subjects must consent to allow a pre-treatment tumor biopsy (eg, lymph node) to be 
performed (all subjects). If a pre-treatment tumor biopsy is not clinically feasible, 
subject must consent to allow the acquisition of an archived tumor sample (eg, primary 
tumor, lymph node, etc). Subjects unable to provide a fresh pre-treatment tumor biopsy 
or archived tumor sample must seek approval of the BMS Medical Monitor before 
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enrolling. Subjects whose pre-treatment biopsy yields inadequate tissue quantity or 
quality will not be ineligible on this basis alone.
ii) Subjects enrolled in Part B and C with Hodgkin lymphoma whose disease progresses 
while-on or within 3 months of treatment with anti-PD-1 or anti-PD-L1 antibody must 
consent to allow a pre-treatment tumor biopsy (eg, lymph node) to be performed. If a 
pre-treatment tumor biopsy is not clinically feasible, subject must consent to allow the 
acquisition of an archived tumor sample (eg, primary tumor, lymph node, etc) collected 
after the most recent therapy. Subjects unable to provide a fresh pre-treatment tumor 
biopsy or archived tumor sample must seek approval of the BMS Medical Monitor. 
Subjects whose pre-treatment biopsy yields inadequate tissue quantity or quality will 
not be ineligible on this basis alone. 
iii) The first three subjects in each cohort enrolled in the Part C, dose escalation, must 
consent to allow on-treatment tumor biopsy (eg, lymph node) to be performed at Week 
4 during cycle 1 independently of the disease status. Subjects unable to provide a fresh 
on-treatment tumor biopsy must seek approval of the BMS Medical Monitor.
iv) All subjects in Part D must consent to allow on-treatment tumor biopsy (eg, lymph 
node) to be performed at Week 4 during cycle 1 independently of the disease status.  
Note: If a fresh pre-treatment tumor biopsy was not medically feasible and enrollment 
was approved by the Medical Monitor, the on-treatment tumor biopsy will not be 
required.
v) Subjects enrolled in Part A and B must consent to allow a pre-treatment unilateral bone 
marrow biopsy and/or aspirate to be performed (all subjects). Subjects who had a bone 
marrow biopsy and/or aspirate since completion of their last therapy may not use those 
results in lieu of the required baseline bone marrow biopsy.
vi) Subjects enrolled in the 
 mg monotherapy escalation cohort must consent to allow 
on-treatment unilateral bone marrow biopsy and/or aspirate to be performed at Week 4 
during cycle 1 independently of the disease status. Subjects unable to provide a fresh 
on-treatment tumor biopsy are not eligible.
vii)Subjects enrolled in the 
 mg monotherapy escalation cohort must consent to allow 
on treatment unilateral bone marrow biopsy and/or aspirate to be performed to 
document complete response (CR), partial response (PR), or progressive disease (PD) 
shall be performed as clinically indicated.
viii)
Subjects enrolled in Part B, expansion monotherapy cohort, must consent to allow 
on-treatment unilateral bone marrow biopsy and/or aspirate to be performed (first three 
subjects in each cohort) at Week 4 during cycle 1 independently of the disease status.
Subjects unable to provide a fresh on-treatment tumor biopsy are not eligible.
ix) Subjects enrolled in Part B, expansion monotherapy, must consent to allow on 
treatment unilateral bone marrow biopsy and/or aspirate to be performed to document 
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complete response (CR), partial response (PR), or progressive disease (PD) shall be 
performed as clinically indicated.
c) Consent for biopsy samples in subjects with Multiple Myeloma.
i)
Subjects must consent to allow a pre-treatment unilateral bone marrow biopsy and/or 
aspirate to be performed (all subjects).
2) Target Population
a) Subjects must have histologic or cytologic confirmation of chronic lymphocytic leukemia, 
Hodgkin lymphoma, Non-Hodgkin lymphoma, or Multiple Myeloma and have relapsed 
following prior treatment or been refractory to prior treatment.
b) Part A Dose Escalation Relatlimab Monotherapy.
i)
Chronic lymphocytic leukemia.
ii) Hodgkin lymphoma.
iii) Non-Hodgkin lymphoma.
iv) Multiple Myeloma by modified IMWG Criteria63 (Appendix 6).
c) Part B Cohort Expansion Relatlimab Monotherapy 
 mg.
i)
Chronic lymphocytic leukemia.
ii) Diffuse large B-cell lymphoma.
iii) Indolent non-Hodgkin lymphoma.
iv) Hodgkin Lymphoma.
d) Part C Dose Escalation Relatlimab in Combination with Nivolumab.
i)
Hodgkin Lymphoma.
ii) Diffuse Large B-Cell Lymphoma.
e) Part D Dose Expansion Relatlimab in Combination with Nivolumab.
i)
Hodgkin Lymphoma naive to anti-PD-1/PD-L1.
ii) Hodgkin Lymphoma whose disease progresses while-on or within 3 months of 
treatment with anti-PD-1 or anti-PD-L1 antibody as most recent therapy.
iii) Diffuse Large B-Cell Lymphoma.
f)
In Part A, and selected cohort in Part D, (ie, Hodgkin Lymphoma anti-PD-1/PD-L1 naive 
cohort), only subjects without prior exposure to immune cell-modulating antibody 
regimens (ICMARs), such as but not limited to anti PD-1, anti PD-L1, anti PD-L2, anti 
CTLA-4, anti-KIR, and/or anti-OX40 antibodies, are allowed. Prior anti-CD20, 
alemtuzumab, and/or anti-CD30 antibody therapy is allowed.
In Part B, Part C, and selected cohort in Part D (ie Hodgkin Lymphoma subjects who 
progresses while on or within 3 months of treatment with anti PD-1/PD-L1 as most recent 
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therapy and Diffuse Large B-Cell Lymphoma subjects), only subjects without prior 
exposure to immune cell-modulating antibody regimens (ICMARs), such as, but not 
limited to anti-CTLA-4, anti-CD137, anti PD-L2, anti-KIR, and/or anti-OX40 antibodies 
are allowed. Prior anti-PD-1, anti-PD-L1, anti-CD20, alemtuzumab, and/or anti-CD30 
antibody therapy is allowed.
g) Definition of Measurable Disease.
i)
Subjects with lymphomas and CLL must have at least one measureable lesion > 1.5 cm 
as defined by the Lymphoma (Revised Response Criteria for Malignant Lymphoma)63
and CLL (Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic 
Leukemia)62 response criteria (Appendices 1 and 2). Tumor sites that are considered 
measureable must not have received prior radiation therapy.
h) Subjects must have progressed or been refractory to, at least one prior standard therapy, 
including radiation, immunomodulatory agents (eg, lenalidomide), immunotherapy, 
cytotoxic chemotherapy, and select antibody (anti-CD20, alemtuzumab, or anti-CD30) 
therapy. The following are not considered separate lines of treatment: addition of a 
compound to an ongoing regimen, restarting the same regimen after a drug holiday, or 
switching from IV to oral therapy.
i)
Subjects are not eligible for transplantation or any standard therapy known to be 
life-prolonging or life-saving. (Subjects who are eligible for transplantation or any standard 
therapy known to be life-prolonging or life-saving and who have declined transplantation 
or any standard therapy known to be life-prolonging or life-saving are eligible for the 
study.)
j)
Subjects must be more than 100 days post autologous transplant.
k) Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
l)
Life expectancy of 10 weeks at the time of informed consent per Investigator assessment.
m) Adequate organ function as defined by the following:
i)
Neutrophils 750/L (stable off any growth factor within 2 weeks of first study drug 
administration).
ii) Platelets 50 103/L (transfusion to achieve this level is not permitted within 
2 weeks of first study drug administration).
iii) Hemoglobin 8.5 g/dL (transfusion to achieve this level is not permitted within 1 week 
of first study drug administration).
iv) Creatinine < 1.5 ULN or creatinine clearance 40 mL/min (Cockcroft-Gault 
formula).
v) ALT and AST 3 ULN.
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vi) Total bilirubin 1.5 x ULN (except subjects with Gilbert’s syndrome who must have 
a total bilirubin level of < 3.0 x ULN).
vii)Normal thyroid function, or stable on hormone supplementation per Investigator 
assessment.
n) Ability to comply with treatment, PK, and pharmacodynamic sample collection and 
required study follow-up.
o) Subject re-enrollment:  This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized or 
treated). If re-enrolled, the subject must be re-consented.
p) Adequate cardiac function as defined by the following:
i)
LVEF 50% by either TTE or MUGA (TTE preferred test) within 6 months of first 
drug administration.
3) Age and Reproductive Status
a) Men and women, ages 18 years at the time of informed consent. 
b) Women of childbearing potential (WOCBP) 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.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with relatlimab plus 5 half-lives of relatlimab (135 days) plus 30 days 
(duration of ovulatory cycle) for a total of 165 days (24 weeks) after completion of 
treatment. The terminal half-life of nivolumab is up to 25 days. WOCBP who are treated 
with combination of relatlimab and nivolumab should follow the requirements for 
relatlimab which has a slightly longer half-life than nivolumab.
e) Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with relatlimab plus 5 half-lives of relatlimab
(135 days) plus 90 days (duration of sperm turnover) for a total of 225 days (33 weeks) 
after completion of treatment. Those treated with the combination of relatlimab and 
nivolumab should follow the requirements for relatlimab which has a slightly longer half-
life than nivolumab.
f)
Azoospremic males and 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.
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 
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use of highly effective methods of contraception. Highly effective methods of contraception
(Appendix 3) have a failure rate of < 1% per year when used consistently and correctly.
3.3.2
Exclusion Criteria
1) Target Disease Exceptions
a) Lymphomas and Multiple Myeloma.
i)
Subjects with primary cutaneous lymphoma, lymphoproliferative diseases associated 
with primary immune deficiencies, and lymphomas associated with human 
immunodeficiency virus (HIV) infection are excluded. 
ii) Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma 
cell dyscrasia.
iii) Monoclonal gammopathy of undetermined significance (MGUS), smoldering 
myeloma or Waldenström’s macroglobulinemia.
iv) Active plasma cell leukemia (defined as either 20% of peripheral WBC comprised of 
plasma/CD138+ cells or an absolute plasma cell count of 2 x 109 /L). 
b) Subjects with known or suspected central nervous system (CNS) metastases or with the 
CNS as the only site of active disease are excluded: 
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 
after radiation or surgical treatment at the time of consent. Subjects must have been off 
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 computed tomography (CT) or magnetic resonance imaging 
(MRI).
2) Medical History and Concurrent Diseases
a) Subjects with a prior malignancy are excluded, except adequately treated basal cell or 
squamous cell skin cancer, carcinoma in situ of the cervix or of the bladder, or in situ ductal 
or lobular carcinoma of the breast. Subjects with other prior malignancies diagnosed more 
than 2 years previously (at the time of informed consent) who have received therapy with 
curative intent with no evidence of disease during the interval and who are considered by 
the Investigator to present a low risk for recurrence will be eligible.
b) Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitis, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. Subjects with 
well-controlled asthma and/or mild allergic rhinitis (seasonal allergies) are eligible.
c) Subject has autoimmune hemolytic anemia (AIHA) or autoimmune thrombocytopenia 
(ITP) requiring therapeutic doses of systemic steroids.
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d) Subject has undergone any allogeneic transplant.
e) Subject has received autologous/allogeneic T-cells transfer.
f)
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 procedures and/or 
study therapy, or confound the ability to interpret the tolerability of relatlimab in treated 
subjects.
g) Requirement for daily supplemental oxygen.
h) Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following:
i)
Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) 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 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 [NYHA] functional 
classification III-IV, pericarditis, significant pericardial effusion, significant coronary 
stent occlusion, deep venous thrombosis, etc ).
vi) Cardiovascular disease-related requirement for daily supplemental oxygen.
vii) Not applicable per Revised Protocol 07.  See criteria xi) below for cardiac troponin. 
Cardiac Troponin T (cTnT) or I (cTnI) 2 × institutional ULN. Subjects with cTnT or
cTnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours
are 1 ULN.
(1) If cTnT or cTnI levels are > 1 ULN at 24 hours, the subject may undergo a cardiac
evaluation and be considered for treatment, following a discussion with the BMS
Medical Monitor or designee.
viii)
History of myocarditis, regardless of etiology.
ix) History of two or more MIs or two or more coronary revascularization procedures.
x) A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year 
prior to informed consent.
xi) Troponin T (TnT) or I (TnI) > 2 × institutional ULN. 
Note: Subjects with TnT or TnI levels between > 1 to 2 × ULN will be permitted if 
repeat levels within 24 hours are 1 x ULN.  If TnT or TnI levels are >1 to 2 × ULN 
within 24 hours, the subject may undergo a cardiac evaluation and be considered for 
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treatment, following a discussion with the BMS Medical Monitor or designee. When 
repeat levels within 24 hours are not available, a repeat test should be conducted as 
soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject 
may undergo a cardiac evaluation and be considered for treatment, following a 
discussion with the BMS Medical Monitor or designee.
i)
Positive blood screen for HIV or known acquired immunodeficiency syndrome (AIDS).
j)
Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, Hepatitis B surface antigen (HBsAg), Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
k) Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal 
therapy 7 days prior to initiation of study drug therapy.
l)
Any other significant acute or chronic medical illness.
m) Subjects who are unable to undergo venipuncture and/or tolerate venous access.
n) Any other sound medical, psychiatric, and/or social reason as determined by the 
Investigator.
o) 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 co-stimulation or immune checkpoint pathways) except those that are unlikely to re-
occur with standard countermeasures (eg, hormone replacement after endocrinopathy).
p) Any of the following procedures or medications:
i)
Within 2 weeks prior to study drug administration:
(1) Subjects with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications 
within 14 days of relatlimab administered as monotherapy or in combination with 
nivolumab. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
ii) Within 4 weeks prior to study drug administration:
(1) Any investigational drug or placebo.
(2) Any anticancer therapy (IMIDs [eg, lenalidomide], proteasome inhibitors, 
chemotherapy, monoclonal antibody for antineoplastic intent [eg, anti-CTLA-4, 
anti PD-1, anti PL-1, anti PDL-2, anti-CD20, anti-CD30, or alemtuzumab antibody 
therapy], therapeutic vaccines, radiotherapy, or hormonal treatment).
(3) Non-oncology vaccines containing live / attenuated virus within 30 days of first 
treatment.
(4) Allergen hyposensitization therapy.
(5) Major surgery.
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iii) Within 6 weeks prior to study drug administration:
(1) Nitrosureas, fludarabine.
iv) Within 10 weeks prior to study drug administration:
q) Radio-immunoconjugates.
3) Allergies and Adverse Drug Reaction
a) History of allergy to antiPD-1 or antiPD-L1 antibody therapy or to other monoclonal 
antibodies or related compounds or to any of their components (eg, history of severe 
hypersensitivity reactions to drugs formulated with polysorbate 80).
4) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
(Note: under specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included as a participant. Strict conditions apply and Bristol-Myers 
Squibb [BMS] approval is required).
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/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
A woman of childbearing potential (WOCBP) is defined as any female who has 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 additional, 
women under the age of 55 must have a serum follicle stimulating hormone (FSH) level
> 40 mIU/mL to confirm menopause.
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. 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.

8 week minimum for oral products.
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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 
Section 3.4.3.

Concurrent administration of any anticancer therapies (investigational or approved) with the 
exception of subjects in the survival period of the study.

Use of allergen hyposensitization therapy.

Use of growth factors unless prior discussion and agreement with BMS Medical Monitor.

Use of cannabis or other recreational drugs.

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.
Palliative radiotherapy is permitted only under certain conditions as described in Section 3.4.3.
3.4.2
Other Restrictions and Precautions
3.4.2.1
Vaccinations
Any vaccination containing attenuated or inactivated virus may be permitted if clinically indicated. 
However, this must be discussed and documented with the BMS Medical Monitor prior to 
administration and may require a study drug washout period prior to and after administration of 
the vaccine. Inactivated influenza vaccination will be permitted on study without restriction. Any 
vaccination containing live virus is prohibited.
3.4.2.2
Imaging Restrictions and Precautions
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 
[eGFR] 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI 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.
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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. 
Subjects may continue to receive HRT.
Oral antiviral therapy (acyclovir or equivalent) may be required to reduce the risk of herpes zoster 
reactivation. Discussion with medical monitor is required for any subject planned to receive oral 
anti-viral therapy.
Palliative 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 radiation in subjects who have not yet completed the DLT evaluation interval (Part A).
The potential for overlapping toxicities with radiotherapy and relatlimab administered as 
monotherapy or in combination with 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 2 weeks 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 
re-initiating 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 (CRF). Details in the source records should include dates of treatment, anatomical site, 
dose administered and fractionation schedule, and AEs. Symptoms requiring palliative 
radiotherapy should be evaluated for objective evidence of disease progression. Administration of 
additional relatlimab, as monotherapy or in combination with nivolumab to subjects who receive 
limited-field palliative radiation, should follow guidelines specified in Section 4.3.5. Subjects 
receiving palliative radiation of index 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 radiation occurs.
For subjects who need to undergo elective surgery (not tumor-related) during the study, it is 
recommended to hold study drug 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 consultation with the 
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Investigator. The BMS Medical Monitor must be consulted prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks after the last dose.
3.4.4
Treatment of Relatlimab or Nivolumab-Related Infusion Reactions
Since relatlimab and nivolumab 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 version 4.0 guidelines. If a subject has an infusion reaction with nivolumab, the relatlimab
infusion can be given (without prophylactic medications) if the infusion reaction resolves within 
3 hours. For scheduling purposes after a nivolumab infusion reaction, the relatlimab infusion may 
be given the next day. Prophylactic pre-infusion 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, non-steroidal 
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 hydrocortisone 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 (SC) 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. Treatment with study drug 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 Nivolumab Management Algorithms.
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment.

Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
Investigator, indicates that continued participation in the study is not in the best interest of the 
subject.

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. (Note: Under 
specific circumstances, and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required).

Inability to comply with protocol requirements.

Progressive disease (PD; see also Section 4.3.4 for details regarding continuing treatment 
beyond initial assessment of PD).

Clinical deterioration as assessed by the investigator.

Protocol-defined reasons for discontinuation (Section 4.3.5).
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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).
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 CRF page.
3.6
Post Treatment Study Follow-Up
In this study, overall survival 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. 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).
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 three documented phone calls, 
faxes, or emails as well as lack of response by subject to one 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 third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
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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.
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4
TREATMENTS
All protocol-specified investigational and non-investigational products are considered study drug.
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, summary of product characteristics (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, 
 mg/vial or 
 mg/vial
(
 mg/mL)
mg/mL
 mL or 
 mL 
vial/open label
 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,
 mg/vial (
 mg/mL)
mg/mL
 mL vial/open label
 or 
 
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
a Relatlimab; designated as BMS-986016 in the protocol
b Nivolumab; designated as BMS-936558 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 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: relatlimab (BMS-986016) and nivolumab 
(BMS-936558).
4.1.2
Non-investigational 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 
non-investigational products. 
In this study, non-investigational product(s) are not applicable. 
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 treatment visits in Parts C, and D, where both relatlimab and nivolumab are administered, 
nivolumab will be administered first followed by relatlimab within 30 minutes after completion of 
the nivolumab infusion. Nivolumab infusion will be administered over 30 minutes. Further details 
regarding preparation and administration will be provided separately in site/pharmacy training 
materials.
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, SmPC, or similar.
4.2
Method of Assigning Subject Identification
This is an open-label study. All subjects will be assigned a subject number upon providing signed 
written informed consent. The investigative site will call into the enrollment option of the 
Interactive Voice Response System (IVRS) designated by BMS for assignment of a 5-digit subject 
number that will be unique across all sites. Enrolled subjects, including those not dosed, will be 
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assigned sequential subject numbers starting with
. The 
patient identification number (PID) will ultimately be comprised of the site number and subject 
number. For example, the first subject screened (ie, enrolled) at site number 1, will have a PID of 
. Specific instructions for using IVRS will be provided to the investigative sites in a 
separate document.
Once it is determined that the subject meets the eligibility criteria, the investigative site will call 
the IVRS prior to first study drug administration for the subject to be either:

Assigned to a part (Parts A, D) and dose cohort in the dose escalation portion of the study.

Assigned to an expansion cohort in the cohort expansion portion (Part B and D) of the study.
During dose escalation (Part A and C), subjects who are not evaluable for DLT determination may 
be replaced. Replacement subjects will be assigned to the same dose cohort, but will be assigned 
a new subject number. 
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 relatlimab or nivolumab 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 relatlimab or nivolumab 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 relatlimab and nivolumab Investigator’s 
Brochures.58.14 Additionally, management algorithms have been developed to assist Investigators 
with select toxicities and can be found in Appendix 4.
Toxicities for which management algorithms have been developed include:

Pulmonary.

Gastrointestinal.

Hepatic.

Endocrine.

Renal.

Dermatologic.

Neurologic.

Myocarditis.
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Subjects who experience the following must have all study drugs(s) delayed:

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.

All troponin elevations require a dose delay to allow for prompt cardiac evaluation.

Single grade increase shift from baseline (at least to Grade 2) of AST, ALT, and 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.

Any AE, laboratory abnormality, or intercurrent illness, which in the judgment of the 
Investigator, warrants delaying the dose of study medication.
Subjects may be dosed no less than 
 days from the previous dose and no more than  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  weeks after the 
delayed dose. A dose given more than  days after the intended dose date will be considered a 
delay. A maximum delay of  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 study drug. All other subjects will be permitted to resume 
therapy with study drug 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 and management with corticosteroids, if needed, is complete, provided the criteria for 
permanent discontinuation are not met.

Subjects may resume treatment in the presence of Grade 2 fatigue.

Subjects with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment.

Troponin elevations will require the participants 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.
4.3.4
Treatment Beyond Disease Progression
Accumulating evidence indicates that a subset of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD. Participants treated with relatlimab + nivolumab or 
with relatlimab alone, will be permitted to continue their study treatment beyond initial 
investigator assessment of progression, provided the following criteria are met:

Subject is deriving clinical benefit as assessed by the Investigator.

Disease progression is not rapid as assessed by the Investigator.

Subject continues to meet relevant eligibility criteria as determined by the BMS Medical 
Monitor in discussion with the Investigator.

Subject tolerates study drug.

Subject has stable performance status.

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases).

Subjects have provided written informed consent prior to receiving additional study drug.
The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
subject is clinically deteriorating and unlikely to receive any benefit from continued treatment. If 
the Investigator feels that the subject continues to achieve clinical benefit by continuing treatment, 
the subject should remain on the study and continue to receive monitoring according to the Time 
and Events Schedule (Table 5.1-2). The decision to continue treatment should be discussed with 
the BMS Medical Monitor and documented in the study records.
Subjects that meet the above criteria and continue on study therapy beyond initial PD. must 
discontinue relatlimab (and nivolumab, if part of the combination cohorts) upon the next 
documented event of PD. A follow-up efficacy assessment should be performed at the next 
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scheduled evaluation 8 weeks later (but no sooner than 4 weeks later) to determine whether there 
is continued PD.
4.3.5
Guidelines for Permanent Discontinuation
Subjects meeting any of the following criteria will be required to permanently discontinue all study 
drug(s) (relatlimab in Part A and B; relatlimab and nivolumab in Parts C and D):

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, infusion reactions, and endocrinopathies.

Grade 3 drug-related myocarditis, uveitis, pneumonitis, bronchospasm, or hypersensitvity 
reaction of any duration.

Grade 3 infusion reaction that does not return to Grade 1 in 6 hours or less.

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 re-treatment period OR requires 
systemic treatment.

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:

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 neutropenia 7 days in duration.

Grade 4 lymphopenia or leukopenia.

Isolated Grade 4 lipase and/or amylase 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 adverse events, such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones) or glucose-controlling agents, respectively, may not require discontinuation 
after discussion with and approval from the BMS Medical Monitor.

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except:

Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation.

AST, ALT, or bilirubin abnormalities that meet DLT criteria (Section 3.1.6) (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 3.1.6).
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
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement do not require discontinuation.

Any event that leads to dosing delays 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 re-initiating treatment in a subject with a dosing interruption lasting > 6 
weeks after 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 non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor. Prior to re-initiating 
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 and subjects must otherwise meet the criteria for 
continued treatment at the time re-initiation of study therapy is considered. 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 adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued relatlimab or 
nivolumab dosing.

PD (see also Section 4.3.4 for details regarding continuing treatment beyond initial assessment 
of PD).

Clinical deterioration as assessed by the Investigator.

Completion of the maximum number of twelve 8-week cycles.
The consideration to re-initiate 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. 
4.4
Blinding/Unblinding
Not applicable.
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 relatlimab and 
nivolumab administration in subjects’ medical records and CRF.
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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 can 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 SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, 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 BMS. The return of study 
drug will be arranged by the responsible BMS Study Monitor. 
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
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5.1
Flow Chart/Time and Events Schedule
Study assessments and procedures are presented in Table 5.1-1 (screening), Table 5.1-2
(on-treatment), and Table 5.1-3 (follow-up).
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Table 5.1-1:
Screening Procedural Outline (CA224022)
Procedure
Eligibility Assessments
Informed consent
Inclusion/exclusion criteria
Medical history
Safety Assessments
Physical examination (PE)
Performance status
Physical measurements
Vital signs
Oxygen saturation
Electrocardiogram (ECG)
LVEF Assessment (either 
TTE or MUGA)
Cardiac Troponin T (cTnt) 
or I (cTnI) 
Chest radiograph
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Table 5.1-1:
Screening Procedural Outline (CA224022)
Procedure
Safety laboratory tests
Pregnancy test 
Follicle-stimulating hormone 
(FSH)
Concomitant medications
Clinical complaints 
Adverse Event Reporting
Monitor for serious adverse 
events
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Table 5.1-1:
Screening Procedural Outline (CA224022)
Procedure
Baseline Assessments
Lymphomas and CLL
Tumor tissue sample (eg, 
primary tumor, lymph node)
Bone marrow biopsy and/or 
aspirate
Diagnostic Imaging
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Table 5.1-1:
Screening Procedural Outline (CA224022)
Procedure
Brain imaging
PET or PET/CT scan
Photography
Baseline Assessments
Myeloma
Skeletal survey
Documentation of 
extramedullary soft tissue 
plasmacytomas, if clinically 
indicated
Bone Marrow 
Aspiration/Biopsy
Myeloma serum tests
Myeloma urine tests
Note: Re-challenge subjects must be screened.
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Table 5.1-2:
On-Treatment Procedural Outline
Procedure
IVRS Assignment
IVRS assignment
Safety Assessments
Physical examination (PE)
Neurological Exam (NE)
Performance status
Weight
Vital signs
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Table 5.1-2:
On-Treatment Procedural Outline
Procedure
12-lead electrocardiogram (ECG)
Cardiac Troponin T (cTnt) or I 
(cTnI) 
Oxygen saturation
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Table 5.1-2:
On-Treatment Procedural Outline
Procedure
Safety laboratory tests
Endocrine Panel
Immunoglobulins and 
Complement
Cytogenetics
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Table 5.1-2:
On-Treatment Procedural Outline
Procedure
Mutations & molecular markers
Pregnancy test (WOCBP)
Assess adequate contraceptive use
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Table 5.1-2:
On-Treatment Procedural Outline
Procedure
Adverse Event and Con Med 
Assessment
Monitor for non-serious adverse 
events
Monitor for serious adverse events
Con Med assessment
Sample Collection
Pharmacokinetic (PK) 
assessments
Immunogenicity assessments 
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Table 5.1-2:
On-Treatment Procedural Outline
Procedure
Biomarker assessments
On-treatment tumor or lymph 
node biopsy
Efficacy Assessments
Lymphomas and CLL
Diagnostic Imaging
Brain imaging
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Table 5.1-2:
On-Treatment Procedural Outline
Procedure
Photography
Bone marrow biopsy and/or 
aspirate
Response assessment 
Efficacy Assessments
Myeloma
Skeletal survey
Documentation of extramedullary 
soft tissue plasmacytoma
Bone Marrow Aspiration/ Biopsy
Flow cytometry
Myeloma tests in serum
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Table 5.1-2:
On-Treatment Procedural Outline
Procedure
Myeloma tests in urine
Study Drug Administration
Relatlimab (BMS-986016) 
administration
Nivolumab (BMS 936558)
administration
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Table 5.1-3:
Follow-Up Procedural Outline (CA224022)
Procedure
Safety Assessments
Physical 
examination (PE)
Performance status
Weight
Vital signs
12-lead 
electrocardiogram 
(ECG)
Oxygen saturation
Safety Laboratory 
tests
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Table 5.1-3:
Follow-Up Procedural Outline (CA224022)
Procedure
Pregnancy test
Assess adequate 
contraceptive use
Adverse Event and 
Con Med 
Assessment
Monitor for non-
serious adverse 
events
Monitor for serious 
adverse events
Con Med assessment
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Table 5.1-3:
Follow-Up Procedural Outline (CA224022)
Procedure
Sample Collection
Pharmacokinetic 
(PK) assessments
Immunogenicity 
(ADA) assessments
Efficacy 
Assessments
Lymphomas and 
CLL
Diagnostic Imaging
Brain Imaging
Response assessment
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Table 5.1-3:
Follow-Up Procedural Outline (CA224022)
Procedure
Efficacy 
Assessments
Myeloma 
Documentation of 
extramedullary soft 
tissue plasmacytoma
Myeloma tests in 
serum
Myeloma tests in 
urine
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Table 5.1-3:
Follow-Up Procedural Outline (CA224022)
Procedure
Survival Status
Assessment of 
subject survival 
status
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In the event of multiple procedures are required at a single time point, the following is a list of 
procedures from highest to lowest priority:
1) Safety (ECG).
2) Pharmacokinetic Sampling.
3) Safety (clinical labs).
4) Oxygen saturation.
5.2
Study Materials
The following materials will be provided at study start:

NCI CTCAE version 4.0.

Relatlimab and BMS-936558 IBs.

Pharmacy Binder.

Laboratory kits and 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 NCI CTCAE version 4.0 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 Medical Dictionary for Regulatory Activities (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
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.3.2
Genomic Analysis
In order to identify potential polymorphisms associated with safety and efficacy of relatlimab, 
selected genes will be evaluated for single nucleotide polymorphisms (SNP). Analysis will include 
but not be limited to sequence polymorphisms linked to genes and pathways associated with 
 and 
 
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DNA may also be utilized for DNA sequencing to identify germline sequences to 
compare with tumor sequences.
5.3.3
Laboratory Test Assessments
A central/local laboratory will perform the analyses and will provide reference ranges for these 
tests.
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 timeframes 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 test must be reviewed prior to 
dosing. 
The following clinical laboratory tests will be performed:
Hematology (Local Laboratory)
Complete blood count (CBC) with differential
Platelet count
INR (screening only)
Serum Chemistry (Local Laboratory)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood urea nitrogen (BUN)
Uric acid
Fasting or non-fasting glucose
Amylase
Lipase
C-reactive protein
Albumin
Sodium
Potassium
Chloride
CO2
Calcium
Magnesium
Phosphorus
Creatine clearance (CLcr)* - screening 
only *Cockcroft-Gault formula
Cardiac Troponin T (cTnT) or Cardiac Troponin I  
cTnI
For those subjects receiving on-going treatment with relatlimab and nivolumab, troponin
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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Endocrine Panel (Local Laboratory)
Thyroid-stimulating hormone (TSH) with reflex to free T3 and free T4 as applicable. Subjects 
with controlled hyperthyroidism must be negative for thyroglobulin and thyroid peroxidase 
antibodies with thyroid stimulating immunoglobulin (screening only).
Urinalysis (Local Laboratory)
Total protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein, or leukocytes esterase are positive 
on the dipstick
Serology (Local Laboratory)
Hepatitis B surface antigen (HBsAg) and/or hepatitis B core antigen
Qualitative hepatitis C viral load by PCR
HIV-1,-2 antibody
Immunoglobulins and Complement (Local Laboratory)
Mutation and Molecular Markers (Local Laboratory)
expression 
 expression
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Cytogenetics Analysis (Local Laboratory)
Cytogenetics Analysis (Central Laboratory)
Multiple Myeloma Tests

Serum: specific alkaline phosphatase, total serum protein, immunoglobulin assay, serum 
protein electrophoresis (SPEP) with M-protein quantitation and serum free light chain. 
Serum immunofixation as indicated in Table 5.1-2

Urine: 24-hour urine collection for creatinine (spot urine is not acceptable), total urine 
proteins, and UPEP with M-protein (urinary light chain) quantitation. Urine immunofixation 
as indicated in Table 5.1-2.

Bone marrow: flow cytometry evaluation of percentage 
 cells and clonality (based 
on 
) to confirm 
.
Reproductive Analyses (Local Laboratory)
Pregnancy testing: 

Clinic: serum or urine (urine pregnancy test: minimum sensitivity 25 IU/L or equivalent 
units of human chorionic gonadotropin [hCG])

Home pregnancy test kits
Follicle-stimulating hormone (FSH); if needed to document post-menopausal status as defined 
in Section 3.3.3)
Other Analyses
Additional measures including non-study 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 
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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
Study evaluations will take place in accordance with the Schedule of Activities in Section 5.1. 
Efficacy assessments will be conducted and reported by the investigator on the CRF using the 
appropriate efficacy assessment based on tumor type. 

Subjects with NHL or HL will be evaluated using the 2007 IWG Response Criteria for 
Malignant Lymphoma62 (Appendix 1). Disease assessments for subjects with HL and DLBCL 
will occur between Days 
 and 
 of each treatment cycle 
 
cycles) and at the 
.

Since the conception of this protocol, new response criteria known as Lugano 2014 criteria 
(Appendix 7) have been developed to refine tumor metabolic response. A retrospective 
exploratory assessment of tumor metabolic response will be evaluated according to the Lugano 
2014 criteria using the Deauville 5-point scale on Part D subjects with NHL or HL who had 
fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans performed in the pre-
treatment period (defined as within 60 days before the first dose, providing no other therapy 
was given during this time) and during this study.   

For these PET-based assessments, a response of complete metabolic response (CMR), 
partial metabolic response (PMR), no metabolic response, or progressive metabolic disease 
(PMD) will be determined. The PET scan metabolic uptake will be graded using the 
Deauville 5-point scale, with a score of 1, 2, or 3 considered to represent a CMR (see 
Appendix 7). Assessments will be performed by PET scan with CT/MRI of diagnostic 
quality, with disease involvement determined by focal FDG uptake in nodal and extranodal 
lesions (including the spleen and liver).

Subjects with CLL will be evaluated using the 2008 IWG Response Criteria for CLL with 
Modifications64 (Appendix 2). Disease assessments for subjects with CLL will occur between 
Days 
 and 
 of each treatment cycle (up to twelve 8-week treatment cycles) and at the 
.

Subjects with MM will be evaluated using Response Criteria Modified from IMWG for 
Multiple Myeloma63 (Appendix 6). 65,66 Disease assessments for subjects with MM will occur 
on Day 
 and Day 
 of each cycle and at the 
. According to study 
design, the results on 
 will be used to define continuation of therapy or not 
in all subjects.
5.5
Pharmacokinetic Assessments
Serum samples for relatlimab and nivolumab PK and anti-drug antibody (ADA) assessments will 
be collected for all subjects.
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5.5.1
Pharmacokinetics - Collection and Processing
Pharmacokinetic blood samples will be drawn from study subjects receiving relatlimab as 
monotherapy or in combination with nivolumab at the time points indicated in Table 5.5.1-1 and
Table 5.5.1-2. All time points are relative to the start of study drug administration. All samples 
collected pre-dose 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)
from the contralateral arm (ie, the arm not used for the infusion). On-treatment samples are 
intended to be drawn relative to actual dosing days. If a dose occurs on a different day within the 
cycle due to minor schedule adjustments or dose delays, PK samples should be adjusted 
accordingly. Further details of sample collection, processing, and shipment will be provided in the 
Laboratory Procedures Manual. 
Table 5.5.1-1:
PK and ADA Sampling Schedule for Relatlimab and Nivolumab in 
all Subjects in Part A, B, C and 
 Subjects in Part D and for 
Cohorts with Re-Challenge
Study Day of 
Sample Collection
(1 Cycle = 56 Days
[8 Weeks])
Event
Time
(Relative to
Start of Infusion) 
Hour: Min
Relatlimab
PK Sample
(All Subjects)
Relatlimab
ADA Sample
(All Subjects)
Nivolumab
PK Sample
(Part C & D 
Only)
Nivolumab
ADA Sample
(Part C & D 
Only)
Cycle 1
1
predosea
00:00
X
X
X
X
1
EOIb
01:00
X
X
1
04:00
X
2
24:00
X
3-5
48:00 - 96:00c
X
7-9
144:00 - 192:00c
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
X
X
15
predosea
00:00
X
X
29
predosea
00:00
X
X
Cycle 3
1
predosea
00:00
X
X
X
X
1
EOIb
01:00
X
X
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Table 5.5.1-1:
PK and ADA Sampling Schedule for Relatlimab and Nivolumab in 
all Subjects in Part A, B, C and 
 Subjects in Part D and for 
Cohorts with Re-Challenge
Study Day of 
Sample Collection
(1 Cycle = 56 Days
[8 Weeks])
Event
Time
(Relative to
Start of Infusion) 
Hour: Min
Relatlimab
PK Sample
(All Subjects)
Relatlimab
ADA Sample
(All Subjects)
Nivolumab
PK Sample
(Part C & D 
Only)
Nivolumab
ADA Sample
(Part C & D 
Only)
1
04:00
X
2
24:00
X
3-5
48:00 - 96:00b
X
7-9
144:00 - 192:00b
X
15
predosea
00:00
X
X
Subsequent Odd # Treatment Cycles
1
predosea
00:00
X
X
X
X
Follow-up Period
FU2d
FU2
X
X
X
X
FU3d
FU3
X
X
X
X
a Predose: All predose samples for relatlimab and nivolumab should be collected within 30 minutes prior to the start 
of nivolumab infusion.
b EOI: End of Infusion. For subjects receiving relatlimab in combination with nivolumab,  EOI samples for both 
relatlimab and nivolumab should be collected after the end of relatlimab infusion (preferably within 2 minutes prior 
to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion duration, the collection of 
this sample should also be delayed accordingly. EOI samples may not be collected from the same IV access as drug 
was administered; refer to the Laboratory Procedures Manual for additional restrictions.
c A single PK sample is to be drawn during this time range.
d FU2 and FU3 corresponds to 60 and 135 day follow up visit, respectively.
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relatlimab
Table 5.5.1-2:
PK and ADA Sampling Schedule for Relatlimab and Nivolumab for 
Dose Expansion Part D after 
 Subjects
Study Day of 
Sample Collection
(1 Cycle = 56 Days
[8 Weeks])
Event
Time
(Relative to
Start of Infusion)
Hour: Min
Relatlimab
PK Sample
(All Subjects)
Relatlimab
ADA Sample
(All Subjects)
Nivolumab
PK Sample
(Part C & D 
Only)
Nivolumab
ADA Sample 
(Part C & D 
Only)
Cycle 1
1
predosea
00:00
X
X
X
X
1
EOIb
01:00
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
X
X
15
predosea
00:00
X
X
Cycle 3
1
predosea
00:00
X
X
X
X
1
EOIb
01:00
X
X
15
predosea
00:00
X
X
Subsequent Odd # Treatment Cycles
1
predosea
00:00
X
X
X
X
Follow-up Period
FU2c
FU2
X
X
X
X
FU3c
FU3
X
X
X
X
a Predose: For subjects receiving relatlimab in combination with nivolumab, all predose samples for relatlimab and 
nivolumab should be collected within 30 minutes prior to the start of nivolumab infusion.
b EOI: End of Infusion. For subjects receiving relatlimab in combination with nivolumab, EOI samples for both 
relatlimab and nivolumab should be collected after the end of relatlimab infusion (preferably within 2 minutes prior 
to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion duration, the collection of 
this sample should also be delayed accordingly. EOI samples may not be collected from the same IV access as drug 
was administered; refer to the Laboratory Procedures Manual for additional restrictions.
c FU2 and FU3 corresponds to 60 and 135 day follow up visit, respectively.
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5.5.2
Pharmacokinetic Sample Analyses
The serum samples will be analyzed for relatlimab and nivolumab concentrations by a validated 
immunoassay. In addition, selected serum samples may be analyzed by an exploratory orthogonal 
method (eg, liquid chromatography [LC]-mass spectrometry [MS]/MS) that measures total 
relatlimab 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.
5.5.3
Labeling and Shipping of Biological Samples
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the Laboratory Procedures Manual.
5.6
Biomarker Assessments
Not applicable.
5.7
Exploratory Biomarker Assessments
Tumor tissue will be collected prior to therapy and at selected time points on treatment in all 
subjects in Parts A, B, C, and D. Bone Marrow and/or aspirate will be collected prior to therapy 
and at selected time points on treatment in all subjects in Parts A and B. Peripheral blood will be 
collected prior to therapy and at selected time points on treatment in up to 
 subjects enrolled in 
each dose level in Part A and in all subjects in Part B, C, and D. If biomarker samples are drawn 
but study drug is not administered, samples will be retained. A schedule of pharmacodynamic 
evaluations is provided in Table 5.7-1 and detailed descriptions of each assay system are provided 
in the sections that follow.
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Table 5.7-1:
Biomarker Sampling Schedule
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5.7.1
Soluble Biomarkers
Soluble factors, including but not limited to cytokines, chemokines, soluble receptors, and 
antibodies to tumor antigens will be characterized and quantified by immunoassays in serum. 
Analyses may include, but not necessarily be limited to, 
 
. Collected serum samples may also be used for the assessment of 
tumor antigen-specific antibody responses elicited following treatment.
5.7.2
Immunophenotyping of PBMC and Bone Marrow Aspirates
The proportion of specific lymphocyte subsets and expression levels of T-cell co-stimulatory 
markers in PBMC preparations will be quantified by cytometry. Analyses may include, but not 
necessarily be limited to, 
 
5.7.3
Ex Vivo Functional Assays
To explore whether relatlimab alone or with nivolumab will 
 
 
 
5.7.4
Peripheral Blood Gene Expression
The expression level of genes related to response to relatlimab will be quantified using molecular 
methods including but not limited to
 
 
 
5.7.5
Relatlimab Receptor Occupancy
 
 
 
 
Samples will be taken prior to treatment to 
define a baseline and at the time of bone marrow aspirate collection. Analysis of peripheral blood 
and bone marrow aspirates will be done in fresh samples; therefore, it is critical that samples be 
shipped promptly after collection.  
5.7.7
Tumor-Based Biomarker Measures
Tumor biopsy specimens (eg, primary tumor, lymph nodes) will be obtained prior to and after 
treatment with relatlimab alone or with nivolumab to characterize 
 and 
expression of selected tumor markers. 
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A pre-treatment tumor biopsy (eg, primary tumor, lymph node) will be collected in all consenting 
subjects.  
If a pre-treatment tumor biopsy is not clinically feasible, after approval by the medical monitor, an 
archived tumor tissue sample (eg, primary tumor, lymph node, etc), 
 
 should be provided for
performance of correlative studies. If slides are submitted, the recommended tissue section 
thickness is 4 microns and the slides must be positively charged. Slides should be shipped 
refrigerated at 2-8C.
The pathology report should be submitted with the archived or fresh biopsy sample. If both a fresh 
biopsy and an archived sample are available, both samples should be sent.  
On-treatment tumor biopsies will be collected in up to 
 
The 
biopsy should be obtained during 
The biopsy may be 
coordinated with protocol-specified diagnostic imaging.
When a fresh biopsy is taken, up to 3 to 4 core biopsies, and a minimum of two are recommended. 
An assessment of biopsy quality by a pathologist is strongly encouraged at the time of the 
procedure. The tumor tissue that is obtained from these biopsies will be divided equally into 
 
Biopsy samples should be excisional, incisional, or core needle. Fine needle aspirates are not 
allowed. It is recommended that samples be fixed in 
 
.  
Sample shipments should include a completed requisition form containing collection date, 
collection method, primary tumor and lymph node and/or metastasis, site, fixation conditions, and 
a copy of pathology report, if available.
The investigator, in consultation with the radiology staff, must determine the degree of risk 
associated with the procedure and find it acceptable and feasible. 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. Subjects should have at 
least one lesion large enough to undergo repeated biopsies (pre- and on-treatment biopsies) via 
core needle (minimum size 18 gauge) or have at least 
 for core needle or 
excisional biopsies. The expected core needle length should be greater than  mm. Fine needle 
aspirate biopsies are not accepted. At least 
 biopsies will be taken at each time point, but 
collection of additional cores is strongly encouraged if deemed clinically safe by the investigator. 
An assessment of biopsy quality by a pathologist is strongly encouraged at the time of the 
procedure. All biopsies collected must have a detailed pathology report submitted with the 
specimen. Detailed instructions regarding the acquisition, processing, labeling, handling, storage, 
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and shipment of biopsy specimens will be provided in a separate procedure manual prior to study 
initiation.
On-treatment tumor biopsies will be collected in up to six patients treated on 
 
 
 
The biopsy may be coordinated with protocol-specified diagnostic imaging.
Biopsy and bone marrow samples may be used for the following assessments:

Characterization of 
. 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 after exposure to relatlimab and nivolumab. These IHC analyses will 
include, but not necessarily be limited to, the following markers: 
 
 
 be made between assays performed if deemed to be informative.

 
 

 
 

Gene expression profiling. Tumor biopsies that are collected in RNAlater or similar reagent 
will be examined for mRNA gene expression by techniques including but not limited to 
 


Subjects whose screening biopsy yields inadequate tissue quantity or quality will be allowed to 
continue in the study. If on-treatment biopsy is not successful, subjects may also continue on study. 
Such subjects may be replaced in order to obtain 48 subjects with adequate paired tumor biopsies. 
If subjects have a major response to treatment, on-treatment biopsies might not be possible. In this 
case, subjects may also continue on study. 
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.
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Bone Marrow and/or Aspirates in Subjects enrolled in Part A and B 
Unilateral bone marrow biopsy and/or aspirate will be done
 
 Subjects who had a bone marrow 
aspirate and biopsy result since completion of their last therapy may not use those bone marrow 
results in lieu of the baseline bone marrow required for this study. 
 
 
 
 as clinically indicated, 
and may be coordinated with protocol-specified diagnostic imaging.
Bone marrow biopsy and/or aspirates will be obtained using institutional standards for these 
procedures. Detailed instructions for bone marrow biopsy and aspirate collection will be provided 
in the Laboratory Procedures Manual. In brief, 
 
 
approximately 10 mL of aspirate will be collected in a sodium heparin tube and 
shipped ambiently. A second bone marrow biopsy will be harvested for RNA later. The pathology 
report should be submitted with the biopsy sample.
 
 No additional sampling is required for 
residual collections. Retention is mandatory for all subjects, except where prohibited by local laws 
or regulations. Detailed instructions of the obtaining, processing, labeling, handling, storage and 
shipment of specimens will be provided in a separate Laboratory Procedures Manual at the time 
of study initiation.
5.7.8
Additional Research Collection
This protocol will include residual sample storage for additional research (AR).
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 R&D capability at 
BMS, and will support as yet undefined research aims that will advance our understanding of 
disease and options for treatment. It may also be used to support health authority requests for 
analysis, and advancement of pharmacodiagnostic development to better target drugs to the right 
patients.  This may also include genetic/genomic exploration aimed at exploring disease pathways, 
progression and response to treatment etc. 
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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 5.7.8-1 will also be 
retained for additional research purposes.
Samples kept for future research will be stored at the BMS Biorepository in 
 USA or 
an independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Table 5.7.8-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Time points for which residual samples will be retained
Tumor Biopsies
Biomarker Blood Collections 
PK Blood Collections
5.8
Outcomes Research Assessments
Not applicable.
5.9
Other Assessments
5.9.1
Immunogenicity Assessments
Blood samples for immunogenicity analysis of relatlimab and nivolumab will be collected 
according to the schedule given in Table 5.5.1-1 and Table 5.5.1-2. These samples will be 
evaluated for the development of anti-drug antibody (ADA) for relatlimab and nivolumab by 
validated immunoassays. Additional characterization (eg, neutralizing antibody (NAB) assay) for 
any detected ADA may also be performed using a validated assay. On-treatment samples are 
intended to be drawn relative to actual dosing days. If a dose occurs on a different day within the 
cycle, immunogenicity samples should be adjusted accordingly. 
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Selected serum samples may be analyzed by an exploratory orthogonal method that measures 
anti-relatlimab or anti-nivolumab. Potential results generated from any orthogonal method are 
intended as informational for technology exploration purposes and will not be reported.
Selected immunogenicity samples also may be analyzed for exploratory analyses; exploratory 
results 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 relatlimab on QTc interval when administered as monotherapy or in combination 
with nivolumb 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 electrocardiogram 
machines. 
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6
ADVERSE EVENTS
An Adverse Event (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.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following:

Related: There is a reasonable causal relationship between study drug administration and the 
AE.

Not related: There is not a reasonable causal relationship between study drug administration 
and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
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 
AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context 
of known adverse events, when appropriate for the program or protocol. 
6.1
Serious Adverse Events
A Serious Adverse Event (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).

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 drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.).
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Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
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).
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 or until starting a new anti-neoplastic treatment (whichever 
occurs first). If applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (eg, a follow-up skin biopsy). 
All SAEs that occur during the screening period and within 100 days after discontinuation of 
dosing must be collected except in cases where a study participant has started a new anti-neoplastic 
treatment. 
However, any SAE occurring after the start of a new anti-neoplastic treatment that is suspected to 
be related to study treatment by the investigator should be reported as an SAE.
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. 
An SAE report 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.
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SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports 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
Non-serious Adverse Events
A non-serious adverse event is an AE not classified as serious.
6.2.1
Non-serious Adverse Event Collection and Reporting
The collection of non-serious AE information should begin at initiation of study drug and for 
135 days after discontinuation of dosing or until starting a new anti-neoplastic treatment 
(whichever occurs first). Non-serious AE information should also be collected from the start of a 
placebo lead-in period or other observational period intended to establish a baseline status for the 
subjects. 
Non-serious 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 non-serious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified non-serious AEs must be recorded and described on the non-serious AE
page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
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exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the subject’s case report form.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious 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 versus 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 + 30 days (165 days) after product administration, the 
investigational product will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). 
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.
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.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and if any sexual activity (eg, vaginal, anal, oral) has occurred between a male 
participant and a pregnant WOCBP partner(s), the information should be reported to the Sponsor 
or designee, even if the male participant has undergone a successful vasectomy. In order for 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the female partner(s) must sign an informed consent form for disclosure of this information. 
Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
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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. 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. 
All occurrences of intentional overdose must be reported as an SAE (see Section 6.1.1 for reporting 
details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1) Aminotransferase (ALT or AST) elevation > 3 times upper limit of normal (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 aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
radiologic exams, any other potential safety assessment required or not required by protocol should 
also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable.
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
8.1.1
Parts A and C - Dose Escalation 
The sample size at each dose depends on observed toxicity and cannot be precisely determined. 
Part A will have  to  subjects in each cohort.
8.1.2
Part B Cohort Expansion for Monotherapy
8.1.3
Part D Cohort Expansion for Combination Therapy
The objective of this expansion in combination with nivolumab is, in addition to demonstrating 
adequate safety and tolerability, to evaluate a favorable risk/benefit assessed by signal seeking for 
anti-PD-1/PD-L1 progressed nivolumab HL, improvement in complete response (CR) rate for 
anti-PD-1/PD-L1 naive HL relative to PD-1 monotherapies, and improvement in objective 
response rate (ORR) for DLBCL relative to existing available therapies.
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Table 8.1.3-1:
Example of a Two-stage Design Characteristics
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8.2
Populations for Analyses

All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IVRS.

All Treated Subjects: All subjects who received at least one dose of study medication.  This 
is the primary population for safety and efficacy analyses.

Response-Evaluable Subjects: All treated subjects with measurable disease at baseline and 
one of the following: 1) at least one post-baseline tumor assessment, 2) clinical progression, 
or 3) death (if death occurred within 135 days after last relatlimab dose).

Pharmacokinetic Subjects: All subjects who received at least one dose of relatlimab or 
nivolumab and have evaluable plasma/serum concentration data.

Immunogenicity Subjects: All treated subjects with relatlimab or nivolumab who have 
baseline and at least one post baseline immunogenicity assessment.

Biomarker Subjects: All treated subjects with available biomarker data.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary endpoint of this Phase 1 study is safety as measured at the study level by the rate of 
AEs, SAEs, AEs leading to discontinuation, deaths, and laboratory abnormalities, assessed during 
treatment and for up to 135 days after the last treatment. All subjects who receive at least one dose 
of relatlimab alone or in combination with nivolumab will be analyzed for safety.
Co-primary endpoint in Part D is objective response rate (ORR) and duration of response (DOR) 
(see Section 8.3.2.3 for details).
8.3.2
Secondary Endpoint(s)
8.3.2.1
Pharmacokinetics
The PK of relatlimab administered both alone and in combination with nivolumab will be assessed 
as a secondary objective using the following endpoints derived from serum concentration versus 
time data at time points indicated in Table 5.5.1-1.
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The PK parameters to be assessed include:
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 one 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; 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
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.
8.3.2.2
Immunogenicity
Incidence of ADA to either relatlimab or nivolumab will be assessed during treatment and for up 
to 135 days after their last treatment in post-treatment follow-up. Baseline ADA positive subject 
is defined as a subject with positive seroconversion detected in the last sample before initiation of 
treatment. ADA-positive subject is a subject with at least one ADA-positive sample relative to 
baseline after initiation of the treatment.
8.3.2.3
Efficacy
All efficacy analyses will be based on the all treated analysis population except otherwise stated.
Co-primary, secondary and exploratory efficacy endpoints for Part D subjects are as follows:
Objective Response Rate (ORR)
ORR based on investigator assessment, according to the applicable criteria based on tumor type,
will be co-primary endpoint in Part D. For the NHL and HL subjects, the ORR will be based on 
the IWG (2007) response criteria. In addition to the primary ORR endpoint, an exploratory 
endpoint of ORR based on the Lugano (2014) response criteria in the NHL and HL subjects in Part 
D will be assessed. For the Lugano criteria, response is defined as CMR and PMR. 
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Duration of Objective Response (DOR)
DOR is defined as the time between the date of first documented response (CR or PR) to the date 
of the first objectively documented progression as per criteria relevant to each disease type in Part 
D (Appendices 1, 2, and 6), or death due to any cause, whichever occurs first. For subjects who 
neither progress nor die, DOR will be censored on the date of their last tumor assessment. Subjects 
who start subsequent therapy without a prior reported progression will be censored at the last tumor 
assessments prior to initiation of the subsequent anticancer therapy. This endpoint will only be 
evaluated in subjects with objective response of CR or PR. DOR will be evaluated based on 
investigator assessments. DOR is a co-primary endpoint in Part D. DOR based on the Lugano 
(2014) response criteria, response defined as CMR or PMR, will be assessed for the NHL/HL 
subjects in Part D as an exploratory endpoint.
Complete Response (CR) Rate and Duration
The CR rate is defined as the number of subjects with a best overall response (BOR) of CR
according to the applicable criteria based on tumor type, based on IWG criteria for NHL and HL 
subjects, divided by the number of treated subjects. The duration of CR (DoCR) will only be 
evaluated in subjects with BOR of CR and is defined as the time from first documentation of CR 
(the date of first negative FDG-PET scan) to the date of initial objectively documented progression 
as determined using the applicable criteria based on tumor type or death due to any cause, 
whichever occurs first. Censoring will be applied as per DOR definition.  CR rate and DoCR will 
be evaluated based on investigator assessments. CR rate is an exploratory endpoint in this study.
Progression Free Survival (PFS) Rate
PFS is defined as the time from first dose to the date of first objectively documented progression, 
per applicable criteria based on tumor type or death due to any cause, whichever occurs first. 
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 anti-cancer 
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 anti-cancer 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. PFSR will be assessed at 
Weeks 16, 24, 32, 40, and 100, and evaluated based on investigator assessments. PFS will be an 
exploratory endpoint in this study.
Overall Survival (OS) Rate
OS is defined as the time between the date of first dose and the date of death. For subjects without 
documentation of death, OS will be censored on the last date the subject was known to be alive. 
The overall survival rate at time T is defined as the probability that a subject is alive at time T 
following first dose OS will be assessed at various time points in HL patients in Part D. 
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8.3.3
Exploratory Endpoint(s)
8.3.3.1
Biomarkers
Biomarkers endpoints from peripheral blood may include measures such as levels of soluble 
factors, as well as activation and proliferation of subsets of immune cells including but not limited 
to subset of T cells characterized by immunophenotyping, at each scheduled time point. Biomarker 
endpoints from tumor biopsies may include, but will not be limited to, 
 
 
8.3.3.3
Other Efficacy Endpoints
PFS based on Lugano (2014) Criteria:
PFS for a subject is defined as the time from the first dosing date to the date of first progressive 
metabolic disease or death due to any cause (death occurring after retreatment will not be 
considered), whichever occurs first. Subjects who died without a reported prior progression will 
be considered to have progressed on the date of their death. The censoring rules applied to the PFS 
endpoint based on the IWG criteria will also be used for this endpoint.
Complete Metabolic Response Rate based on Lugano 2014 Criteria:
The CMR rate is defined as the number of subjects with a BOR of CMR based on the Lugano 
(2014) criteria divided by the number of treated subjects. The duration of CMR (DoCMR) will 
only be evaluated in subjects with BOR of CMR and is defined as the time from first 
documentation of CMR (the date of first negative FDG-PET scan) to the date of initial objectively 
documented PMD based on the Lugano (2014) criteria or death due to any cause, whichever occurs 
first. Censoring will be applied using the DOR definition. CMR rate and DoCMR will be evaluated 
based on investigator assessments. 
8.4
Analyses
Unless otherwise specified, safety data from Parts A-D will be summarized both (1) overall by 
dose level and across all dose levels and (2) by dose level and across all dose levels within each 
tumor type. Efficacy data will be summarized by dose level within each tumor type and patient 
population.
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender and race will be tabulated. Summary statistics for age, body 
weight, height, and body mass index (BMI), and baseline laboratory results will be tabulated. 
Baseline disease characteristics will be summarized for expansion cohorts for different disease 
cohorts separately, as appropriate.
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8.4.2
Efficacy Analysis
Individual ORR, CR rate, DOR, CMR, PMR, and PFS (based on IWG and Lugano criteria) will 
be determined.  BOR outcomes will be summarized using frequency tables together with 2-sided 
95% confidence intervals. Time to event distribution (eg, PFS, DOR, and DoCMR) will be 
estimated using Kaplan-Meier (K-M) method. When appropriate, the median along with 95% CI 
will be provided using Brookmeyer and Crowley methodology (using log-log transformation for 
constructing the confidence intervals). Rates at fixed time points (eg, PFSR 24 weeks) will be 
derived from the K-M estimate and corresponding confidence interval will be derived based on 
Greenwood formula. Confidence intervals for binomial proportions will be derived using the 
Clopper-Pearson method. OS data will be analyzed similarly to PFS data analysis.
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 be graded using the NCI 
CTCAE version 4.0. AEs will be listed and subjects with AEs will be summarized based on the 
event with worst CTC 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. 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 v 4) 
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.
8.4.4
Pharmacokinetic Analyses
PK parameters for relatlimab as monotherapy and in combination with nivolumab will be 
calculated using noncompartmental analyses. Summary statistics will be tabulated for the PK 
parameters of relatlimab by treatment and study day/week. To describe the dependency on dose of 
relatlimab, scatter plots of Cmax and AUC (TAU) versus dose may be provided for each day 
measured. Dose proportionality of relatlimab will also be assessed based on a power model.
Summary statistics of nivolumab exposure at trough and end of infusion will be tabulated 
separately.
8.4.5
Exploratory Biomarker Analyses
The pharmacodynamic effect on 
 
in subjects who undergo biopsy will be 
summarized using summary statistics and plots. In addition, the correlation of 
 changes 
and tumor marker expression with measures of peripheral blood markers may be explored 
graphically, and using appropriate modeling approaches based on data availability. Associations 
of biomarker measures from peripheral blood or tumor biopsy with clinical outcomes may also be 
explored graphically and further assessed as needed by methods such as, but not limited to, logistic 
regression and characterized by appropriate statistics.
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8.4.6
Outcomes Research Analyses
Not applicable.
8.4.7
Other Analyses
8.4.7.1
Immunogenicity Analyses
A listing will be provided for all available immunogenicity data. The number and percent of 
subjects who meet specified endpoint definitions in the statistical analysis plan (SAP) will be 
summarized for each drug. 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, 
pharmacodynamic markers, and/or PK may also be explored.
8.5
Interim Analyses
Data emerging from this open-label exploratory study may be needed for safety monitoring, and 
to make timely decisions about adjustments to study procedures, including potential early 
termination of the study. Analyses will only consist of listings, summaries, and graphs of the 
available data. No formal inferences requiring any adjustment to statistical significance level will 
be performed. 
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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
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
BMS 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.
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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 
is inventoried and dispensed. Records or logs must comply with applicable regulations and 
guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

non-study disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, 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.
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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 electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
paper or electronic SAE 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 electronic data capture tool. The 
investigator must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
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 
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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 adverse event 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, 
Investigator Brochure for an unapproved investigational 
product)
Serious Adverse Event
Serious adverse event defined as 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; 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, intentional overdose, 
and cancer as important medical events.
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LIST OF ABBREVIATIONS
Term
Definition
Ab
antibody
ADA
anti-drug antibody
AE
adverse event
AI
accumulation index
AI_AUC
AUC accumulation index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Ceoinf
Ceoinf accumulation index; ratio of Ceoinf at steady state to Ceoinf after 
the first dose
AI_Cmax
Cmax accumulation index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau accumulation index; ratio of Ctau at steady state to Ctau after the 
first dose
AIDS
acquired immunodeficiency virus
AIHA
autoimmune hemolytic anemia
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(TAU)
area under the concentration-time curve in one dosing interval
BMI
body mass index
BMS
Bristol-Myers Squibb
BOR
best overall response
BUN
blood urea nitrogen
CBC
complete blood count
Ceoinf
concentration observed at the end of infusion
CFR
Code of Federal Regulations 
CHL
classical Hodgkin lymphoma
CHO
Chinese hamster ovary
CLcr
creatinine clearance
CLL
chronic lymphocytic leukemia
CLT
total body clearance
CLTp
systemic clearance
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Term
Definition
Cmax
maximum observed concentration
CMV
cytomegalovirus
CMR
complete metabolic response
CNS
central nervous system
CR
complete response/complete remission
CRF
case report form, paper or electronic
CRO
contract research organization
Css,avg
average concentration over a dosing interval ([AUC(TAU)/tau]
CT
computed tomography
Ctau
Concentration in 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 oncentration
DF
degree of fluctuation or fluctuation index ([Cmax - Ctau]/Css,avg)
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DoCMR
duration of complete metabolic response
DOR
duration of objective response
EBV
Epstein Barr virus
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EOI
end of infusion
FDG
fluorodeoxyglucose
FSH
follicle-stimulating hormone
FU
Follow-up
GCP
Good Clinical Practice
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Term
Definition
G-CSF
granulocyte colony stimulating factor
GLP
Good Laboratory Practice
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HED
human equivalent dose
HepA
hepatitis A
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HL
Hodgkin lymphoma
HNSTD
highest non-severely toxic dose
HRS
Hodgkin-Reed-Sternberg
IB
Investigator Brochure
ICH
International Conference on Harmonisation 
ICMAR
immune cell-modulating antibody regimen
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IGHV
immunoglobulin heavy variable
IHC
immunohistochemistry
IRB
Institutional Review Board
ITP
idiopathic thrombocytopenia purpura
IU
International Unit
IV
intravenous(ly)
IVRS
interactive voice response system
IWG
International Working Group
LAG-3
lymphocyte activation gene 3
LCMV
lymphocytic choriomeningitis virus
LDH
lactate dehydrogenase
LPHL
lymphocyte-predominant Hodgkin lymphoma
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Term
Definition
mAb
monoclonal antibody
MAD
maximum administered dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MFI
mean fluorescent intensity
MHC
major histocompatibility complex
MM
Multiple myeloma
MRI
magnetic resonance imaging
MRSD
maximum recommended starting dose
MTD
maximum tolerated dose
N
number of subjects or observations
N/A
not applicable
NCI
National Cancer Institute
NHL
non-Hodgkin lymphoma
NK
natural killer
NOAEL
no-observed-adverse-effect level
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ORR
objective response rate
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death protein ligand 1
PE
physical examination
PET
positron emission tomography
PFS
progression-free survival
PFSR
progression-free survival rate
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Term
Definition
PID
patient identification number
PK
pharmacokinetic(s)
PMR
partial metabolic response
PPK
population pharmacokinetics
PR
partial response/partial remission
Q2W
every 2 weeks
QW
every week
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
SLL
small lymphocytic leukemia
SmPC
summary of product characteristics
SOP
standard operating procedure
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)
T/HRBCL
T cell/histiocyte-rich B-cell lymphoma
TIA
transient ischemic attack
Tmax
time of maximum observed concentration
TMDD
target-mediated binding and/or disposition
Treg
regulatory T cell
ULN
upper limit of normal
VGPR
Very good partial response
Vss
Volume of distribution at steady state
WHO
World Health Organization
WOCBP
women of childbearing potential
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12
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58 Relatlimab (BMS-986016) Investigator Brochure. Bristol-Myers Squibb Research and 
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APPENDIX 1
2007 INTERNATIONAL WORKING GROUP (IWG) RESPONSE 
CRITERIA FOR MALIGNANT LYMPHOMA
2007 IWG Response Criteria for Malignant Lymphoma1
Response
Definition
Nodal masses
Spleen, Liver
Bone marrow
CR
Disappearance 
of all evidence 
of disease
(a) FDG-avid or PET positive 
prior to therapy; residual mass of 
any size permitted if PET negative
(b) Variably FDG-avid or PET 
negative; regression to normal 
size on CT
Not palpable, 
nodules 
disappeared
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology,
immunohistochemistry
should be negative
PR
Regression of 
measurable 
disease and no 
new sites
50% decrease in SPD of up to 6 
largest dominant masses (index 
lesions); no increase in size of 
other nodes (non-index lesions)
(a) FDG-avid or PET positive 
prior to therapy; one or more PET 
positive at previously involved 
site
(b) Variably FDG-avid or 
PET negative; regression 
on CT
50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen
Irrelevant if positive 
prior to therapy; cell 
type should be specified
SD
Failure to attain 
CR/PR or PD
(a) FDG-avid or PET positive 
prior to therapy; PET positive at 
prior sites of disease and no new 
sites on CT or PET
(b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT
N/A
N/A
Relapsed 
disease
or PD
Any new lesion 
or increase by 
50% of 
previously
involved sites 
from nadir
Appearance of a new lesion(s) 
> 1.5 cm in any axis, 50% 
increase in SPD of more than one 
node (index lesions), or 50% 
increase in longest diameter of a 
previously identified node > 1 cm 
in short axis.
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior 
to therapy
> 50% increase 
from nadir in the 
SPD of any 
previous lesions
New or recurrent 
involvement
Key: CR = complete remission, CT = computed tomography; FDG = [18F] fluorodeoxyglucose; IWG = 
International Working Group; NA = Not applicable; PD = progressive disease; PET = positron-emission 
tomography; PR = partial remission; SD = stable disease; SPD = sum of the product of the diameters.
1 Cheson, BD, Pfistner, B, Juweid, ME, et al. Revised criteria for malignant lymphoma. J Clin 
Oncol. 2007; 25:579.
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CR (Complete Remission)
The designation of CR requires the following:
APPENDIX 1
Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms, if present before therapy.
APPENDIX 2
Typically [18F] fluorodeoxyglucose (FDG)-avid lymphoma: in patients with no pretreatment 
positron emission tomography (PET) scan or when the PET scan was positive before therapy, a post-treatment 
residual mass of any size is permitted as long as it is PET negative.
APPENDIX 3
Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment PET 
scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on 
computed tomography (CT) scan to normal size (1.5 cm in their greatest transverse diameter for nodes > 1.5 
cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long axis and > 1.0 cm in their 
short axis before treatment must have decreased to 1.0 cm in their short axis after treatment.
APPENDIX 4
The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be considered normal size 
by imaging studies, and nodules related to lymphoma should disappear. However, determination of splenic 
involvement is not always reliable because a spleen considered normal in size may still contain lymphoma, 
whereas an enlarged spleen may reflect variations in anatomy, blood volume, the use of hematopoietic growth 
factors, or causes other than lymphoma.
APPENDIX 5
If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared 
on repeat bone marrow biopsy. The biopsy sample on which this determination is made must be adequate (with 
a goal of > 20 mm unilateral core). If the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry. A sample that is negative by immunohistochemistry but demonstrates a small 
population of clonal lymphocytes by flow cytometry will be considered a CR until data become available 
demonstrating a clear difference in patient outcome.
PR (Partial Remission)
The designation of PR requires all of the following:
1.
At least a 50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant 
nodes or nodal masses. These nodes or masses should be selected according to all of the following: they should 
be clearly measurable in at least 2 perpendicular dimensions; if possible they should be from disparate regions 
of the body; and they should include mediastinal and retroperitoneal areas of disease whenever these sites are 
involved.
2.
No increase should be observed in the size of other nodes, liver, or spleen.
3.
Splenic and hepatic nodules must regress by 50% in their SPD or, for single nodules, in the greatest transverse 
diameter.
4.
With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no 
measurable disease should be present.
5.
Bone marrow assessment is irrelevant for determination of a PR, if the sample was positive before treatment. 
However, if positive, the cell type should be specified (e.g., large-cell lymphoma or small neoplastic B cells). 
Patients who achieve a CR by the above criteria but have persistent morphologic bone marrow involvement will 
be considered partial responders. When the bone marrow was involved before therapy and a clinical CR was 
achieved but with no bone marrow assessment after treatment, patients should be considered partial responders.
6.
No new sites of disease should be observed.
7.
FDG:
a.
Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET scan was positive 
before therapy, the post-treatment PET should be positive in at least 1 previously involved site.
b.
Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment PET scan, or if 
a pretreatment PET scan was negative, CT criteria should be used. In patients with follicular lymphoma or 
mantle-cell lymphoma, a PET scan is only indicated with 1 or at most 2 residual masses that have regressed 
by > 50% on CT; those with more than 2 residual lesions are unlikely to be PET negative and should be 
considered partial responders.
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SD (Stable Disease)
1.
A patient is considered to have SD when he or she fails to attain the criteria needed for a CR or PR but does not 
fulfill those for progressive disease (see Relapsed Disease [after CR]/Progressive Disease [after PR, SD]).
2.
Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with no new areas of 
involvement on the post-treatment CT or PET scan.
3.
Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment PET scan or if the 
pretreatment PET was negative, there must be no change in the size of the previous lesions on the post-
treatment CT scan.
PD: Relapsed Disease (after CR)/Progressive Disease (after PR, SD)
Lymph nodes should be considered abnormal if the long axis is > 1.5 cm regardless of the short 
axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if 
its short axis is > 1.0. Lymph nodes 1.0 x 1.0 cm will not be considered abnormal for relapse 
or progressive disease.
1.
Appearance of any new lesion > 1.5 cm in any axis during or at the end of therapy, even if other lesions are 
decreasing in size. Increased FDG uptake in a previously unaffected site should only be considered relapsed or 
PD after confirmation with other modalities. In patients with no prior history of pulmonary lymphoma, new 
lung nodules identified by CT are mostly benign. Thus, a therapeutic decision should not be made solely on the 
basis of the PET without histologic confirmation.
2.
At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, 
or the size of other lesions (e.g., splenic or hepatic nodules). To be considered PD, a lymph node with a 
diameter of the short axis of < 1.0 cm must increase by 50% and to a size of 1.5 x 1.5 cm or > 1.5 cm in the 
long axis.
3.
At least a 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis.
4.
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive 
before therapy unless the lesion is too small to be detected with current PET systems (< 1.5 cm in its long axis 
by CT).
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these recommendations, the spleen is considered nodal disease. Disease that is only 
assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent only, 
unless, while an abnormality is still noted by imaging studies or physical examination, it is found 
to be histologically negative.
In clinical trials where PET is unavailable to the vast majority of participants, or where PET is 
not deemed necessary or appropriate for use (e.g., a trial in patients with MALT lymphoma), 
response should be assessed as above, but only using CT scans. However, residual masses should 
not be assigned CRu status, but should be considered partial responses.
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APPENDIX 2
2008 INTERNATIONAL WORKING GROUP (IWG) RESPONSE 
CRITERIA FOR CLL WITH MODIFICATIONS
2008 IWG Response Criteria for CLL with Modifications1
COMPLETE REMISSION (CR)

Absence of lymphadenopathy by physical examination and appropriate radiographic techniques. Lymph 
nodes should not be larger than 1.5 cm in diameter.

No hepatomegaly or splenomegaly by physical examination or appropriate radiographic techniques if in a 
clinical trial.

Absence of constitutional symptoms.

Normal CBC as exhibited by:

Polymorphonuclear leukocytes 1,500/L

Blood lymphocytes < 4000/L

Platelets > 100,000/L

Hemoglobin > 11.0 g/dL (without transfusion or exogenous erythropoietin)

Bone marrow aspirate and biopsy should be performed after clinical and laboratory results demonstrate that 
all of the requirements listed above have been met, to demonstrate a CR has been achieved. The bone 
marrow should be analyzed by flow cytometry and/or immunohistochemistry (IHC) to demonstrate that the 
marrow is free of clonal B-CLL cells. The marrow sample must be at least normocellular for age, with 
< 30% of nucleated cells being lymphocytes. Lymphoid nodules should assessed by IHC to define whether 
they are comprised primarily of T cells or lymphocytes other than CLL cells or of CLL cells. Cases with 
residual CLL cells by conventional flow cytometry or IHC are defined as partial remission (PR). If the 
bone marrow is hypocellular, a repeat determination should be made in 4 – 6 weeks. Samples should be re-
reviewed in conjunction with the prior pathology.
Minimal residual disease (MRD): performed by MRD 4-color flow, allele-specific oligonucleotide PCR with 
sensitivity to 1 CLL cell per 10,000 leukocytes.
COMPLETE REMISSION with incomplete bone marrow recovery (CRi)
Otherwise CR, but who have persistent anemia, thrombocytopenia or neutropenia that appears to be related to 
persistent drug toxicity rather than to disease activity. The long-term outcome for these patients may be 
different from the noncytopenic CR.
PARTIAL REMISSION (PR) 
At least 2 of the following:

50% decrease in peripheral blood lymphocyte count from the pretreatment baseline.

50% reduction in the noted pretreatment enlargement of the spleen or liver.

50% reduction in marrow infiltrate, or B-lymphoid nodules.

50% reduction in lymphadenopathy (preferably by CT) as defined by the following:

A decrease in lymph node size by 50% or more either in the sum products of up to 6 lymph nodes, or 
in the largest diameter of the enlarged lymph node(s), detected prior to therapy.

No increase in any lymph node, and no new enlarged lymph node. In small lymph nodes (< 2 cm), an 
increase of less than 25% is not considered to be significant.

A reduction in the noted pretreatment enlargement of the spleen or liver by 50% or more, as detected 
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by CT scan (preferably).
At least one of the following:

Polymorphonuclear leukocytes 1,500/L or 50% improvement over baseline without need for exogenous 
growth factors.

Platelets > 100,000/μL or 50% improvement over baseline.

Hemoglobin > 11.0g.dL or 50% improvement over baseline without transfusions.
PROGRESSIVE DISEASE (PD)
At least one of the following:

Appearance of any new lesion, such as enlarged lymph nodes (> 1.5 cm), de novo splenomegaly, de novo 
hepatomegaly or other organ infiltrates. 

An increase by 50% in greatest determined diameter of any previous site. A lymph node of 1 to 1.5 cm 
must increase by 50% or more to a size greater than 1.5 cm in the longest axis. A lymph node of more than 
1.5 cm must increase to more than 2.0 cm in the longest axis.

An increase of 50% or more in the sum of the product of diameters of multiple nodes. 

50% increase in the size of the liver or spleen.

50% increase in the absolute number of circulating lymphocytes with 5,000 B lymphocytes per 
microliter.

Transformation to a more aggressive histology (eg, Richter’s syndrome). Whenever possible, this diagnosis 
should be established by lymph node biopsy.

During therapy, cytopenias cannot be used to define disease progression. After treatment the progression of 
any cytopenia (unrelated to autoimmune cytopenia), as documented by:

Decrease of Hb levels by > 20 g/L (2 g/dL) or to < 100 g/L (10 g/dL), or 

Decrease of platelet counts by more than 50% or to less than 100 x 109/L (100,000/µL), which occurs 
at least 3 months after treatment, defines disease progression, if the marrow biopsy demonstrates an 
infiltrate of clonal CLL cells.
STABLE DISEASE (SD)
Subjects who have not achieved a CR or a PR, or who have not exhibited PD.
RELAPSE:  defined as a patient who has previously achieved the above criteria (“Complete remission,” 
“Partial remission”) of a CR or PR, but after a period of 6 or more months, demonstrate evidence of disease 
progression (see preceding discussion of progressive disease).
1 Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National 
Cancer Institute-Working Group 1996 guidelines. Blood 2008;111(12):5446-56.
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APPENDIX 3
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
Anti-LAG-3 has not undergone the requisite preclinical testing for teratogenicity and therefore 
requires two forms of contraception. One method must be highly effective and the second 
method may also be highly effective or selected from the list of other contraceptive methods.
Women and men who are not capable of reproduction or choose to be abstinent shall be exempt 
from following the pregnancy prevention requirements specified below.
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 oopherectomy.
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.
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 135 days after the end of 
study treatment, plus 30 days, a total of 24 weeks.
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 ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 
injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)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.
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
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 3.3.1.

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence 
that the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal(coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
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CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until the end of 
relevant systemic exposure defined as 33 weeks after the end of treatment in the male 
participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 33 weeks after the end of treatment. 

Refrain from donating sperm for the duration of the study treatment and for 33weeks after 
the end of treatment.
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 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
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 6
RESPONSE CRITERIA MODIFIED FROM IMWG FOR MULTIPLE 
MYELOMA
Response Subcategory
Response Criteria1
Stringent Complete Response (sCR)
CR, as defined below, plus the following:
Normal FLC ratio and absence of clonal cells in bone marrow2 by 
immunohistochemistry or immunofluorescence.3
Complete Response (CR)

Negative immunofixation on the serum and urine.

5% plasma cells in bone marrow.
Very Good Partial Response (VGPR)
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 90% reduction in serum M-protein level plus urine 
M-protein level < 100 mg per 24 hour.
Partial Response (PR)
50% reduction of serum M-protein and reduction in 24-hour urinary 
M-protein by 90% or to < 200 mg per 24 hour.
Minor (Minimal) Response (MR)
Subjects who have reduction in M-protein but do not meet the criteria for 
PR are classified as MR if they meet all the following definition:

Between 25 - 49% reduction in serum M-protein.

Between 50 - 89% reduction in urinary light chain excretion which 
still exceeds 200 mg/24 hours.

If a skeletal survey is performed, no development of lytic lesions.
Stable Disease (SD)
Not meeting criteria for CR, VGPR, PR, MR, or progression.
Progression Subcategory
Progression Criteria
Progressive disease,4
Requires an increase of 25% from lowest response level (nadir) in any 
one or more of the following:

Serum M-component (the absolute increase must be 0.5 g/dL).5

Urine M-component (the absolute increase must be 200 mg/24 
hour).

Bone marrow plasma cell percentage: the absolute % must be 
10%. 

Definite development of new bone lesions or soft tissue 
plasmacytomas.

Development of hypercalcemia (corrected serum calcium > 11.5 
mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma 
cell proliferative disorder.
Progression to Active Myeloma
Evidence of progression based on IMWG criteria for progressive disease 
in myeloma and any one or more of the following felt related to the 
underlying clonal plasma cell proliferative disorder:

Development of new soft tissue plasmacytomas or bone lesions.

Hypercalcemia (> 11 mg/dL)

Decrease in hemoglobin of 2 g/dL 

Rise in serum creatinine by 2 mg/dL or more
1 All response categories require 2 consecutive assessments made at any time before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies 
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were performed. Radiographic studies are not required to satisfy these response requirements. The second of the 2 
consecutive assessments should occur at the next planned tumor assessment.
2 Confirmation with repeat bone marrow biopsy not needed.
3 Presence or absence of clonal cells is based upon the /. An abnormal /ratio by immunohistochemistry and/or 
immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence 
of an abnormal clone is /of > 4:1 or < 1:2.
4 To be used for calculation of time to progression and progression-free survival endpoints for all subjects, 
including those in CR (includes primary progressive disease and disease progression on or off therapy).
5 For progressive disease, serum M-component increase of ≥ 1 gm/dl is sufficient to define progression if starting 
M-component is ≥ 5 g/dL.
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APPENDIX 7
LUGANO 2014 RESPONSE CRITERIA
For PET-based assessments, a clinical response of progressive metabolic disease (PMD), no 
metabolic response (NMR), partial metabolic response (PMR), or complete metabolic response 
(CMR) will be determined. PMD/PD includes radiological evidence of progression per Lugano 
Classification Revised Staging System for malignant lymphoma. The PET scan metabolic uptake 
will be graded using the Deauville 5-point scale, with a score of 3 considered to represent a 
CMR. 
Deauville 5-point scale: 1- no uptake above background; 2- uptake mediastinum; 3- uptake 
> mediastinum but liver; 4= uptake moderately > liver; 5- uptake markedly higher than liver 
and/or new lesions; X- new areas of uptake unlikely to be related to lymphoma.
Table 1:
CMR / CR
Response/Site
FDG PET-CT-Based
(Complete Metabolic Response)
CT-Based (CR)a
All of the following:
Lymph nodes and extralymphatic 
sites
Score 1, 2 or 3 with or without a 
residual mass on 5-Point-Scale
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or marrow 
(eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake 
may be greater than normal 
mediastinum and/or liver. In this 
circumstance, complete metabolic 
response may be inferred if uptake 
at sites of initial involvement is no 
greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake.
Target nodes/nodal masses must 
regress to 1.5 cm in LDi
No extralymphatic sites of disease
Non-measured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease 
in marrow
Normal by morphology; if 
indeterminate, IHC negative
a CT-Based could also apply to MRI-Based  
Note: Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059-68.
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Table 2:
PMR / PR
Response/Site
FDG PET-CT-Based
(Partial Metabolic Response)
CT-Based (PR)a
All of the following:
Lymph nodes and extralymphatic 
sites
Score 4 or 5 with reduced uptake 
compared with baseline and 
residual mass(es) of any size
At interim, these findings suggest 
responding disease
At end of treatment, these findings 
suggest residual disease
50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites
When a lesion is too small to 
measure on CT, assign 5 mm X 
5 mm as the default value; when no 
longer visible, 0 X 0 mm; for a 
node > 5 mm X 5 mm, but smaller 
than normal, use actual 
measurement for calculation
Non-measured lesion
Not applicable
Absent/normal, regressed, but no 
increase
Organ enlargement
Not applicable
Spleen must have regressed by 
> 50% in length beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline
(diffuse uptake compatible with 
reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the 
marrow in the context of a nodal 
response, consideration should be 
given to further evaluation with 
MRI or biopsy or an interval scan.
Not applicable
a CT-Based could also apply to MRI-Based  
Note: Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059-68. 
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Table 3:
NMR / SD
Response/Site
FDG PET-CT-Based
(NMR)
CT-Baseda
(SD)
Target nodes/nodal masses, 
extranodal lesions
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment
< 50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites; no criteria for 
Progressive Disease met
Non-measured lesion
Not applicable
No increase consistent with 
Progression
Organ enlargement
Not applicable
No increase consistent with
Progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
a CT-Based could also apply to MRI-Based  
Note: Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059-68.
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Table 4:
PMD / PD
Response/Site
FDG PET-CT-Based
(PMD)
CT-Based (PD)a
At least one of the following:
Individual target nodes/nodal 
masses
Extranodal lesions
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or new FDG-avid foci 
consistent with lymphoma at 
interim or end-of-treatment 
assessment
An individual node/lesion must be 
abnormal with:
LDi > 1.5 cm &
Increase by 50% from PPD nadir &
An increase in LDi or SDi from nadir
     0.5 cm for lesions 2 cm
     1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by 
> 50% of the extent of its prior 
increase beyond baseline (eg, a 15 
cm spleen must increase to 16 cm). If 
no prior splenomegaly, must increase 
by at least 2 cm from baseline
New or recurrent splenomegaly 
Non-measured lesion
None
New or clear progression of 
preexisting nonmeasured lesions
New lesions
New FDG-avid foci consistent 
with lymphoma rather than 
another etiology (e.g., infection, 
inflammation). 
If uncertain regarding etiology of 
new lesions, biopsy or interval 
scan may be considered.
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma. 
Assessable disease of any size 
unequivocally attributable to 
lymphoma.
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
a CT-Based could also apply to MRI-Based  
Note: Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059-68.
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APPENDIX 8
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol Revised Protocol 08, 11-Oct-2019
The revised protocol changes Study Director and Medical Monitor, adds the current packaging of
relatlimab (BMS-986016) to the study formulary, and updates safety information based on the 
current relatlimab Investigator Brochure. 
Additionally, the revised protocol adds exclusions and restrictions on participants receiving live / 
attenuated vaccines, requirements for reporting sexual activity in cases where study drug can be 
present in seminal fluid, and provides updates to Appendix 4.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 08
Section Number
& Title
Description of Change
Brief Rationale
Title Page
Changed Study Director from:
Changed Medical Monitor from:
Changed Study Director.
Changed Medical Monitor as per 
Administrative Letter 07.
Title Page;
Synopsis
Short Title added.
Short Title added for clarity and 
alignment with Short Title 
provided on ClinicalTrials.gov.
1.4.1.5: Clinical Safety-
Monotherapy (Part A and 
Part B) and Combination 
Therapy (Part C and D) in 
CA224022;
1.4.1.6: Serious Adverse 
Events;
1.4.1.7: Infusion Reactions;
1.4.1.8: Adverse Events 
Leading to Discontinuation;
1.4.1.9: Deaths;
1.5: Clinical Safety -
Monotherapy (Part A and 
A1) and Relatlimab in 
Combination with 
Nivolumab Therapy (Parts B, 
C, and D) in Solid  Tumor 
Study CA224020;
1.5.1: Adverse Events;
1.5.2: Serious Adverse 
Events
1.5.3: Infusion Reactions;
1.5.4: Adverse Events 
Leading to Discontinuation;
1.5.5
Deaths;
Updated safety information based on 
current studies and current relatlimab 
Investigator Brochure.
To provide current clinical safety 
data.
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BMS-986016
relatlimab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 08
Section Number
& Title
Description of Change
Brief Rationale
1.6: Clinical Efficacy -
Studies CA224020 and 
CA224022;
1.8: Overall Risk/Benefit
Assessment
4.1: Study Treatments
Relatlimab Injection 
 mg/vial added to 
Table 4, Product Description and Dosage 
Form.
Study formulary updated to reflect 
current packaging of relatlimab.
5.1: Flow Chart/Time and 
Events Schedule
Removed the PK and immunogenicity 
assessments scheduled on follow-up visit 1 
in Table 5.1-3, Follow-Up Procedural 
Outline (CA224022).
Table 5.1-3 updated as per 
Administrative Letter 06.
3.3.2: Exclusion Criteria, 4), 
a);
3.5: Discontinuation of 
Subjects from Treatment
Prisoners or subjects who are involuntarily 
incarcerated. (Note: under specific 
circumstances, and only in countries 
where local regulations permit, a person 
who has been imprisoned may be included 
as a participant. Strict conditions apply and 
BMS approval is required.)
The phrase in bold was added to 
align with BMS exclusion for 
prisoners.
3.3.2: Exclusion Criteria, 2), 
p), ii), (3);
3.4.1: Prohibited and/or 
Restricted Treatments
Participants who have received a 
live / attenuated vaccine within 30 days 
of first treatment.
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.
The phrase in bold was added to 
align with Nivolumab Investigator 
Brochure.
The text was added to align with 
Nivolumab Investigator Brochure.
4.3.2: Dose Delay Criteria
Myocarditis added to the list of toxicities 
for which management algorithms have 
been developed.
Added to reflect the current safety 
information for immuno-oncology 
agents.
6.4: Pregnancy
Added additional requirements for 
reporting sexual activity in cases where 
study drug can be present in seminal fluid.
To align with BMS policy on 
women of childbearing potential, 
exposure, and contraception.
6.5: Overdose
The following text was added, “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.”
Previous text was modified to now read: 
“All occurrences of intentional overdose 
Text was added to clarify the need 
for the investigator to report the 
specific term of “intentional 
overdose” as an AE term. All other 
types of overdose should NOT be 
reported as an AE but should be 
recorded elsewhere on the CRF. 
There are no changes to the 
reporting of AEs associated with 
any type of overdose.
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relatlimab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 08
Section Number
& Title
Description of Change
Brief Rationale
must be reported as an SAE (see Section 
6.1.1 for reporting details).”
Overdoses that meet the regulatory 
definition of SAE will be reported 
as an SAE.
10: Glossary of Terms
Serious Adverse Event: Section modified 
to read: “For reporting purposes only, 
BMS also considers the occurrence of 
pregnancy, intentional overdose, and 
cancer as important medical events.”
Added the word “intentional” to 
align this section with clarifying 
updates made to overdose 
language.
Appendix 4: Management 
Algorithms
Hepatic Adverse Event Management 
Algorithm: Footnote stating I-O therapy 
may be delayed rather than discontinued if 
AST/ALT 8 x ULN or T.bili 5 x ULN 
was removed.
“Myocarditis Adverse Event Management 
Algorithm” table was added.
Language was modified to align 
protocol with current Nivolumab 
Investigator Brochure and 
nivolumab program safety 
parameters.
Updating Management Algorithms 
to most recent version.
All
BMS-986016 has been replaced by its 
generic name, relatlimab, throughout the 
sections as appropriate.
Minor formatting and typographical 
corrections.
Clarification.
Minor, therefore have not been 
summarized.
Overall Rationale for the Revised Protocol Revised Protocol 07, 28-Mar-2018
The purpose of Revised Protocol 07 is to: 1) require pre-and on-treatment biopsies for all subjects 
in Part D 2) add Survival Follow-up and 3) clarify eligibility criteria; and 4) to update safety and 
clinical pharmacology information and criteria for dose delay and permanent discontinuation. See 
below for further details.
Biopsies required for 
 subjects in Part D 
, which will allow a 
more comprehensive investigation of markers associated to response and mechanisms of 
resistance. Survival Follow-up is defined and may continue for up to 5 years from the first dose in 
HL patients in Parts C and D. Subjects who were progressed on PD-1/PD-L1 inhibitors within 3 
months of exposure are also allowed. Safety and clinical pharmacology information and criteria 
for dose delay and permanent discontinuation were updated based on the most recent IB 
 and emerging data.
Additionally, the revised protocol incorporates 
 
change in Study 
Director and Medical Monitor, grammatical revisions and reference updates were also included.
Revisions apply to future participants enrolled in the study and where applicable to all participants 
currently enrolled.
Revised Protocol No.: 09
Date: 17-Nov-2020
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BMS-986016
relatlimab
Summary of key changes of Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Synopsis was updated
Synopsis was updated to 
reflect the changes made in 
the protocol
Section 1.3 Objectives, 
Synopsis
Aligned objectives with 
endpoints Removed two safety 
secondary objectives. Added an 
exploratory objective to assess 
the overall survival rates and 
PFS rates  at various time points 
in selected patients in Part D  
Alignment of objectives with 
endpoints. The two 
secondary objectives were 
repetitive with primary safety 
objective.  The exploratory 
objective was added to assess 
the 
in 
selected patient populations.
Section 1.4.1.4 Clinical 
Pharmacology
Clinical pharmacology 
information was updated based 
on current studies and updated 
Investigator Brochures (IB).
To provide current clinical 
pharmacology data.
Section 1.4.1.5 Clinical 
Safety Monotherapy (Part A 
and Part B) and 
Combination Therapy (Part 
C) in CA224022, Section 
1.4.1.6 Serious Adverse 
Events, Section 1.4.1.7 
Infusion Reactions, Section 
1.4.1.8 Adverse Events 
Leading to Discontinuation, 
1.5 Clinical Safety -
Monotherapy (Part A) and 
BMS-986016 in 
combination with 
Nivolumab Therapy (Parts 
B and C) in Solid Tumor 
Study CA224020, 1.5.1
Adverse Events, 1.5.2 
Serious Adverse Events, 
1.5.3 Infusion Reactions, 
1.5.4 Adverse Events 
Leading to Discontinuation, 
1.5.5 Deaths, 1.6 Clinical 
Efficacy Monotherapy (Part 
A and Part B): CA224022 
Study 
Updated safety information 
based on current studies and 
updated IB.
To provide current clinical 
safety data.
Revised Protocol No.: 09
Date: 17-Nov-2020
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CA224022
BMS-986016
relatlimab
Summary of key changes of Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
1.8 Overall Risk/Benefit 
Assessment
Updated safety information 
based on current studies.
To provide current 
risk/benefit assessment based 
on updated clinical safety 
data.
Section 3.1 Figure 3.1-1 
Study Design Schematic, 
Figure 3.1-2 Study 
Schematic
Removed the dose combination 
of 
 
nivolumab, and added the dose 
combination of 
 
 mg nivolumab in Part 
C Figure 3.1-1. Also clarified 
the figure notes.
The LAG-3 dose of 
 mg 
was removed and 
 mg 
was added due to the 
toxicity, safety and clinical 
pharmacology findings in 
Parts A and B.
Added Survival Follow-up to 
Figure 3.1-2 schematic for Pats 
C and D of the study.  Edited 
the text accordingly for 
Survival Follow Up.
Survival Follow Up was 
added to allow selected 
participants to be followed 
for a longer time period to 
obtain additional data
Treatment during the Re-
challenge period was changed 
from 12 additional eight-week 
cycles to 6 additional eight-
week cycles.
Decreasing re-challenge 
period ensures the study data 
can be concluded in a 
reasonable time period. 
Based on previous study 
experience, the re-challenge 
data is not expected to have 
significant impact on study 
conclusion.
Section 3.3.1 Part C Dose 
Escalation Combination 
Therapy, Section 3.3.1 
Inclusion Criteria 2 e) ii
Allowed patients progressed 
within 3 months of previous 
anti-PD1 or anti-PD-L1 
treatment.
Progression within 3 months 
of previous anti-PD1/PD-L1 
is allowed according to the 
MOA.
Section 3.3.1: Inclusion 
Criteria 1 b) iv)
Changed the requirement for 
“the first 6 subjects” to “All 
subjects” in Part D must 
consent to allow on-treatment 
biopsy. Additionally if a fresh 
pre-treatment tumor biopsy was 
not medically feasible and 
enrollment was approved by the 
Medical Monitor with an 
archival tumor sample, the on-
The requirement for All 
subjects to consent for on-
treatment biopsy was 
changed which will allow a 
more comprehensive 
investigation of markers 
associated to response and 
mechanisms of resistance.
With the BMS Medical 
Monitor approval of 
Revised Protocol No.: 09
Date: 17-Nov-2020
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CA224022
BMS-986016
relatlimab
Summary of key changes of Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
treatment tumor biopsy will not 
be required.
enrollment without a fresh 
pre-treatment biopsy, the on-
treatment biopsy is also not 
required.
Section 3.3.2: Exclusion
Criteria
Exclusion Criteria 2h) vii) 
details of Cardiac Troponin test 
results were clarified.
The exclusion criterion text 
for Troponin and cardiac 
evaluation is revised to align 
with the most recent program 
requirements based on 
updated safety information.
2J i), ii), iii) was revised to 
clarify hepatitis exclusion 
criteria.
Exclusion criteria for 
hepatitis was updated to 
align with the standard 
program requirements
Section 3.4.2.2 Imaging 
Restrictions and Precautions
Added Imaging Restrictions and 
Precautions
Imaging restrictions and 
precautions were added to 
the study to provide guidance 
when using contrast. 
Section 4.3.2 Dose Delay 
Criteria
Updated the dose delay criteria.  
Removed Grade 3 skin and 
added Grade 1 myocarditis and 
troponin elevations. Also added 
text defining delayed doses, 
maximum delays, and 
subsequent dosing.
To align with most recent 
program requirements based 
on updated safety 
information.
Section 4.3.3 Criteria to 
Resume Treatment after 
Dose Delay
Removed some of the 
exceptions to permanent 
discontinuation.  See the revised 
document for the specific 
changes. Added troponin 
evaluations requiring cardiac 
evaluation and discussion with 
BMS Medical monitor.
To align with most recent 
program requirements based 
on updated safety 
information.
Section 4.3.5 Guidelines to 
Permanent Discontinuation
Added and removed criteria for 
permanent discontinuation of all 
study drugs.  See revised 
document for details.
To align with most recent 
program requirements based 
on updated safety 
information.
Table 5.1-1 Screening 
Procedural Outline, Tumor 
Updated to clarify tumor biopsy
sample requirement for Part D 
and add footnote that re-
All subjects in Part D must 
consent to allow pre-
treatment tumor biopsy or if 
Revised Protocol No.: 09
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BMS-986016
relatlimab
Summary of key changes of Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
tissue sample (eg, primary 
tumor, lymph node) 
challenge subjects must be re-
screened.
not clinically feasible, and 
approved by the Medical 
Monitor, must consent to 
allow the acquisition of an 
archived tumor sample.
Table 5.1-2 On-Treatment 
Procedural Outline, On-
treatment tumor or lymph 
node biopsy
Updated Part D requirement for 
on-treatment tumor biopsy.
To allow a more 
comprehensive investigation 
of markers associated to 
response and mechanisms of 
resistance.
Table 5.1-3 Follow-Up 
Procedural Outline
Follow-Up Procedural Outline 
was updated to include Survival 
Follow-Up for HL participants 
in Parts C and D.
To align with study design.
Section 5.3.3: Laboratory 
Test Assessments
Removed requirement for
Hepatitis A test.
Hepatitis A test was removed 
because to align with the 
standard nivolumab 
requirements.
Table 5.7-1 Biomarker 
Sampling Schedule & 5.7.7 
Tumor-Based Biomarker 
Measures
Table titles were revised for re-
challenge; updated table notes 
regarding biopsy and archival 
tissue requirements.
To align with study design 
and biomarker sampling
requirements.
New Section 5.7.8 
Additional Research 
Collection
Added the section which 
describes the retention of 
residual samples 
To allow residual samples to 
be retained for possible 
future testing.
Section 8 Statistical 
Consideration 
All applicable sections updated 
to include all revised parts of 
the study.
To align statistical language 
with study objectives.
Section 8.3.2.3 Receptor 
Occupancy
Receptor Occupancy was 
added.
Receptor Occupancy was 
added to provide additional 
data.
Section 8.3.2.3 ORR, DOR, 
CRR, PFS, and OS
Added definitions for each of 
the endpoints.
To provide robust definitions 
of the endpoints
Section 8.4.2 Efficacy 
Analysis
Individual ORR, CRR, DOR, 
and PFS will be determined. 
To describe analyses and 
methodologies used.
Section 8.4.3 Safety 
Analyses
Description of how AEs will be 
listed and summarized was 
updated. 
To provide more description 
of the analyses.
Revised Protocol No.: 09
Date: 17-Nov-2020
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Clinical Protocol
CA224022
BMS-986016
relatlimab
Summary of key changes of Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Appendix 3 Guidance on 
Contraception Women of 
Childbearing Potential and 
Methods of Contraception 
Adds definition of Women of 
Childbearing Potential and 
revised methods of 
contraception.
To align with current BMS 
SOP.
All
Minor formatting and 
typographical corrections.
Minor, therefore have not 
been summarized.
Revised Protocol No.: 09
Date: 17-Nov-2020
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