A Phase 2 Study of Nivolumab + BMS-986016 (Relatlimab) in Patients With Metastatic Uveal Melanoma
Phase: PHASE2
Conditions: Metastatic Uveal Melanoma
Sponsor: Jose Lutzky, MD

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A Phase 2 Study of Nivolumab + BMS-986016 (Relatlimab) 
in Patients with Metastatic Uveal Melanoma.
Bristol-Myers #: CA224-094
eProst#: 20200847
IND#:152402
NCT04552223
Sponsor Investigator/Principal 
Investigator
Jose Lutzky, MD
University of Miami
Sylvester Comprehensive Cancer Center
1475 NW 12th Ave
Miami, FL 33136
J. William Harbour, MD
Co-Investigators
Lynn Feun, MD
Funding Collaborator
Bristol-Myers Squibb Research and 
Development 
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Study Drug(s) Name
Nivolumab (also referred to as BMS-
936558, MDX1106, or ONO-4538) and 
Relatlimab (also referred to as BMS-
986016)
Version 3.0
Version date
4 February 2023
Confidentiality Statement
All information contained in this document is privileged and confidential. Any distribution, 
copying, or disclosure is strictly prohibited without prior written approval by the Sponsor.
      
 
 
        
 
 

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Investigational Agent(s):
Nivolumab (also referred to as BMS-
936558, MDX1106, or ONO-4538) 
and Relatlimab (also referred to as 
BMS-986016)
IND Status:
IND#: 152402
      
 
 
        
 
 

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STATEMENT OF COMPLIANCE
I confirm that I have read this protocol, I understand it, and I will work according to 
this protocol and to the ethical principles stated in the latest version of the 
Declaration of Helsinki, the applicable ICH guidelines for good clinical practices, and 
the applicable federal, state, and local laws, rules, and regulations relating to the 
conduct of the protocol.  
I have read and understand the information in the Investigators’ Brochure (and/or 
other such pertinent safety information) regarding the risks and potential benefits.  
I agree to inform all those who assist/collaborate with me in the conduct of this study 
of their responsibilities and obligations. 
Once the protocol has been reviewed and approved by the Institutional Review 
Board (IRB) I understand that any change(s) made during the course of the study 
must also (first) be approved by the IRB prior to implementation, except when such 
modification is made to remove any immediate hazard(s) to the subject(s).  
I certify that I and the study staff responsible, have received the requisite training to 
conduct this research protocol.  
I agree to maintain adequate and accurate records in accordance with the University 
of Miami policies, federal, state and local laws and regulations.  
I agree to maintain the confidentiality of all information received and/or developed in 
connection with this protocol.
eProst Number: 
20200847
Protocol Version Number:
Version 3.0
Protocol Version Date:
4 February, 2023
Signature of Investigator:
Date:
Name of Investigator (printed):
Institution:
      
 
 
        
 
 

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TABLE OF CONTENTS
List of Study Contacts ..............................................................................................2
Protocol Revision History.........................................................................................4
Statement of Compliance .........................................................................................5
List of Abbreviations and Definitions....................................................................11
Protocol Summary...................................................................................................13
Schema..................................................................................................................17
1
Introduction...................................................................................................18
1.1
Clinical Background on Uveal Melanoma ...................................................18
1.2
Lymphocyte activation gene 3 (LAG-3) and recent pre-clinical data: .........19
1.3
Background on Nivolumab..........................................................................21
1.3.1
Nonclinical Studies............................................................................21
1.3.2
Clinical Studies .................................................................................22
1.4
Background on Relatlimab (BMS-986016) .................................................23
1.4.1
Non-Clinical Studies..........................................................................23
1.4.2
Clinical Studies .................................................................................25
1.5
Combination Treatment Phase 1 Trials.......................................................26
1.6
Hypothesis ..................................................................................................26
1.7
Rationale.....................................................................................................27
1.7.1
Rationale for Current Study ..............................................................27
1.7.2
Rationale for Study Design ...............................................................27
1.7.3
Rationale for Patient Population .......................................................27
1.7.4
Rationale for Dose Selection: ...........................................................27
1.8
Risk/Benefit Assessment ............................................................................27
1.8.1
Nivolumab Known Potential Risks ....................................................27
1.8.2
Known Potential Benefits..................................................................28
1.8.3
Relatlimab Known Potential Risks ....................................................28
1.8.4
Nivolumab and Relatlimab Combination Therapy Potential Risks....28
1.8.5
Assessment of Potential Risks and Benefits.....................................29
2
Objectives and Endpoints............................................................................30
3
Study design .................................................................................................31
3.1
Overall Design.............................................................................................31
4
Study Population ..........................................................................................32
4.0
Inclusion Criteria .........................................................................................32
Patients participating in this study must:................................................................32
4.1
Exclusion Criteria ........................................................................................33
4.2
Strategies for Recruitment and Retention...................................................35
5
Treatment Plan..............................................................................................36
      
 
 
        
 
 

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5.1
Method of Treatment Assignment...............................................................36
5.2
Dosing and Administration ..........................................................................36
5.3
Missed doses ..............................................................................................36
5.4
Concomitant Therapy..................................................................................36
5.5
Premedication .............................................................................................36
5.6
Prohibited Therapies...................................................................................36
5.7
Study Intervention Compliance ...................................................................37
5.8
Contraception..............................................................................................37
5.9
Breast Feeding............................................................................................39
5.10
Blood Donation............................................................................................39
5.11
Duration of Follow Up..................................................................................39
5.12
End of Study Definition................................................................................39
6
Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal ...................................................................................40
6.1
Discontinuation of Study Intervention .........................................................40
6.2
Participants Taken Off Study ......................................................................40
6.3
Participant Discontinuation/Withdrawal from the Study ..............................40
6.3.1
Data Retention When Subjects Withdraw from FDA-Regulated 
Clinical Trials.....................................................................................41
6.4
Participant Replacement Criteria ................................................................41
6.5
Lost to follow up ..........................................................................................41
7
TREATMENT DISCONTINUATION AND ADVERSE EVENT MANAGEMENT
42
8
Nivolumab .....................................................................................................44
8.1
Description of Investigational Product.........................................................44
8.2
Mechanism of Action...................................................................................44
8.3
Dosage Form, Agent Preparation, Handling & Storage Guidelines ............44
8.3.1
Dosage Form ....................................................................................44
8.3.2
Acquisition and Accountability ..........................................................44
8.3.3
Preparation and Administration.........................................................45
8.3.4
Packaging, Labeling, and Storage....................................................45
8.4
Disposal and Destruction ............................................................................45
9
Relatlimab......................................................................................................46
9.0
Description of Investigational Product.........................................................46
9.1
Mechanism of Action...................................................................................46
9.2
Dosage Form, Agent Preparation, Handling & Storage Guidelines ............46
9.2.1
Dosage Form ....................................................................................46
9.2.2
Acquisition and Accountability ..........................................................46
9.2.3
Preparation and Administration.........................................................46
      
 
 
        
 
 

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9.2.4
Packaging, Labeling, and Storage....................................................47
9.3
Disposal and Destruction ............................................................................48
10
Schedule of Assessments ...........................................................................49
10.1
Screening....................................................................................................49
10.2
Cycle 1, 3, 5, 7, Day 1 + or – 3 days...........................................................49
10.3
Cycles 2, 4, 6, 8, Day 1 + or – 3 days.........................................................50
10.4
Subsequent Treatment Cycles....................................................................50
10.5
End of Treatment Visit, 28 days after the last dose of Nivolumab and 
Relatlimab combination treatment (+ or – 14 days)..........................................50
10.6
Safety Follow-Up, 30 days (+ or – 7 days) post discontinuation.................51
10.7
Survival Follow-Up, Every 12 weeks (+ or – 7 days) for 2 years ................51
10.8
STUDY CALENDAR ...................................................................................53
11
Correlative Studies.......................................................................................56
12
Evaluation Criteria........................................................................................58
12.1
Parameters of Outcome –RECIST 1.1 Criteria ...........................................58
12.2
Definition of Measurable Lesions................................................................58
12.3
Treatment Beyond Progression ..................................................................58
12.4
Baseline documentation of “Target” and “Non-Target” lesions ...................58
12.5
Definition of disease progression................................................................59
12.6
Progression for Patients with Non-Measurable Disease at Baseline..........59
12.7
Progression-Free Survival...........................................................................59
12.8
Subjective Parameters................................................................................59
13
Adverse Events and Serious Adverse Events ...........................................61
13.1
Definition of Adverse Events.......................................................................61
13.2
Definition of Serious Adverse Events..........................................................61
13.3
Non-Serious Adverse Event........................................................................62
13.4
Classification of an Adverse Event..............................................................63
13.4.1
Severity of Event...............................................................................63
13.4.2
Relationship to Study Intervention ....................................................63
13.4.3
Expectedness ...................................................................................63
13.4.4
Time Period and Frequency for Event Assessment and Follow-Up .64
13.5
Adverse Event Reporting ............................................................................64
13.6
Serious Adverse Event Reporting...............................................................64
13.7
Adverse Event Collection and Reporting Information: ................................65
13.8
Reporting Events to Participants.................................................................67
13.9
Events of Special Interest ...........................................................................68
13.9.1
Pregnancy.........................................................................................68
13.9.2
Other Safety Considerations.............................................................69
      
 
 
        
 
 

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14
Unanticipated Problems...............................................................................70
14.1
Definition of Unanticipated Problems..........................................................70
14.2
Unanticipated Problem Reporting ...............................................................70
14.3
Reporting Unanticipated Problems to Participants .....................................70
15
Data reporting ...............................................................................................71
15.1
Data submission..........................................................................................71
15.2
Data and Safety Monitoring.........................................................................71
15.3
Early Stopping Guidelines...........................................................................71
15.4
Early Stopping Due to Safety......................................................................72
15.5
Early Stopping Due to a Lack of Efficacy....................................................72
16
Statistical Methods.......................................................................................73
16.1
Statistical Hypothesis..................................................................................73
16.2
Sample Size Determination.........................................................................73
16.3
Statistical Analyses .....................................................................................73
16.3.1
Exploratory Analyses ........................................................................74
17
Supporting Documentation and Operational Considerations..................75
17.1
Informed Consent Process..........................................................................75
17.1.1
Consent/Assent and other Informational Documents Provided to 
Participants .......................................................................................75
17.1.2
Consent Procedures and Documentation.........................................75
17.2
Study Discontinuation and Closure.............................................................76
17.3
Confidentiality and Privacy..........................................................................76
17.4
Future Use of Stored Specimens and Data ................................................77
17.5
Study Auditing and Monitoring ....................................................................78
17.5.1
Trial Monitoring, Auditing, and Inspecting.........................................78
17.6
Quality Assurance and Quality Control .......................................................78
17.7
Data Handling and Record Keeping ...........................................................78
17.7.1
Data Collection and Management Responsibilities...........................78
17.7.2
Study Records Retention..................................................................79
17.8
Compliance with Protocol............................................................................80
17.9
Publication and Data Sharing .....................................................................81
17.10 Conflict of Interest Policy.............................................................................81
18
References ....................................................................................................82
APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING 
REQUIREMENTS......................................................................................................84
APPENDIX B: PERFORMANCE STATUS SCALES ...............................................86
APPENDIX C: BIOMARKER, CORRELATIVE AND SPECIAL STUDIES ..............87
      
 
 
        
 
 

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Table 1. Adequate Organ Function Laboratory Values ..............................................32
Table 2.Dosing and Administration Schedule Nivolumab + Relatlimab 
Combination Treatment (All cycles) .....................................................36
Table 3. Adverse Event Management Rules...........................................................43
Table 4. Stopping Rules for Safety..........................................................................70
      
 
 
        
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS
Abbreviation
Definition
ADA
Anti-drug antibodies
AE
Adverse event
AUC
Area under the curve
BMS
Bristol-Myers Squibb
CHO
Chinese hamster ovary
CTCAE
Criteria for Adverse Events
CTLA-4
Cytotoxic T lymphocyte antigen 4
CNS
Central nervous system
CR
Complete response
CRT
Case report form
DCR
Disease control rate
DOR
Duration of response
EC
Effective concentration
ePPND
Enhanced pre- and postnatal development
FDC
Fixed dose combination
HIV 
Human immunodeficiency virus
HSCT
Hematopoietic stem cell transplantation
GLP
Good laboratory practice
IB
Investigator’s brochure
IFN-γ
interferon-gamma
IGG4
Immunoglobulin G4
IgSF
Immunoglobulin superfamily
IO
Immuno-oncology
irAEs
Immune related adverse events
IRB
Institutional review board
IV
Intravenous
LAG-3
lymphocyte activation gene 3
mDOR
Median duration of response
MHC
Major histocompatibility complex
MLR
Mixed lymphocyte reaction
MTD
Maximum tolerated dose
NK
Natural killer
NOAEL
No-observed-adverse-effect-level
ORR
Overall response rate
OAS
Overall survival
      
 
 
        
 
 

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OS
Overall survival
PD-1
Programmed death-1
PD-L1
Programmed death ligand-1
PD-L2
Programmed death ligand-2
PFS
Progression free survival
Q2W
Every 2 weeks
Q4W
Every 2 weeks
SAE
Serious adverse event
SCCC
Sylvester Comprehensive Cancer Center
ULN
Upper limit of normal
UM
Uveal melanoma
T-Half
 Elimination half life
TIL
Tumor infiltrating lymphocytes
TME
Tumor microenvironment
      
 
 
        
 
 

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PROTOCOL SUMMARY
Title
A phase 2 study of nivolumab + BMS-986016 (relatlimab) in 
patients with metastatic uveal melanoma.
Background
The standard of care treatment for cutaneous melanoma has 
experienced rapid and significant changes. It has evolved from 
mostly ineffective chemotherapy and minimally successful 
immunotherapy to the current anti-CTLA4 and anti-
PD1/checkpoint inhibitors that have resulted in survival 
prolongation. For patients whose tumors harbor a BRFA V600 
mutations, combinations of BRAF plus MEK inhibitors provide 
another highly successful treatment option.
On the other hand, progress in the treatment of metastatic 
uveal melanoma has remained dismal. Uveal melanoma (UM) 
is a rare malignancy that arises from melanocytes within the 
uveal tract of the eye. The overall mean age-adjusted 
incidence of primary uveal melanoma in the US over the 41-
year period from 1973 to 2013 was 5.2 per million population 
(95% CI 5.0–5.4).
Although UM is often diagnosed at an early stage, 50% of 
patients will develop metastatic disease with 6–12 months 
survival from metastatic diagnosis. 
A meta-analysis of 796 patients treated for metastatic uveal 
melanoma with various forms of therapy demonstrated an 
overall response rate of 10.3% with 0.6% complete responses 
(CRs). For patients treated with immunotherapy the median 
PFS was 2.8 months and the median OAS was 8.9 months.1
The various treatment modalities used to treat metastatic 
uveal melanoma include liver-directed therapies, 
immunotherapy, targeted therapy and chemotherapy. 
Chemotherapy has been found to be largely ineffective.
A number of phase II trials with the anti-CTLA-4 blocking 
antibodies ipilimumab and tremelimumab have reported ORR 
between 0-7.7% and median OS of 5.2-10.3 months.
Algazi et al. summarized the clinical experience from various 
institutions with PD-1/PD-L1 blocking antibody treatment for 
metastatic uveal melanoma in 56 patients. The ORR was 
3.6% with a median PFS of 2.6 months and median OS of 7.6 
months. 2
      
 
 
        
 
 

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Outcomes appear to be improved when a the combination of 
ipilimumab (3 mg/kg) and nivolumab (1 mg/kg)have been used 
in two recent reports comprising a total of 135 patients.The 
ORR, median PFS and OS  were respectively 12%/9%, 
3.3/2.7 months and 12.7/15 months (Rodriguez, 2018; Najar, 
2018). Another recent abstract on 30 patients with metastatic 
uveal melanoma treated with ipilimumab plus nivolumab 
reported a 17% ORR with 3% CR.3
Molecularly targeted therapies for the MAPK 
and/or the PI3K/AKT pathways have demonstrated only 
limited activity. Other areas of clinical research include studies 
of HDAC inhibitors and BET protein inhibitors.
Phase:
Phase 2
Objectives/Endpoints
Objectives
Endpoints
Primary
To evaluate efficacy of the 
combination of nivolumab and 
BMS-986016 in terms of 
objective response rate 
(ORR) according to 
RECISTv1.1
Primary endpoint for this 
study will be best objective 
response rate (ORR).
Secondary
To evaluate the disease 
control rate (DCR), 
progression-free survival 
(PFS), overall survival (OS), 
duration of response (DOR) 
and safety profile of the 
combination of nivolumab and 
BMS-986016
Secondary endpoints will 
include disease control rate 
(DCR), progression-free 
survival (PFS), overall 
survival (OS), median 
duration of response (mDOR) 
and safety profile (AEs, 
SAEs).
Tumor microenvironment 
(TME) in fresh biopsies pre- 
and post-treatment and at 
progression
Evaluate pre-treatment 
characteristics of the TME 
that may predict for response 
or lack of response.
Learn the effects of treatment 
on the TME
Exploratory
Blood samples at baseline 
and predetermined post-
treatment time points and at 
progression
T cell receptor profiling
Circulating tumor cell DNA
Study Drug(s)
Nivolumab (also referred to as BMS-936558, MDX1106, or 
ONO-4538) and Relatlimab (also referred to as BMS-986016)
Indication
Metastatic uveal melanoma.
      
 
 
        
 
 

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Study Design
This is an open-label, single arm, single site investigator-
initiated phase II study based Simon minimax two-stage 
design.
Treatment Plan
Enrolled patients will be treated in the outpatient setting. 
Nivolumab 480 mg will be mixed in the same bag with 
Relatlimab 160 mg and will be administered intravenously over 
60 minutes (+ or –5 minutes) every 4 weeks. Each cycle will 
be approximately 4 weeks in length. Both drugs will be 
administered until disease progression or intolerable toxicity 
for up to 24 months. 
Correlative Studies
Correlative studies will be conducted for research use only. 
For participants who consent to additional correlative studies, 
archival tissue, blood, and fresh/fresh-frozen tumor from pre- 
and post- treatment biopsy will be collected for correlative 
biomarker analysis including but not limited to tumor single-cell 
RNA-sequencing with single-cell TCR/BCR profiling, 
metastatic tumor mutation profiling, blood-based bulk TCR 
profiling, and blood-based cell-free DNA mutation profiling. 
Correlative Studies, Solid Tumors:
Archival FFPE primary or previous metastatic tumor specimen, 
if available, may be collected from previous/current surgeries 
or biopsies for biomarker analysis including but not limited to 
mutation analysis and immunohistochemistry of LAG-3 and 
PD-1. A minimum of 3 10-micron sections will be required. 
Fresh/fresh-frozen tumor tissue from pre- and post- treatment 
biopsies will be collected for biomarker analysis including but 
not limited to tumor single-cell RNA-sequencing with single-
cell TCR/BCR profiling. Mutation analysis may be conducted 
on fresh-frozen tumor tissue from pre- and post- treatment 
biopsy, if quantity permits.
Correlative Studies, Blood: 
Blood will be obtained using EDTA purple top tubes and will 
be stored as plasma and buffy coat at -80 °C. Blood sample 
analysis will consist of but is not limited to bulk TCR profiling 
and cell-free DNA profiling.
Number of Patients
During the first stage, the investigational treatment will be 
tested on 13 patients. The trial will be terminated if there are 
no responses in these 13 patients. If the trial goes on to the 
second stage, an additional 14 patients will receive the 
investigational treatment.
Target Population
Up to 27 participants (13 in stage 1, 14 in stage 2) will be 
enrolled in the study. 
      
 
 
        
 
 

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Expected number of 
centers
One Center:

Sylvester Comprehensive Cancer Center (SCCC) 
inclusive of the constituent satellite sites.
Participant duration
Following enrollment, participants will be treated with an 
investigational treatment of nivolumab 480 mg and relatlimab 
160 mg every 4 weeks. Both drugs will be administered until 
disease progression or intolerable toxicity for a total treatment 
duration of up to 24 months. Patients will be followed for 2 
years to obtain information on disease progression and overall 
survival. Total participant duration is approximately 3 years.
Study Duration
The expected study duration is 4 to 4.5 years. The expected 
enrollment is a total of 27 evaluable patients within a period of 
2 to 2.5 years.
      
 
 
        
 
 

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1
INTRODUCTION
1.1
Clinical Background on Uveal Melanoma
The standard of care treatment for cutaneous melanoma has experienced rapid and 
significant changes. It has evolved from mostly ineffective chemotherapy and minimally 
successful immunotherapy to the current anti-CTLA4 and anti-PD1/checkpoint inhibitors 
that have resulted in survival prolongation. For patients whose tumors harbor a BRFA 
V600 mutations, combinations of BRAF plus MEK inhibitors provide another highly 
successful treatment option.
On the other hand, progress in the treatment of metastatic uveal melanoma has 
remained dismal. Uveal melanoma (UM) is a rare malignancy that arises from 
melanocytes within the uveal tract of the eye. The overall mean age-adjusted incidence 
of primary uveal melanoma in the US over the 41-year period from 1973 to 2013 was 
5.2 per million population (95% CI 5.0–5.4).
Although UM is often diagnosed at an early stage, 50% of patients will develop 
metastatic disease with 6–12 months survival from metastatic diagnosis. 
A meta-analysis of 796 patients treated for metastatic uveal melanoma with various 
forms of therapy demonstrated an overall response rate of 10.3% with 0.6% CRs. For 
patients treated with immunotherapy the median PFS was 2.8 months and the median 
OAS was 8.9 months.1 
The various treatment modalities used to treat metastatic uveal melanoma include liver-
directed therapies, immunotherapy, targeted therapy and chemotherapy. Chemotherapy 
has been found to be largely ineffective.
A number of phase II trials with the anti-CTLA-4 blocking antibodies ipilimumab and 
tremelimumab have reported ORR between 0-7.7% and median OS of 5.2-10.3 months.
Algazi et al. summarized the clinical experience from various institutions with PD-1/PD-
L1 blocking antibody treatment for metastatic uveal melanoma in 56 patients. The ORR 
was 3.6% with a median PFS of 2.6 months and median OS of 7.6 months. 2
Outcomes appear to be improved when a the combination of ipilimumab (3 mg/kg) and 
nivolumab (1 mg/kg)have been used in two recent reports comprising a total of 135 
patients.The ORR, median PFS and OS  were respectively 12%/9%, 3.3/2.7 months 
and 12.7/15 months (Rodriguez, 2018; Najar, 2018). Another recent abstract on 30 
patients with metastatic uveal melanoma treated with ipilimumab plus nivolumab 
reported a 17% ORR with 3% CR.3 
Molecularly targeted therapies for the MAPK and/or the PI3K/AKT pathways have 
demonstrated only limited activity. Other areas of clinical research include studies of 
HDAC inhibitors and BET protein inhibitors.
      
 
 
        
 
 

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1.2
Lymphocyte activation gene 3 (LAG-3) and recent pre-clinical data:
LAG-3 is an immune checkpoint receptor with a biological role in T cell regulation. 
Analysis of immune-cell infiltrates from human tumors show that a subset of CD4+ 
and/or CD8+ cells co express LAG-3 and PD-1 and may be associated with decreased 
T-cell effector function and tumor escape.4 Preclinical models have provided evidence 
that dual inhibition of LAG-3 and PD-1 blockade offers synergistic anti-tumor activity.5
Recently published data from Dr. William Harbour’s laboratory at the University of 
Miami/Bascom Palmer Eye Institute has shed light on relevant new data regarding uveal 
melanoma.6
The uveal melanoma tumor microenvironment (TME) was interrogated at single-cell 
resolution using sc-RNA-seq of 59,915 tumor and non-neoplastic cells from 8 primary 
and 3 metastatic samples.  Analysis of tumor cells confirms the global genomic 
landscape established from bulk analysis and reveals newly described subclonal 
genomic complexity and transcriptional states consistent with phenotype plasticity.  The 
immune compartment was shown to be comprised of a previously unrecognized 
diversity of cell types, including CD8+ T cells expressing the checkpoint marker LAG3, 
as opposed to PD1 or CTLA4.
As seen in Figure 1 below, T cells are present in all samples but are most prevalent in 
class 2 primary tumors and in metastatic samples.  Most T cells are CD8+, with smaller 
populations of CD4+ cells, including follicular helper cells, FOXP3+ regulatory cells, and 
naïve lymphocytes.  V(D)J recombination analysis of T and B cell receptors from sc-
RNA-seq data reveals clonally expanded T cells in only three samples, all class 2 
primary tumors. CD8+ T cell expression of exhaustion-associated immune checkpoint 
molecules is strongest for LAG3, variable for TIGIT, and minimal for PD1, CTLA4, TIM3, 
and TNFRSF9.  Protein expression of LAG3, CTLA4 and PD1 were orthogonally 
validated using multi-color IHC in 18 samples. These findings, coupled with the absence 
of PD-L1 and PD-L2 expression in tumor cells may explain the ineffectiveness of CTLA 
and PD1 blockade in metastatic UM.7CD14+ monocytes/macrophages are present in all 
primary and metastatic samples, with CD68+ macrophages displaying a spectrum from 
M1- to M2-polarization, the latter being enriched in class 2/BAP1mut samples, consistent 
with previous reports from bulk analysis. Few NK cells are present, and they are 
distributed equally across tumor samples without class predilection. B cells and plasma 
cells are rare in most samples.
The discovery of LAG3 as the dominant exhaustion marker in UM may explain the 
failure of previous checkpoint blockade targeting CTLA4 and PD1, and it nominates 
LAG3 as a potential candidate for checkpoint inhibitor immunotherapy in UM. 
Additionally, early data from Karlsson’s group from Sweden seem to corroborate these 
findings in several samples of metastatic uveal melanoma.7
      
 
 
        
 
 

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Figure 1.Immune microenvironment of uveal melanomas with V(D)J 
recombination repertoire sequencing of B- and T- lymphocytes
a.
b. 
c.
a.
Ridge plot of CD8+ T cell subset demonstrating strong expression of LAG3, moderate expression 
of TIGIT, and minimal expression of PD1, CTLA4, TIM3, and TNFRSF9.
b.
Quantification of multi-color IHC for CD8, LAG3, PD1, CTLA4, and DAPI. 18 total samples were 
analyzed by IHC including 7 that were analyzed by scRNA-seq and an additional 11 samples. 
Metastatic samples include BSSR0022 and UMM067L. Other samples represent primary tumors. 
Quantitation of each sample was performed by whole-slide scanning of a single slide. Source data 
are provided as a Source Data file. 
c.
Representative multi-color IHC images of a primary and a metastatic class 2 UM stained for CD8, 
LAG3, PD1, CTLA4, and DAPI (scale bar, 50 μm).
From: Durante, M.A., Rodriguez, D.A., Kurtenchbach, S., et al. Single-cell analysis reveals new 
evolutionary complexity in uveal melanoma. Nature communications. 2020;11(1):496
      
 
 
        
 
 

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1.3
Background on Nivolumab
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human 
monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the 
programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface 
membrane receptor.8 PD-1 is a negative regulatory molecule expressed by activated T 
and B lymphocytes. Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-
L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. Inhibition of 
the interaction between PD-1 and its ligands promotes immune responses and antigen-
specific T-cell responses to both foreign antigens as well as self-antigens. Nivolumab is 
expressed in Chinese hamster ovary (CHO) cells and is produced using standard 
mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration.
OPDIVO™ (nivolumab) is approved for the treatment of several types of cancer in 
multiple regions including the United States (US, Dec-2014), the European Union (EU, 
Jun-2015), and Japan (JP,Jul-2014). Nivolumab is also being investigated in various 
other types of cancer as monotherapy or in combination with other therapies. Single-
dose nivolumab monotherapy was also investigated in a Phase 1b study and a Phase 
1/2 study of patients with sepsis who were also managed according to established best 
practice care for sepsis.
1.3.1 Nonclinical Studies
Nonclinical studies on nivolumab are discussed in detail in the Nivolumab 
Investigator’s Brochure (IB). Nivolumab has been shown to bind specifically to the 
human PD-1 receptor and not to related members of the cluster of differentiation 28 
ICD28) family.9, 10 Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and 
PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) release 
in vitro.11-13 Nivolumab binds with high affinity to activated human T-cells expressing cell 
surface PD-1 and to cynomolgus monkey PD-1.10 In a mixed lymphocyte reaction 
(MLR), nivolumab promoted a reproducible concentration-dependent enhancement of 
IFN- γ release.14
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab 
was well tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at 
doses up to 50 mg/kg, administered twice weekly for 27 doses. While nivolumab alone 
was well tolerated in cynomolgus monkeys, combination studies have highlighted the 
potential for enhanced toxicity when combined with other immunostimulatory agents.15
In addition, an enhanced pre- and postnatal development (ePPND) study in pregnant 
cynomolgus monkeys with nivolumab was conducted.Administration of nivolumab at up 
to 50 mg/kg twice weekly was well tolerated by pregnant monkeys; however, nivolumab 
was determined to be a selective developmental toxicant when administered from the 
period of organogenesis to parturition at >10 mg/kg (area under the concentration-time 
curve [AUC] from time zero to 168 hours [AUC(0-168 h)] 117,000 µg h/mL). 
Specifically, increased developmental mortality (including late gestational fetal losses 
and extreme prematurity with associated neonatal mortality) was noted in the absence 
      
 
 
        
 
 

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of overt maternal toxicity. There were no nivolumab-related changes in surviving infants 
tested throughout the 6-month postnatal period. Although the cause of these pregnancy 
failures was undetermined, nivolumab-related effects on pregnancy maintenance are 
consistent with the established role of PD-L1 in maintaining fetomaternal tolerance in 
mice.16
1.3.2 Clinical Studies
The PK, clinical activity, and safety of nivolumab have been assessed in approximately 
80 clinical studies sponsored by BMS or ONO. The description and status of studies 
with reference safety information included in Appendix 1 of the Investigator’s Brochure 
are provided in Appendix 5 of the Investigator’s Brochure. Across those studies, 
approximately 23,507 subjects have received nivolumab monotherapy in single- or 
multiple-dose Phase 1/2/3 studies or studies with nivolumab in combination with other 
therapeutics (ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted 
therapies). Results from the ongoing studies are preliminary and are subject to 
change.
Nivolumab has demonstrated clinical activity in NSCLC, melanoma, RCC, cHL, 
SCCHN, UC, CRC, HCC, SCLC, ESCC (approved indications) and other tumor types 
(Section 5.4 of the Investigator’s Brochure) as monotherapy or in combination with 
ipilimumab or other therapeutics. The majority of responses were durable and exceeded 
6 months. In randomized, controlled studies, nivolumab monotherapy demonstrated 
statistically significant improvement in OS over standard of care in subjects with 
advanced or metastatic melanoma, subjects with advanced or metastatic NSCLC, 
subjects with advanced RCC, and subjects with recurrent or metastatic SCCHN (see 
Appendix 2 and Appendix 3 of the Investigator’s Brochure). In randomized, controlled 
studies, nivolumab in combination with ipilimumab demonstrated statistically significant 
improvement in PFS and ORR over ipilimumab monotherapy in subjects with advanced 
or metastatic melanoma (see Appendix 2 and Appendix 3 of the Investigator’s 
Brochure).
All available data suggest that nivolumab monotherapy has a consistent AE profile 
across tumor types. The safety profile is generally consistent across completed and 
ongoing clinical trials, with no maximum tolerated dose (MTD) reached at any 
monotherapy dose tested up to 10 mg/kg. The safety profile of nivolumab in 
combination with ipilimumab was consistent with the mechanisms of action of nivolumab 
and ipilimumab. The nature of the AEs was similar to that observed with either agent 
used as monotherapy; however, both frequency and severity of most AEs were 
increased with the combination. A dose of 3 mg/kg nivolumab/3 mg/kg ipilimumab 
exceeded the MTD, and both 1 mg/kg nivolumab/3-mg/kg ipilimumab and 3 mg/kg 
nivolumab/1 mg/kg ipilimumab were identified as the MTD.17 Across all studies 
conducted to date, drug-related AEs have included pulmonary toxicity, renal toxicity 
(including acute renal failure), endocrine abnormalities, GI toxicity, dermatologic toxicity 
(including rash, Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN]), 
hepatotoxicity, and myotoxicity. For nivolumab monotherapy and combination therapy, 
the majority of these AEs have been managed successfully with supportive care and, in 
      
 
 
        
 
 

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more severe cases, a combination of dose delay, permanent discontinuation, and/or 
use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed 
in the management guidelines provided in Appendix 3.
1.4
Background on Relatlimab (BMS-986016)
Relatlimab (also referred to as BMS-986016, BMS-986016-01, and anti-lymphocyte 
activation gene 3 [LAG-3]) is a fully human LAG-3-specific antibody that was isolated 
following immunization of transgenic mice expressing human immunoglobulin (Ig) 
genes. It is expressed as an immunoglobulin G4 (IgG4) isotype antibody and includes a 
stabilizing hinge mutation (S228P). Relatlimab binds to the LAG-3 receptor with high 
affinity and blocks LAG-3 interactions with its known ligand, major histocompatibility 
complex (MHC) Class II, which is the peptide antigen presentation molecule recognized 
by CD4+ T cells. Relatlimab binding inhibits the negative regulatory function of LAG-3 
in vitro. By blocking the downregulatory pathway, relatlimab enhances the anti-tumor 
immune response and, thus, has the potential to inhibit the growth of multiple 
malignancies when administered as a single agent or in combination with other 
therapeutic immuno-oncology (IO) monoclonal antibodies (mAbs). BMS-986213 is a 
fixed dose combination (FDC) of relatlimab plus nivolumab at a 1:3 ratio and is reported 
in a separate IB.
1.4.1 Non-Clinical Studies
The nonclinical pharmacology of relatlimab and surrogate LAG-3 antibodies has been 
studied in vitro using binding and functional assays as well as in vivo in mouse 
syngeneic tumor models. Briefly, relatlimab binds with high affinity to both human and 
cynomolgus monkey LAG-3 receptor expressed on activated primary T cells (half  
maximal effective concentration [EC50] = 0.11 nM and 29.11 nM, respectively) and 
prevents binding of LAG-3 to cells bearing its ligand, MHC Class II, the peptide antigen 
presentation molecule recognized by CD4+ T cells. Relatlimab binding inhibits the 
negative regulatory function of LAG-3 in vitro, leading to enhancement of effector T cell 
function. Relatlimab does not bind to mouse LAG-3; therefore, surrogate antibodies 
recognizing mouse LAG-3 (clones C9B7W and 19C7), which block the negative 
regulation following interaction between LAG-3 and MHC Class II, were used to assess 
anti-tumor activity mediated by LAG-3 blockade, both alone and in combination with 
programmed cell death protein 1 (PD-1) or cytotoxic T lymphocyte antigen 4 (CTLA-4) 
blockade, in Sa1N fibrosarcoma and MC38 colon adenocarcinoma or CT26 colon 
adenocarcinoma murine syngeneic in vivo tumor models, respectively. While LAG-3 
monotherapy displays relatively marginal single-agent activity, both in terms of tumor 
growth inhibition and the number of tumor—free mice18, the combination of anti-LAG-3 
with a blocking anti-PD-1 antibody provided enhanced anti- tumor activity compared to 
either agent alone. Therefore, blockade of the LAG-3 negative regulatory pathway has 
the potential to inhibit the growth of multiple malignancies, especially when administered 
in combination with other therapeutic IO mAbs.
In a repeat-dose study in monkeys, following weekly intravenous (IV) doses of 
relatlimab monotherapy (30 and 100 mg/kg) or doses of relatlimab in combination with 
the anti-PD-1 antibody nivolumab (100 mg/kg of relatlimab and 50 mg/kg of nivolumab) 
      
 
 
        
 
 

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for 4 weeks, the total serum clearance (CLT) of relatlimab was 0.12 mL/h/kg, and the 
elimination half-life (T-HALF) was 414 hours (estimated by population pharmacokinetic 
[PK] analysis of pooled data from all 3 groups). There was no apparent PK drug-drug 
interaction between relatlimab and nivolumab.
The cynomolgus monkey was selected as the toxicology species because relatlimab 
binds to macaque LAG-3, albeit less strongly than to human LAG-3, and is 
pharmacologically active in monkeys (i.e. increases T cell subsets and responses to 
immunogenic challenge).19-21 In Good Laboratory Practice (GLP)-compliant studies up 
to 3 months in duration, relatlimab was generally well tolerated by cynomolgus monkeys 
when administered IV QW up to 100 mg/kg. In the 3- month study, 1 male monkey at 30 
mg/kg exhibited clinical observations (including tremors, decreased activity, hunched 
posture, retching, and/or emesis) and complement activation that were considered to be 
secondary to relatlimab-related treatment-emergent anti-drug antibodies (ADAs) and, 
therefore, were not factored in determining the no-observed-adverse-effect-level 
(NOAEL). The NOAEL was considered to be 100 mg/kg/week (mean sex-combined 
AUC(0-168h)] = 1,180,000 gh/mL). In the 1-month study, relatlimab was also 
administered at 100 mg/kg in combination with 50 mg/kg of nivolumab (mean 
relatlimab AUC[0-168h] = 514,000 gh/mL) and was generally well tolerated in 8 of 9 
monkeys with no clinical signs, with the exception of moribundity in 1 male monkey 
attributed to central nervous system  vasculitis. Histopathological findings in this monkey 
included the following: slight lymphoplasmacytic inflammation of the choroid plexus; 
minimal to moderate lymphohistiocytic inflammation of the vasculature of the brain 
parenchyma, meninges, and spinal cord; and minimal to moderate mixed-cell 
inflammation of the epididymis, seminal vesicles, and testes. Additional findings in the 
combination therapy group were limited to minimal to slight irreversible 
lymphoplasmacytic inflammation of the choroid plexus in the brain in both sexes and 
minimal lymphohistiocytic inflammation of the vasculature of the brain parenchyma in 1 
male monkey.
In an exploratory  4-week toxicity study, LAG3.1-G4P, a predecessor nonclinical 
molecule differing from relatlimab by 2 amino acids, was clinically well tolerated by 
cynomolgus monkeys, with no adverse findings when administered IV QW as a 
monotherapy at 50 mg/kg or when administered at 10 or 50 mg/kg in combination with 
50 mg/kg of nivolumab. Therefore, the NOAEL was considered to be 50 mg/kg/week for 
LAG3.1-G4P monotherapy (combined sex mean AUC[0-168h] = 231,000 μgh/mL) and 
50/50 mg/kg/week for LAG3.1-G4P/nivolumab combination therapy (combined sex 
mean LAG3.1-G4P AUC[0-168h] = 210,000 μgh/mL; combined sex mean nivolumab 
AUC[0-168h] = 159,500 μgh/mL).
In exploratory in vitro assays, neither relatlimab alone nor relatlimab in combination with 
nivolumab induced cytokine release or resulted in T, B, or natural killer (NK) cellular 
activation in human peripheral blood mononuclear cells (PBMCs).
Developmental and reproductive toxicology studies were conducted in mice using both 
syngeneic and allogeneic breedings, the latter of which is designed to elicit feto-
      
 
 
        
 
 

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maternal tolerance through mating of genetically distinct mouse strains in which 
paternally contributed alloantigens induce an immune response in the pregnant dam. 
Due to the lack of cross-reactivity of relatlimab in rodent species, surrogate anti-mouse 
LAG-3 antibodies (clone MLAG3.4 MG1-D265A [19C7] or C9B7W) were used. Both 
antibodies were well tolerated by dams at the highest dose tested, and there were no 
maternal or developmental toxicities detected in either syngeneic or allogeneic 
breedings, with resulting maternal and developmental NOAELs of 50 mg/kg (MLAG3.4 
MG1-D265A [19C7]) and 51.5 mg/kg (C9B7W). Despite these results, the risk for 
adverse human pregnancy outcomes associated with relatlimab administration is 
considered to be of concern for 2 reasons: 1) checkpoint targets, including LAG-3, are 
likely to have a role in maintaining maternal tolerance to the developing fetus and 2) the 
present indication requires that relatlimab be administered in combination with 
nivolumab, which has been shown to increase third trimester pregnancy loss in 
cynomolgus monkeys.
Overall, the nonclinical toxicology assessment of relatlimab has demonstrated an 
acceptable profile, supporting its continued clinical use in humans.
1.4.2 Clinical Studies
Safety information presented in this Investigator Brochure (IB) focuses primarily on 
information obtained from Phase 1/2a studies (Studies: CA224020 [advanced solid 
tumors], CA224022 [advanced hematologic malignancies], CA224034 [advanced solid 
tumors] a Phase 1 study conducted in Japan and CA224048 [advanced malignant 
tumors]). Dose levels studied include 4 ascending flat doses of relatlimab monotherapy 
(20, 80, 240, and 800 mg) given every 2 weeks (Q2W) and ascending flat doses of 
relatlimab and nivolumab combination therapy given Q2W or every 4 weeks (Q4W). The 
combination doses include 20 mg relatlimab/80 mg nivolumab Q2W, 20 mg 
relatlimab/240 mg nivolumab Q2W, 80 mg relatlimab/240 mg nivolumab Q2W, 160 mg 
relatlimab/240 mg nivolumab Q2W, 240 mg relatlimab/240 mg nivolumab Q2W, as 
well  as 160 mg relatlimab/480 mg nivolumab Q4W, 240 mg relatlimab/480 mg 
nivolumab Q4W, 320 mg relatlimab/480 mg nivolumab Q4W and 480 mg 
relatlimab/480 mg nivolumab Q4W. Study CA224048 is a triple combination of 
relatlimab, nivolumab and BMS-986205 (IDO-1 inhibitor) or ipilimumab. The 
combination doses include relatlimab 80/160 mg Q4W + nivolumab 480 mg Q4W + 
BMS-986205 (IDO-1 inhibitor) (25/50/100 mg QD) or ipilimumab 1mg/kg Q8W.
As of the clinical data cutoff dates of 15-May-2019 for CA224034 and CA224048 and 
03-Jun-2019 and 26-Jun-2019 for CA224020 and CA224022 respectively, 1348 
subjects have been treated with relatlimab or relatlimab in combination with nivolumab 
in 4 ongoing studies (Studies CA224020, CA224022, CA224034 and CA224048) 
assessing PK, clinical efficacy, and safety (Table 1.3-1 of the Investigator’s Brochure). 
The current clinical program is evaluating advanced solid tumors (special focus in 
advanced melanoma that has previously progressed on prior anti-PD1  therapy) in 
Study CA224020, relapsed-refractory hematological malignancies (Hodgkin lymphoma) 
in CA224022, advanced solid tumors (special focus in a Japanese population) in Study 
CA224034 and in study CA224048, the focus is on advanced solid tumors including 
      
 
 
        
 
 

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melanoma, non-small cell lung cancer (NSCLC), squamous cell cancer of head and 
neck (SCCHN), renal cell cancer (RCC), and gastric cancer (GC/GEJ).
Exposure to relatlimab as of the database cutoff dates cited above, is summarized in 
Table 1.3-1 of the Investigator’s Brochure.
1.5
Combination Treatment Phase 1 Trials
Lipson et al. (J Immunother Cancer. 2016;4[s1]:173 [P232]) reported first-in-human 
phase I/IIa activity data for BMS-986016, a fully human IgG4 monoclonal antibody that 
targets LAG-3, alone and in combination with nivolumab (anti-PD-1) in 89 patients with 
advanced B cell malignancies or solid tumors. The maximum tolerated dose (MTD) was 
not reached with BMS-986016 monotherapy and when used in combination with 
nivolumab treatment emergent AE’s were infrequent and consisted of manageable 
toxicities typically associated with immune checkpoint blocking agents with no 
treatment-related deaths. Objective tumor regression was observed with LAG-3 
monotherapy, with combination therapy in PD-1-naive patients and in patients with 
disease progression on nivolumab monotherapy.
Additional clinical data from 55 patients with metastatic melanoma who had progressed 
on immunotherapy with checkpoint inhibitors and treated with the combination of BMS-
986016 and nivolumab was presented at the ASCO 2017 annual meeting by Ascierto et 
al. Of the 55 patients, 58%% had prior anti–CTLA-4 and 95% had prior anti-PD1/PD-L1 
treatment.  In the 48 efficacy-evaluable patients, the ORR was 13% and DCR was 54%. 
LAG-3 expression was > 1% in 25/48 and < 1% in14/48 whereas PD-1 expression was 
13% and 21% respectively. ORR in the > 1% LAG-3 expressors was 20% compared to 
7.1% in the <1% LAG-3 expressors. The safety profile was similar to that of nivolumab 
monotherapy.22
Hong et al. presented data on a phase I/II study of LAG525 ± spartalizumab (PDR001) 
in patients with advanced.23 LAG525 + spartalizumab led to durable RECIST responses 
(11 PR, 1 CR) in 121 patients with a variety of solid tumors, including mesothelioma (2/8 
patients) and triple-negative breast cancer (TNBC; 2/5 patients). In TNBC tumor 
biopsies, a trend in conversion of immune-cold to immune-activated biomarker profiles 
was seen.
1.6
Hypothesis
The null hypothesis is that the true response rate is 5%, it will be tested against a one-
sided alternative response rate of 20%. In the first stage, 13 patients will be accrued. If 
there are no responses in these 13 patients, the study will be stopped. Otherwise, 14 
additional patients will be accrued for a total of 27. The null hypothesis will be rejected if 
4 or more responses are observed in 27 patients. This design yields a type I error rate 
of 0.0416 and power of 0.8011 when the true response rate is 20%
      
 
 
        
 
 

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1.7
Rationale
1.7.1 Rationale for Current Study
Our hypothesis is that in light of the preclinical data published by Durante et al. (section 
1.2) documenting the high prevalence of LAG-3 expression in metastatic uveal 
melanoma cells, the combination of nivolumab and BMS-986016 will result in superior 
response rates when compared with historical PD-1/PD-L1 blocking antibody response 
data in patients with metastatic uveal melanoma. The addition of relatlimab might 
engender enhancement of the therapeutic activity of nivolumab in patients whose tumor 
infiltrating lymphocytes (TIL) express LAG-3 constitutively and may abrogate the 
upregulation of LAG-3 expression in TIL that do not.
1.7.2 Rationale for Study Design
This is an exploratory trial based on new preclinical data and a two-stage design was 
felt to be most appropriate to detect a signal in this limited population of patients with a 
rare disease. Additional patient cohorts may be added in the future depending on the 
initial outcomes of this trial.
1.7.3 Rationale for Patient Population
Uveal melanoma is a rare but often lethal disease with about 50% of patients eventually 
developing metastatic disease, primarily to the liver. Metastatic melanoma has been 
uniformly fatal with very limited options and no curative approaches so far. The new 
insight into the biology of the tumor microenvironment and the discovery of high levels 
of expression of LAG-3 in the T-cells infiltrating these tumors is a promising new avenue 
of research. The selection of patients with no previous exposure to PD-1 and/or LAG-3 
exposure is meant to enrich the patient population with the individuals most likely to 
respond to this intervention.
1.7.4 Rationale for Dose Selection:
The dose and schedule for this trial has been based on the most recent phase I data on 
the combination of nivolumab in combination with relatlimab. An alternative dosing 
schedule is the sequential administration of both drugs. The current schedule was 
selected because of the patient convenience afforded by a single infusion of both drugs.
1.8
Risk/Benefit Assessment 
1.8.1 Nivolumab Known Potential Risks
The potential risks from treatment with nivolumab are described in detail in section 7.1 
of the investigator’s brochure. These include the following adverse events: pulmonary, 
gastrointestinal, hepatic, endocrinopathies, dermatologic, renal, neurologic, infusion 
reactions, lipase/amylase elevations, uveitis and visual complaints, and other immune-
mediated adverse events such as myotoxicity (myositis, myocarditis, and 
rhabdomyolysis), solid organ and tissue transplant rejection, rapid-onset and severe 
graft-versus-host-disease GVHD, and complications of allogenic hematopoietic stem 
cell transplantation (HSCT). 
      
 
 
        
 
 

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1.8.2 Known Potential Benefits
As noted in the protocol background section treatment with single agent nivolumab 
results in response rated in the single digits. Patients who respond, however, do seem 
to derive clinical benefit. Toxicity of single agent immunotherapy is quite modest and 
tolerable in patients of all age groups. The response rate in the phase I data of the 
combination of nivolumab and relatlimab  in patients with cutaneous melanoma 
refractory to PD-1 blocking antibodies was as high as 20% in patients with LAG-3 
expression > 1%. Preclinical data previously mentioned documented the high level of 
LAG-3 expression in samples of both primary and metastatic melanoma suggesting 
potentially increased activity for this combination in the clinical setting.
1.8.3 Relatlimab Known Potential Risks
The potential risks from treatment with relatlimab are described in detail in Section 7.1 
of the investigator’s brochure. These include the following immune-mediated adverse 
events: pneumonitis, colitis, hepatitis, nephritis, endocrinopathy, and neurologic and 
dermatologic AEs.
Across 4 studies with clinical data cutoff dates, (Studies; CA224020, 03-June-2019, 
CA224022, 26-June-2019, CA224034 and CA224048, 15-May-2019), relatlimab 
monotherapy has been administered to 66 subjects across multiple doses: 20 mg (8 
subjects), 80 mg (13 subjects), 240 mg (27 subjects) and 800 mg (18 subjects) 
relatlimab, flat dose, Q2W. The safety profile of relatlimab monotherapy appears 
manageable with no maximum tolerated dose (MTD) reached. The MAD was 800 mg 
Q2W. There were 4 drug-related SAEs in monotherapy: Grade 3 pneumonitis, Grade 2 
pneumonitis, and Grade 3 allergic reaction in monotherapy in Study CA224020 at a 
dose of 800 mg relatlimab Q2W; and a Grade 3 aseptic meningitis in monotherapy in 
Study CA224022 at a dose of 800 mg relatlimab Q2W. There was no apparent 
relationship in the incidence, severity, or causality of AEs to relatlimab at these dose 
levels. (Section 5.5 of the Investigator’s Brochure). All AEs were reversible or 
manageable (in the setting of immune-mediated endocrine events) by withholding drug 
administration and following treatment algorithms specified in the protocols where 
applicable. There were 5 Grade 1 to Grade 2 infusion-related reactions with relatlimab 
monotherapy (1 in Study CA224020 and 4 in Study CA224022), which were 
manageable and reversible with recommended treatment guidelines in the protocol. A 
total of 27 subjects died due to malignant neoplasm progression following relatlimab 
monotherapy (19 in Study CA224020, 7 in Study CA224022, and 1 in Study 
CA224034).
1.8.4 Nivolumab and Relatlimab Combination Therapy Potential Risks
The potential risks from treatment with relatlimab in combination are described in detail 
in Section 7.1 the investigator’s brochure. These include the following immune-
mediated adverse events: neurotoxicity, infusion related reaction and cytokine release, 
immunosuppression, cardiovascular events such as myocarditis. 
As of the clinical data cutoff dates, cited in section 1.8.3 of this protocol, the treatment 
with relatlimab in combination with nivolumab or ipilimumab or BMS 986205 has been 
      
 
 
        
 
 

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administered to 1282 subjects, in Studies CA224020 (1166 subjects), CA224022 (66 
subjects), CA224034 (26 subjects) and CA224048 (24 subjects). The safety profile of 
relatlimab combined with nivolumab is manageable with currently no MTD reached, as 
combination dose evaluation remains ongoing.
Across Studies CA224020, CA224022, CA224034 and CA224048, overall drug-related 
AEs were reported in 847 subjects. The most frequent drug-related AEs included 
fatigue, decreased appetite, pruritus, diarrhea, rash, rash maculo-papular, anemia, 
asthenia, hypothyroidism, and hyperthyroidism. The types of drug-related AEs, as well 
as the rates of these drug-related AEs, appeared comparable to historical nivolumab 
monotherapy rates. The majority of all drug-related AEs, except for 1 Grade 4 
myocarditis (240 mg relatlimab/240 mg nivolumab Q2W), as well as 1 Grade 4 potential 
drug-induced liver injury, 1 Grade 5 dyspnea, and 1 Grade 3 pneumonitis (all at a dose 
level of 80 mg relatlimab/240 mg nivolumab Q2W), were reversible or manageable by 
withholding study drug administration, providing standard medical care, and/or following 
immune-related AE algorithms. Safety results to date indicate that sequential, 
coadministration and the FDC of relatlimab + nivolumab have similar safety profiles
1.8.5 Assessment of Potential Risks and Benefits
The safety profile of nivolumab in combination with relatlimab has been assessed in the 
dose finding studies mentioned above. The important identified risks are irAEs. Based 
on the currently available safety information the adequate risk identification and 
minimization described in the investigator’s brochure, the emerging preliminary activity 
of this combination in patients with PDL-1 antibody refractory cutaneous melanoma and 
the preclinical data suggesting significant potential for clinical activity in uveal 
melanoma, the benefit-risk is considered favorable for continued clinical studies in these 
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2
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate efficacy of the combination 
of nivolumab and BMS-986016 in 
terms of objective response rate (ORR) 
according to RECIST v1.1.
Primary endpoint for this study will be 
best objective response rate (ORR).
Secondary
To evaluate the disease control rate 
(DCR), progression-free survival 
(PFS), overall survival (OS), duration of 
response (DOR) and safety profile of 
the combination of nivolumab and 
BMS-986016
Secondary endpoints will include 
disease control rate (DCR), 
progression-free survival (PFS), 
overall survival (OS), median 
duration of response (mDOR) and 
safety profile (AEs, SAEs).
Exploratory
Tumor microenvironment (TME) in 
fresh biopsies pre- and post-treatment 
and at progression
Evaluate pre-treatment 
characteristics of the TME that may 
predict for response or lack of 
response. Learn the effects of 
treatment on the TME.
Blood samples at baseline and 
predetermined post-treatment time 
points and at progression
T cell receptor profiling
Circulating tumor cell DNA.
      
 
 
        
 
 

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3
STUDY DESIGN
3.1
Overall Design
This is an open-label, single arm, single site investigator-initiated phase II study. 
Approximately 27 patients will be enrolled based on Simon minimax two-stage design. 
The primary objective is to evaluate efficacy of the combination of nivolumab and BMS-
986016 in terms of objective response rate (ORR) in patients with biopsy-proven 
metastatic uveal melanoma either untreated or previously treated with up to 5 lines of 
therapy.
1. Study Design: This is an open-label, single arm, single site investigator-initiated 
phase II study based Simon minimax two-stage design. 
2. Study Population and Setting: During the first stage, the investigational 
treatment will be tested on 13 patients. The trial will be terminated if there are no 
responses in these 13 patients. If the trial goes on to the second stage, an 
additional 14 patients will receive the investigational treatment. 
3. Intervention: Participants will be treated with a combination treatment of 
Nivolumab 480 mg and Relatlimab 160 mg which will be administered 
intravenously over 60 minutes (+ or –5 minutes) every 4 weeks. Each treatment 
cycle is four weeks in length and the nivolumab and relatlimab combination 
treatment will be administered until disease progression or intolerable toxicity for 
up to 24 months. 
4. Description of facilities enrolling patients: This study will identify, recruit, 
enroll, and treat patients at the University of Miami Sylvester Comprehensive 
Cancer Center inclusive of the constituent satellite sites.
5. Participant Duration: Following enrollment, participants will be treated with an 
investigational treatment of nivolumab in combination with relatlimab until 
disease progression or intolerable toxicity for up to 24 months. Patients will be 
followed for 2 years to obtain information on disease progression and overall 
survival. Total participant duration is approximately 3 years.
6. Study Duration: The expected study duration is 4-5 years. The expected 
enrollment is 27 evaluable patients within a period of 2 to 2.5 years.
      
 
 
        
 
 

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4
STUDY POPULATION
4.0
Inclusion Criteria
Patients participating in this study must:
1. Have a biopsy-proven diagnosis of metastatic uveal melanoma, previously 
untreated with anti-PD-1,CTLA-4 and/or LAG-3 blocking antibodies.
2. Agree to undergo a pre-treatment and a post-treatment fresh biopsy of the tumor, 
if needed, safe and feasible as determined by the investigator.
3. Have completed all previous therapy for a minimum of 3 weeks before the first 
dose of experimental treatment. All adverse events of previous therapy must have 
resolved. Palliative radiation therapy to a limited field is allowed within this 3 week 
period.
4. Be willing and able to provide written informed consent/assent for the trial.
5. Be  18 years of age on day of signing informed consent.
6. Have measurable disease based on RECIST 1.1.  
7. Have a performance status of 0-2 on the ECOG Performance Scale.
8. LVEF assessment with documented LVEF >50% by either TTE or MUGA (TTE 
preferred test) within 6 months from first study drug administration
9. Demonstrate adequate organ function as defined in Error! Reference source not 
found.. All screening labs should be performed within 10 days of treatment 
initiation.  
Table 1. Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L (within 7 days of assessment)
Renal
Serum creatinine OR
Measured or calculateda creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥30 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels 
> 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with liver metastases
Albumin
>2.5 mg/dL
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy
      
 
 
        
 
 

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as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
10.If a female of childbearing potential, have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.  If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.  
11.If a female of childbearing potential, be willing to use an adequate method of 
contraception as outlined in Section 5.8 Contraception, for the course of the study 
through 24 weeks after the last dose of study medication. Must abstain from ova 
donation for a minimum of 5 months after the end of treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
12.If a male of childbearing potential, agree to use an adequate method of 
contraception as outlined in Section 5.8- Contraception, starting with the first dose 
of study therapy through 7 months after the last dose of study therapy. Must 
abstain from sperm donation for a minimum of 24 weeks after the end of treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject
4.1
Exclusion Criteria
Patients will be excluded from participation in this trial if they:
1. Are currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an 
investigational device within 3 weeks of the first dose of treatment.
2. Have a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose 
of trial treatment. Patients on replacement doses of corticosteroids and patients 
who received steroids as pre-medication to prevent an imaging contrast allergy are 
allowed. 
3. Have a known history of active tuberculosis  (Bacillus Tuberculosis)
4. Have had prior treatment with a PD-1 and/or LAG-3 targeted agent
5. Have hypersensitivity to nivolumab, relatlimab or any of their excipients.
6. Have had a prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from clinically 
significant adverse events due to agents administered more than 3 weeks earlier.
7. Have had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 3 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 
1 or at baseline) from clinically significant adverse events due to a previously 
administered agent. 
      
 
 
        
 
 

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-
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study.
-
Note:  If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention prior 
to starting therapy.  
-
Note: Patients will be allowed necessary and palliative radiation therapy to 
limited fields during the trial, as long as it does not encompass a target 
lesion.
8. Have a known additional malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy, in situ cervical cancer, 
ductal carcinoma in situ (DCIS), incidentally discovered asymptomatic thyroid 
cancer, PSA recurrence of prostate cancer stable on hormonal therapy with no 
otherwise detectable disease, and a previous diagnosis of malignancy that has 
shown no evidence of disease progression for 5 years or longer. 
9. Have known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis as well as a history of previous or current significant 
brain hemorrhage.  Subjects with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging 
for at least four weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids to treat edema for at least 7 days prior to 
trial treatment.  This exception does not include carcinomatous meningitis, which 
will be excluded regardless of clinical stability.  
10.Have active autoimmune disease that has required systemic treatment in the past 
2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
11.Have known history of, or any evidence of active, non-infectious pneumonitis.
12.Have an active infection requiring systemic therapy.
13.Have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.  
14.Have known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
15.Are pregnant or breast feeding or expecting to conceive or father children within 
the projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment.
      
 
 
        
 
 

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16.Have a diagnosis or known history of Human Immunodeficiency Virus (HIV), 
unless controlled on antiretroviral drugs and have undetectable levels of HIV 
antibodies.
17.Have known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C.
18.Have received a live vaccine within 30 days of planned start of study therapy.
19.Have a history of myocarditis, regardless of etiology
20.Have a troponin T (TnT) or I (TnI) 
-
i) > 2x institutional upper limit of normal (ULN) : patient is excluded. 
-
ii) between > 1 to 2 x ULN enrollment will be permitted if a repeat 
assessment remains < 2 x ULN and participant undergoes a cardiac 
evaluation and is cleared by a cardiologist or cardio-oncologist
21.Are patients with impaired decision-making capacity
22.Are prisoners or participants who are involuntarily incarcerated. (Note: under 
certain specific circumstances a person who has been imprisoned may be included 
as a participant. Strict conditions apply and Bristol-Myers Squibb approval is 
required).
23.Are compulsorily detained for treatment of either a psychiatric or physical (eg, 
infectious disease) illness
24.Have psychological, familial, sociological, or geographical conditions that 
potentially hamper compliance with the study protocol and follow-up schedule; 
those conditions should be discussed with the participant before registration in the 
trial.
4.2
Strategies for Recruitment and Retention
Both men and women of all races and ethnic groups are eligible for this trial. Subjects 
will be recruited at Sylvester Comprehensive Cancer Center (SCCC) via clinical practice 
offices.
      
 
 
        
 
 

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5
TREATMENT PLAN
5.1
Method of Treatment Assignment
All patients will be treated on this single arm, open label, investigator-initiated Phase 2 
study with an investigational treatment of nivolumab in combination with relatlimab until 
disease progression or intolerable toxicity for up to 24 months.
5.2
Dosing and Administration
Enrolled patients will be treated in the outpatient setting. Nivolumab 480 mg will be 
mixed in the same bag with Relatlimab 160 mg and will be administered intravenously 
over 60 minutes (+ or –5 minutes) every 4 weeks. Each cycle will be approximately 4 
weeks in length. Both drugs will be administered until disease progression or intolerable 
toxicity for up to 24 months. 
 
Table 2.Dosing and Administration Schedule Nivolumab + Relatlimab 
Combination Treatment (All cycles)
Drug
Dose
Day 1 (+/– 3 days)
Day 28 (+/– 3 days)
Nivolumab
480 mg
X
X
Relatlimab
160 mg
X
X
5.3
Missed doses
Patients who miss a nivolumab plus relatlimab dose at the usual required time should 
skip additional therapy until the next cycle. 
5.4
Concomitant Therapy
Nivolumab and relatlimab will be administered concomitantly every 4 weeks (qw4) until 
disease progression or intolerable toxicity for up to 24 months. For this protocol, a 
prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report 
Form (CRF) are concomitant prescription medications, over-the-counter medications 
and supplements.
5.5
Premedication
No premedication is recommended or required.
5.6
Prohibited Therapies
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this 
trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol
      
 
 
        
 
 

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
Chemotherapy

Investigational agents other than nivolumab and relatlimab

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
BCG, and typhoid vaccine. 

Radiation therapy 
o
Note:  Palliative radiation therapy or treatment to a symptomatic solitary 
lesion or to the brain may be allowed at the investigator’s discretion as 
previously described

Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology.  The use of 
physiologic/replacement doses of corticosteroids is allowed.

Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the 
trial.  Subjects may receive other medications that the investigator deems to be 
medically necessary.
5.7
Study Intervention Compliance
All doses of study treatments (nivolumab and relatlimab) will be administered at the 
investigational site by designated medical staff.
The information related to each trial drug administration, including the date, time, and 
dose of study drug, will be recorded on Velos. The Investigator will make sure that the 
information entered into the CRF regarding drug administration is accurate for each 
patient. Any reason for noncompliance should be documented.
Noncompliance is defined as a patient missing 2 doses of nivolumab plus relatlimab for 
non-medical reasons.  If > 2 doses of the study drug treatment are missed and the 
interval between the subsequent dose and the last administered treatment is longer 
than 6 weeks for nonmedical reasons, the criteria of insufficient compliance will have 
been met as well. 
Non-compliant patient slots can be replaced by a new eligible patient.
5.8
Contraception
Contraception Requirements for Women:
The study drug may be absorbed into bodily secretions such as vaginal fluids and then 
passed on to the female participant’s partner during sex. Male sexual partners must 
wear a condom to avoid being exposed to the study drug.  
   
The study drug may harm a fetus or a breastfeeding baby.
If a woman is pregnant or breastfeeding, she cannot take part in this study.
      
 
 
        
 
 

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If woman thinks she may be pregnant, she should not volunteer for this study. 
Women of childbearing potential must have a pregnancy test before beginning the study 
and while in the study. 
Women of childbearing potential must not get pregnant or breastfeed while in this study 
and for at least 24 weeks after the last dose of the study drug. Women must not donate 
an egg for at least 5 months after the last dose of study medication.
Women of childbearing potential must take measures to avoid becoming pregnant while 
in this study. 
The following are acceptable measures of contraception:

Abstinence (not having sexual relations with a person of the opposite sex)

Implantable hormone (e.g. Norplant)

Intrauterine Device (IUD)

Male partner has had a vasectomy

Female sterilization 

Hormonal injection 

Oral contraceptives 
Participants must use contraception, at least starting at screening before starting study 
treatment unless they abstain from sexual intercourse. Participants must use 
contraception during study treatment and for at least 24 weeks after stopping study 
treatment.  
Contraception Requirements for Men
Study drug may be absorbed into bodily secretions such as semen and then passed on 
to partners during sex.  Participants must wear a condom to avoid being exposed to the 
study drug.    
There may be risks to the embryo/fetus if female sexual partner is pregnant or becomes 
pregnant while the participant in this study. If the participant’s partner is a woman of 
child bearing potential, the participant and their partner must either practice total 
abstinence or use effective contraception while participating in this study. One of the 
following forms of contraception should be used by the participant and their partner: 

Abstinence (not having sexual relations with a person of the opposite sex)

Implantable hormone (e.g. Norplant)

Intrauterine Device (IUD)

Vasectomy

Female sterilization 

Hormonal injection 

Oral contraceptives 
      
 
 
        
 
 

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Participants must use contraception during study treatment and for at least 7 months 
after stopping study treatment. Participants should also refrain from donating semen 
during therapy and for 24 weeks after stopping the therapy. 
There is theoretical concern that study treatment can result in sperm abnormalities 
and/or can transmit harmful substances in their semen during sex. Therefore, males 
must remain abstinent or use a condom, even if they have undergone a vasectomy.
If a participant’s female partner becomes pregnant or suspects becoming pregnant 
during study treatment or within 24 weeks after completing study treatment, the 
participant must inform the Study Doctor immediately. The Study Doctor may want to 
follow the pregnancy and may ask the female partner to sign a consent form so they 
can collect information about the outcome of the pregnancy. 
5.9
Breast Feeding 
Participants must not breast-feed while receiving study treatment and for 24 weeks 
following the last dose of study treatment.
5.10 Blood Donation
Participants must not donate blood during the study or for 12 weeks after the last dose 
of protocol therapy.
5.11 Duration of Follow Up 
All study subjects will be followed as per standard of care for tumor recurrence.  
Following the completion of the combination nivolumab and relatlimab therapy, patients 
will be followed for 2 years to obtain information on disease progression and overall 
survival.
5.12 End of Study Definition
A study participant is considered to have completed the study once he or she completes 
all phases of the study treatment and study related laboratory tests. The primary and 
secondary clinical aims endpoints will be available for analysis once all patients have 
been followed for 2 years after completing the nivolumab and relatlimab combination 
therapy. Therefore, the clinical trial will be considered completed when the last 
participant has completed all phases of the study including the last visit or the last 
scheduled procedure shown in the Schedule of Activities (SoA), and the clinical 
endpoints are available for analysis.  
      
 
 
        
 
 

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6
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
6.1
Discontinuation of Study Intervention
Discontinuation from nivolumab plus relatlimab does not mean discontinuation from the 
study, and remaining study procedures should be completed as indicated by the 
protocol.  Patients who received at least 2 doses of the combination treatment will be 
considered evaluable and the remaining study procedures should be completed as 
indicated by the protocol in Section 6.2.  
If a clinically significant finding is identified (including, but not limited to changes from 
baseline) after enrollment, the Investigator or qualified designee will determine if any 
change in participant management is needed. Any new clinically relevant finding will be 
reported as an adverse event (AE).
The data to be collected at the time of study intervention discontinuation will include the 
following:

Progression Free Survival

Overall Survival

Adverse events
6.2
Participants Taken Off Study
Patients who are enrolled but do not receive at least one dose of nivolumab or 
relatlimab because of noncompliance or clinical reasons will be taken off study and will 
receive standard treatment. These patients will not be included in the efficacy analysis 
and will replaced.  
6.3
Participant Discontinuation/Withdrawal from the Study
Participants are free to withdraw from participation in the study at any time upon 
request. An Investigator may discontinue or withdraw a participant from the study for the 
following reasons:

Pregnancy

Significant study intervention non-compliance 

Lost-to-follow up; unable to contact subject

Any event or medical condition or situation occurs such that continued collection of 
follow-up  study data would not be in the best interest of the participant or might require 
an additional treatment that would confound the interpretation of the study

Disease progression which requires discontinuation of the study intervention

Participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Participant unable to receive nivolumab and relatlimab combination treatment for 2 
cycles over a period of 12 weeks. 
The reason for participant discontinuation or withdrawal from the study will be recorded 
on the Case Report Form (CRF). 
      
 
 
        
 
 

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6.3.1 Data Retention When Subjects Withdraw from FDA-Regulated Clinical 
Trials 
An investigator may ask a subject who is withdrawing whether the subject wishes to 
provide continued follow-up and further data collection subsequent to their withdrawal 
from the interventional portion of the study.  Under this circumstance, the discussion 
with the subject would distinguish between study-related interventions and continued 
follow-up of associated clinical outcome information, such as medical course or 
laboratory results obtained through non-invasive chart review, and address the 
maintenance of privacy and confidentiality of the subject’s information.   
 
If a subject withdraws from the interventional portion of the study, but agrees to 
continued follow-up of associated clinical outcome information as described in the 
previous bullet, the investigator must obtain the subject’s informed consent for this 
limited participation in the study (assuming such a situation was not described in the 
original informed consent form).  In accordance with FDA regulations, IRB approval of 
informed consent documents would be required (21 CFR 50.25, 56.109(b), 312.60, 
312.66, 812.100). 
6.4
Participant Replacement Criteria
Subjects who sign the informed consent form and do not receive the study intervention 
may be replaced.  Subjects who sign the informed consent, receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the 
study due to non-compliance will be replaced by a new eligible patient. 
6.5
Lost to follow up
A participant will be considered lost to follow-up if he or she fails to return for two 
scheduled treatment cycles over a period of 12 weeks and is unable to be contacted by 
the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site will attempt to contact the participant and reschedule the missed visit 3 
times and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the Investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered 
to have withdrawn from the study with a primary reason of lost to follow-up.
      
 
 
        
 
 

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7
TREATMENT DISCONTINUATION AND ADVERSE EVENT 
MANAGEMENT
Dose reductions or dose escalations are not permitted in this study. Dose delay criteria 
as  noted below apply for all drug-related adverse events regardless of whether or not 
the event is attributed to nivolumab, relatlimab, or both. All study drugs must be delayed 
until treatment can resume. Reasons for permanent treatment discontinuation include 
the following:
• Any drug-related/immune-related Grade 4 toxicity, except for endocrinopathy and 
asymptomatic elevations of amylase and lipase.
• Any Grade 3 elevation of liver function tests or colitis not responding to steroids, 
infliximab and/or mycophenolate mofetil.
• Any other drug-related/immune-related Grade 3 toxicity, EXCLUDING:
−
Grade 3 nausea/vomiting controlled by medical intervention within 72 hours
−
Grade 3 immune-related AEs (other than ocular events, colitis, myocarditis and 
pneumonitis) that improve to Grade ≤ 1 or baseline within 14 days after the 
initiation of supportive care or corticosteroid therapy
−
Grade 3 endocrinopathy that is managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy and the subject is asymptomatic or 
minimally or transiently symptomatic based on Investigator assessment
−
Grade 3 fatigue lasting ≤ 7 days from onset
−
Grade 3 rash in the absence of desquamation, with no mucosal involvement, that 
does not require systemic steroids, that does not interfere with activities of daily 
living and resolves to Grade 1 by the next dose of scheduled treatment or 14 
days, whichever is longer
−
Any grade vitiligo or alopecia
• Grade 2 or higher episcleritis, uveitis, or iritis
• Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of initiation of 
maximal supportive treatment.
If treatment is withheld > 6 weeks from the last dose, the participant must be 
permanently discontinued from study therapy.
      
 
 
        
 
 

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Table 3. Adverse Event Management Rules
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting Treatment
Treatment Discontinuation
2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks
Diarrhea/Colitis
4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 6 weeks of last dose
AST, ALT, or 
Increased 
Bilirubin
3-4
Permanently discontinue
(see exception below)a
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia
T1DM or 
3-4
Hold therapy for new onset Type 1 
diabetes mellitus or Grade 3-4 
hyperglycemia associated with 
evidence of beta cell failure
Resume therapy when patients are clinically and 
metabolically stable
Hypophysitis
2-4
Toxicity resolves to Grade 0-1. 
Therapy can be continued while 
endocrine replacement therapy is 
instituted
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks
Hyperthyroidism 
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy can be continued while 
thyroid replacement therapy is 
instituted
Therapy with can be continued while thyroid replacement 
therapy is instituted
2b
Toxicity resolves to Grade 0-1 
Permanently discontinue if toxicity develops despite adequate 
premedication 
Infusion Reaction
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks
Pneumonitis
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks
Renal Failure or 
Nephritis
3-4
Permanently discontinue
Permanently discontinue
3 or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks
All Other Drug-
Related Toxicityc
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event.
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative 
to baseline and lasts for at least 1 week then patients should be discontinued.
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated  for the next scheduled dose.
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study 
drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 6 weeks 
of the last dose.
      
 
 
        
 
 

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8
NIVOLUMAB
8.1
Description of Investigational Product
Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 
identical heavy chains and 2 identical light chains. Nivolumab is produced from cell 
culture using a Chinese Hamster Ovary (CHO) cell line. The physical and chemical 
properties of nivolumab drug substance are provided in Table 3.1-1 of the Investigator’s 
Brochure. 
8.2
Mechanism of Action
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, 
inhibits T- cell proliferation and cytokine production. Upregulation of PD-1 ligands 
occurs in some tumors and signaling through this pathway can contribute to inhibition of 
active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 
(IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction 
with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune 
response, including the anti-tumor immune response. In syngeneic mouse tumor 
models, blocking PD-1 activity resulted in decreased tumor growth.
Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition 
results in enhanced T-cell function that is greater than the effects of either antibody 
alone, and results in improved anti-tumor responses in metastatic melanoma and 
advanced RCC. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 
resulted in increased anti-tumor activity.
8.3
Dosage Form, Agent Preparation, Handling & Storage Guidelines
8.3.1 Dosage Form
The nivolumab (Opdivo™) dosage forms are provided in Table 3.2.1-1 of the 
Investigator’s Brochure. The drug products are sterile, non-pyrogenic, single-use, 
isotonic aqueous solutions for intravenous (IV) infusion. Nivolumab Injection, 40 mg/Vial 
(10 mg/mL), 100 mg/Vial (10 mg/mL), and 240 mg/Vial (10 mg/mL) are also referred to 
as nivolumab injection.
8.3.2 Acquisition and Accountability
The Investigator or designee is responsible for maintaining accurate dispensing records 
of the study treatment throughout the clinical study. The study treatment accountability 
log includes information including a patient identifier, amount and date dispensed, and 
amount and date returned to the pharmacy, if applicable. Product returned to the 
research pharmacy will be stored under the same conditions as products not yet 
dispensed but will be marked as 'returned' and kept separate from the products not yet 
dispensed. All dispensing and accountability records should be stored as per IND 
regulations. The pharmacist will dispense study treatment for each participant according 
to the pharmacy reference manual.
      
 
 
        
 
 

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8.3.3 Preparation and Administration
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-
micron pore size, low-protein binding (polyethersulfone membrane) in-line filter at the 
protocol-specified doses and infusion times. It is not to be administered as an IV push or 
bolus injection. When the dose is based on patient weight (ie, mg/kg), nivolumab 
injection can be infused undiluted (10 mg/mL) or diluted with 0.9% sodium chloride 
injection or 5% dextrose injection to protein concentrations as low as 0.35 mg/mL. 
When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab injection 
can be infused undiluted or diluted so as not to exceed a total infusion volume of 160 
mL. For patients weighing less than 40 kilograms (kg), the total volume of infusion must 
not exceed 4 mL per kg of patient weight.
During drug product preparation and handling, vigorous mixing or shaking is to be 
avoided. Instructions for dilution and infusion of nivolumab injection will be provided to 
the clinical site. Care must be taken to ensure sterility of the prepared solution as the 
product does not contain any antimicrobial preservative or bacteriostatic agent. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin 
containers and infusion sets, and glass bottles.
8.3.4 Packaging, Labeling, and Storage
Upon supply to site, study drugs will be labeled “for investigational use only” as per FDA 
regulations.  
Nivolumab Injection
Vials of nivolumab injection must be stored at 2C to 8C (36F to 46F) and protected 
from light and freezing. The unopened vials can be stored at room temperature (up to 
25C, 77F) and room light for up to 48 hours.
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container
The administration of nivolumab infusion must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored under 
refrigeration conditions (2°C to 8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 
8 hours of the total 24 hours can be at room temperature (up to 25C, 77F) and room 
light. The maximum of 8 hours under room
temperature and room light conditions includes the product administration period.
8.4
Disposal and Destruction
All unused and/or partially used Investigational Medicinal Product will be destroyed on 
site as per Institutional SOP and the destruction documented. Copy of the drug 
destruction document will be provided to BMS. IMP handling document will be provided 
at the time of Study activation.
      
 
 
        
 
 

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9
RELATLIMAB
9.0
Description of Investigational Product
Relatlimab, also referred to as BMS-986016-01, BMS-986016, or anti-LAG-3, was 
selected for dosage form development. Relatlimab is a soluble protein consisting of 4 
polypeptide chains that include 2 identical heavy chains and 2 identical light chains and 
is a human IgG4 monoclonal antibody directed against human LAG-3. Relatlimab is 
produced from cell culture using a Chinese hamster ovary (CHO) cell line. The physical 
and chemical properties of relatlimab drug substance are summarized in Table 3.1-1 of 
the Investigator’s Brochure.
9.1
Mechanism of Action
Upon administration, relatlimab binds to LAG-3 on tumor infiltrating lymphocytes (TILs). 
This may activate antigen-specific T lymphocytes and enhance cytotoxic T cell-
mediated tumor cell lysis, which leads to a reduction in tumor growth. LAG-3 is a 
member of the immunoglobulin superfamily (IgSF) and binds to major histocompatibility 
complex (MHC) class II. LAG-3 expression on TILs is associated with tumor-mediated 
immune suppression.24
9.2
Dosage Form, Agent Preparation, Handling & Storage Guidelines
9.2.1 Dosage Form
Relatlimab will be given as an intravenous (IV) infusion. There are three drug products 
available for intravenous (IV) administration; information relating to the drug products 
are provided in Table 3.2.1-1 of the Investigator’s Brochure. The drug products are 
sterile, non-pyrogenic, single-use, isotonic aqueous solutions.
9.2.2 Acquisition and Accountability
The Investigator or designee is responsible for maintaining accurate dispensing records 
of the study treatment throughout the clinical study. The study treatment accountability 
log includes information including a patient identifier, amount and date dispensed, and 
amount and date returned to the pharmacy, if applicable. Product returned to the 
research pharmacy will be stored under the same conditions as products not yet 
dispensed but will be marked as 'returned' and kept separate from the products not yet 
dispensed. All dispensing and accountability records should be stored as per IND 
regulations. The pharmacist will dispense study treatment for each participant according 
to the pharmacy reference manual.
9.2.3 Preparation and Administration
9.2.3.1 For Intravenous Administration
Relatlimab Injections
Relatlimab injections (10 mg/mL) are to be administered as an IV infusion through a 
compatible low-protein binding in-line filter at the protocol-specified doses. They are not 
      
 
 
        
 
 

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to be administered as an IV push or bolus injection. Relatlimab injection can be diluted 
with 0.9% (w/v) sodium chloride injection (normal saline, NS) or 5% (w/v) dextrose 
injection (D5W) to protein concentrations no lower than 0.2 mg/mL.
Care must be taken to assure sterility of the prepared solution, as the product does not 
contain any anti-microbial preservative or bacteriostatic agent. No incompatibilities have 
been observed between relatlimab injection and ethylvinyl acetate (EVA), polyolefin 
(PO) or polyvinyl chloride (PVC) IV containers, di(2-ethylhexyl)phthalate (DEHP)-
plasticized PVC IV sets, DEHP-free IV sets, or in-line filters with 0.2 µm or 1.2 µm 
polyethersulfone (PES), 0.2 µm nylon, or 0.2 µm polyvinylidene fluoride (PVDF) 
membranes.
Detailed instructions for drug product dilution and administration are provided in the 
pharmacy manual for the clinical study.
Co-administration of Relatlimab Injection and Nivolumab Injection
Relatlimab injections (10 mg/mL) can be co-administered with nivolumab injection (also 
referred to as BMS-936558 injection) as an IV infusion through a compatible low-
protein-binding in-line filter at the protocol-specified doses. Relatlimab injection 
combined with nivolumab injection can be diluted with NS or D5W to a total protein 
concentration no lower than 0.8 mg/mL (0.2 mg/mL of relatlimab and 0.6 mg/mL of 
nivolumab).
Care must be taken to assure sterility of the prepared solution, as the products do not 
contain any anti-microbial preservative or bacteriostatic agent. No incompatibilities 
between the combined drug products and EVA, PO, or PVC IV containers, DEHP-
plasticized PVC IV sets, DEHP-free IV sets and in-line filters with 0.2 µm or 1.2 µm 
PES, 0.2 µm nylon, or 0.2 µm PVDF membranes.
Detailed instructions for drug product dilution and administration are provided in the 
pharmacy manual for the clinical study.
9.2.4 Packaging, Labeling, and Storage
Upon supply to site, study drugs will be labeled “for investigational use only” as per FDA 
regulations.  
9.2.4.1 For Intravenous Administration
Relatlimab Injection, 10 mg/mL
The drug products should be stored at 2°C to 8°C (36⁰F to 46⁰F) with protection from 
light. Do not freeze the drug products.
Relatlimab Injection Infusions and Combinations of Relatlimab Injection and Nivolumab 
Injection Infusions
The IV administration of relatlimab infusions or combined relatlimab and nivolumab 
infusions must be completed within 24 hours of preparation. If not used immediately, the 
infusion solutions may be stored in a refrigerator at 2⁰C to 8⁰C (36⁰F to 46⁰F) for up to 
24 hours and a maximum of 4 hours of the total 24 hours can be at room temperature 
      
 
 
        
 
 

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(15⁰C to 25⁰C; 59⁰F to 77⁰F) and exposed to room light. The maximum 4-hour period 
under room temperature and room light conditions includes the product administration 
period.
9.3
Disposal and Destruction
All unused and/or partially used Investigational Medicinal Product will be destroyed on 
site as per Institutional SOP and the destruction documented. Copy of the drug 
destruction document will be provided to BMS. IMP handling document will be provided 
at the time of Study activation.
      
 
 
        
 
 

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10
SCHEDULE OF ASSESSMENTS 
10.1 Screening 
Screening assessments are to be conducted within 28 days prior to initiating study 
unless otherwise specified.  At screening, the following procedures/tests will be 
performed:

Informed Consent

Eligibility (Inclusion/Exclusion criteria)

Demographic and medical history 

Prior and concomitant medication review

Physical Exam 

Vital Signs: systolic and diastolic blood pressures, and 
temperature 

ECOG Performance Status

12-Lead ECG

Echocardiogram

Laboratory Evaluations

Pregnancy Test (Urine or Serum β-HCG2)

CBC with differential

Comprehensive metabolic panel

LDH

T3, free T4, TSH

ACTH and serum cortisol 

Amylase

Lipase

Urinalysis

HBsAg, HBsAb, Hep C Ab, HB core antibody

Troponin T

PT/INR

PTT

CT chest plain

MRI brain with and without contrast 

MRI abdomen and pelvis with and without contrast (EOVIST® 
preferred)

Correlative studies

Blood

Archival tissue

Fresh tumor biopsy if needed, safe and feasible as 
determined by investigator
10.2 Cycle 1, 3, 5, 7, Day 1 + or – 3 days 
The following assessments will be performed 

Review adverse events

Review concomitant medication
      
 
 
        
 
 

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
Physical Exam 

Vital Signs: systolic and diastolic blood pressures, and 
temperature 

ECOG Performance Status

Administration of nivolumab plus relatlimab

Laboratory Evaluations

Pregnancy Test (Urine or Serum β-HCG2)

CBC with differential

Comprehensive metabolic panel

LDH

Amylase

Lipase

Urinalysis

Troponin T (Only cycle 1)

CT chest plain (Only for cycles 3,5,7, Day 1 (+ or – 3 days))

MRI abdomen and pelvis with and without contrast (EOVIST® 
preferred) (Only for cycles 3,5,7, Day 1 (+ or – 3 days))

Correlative studies

Blood for correlative studies to be obtained on 

Cycle 1, Day 1 (+ or – 3 days)

Cycle 3, Day 1 (+ or – 3 days) 

upon progression or response

Fresh tumor biopsy if needed, safe and feasible as 
determined by investigator.
10.3 Cycles 2, 4, 6, 8, Day 1 + or – 3 days
The following assessments will be performed at each cycle unless otherwise specified:

Review adverse events

Review concomitant medication 

Physical Exam 

Vital Signs: systolic and diastolic blood pressures, and 
temperature 

ECOG Performance Status

Administration of nivolumab plus relatlimab

Laboratory Evaluations

Pregnancy Test (Urine or Serum β-HCG2)

CBC with differential

Comprehensive metabolic panel

LDH

T3, free T4, TSH

ACTH and serum cortisol

Amylase

Lipase

Urinalysis
      
 
 
        
 
 

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
Troponin T (Only cycle 2)

Correlative Studies

Blood for correlative studies to be obtained on 
Cycle 2, Day 1 (+ or – 3 days)) upon progression 
or response

Fresh tumor biopsy if needed, safe and feasible as 
determined by investigator..
10.4 Subsequent Treatment Cycles
Subsequent treatment cycles are to be repeated every 4 weeks until progression or 
toxicity up to 24 months. Cycles will follow the schedule of assessments outlined in 
section 10.2 (odd cycles) and section 10.3 (even cycles)
10.5 End of Treatment Visit, 28 days after the last dose of Nivolumab and Relatlimab 
combination treatment (+ or – 14 days)
The following assessments will be performed during the end of treatment visit:

Review adverse events

Review concomitant medication 

Physical Exam 

Vital Signs: systolic and diastolic blood pressures, and 
temperature 

ECOG Performance Status

Laboratory Evaluations

Pregnancy Test (Urine or Serum β-HCG2)

CBC with differential

Comprehensive metabolic panel

LDH

T3, free T4, TSH

ACTH and serum cortisol

Amylase

Lipase

Urinalysis
10.6 Safety Follow-Up, 30 days (+ or – 7 days) post discontinuation 
The following assessments will be performed during the end of treatment visit:

Post-study anticancer therapy status

Review adverse events

Review concomitant medication 

Physical Exam 

Vital Signs: systolic and diastolic blood pressures, and 
temperature 

ECOG Performance Status

Laboratory Evaluations

Pregnancy Test (Urine or Serum β-HCG2)
      
 
 
        
 
 

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
CBC with differential

Comprehensive metabolic panel

LDH

T3, free T4, TSH

ACTH and serum cortisol

Amylase

Lipase

Urinalysis
10.7 Survival Follow-Up, Every 12 weeks (+ or – 7 days) for 2 years
The following assessments will be performed during the survival follow-up visit:

Post-study anticancer therapy status

Survival status
      
 
 
        
 
 

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10.8 STUDY CALENDAR
Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-Treatment
To be repeated every 4 
weeks until progression 
or toxicity up to 24 
months
Treatment Cycle/Title:
Screening 
1
2 
3
4
5
6
7
8
EOT (at time of 
discontinuation)
Safety Follow-
up
Survival Follow-Up1
Scheduling Window (Days):
(-28 to -1 
days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
30 days 
(+ or – 7 days) 
post 
discontinuation
Every 12 weeks 
(+ or – 7 days)
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
Review Concomitant Medication
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (temperature/pulse/respiratory 
rate/blood pressure and weight)
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
Echocardiogram
X
Administration of nivolumab plus relatlimab 
over 60 minutes IV
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCG2
X
X
X
X
X
X
X
X
X
X
X
CBC with Differential
X
X
X
X
X
X
X
X
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Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-Treatment
To be repeated every 4 
weeks until progression 
or toxicity up to 24 
months
Treatment Cycle/Title:
Screening 
1
2 
3
4
5
6
7
8
EOT (at time of 
discontinuation)
Safety Follow-
up
Survival Follow-Up1
Scheduling Window (Days):
(-28 to -1 
days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
30 days 
(+ or – 7 days) 
post 
discontinuation
Every 12 weeks 
(+ or – 7 days)
Comprehensive Serum Chemistry Panel
X
X
X
X
X
X
X
X
X
X
X
LDH
X
X
X
X
X
X
X
X
X
X
X
T3, freeT4 and TSH3
X
X
X
X
X
X
X
ACTH and serum cortisol3
X
X
X
X
X
X
X
Amylase3
X
X
X
X
X
X
X
X
X
X
X
Lipase3
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
HBsAg, HBsAb, Hep C Ab, HB core 
antibody4
X
Troponin T3,5
X
X
X
PT/INR and PTT
X
Efficacy Measurements
CT chest plain
X
X
X
X
MRI Brain with and without contrast6
X
MRI abdomen/ pelvis with EOVISTTM with 
and without contrast7
X
X
X
X
Archival Tissue Collection/Correlative Studies Blood
Correlative Studies Blood Collection8
X
X
X
X
X8
One additional blood sample for correlative 
studies 
X9
Archival Tumor Tissue Collection10
X
Fresh Tumor Biopsies 11
X
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1.
For two years.
2.
For women who are able to become pregnant only.
3.
Also as needed according to clinical signs and symptoms
4.
For patients with treated hepatitis C, undetectable viral load is required with positive antibodies
5.
For the first two months then as dictated by clinical signs and symptoms thereafter
6.
At baseline, every 6 months and as needed as dictated by clinical signs and symptoms.
7.
EOVIST contrast preferred but not mandatory
8.
Blood for correlative studies to be obtained on day 1 of cycles 1-3 prior to treatment and upon progression/response
9.
One additional blood sample for correlative studies will also be collected at any point after treatment started and before progression of disease or end of 
treatment
10. If fresh biopsy determined to be not safe and archival tissue available, then fresh biopsy waived.
11.  Fresh tumor biopsies will be obtained at screening and upon progression or response if needed, safe and feasible as determined by the investigator.

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11
CORRELATIVE STUDIES
Research 
Sampling
Time point
Contents
Archival Tissue
Screening
FFPE Tumor Tissue 
Pre-treatment Biopsy
FFPE Biopsy 
Tissue
Treatment Response or Progression
FFPE Biopsy Tissue
Pre-treatment Biopsy
Fresh Tissue, 
Fresh-Frozen 
Tissue
Treatment Response or Progression
Fresh Tumor Tissue, 
Fresh-Frozen Tumor 
Biopsy Tissue
Pre-treatment C1
Pre-Treatment C2
Pre-Treatment C3
One additional blood sample for 
correlative studies will also be 
collected at any point after treatment 
started and before progression of 
disease or end of treatment
Blood 
At time of Response or Progression
4- 10mL EDTA purple top 
tube
Correlative studies will be conducted for research use only. 
For participants who consent to additional correlative studies, archival tissue, blood, 
and fresh/fresh-frozen tumor from pre- and post- treatment biopsy will be collected 
for correlative biomarker analysis including but not limited to tumor single-cell RNA-
sequencing with single-cell TCR/BCR profiling, metastatic tumor mutation profiling, 
blood-based bulk TCR profiling, and blood-based cell-free DNA mutation profiling. 
      
 
 
        
 
 

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Correlative Studies, Solid Tumors:
Archival FFPE primary or previous metastatic tumor specimen, if available, may be 
collected from previous/current surgeries or biopsies for biomarker analysis including 
but not limited to mutation analysis and immunohistochemistry of LAG-3 and PD-1. 
A minimum of 3 10-micron sections will be required. Fresh/fresh-frozen tumor tissue 
from pre- and post- treatment biopsies will be collected for biomarker analysis 
including but not limited to tumor single-cell RNA-sequencing with single-cell 
TCR/BCR profiling. Mutation analysis may be conducted on fresh-frozen tumor 
tissue from pre- and post- treatment biopsy, if quantity permits.
Correlative Studies, Blood: 
Blood will be obtained using EDTA purple top tubes and will be stored as plasma 
and buffy coat at -80 °C. Blood sample analysis will consist of but is not limited to 
bulk TCR profiling and cell-free DNA profiling.
Sample Storage and Analysis
Storage and analysis for tumor and blood will be conducted at:
The laboratory of J. William Harbour
Department of Ophthalmology
1501 NW 10th Ave
Biomedical Research Building
Room 832, Suite H-I
      
 
 
        
 
 

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12
EVALUATION CRITERIA
12.1 Parameters of Outcome –RECIST 1.1 Criteria
12.2 Definition of Measurable Lesions
Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest dimension to be recorded). Each lesion 
must be ≥ 20 mm when measured by conventional techniques, including palpation, 
plain x-ray, CT, and MRI, or ≥ 10 mm when measured by spiral CT. 
12.3 Treatment Beyond Progression
If disease progression is noted on imaging, patients may stay on drug and be re-
evaluated for disease progression with restaging scans within 4 weeks, but no later 
than 6 weeks, after initial determination of progression. Patients who remain on 
therapy after initial disease progression must have stable ECOG status and 
no clinical symptoms and signs of disease progression to qualify 
for continuing treatment until the next imaging assessment. 
12.4 Baseline documentation of “Target” and “Non-Target” lesions 
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in 
total representative of all involved organs should be identified as target lesions and 
will be recorded and measured at baseline. Target lesions should be selected on 
the basis of their size (lesions with the longest dimension) and their suitability for 
accurate repetitive measurements by one consistent method of assessment (either 
by imaging techniques or clinically). A sum of the longest dimension (LD) for all 
target lesions will be calculated and reported as the baseline sum LD. The baseline 
sum LD will be used as reference to further characterize the progression of the 
measurable dimension of the disease. Tumor within a previously irradiated field will 
be designated as “non-target” lesions unless progression is documented or a 
biopsy is obtained to confirm persistence at least 90 days following completion of 
radiation therapy. 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements are not required and each of 
these lesions should be followed as stable (the persistence of a non-target lesion), 
complete response (the disappearance of a non-target lesion) or progressive 
disease (the unequivocal progression of a non-target lesion). 
All baseline evaluations of disease status should be performed as close as possible 
to the start of treatment and never more than 4 weeks before the beginning of 
treatment. 
Measurement of the longest dimension of each target lesion size is required for 
follow-up. Change in the sum of these dimensions affords some estimate of change 
      
 
 
        
 
 

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in tumor size and hence therapeutic efficacy. All disease must be assessed using 
the same technique as baseline. 
12.5 Definition of disease progression 
Progression for patients with measurable disease at baseline is defined as ANY of 
the following: 

At least a 20% increase in the sum of LD target lesions taking as 
reference the smallest sum LD recorded since study entry 

In the case where the ONLY target lesion is a solitary pelvic mass 
measured by physical exam which is not radiographically measurable, 
a 50% increase in the LD is required taking as reference the smallest 
LD recorded since study entry 

The appearance of one or more new lesions 

Death due to disease without prior objective documentation of 
progression 

Global deterioration in health status attributable to the disease 
requiring a change in therapy without objective evidence of 
progression 

Unequivocal progression of existing non-target lesions, other than 
pleural effusions without cytological proof of neoplastic origin, in the 
opinion of the treating physician (in this circumstance an explanation 
must be provided) 
12.6 Progression for Patients with Non-Measurable Disease at Baseline
Defined as increasing clinical, radiological, or histological evidence of disease since 
study entry. Survival is the observed length of life from the date of study entry to 
death or the date of last contact. 
12.7 Progression-Free Survival 
Defined as the period from the date of study entry until disease progression or death 
(whichever occurs first). Cases who have not had an event will be censored at the 
date of last disease assessment documenting the patient was free of progression. 
Progression will be evaluated by RECIST v1.1. 
12.8 Subjective Parameters
The performance status, specific symptoms, and side effects are graded according 
to the CTCAE 5.0.
      
 
 
        
 
 

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13
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event 
reporting.
13.1 Definition of 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 participant 
administered study drug 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.
A non-serious adverse event is an AE not classified as serious. 
13.2 Definition of 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 participant was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)

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.) 

Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via 
the study drug is an SAE. 

Unusual Failure in Efficacy (for Phase IV Canadian studies)
Although pregnancy and potential drug-induced liver injury (DILI), are not always serious by 
regulatory definition, however, these events must be reported within the SAEs timeline.
Any component of a study endpoint that is considered related to study therapy should be 
reported as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, 
anaphylaxis must be reported).
      
 
 
        
 
 

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NOTE: (PI determines if this information regarding hospitalizations are considered SAEs and 
should be included in the protocol. This is supplemental information that is included in 
BMS-sponsored trials)
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).

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
13.3 Non-Serious Adverse Event

Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim 
or final study reports as specified in the agreement or, if a regulatory requirement 
[e.g., IND US trial] as part of an annual reporting requirement. 

Non-serious AE information should also be collected from following the subject’s 
written consent to participate in the study. 
Non-serious Adverse Event Collection and Reporting
The collection of non-serious AE information should begin following the subject’s written 
consent to participate in the study. All non-serious adverse events (not only those deemed 
to be treatment-related) should be collected continuously during the treatment period and for 
a minimum of (100 days) days following the last dose of study treatment. 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious. 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. 
Laboratory Test Abnormalities
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported to BMS as such.
The following laboratory abnormalities should be documented and reported appropriately:
      
 
 
        
 
 

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
any laboratory test result that is clinically significant or meets the definition of an SAE

any laboratory abnormality that required the participant to have study drug 
discontinued or interrupted

any laboratory 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).
13.4 Classification of an Adverse Event
13.4.1 Severity of Event
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity. 
•
Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
•
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning.
•
Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating.  Of note, the term “severe” does not necessarily equate 
to “serious”.
13.4.2 Relationship to Study Intervention
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. (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs.)
13.4.3 Expectedness
The Sponsor-Investigator will be responsible for determining whether an adverse 
event (AE) is expected or unexpected.  An AE will be considered unexpected if the 
      
 
 
        
 
 

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nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the study intervention.
13.4.4 Time Period and Frequency for Event Assessment and Follow-Up
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come 
to the attention of study personnel during study visits and interviews of a study 
participant presenting for medical care, or upon review by a study monitor.
All AEs will be captured on the appropriate case report form (CRF) as well as in the 
Adverse Event reporting section in Velos, a HIPAA AND 21 CFR part 11 compliant 
database and will be reported to the University of Miami’s IRB per institutional 
requirements. 
Any medical condition that is present at the time that the participant is screened will 
be considered as baseline and not reported as an AE. However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as 
an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode.
Study personnel will record all reportable events with start dates occurring any time 
after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for 
SAEs) after the last day of study participation.  At each study visit, the investigator 
will inquire about the occurrence of AE/SAEs since the last visit.  Events will be 
followed for outcome information until resolution or stabilization.
13.5 Adverse Event Reporting
Adverse Events may be spontaneously identified by the patient and/or in response 
to an open question from study personnel or revealed by observation, physical 
examination, or other diagnostic procedures.  Any clinically relevant deterioration in 
laboratory assessments or other clinical finding is considered an AE.  When 
possible, signs and symptoms indicating a common underlying pathology should be 
noted as one comprehensive event.  
The Sponsor-Investigator, is responsible for reporting adverse events (AEs) to any 
regulatory agency, to the Sponsor-Investigator’s IRB and to the Investigational Drug 
Sponsor (See Section 13.3 Non-Serious Adverse Event).  
13.6 Serious Adverse Event Reporting
Generally, any AE considered serious by the PI or Sub-investigator or which meets 
the definition of an SAE included in Section 13.2, Definition of Serious Adverse 
Events. 
      
 
 
        
 
 

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SAEs will be captured on the appropriate case report form (CRF) as well as in the 
Serious Adverse Event reporting section in Velos, a HIPAA AND 21 CFR part 11 
compliant database and will be reported to the University of Miami’s IRB per 
institutional requirements. 
All SAEs that occur following the subject’s written consent through 100 days of 
discontinuation of dosing must be reported to BMS Worldwide Safety, whether 
related or not related to study drug. SAEs will be reported to BMS Worldwide safety 
using the Medwatch 3500A Reporting form.  The Sponsor-Investigator or designee 
will report the SAE to BMS Worldwide within 24 hours of his/her becoming aware 
of these events regardless of relationship of the SAE to the use of study drug.  
According to 21 CFR 312.32(c)(1), “the sponsor must notify FDA in an IND safety 
report of potential serious risks, from clinical trials or any other source, as soon as 
possible, but in no case later than 15 calendar days after the sponsor determines 
that the information qualifies for reporting… In each IND safety report, the sponsor 
must identify all IND safety reports previously submitted to FDA concerning a similar 
suspected adverse reaction and must analyze the significance of the suspected 
adverse reaction in light of previous, similar reports or any other relevant 
information. The sponsor must report any suspected adverse reaction that is both 
serious and unexpected. The sponsor must report an adverse event as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between 
the drug and the adverse event, such as:
(A) A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (e.g., angioedema, hepatic injury, 
Stevens-Johnson Syndrome);
(B) One or more occurrences of an event that is not commonly associated 
with drug exposure, but is otherwise uncommon in the population exposed to 
the drug (e.g., tendon rupture);
(C) An aggregate analysis of specific events observed in a clinical trial (such 
as known consequences of the underlying disease or condition under 
investigation or other events that commonly occur in the study population 
independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical 
control group.”
Furthermore, according to 21 CFR 312.32(c)(2), “the sponsor must also notify FDA 
of any unexpected fatal or life-threatening suspected adverse reaction as soon as 
possible but in no case later than 7 calendar days after the sponsor's initial receipt of 
the information.”
13.7 Adverse Event Collection and Reporting Information:

All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through (100) days of discontinuation of dosing must be 
      
 
 
        
 
 

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reported to BMS Worldwide Safety, whether related or not related to study drug. If 
applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (e.g., a follow-up skin biopsy).

Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, are collected, including those thought to be 
associated with protocol-specified procedures. The investigator should report any SAE 
occurring after these aforementioned time periods, which 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.
An appropriate SAE form (e.g.  ex-US = CIOMS form or USA = Medwatch form) should be 
used to report SAEs to BMS.  If the sponsor-investigator prefers to use their own Institutional 
form, it must be reviewed by the BMS Protocol Manager prior to study initiation to ensure 
that at a minimum all of the data elements on the CIOMS form are present.  Note:  Please 
include the BMS Protocol number on the SAE form or on the cover sheet with the SAE form 
transmission.  
The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i 

The MedWatch form is available at: MedWatch 3500 Form 

For studies with long-term follow-up periods in which safety data are being reported, 
include the timing of SAE collection. 

The Sponsor will reconcile the clinical database AE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). 

The Investigator will request from BMS GPV&E, 
aepbusinessprocess@bms.com the SAE reconciliation report and 
include the BMS protocol number every 3 months and prior to data 
base lock or final data summary

GPV&E will send the investigator the report to verify and confirm all 
SAEs have been transmitted to BMS GPV&E.

The data elements listed on the GPV&E reconciliation report will be 
used for case identification purposes. If the Investigator determines a 
case was not transmitted to BMS GPV&E, the case should be sent 
immediately to BMS (Worldwide.Safety@bms.com).

In addition to the Sponsor Investigator’s responsibility to report events to their local 
HA, suspected serious adverse reactions (whether expected or unexpected) shall be 
reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate 
reports).

In accordance with local regulations, BMS will notify sponsor investigators of all 
reported SAEs that are suspected (related to the investigational product) and 
      
 
 
        
 
 

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unexpected (ie, not previously described in the IB). An event meeting these criteria is 
termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Sponsor 
investigator notification of these events will be in the form of either a SUSAR Report or 
a Semi-Annual SUSAR Report. 

Other important findings which may be reported by BMS as an Expedited Safety 
Report (ESR) include: increased frequency of a clinically significant expected 
SAE, an SAE considered associated with study procedures that could modify the 
conduct of the study, lack of efficacy that poses significant hazard to study 
subjects, clinically significant safety finding from a nonclinical (eg, animal) study, 
important safety recommendations from a study data monitoring committee, or 
sponsor or BMS decision to end or temporarily halt a clinical study for safety 
reasons.

Upon receiving an ESR from BMS, the investigator must review and retain the 
ESR with the IB. Where required by local regulations or when there is a central 
IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. 
The investigator and IRB/IEC will determine if the informed consent requires 
revision. The investigator should also comply with the IRB/IEC procedures for 
reporting any other safety information. 
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
BMS within 24 hours \ 1 Business Day of becoming aware of the event. SAEs must be 
recorded on either CIOMS, MedWatch, or approved site SAE form.  
Pregnancies must be reported and submitted to BMS.  BMS will perform due diligence 
follow-up using the BMS Pregnancy Form which the investigator must complete. 
SAE Email Address:  Worldwide.Safety@BMS.com
SAE Facsimile Number:  +1 609-818-3804
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 \ 1 Business Day 
to BMS using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization.
13.8 Reporting Events to Participants
Not Applicable
      
 
 
        
 
 

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13.9 Events of Special Interest
Select Adverse Events
Category of Select AE
Order in the output
ENDOCRINE ADVERSE EVENT
1 (if applicable)
GASTROINTESTINAL ADVERSE EVENTS
2
HEPATIC ADVERSE EVENTS
3
PLUMONARY ADVERSE EVENTS
4
RENAL ADVERSE EVENTS
5
SKIN
6
HYPERSENSITIVITY/INFUSION 
REACTION
7
Immune-Mediated Adverse Events (IMAE)
Class Name of IMAE
Order in the output
PNEUMONITIS
1
DIARRHEA/COLITIS
2
HEPATITIS
3
ADRENAL INSUFFICIENCY
4
HYPOTHYROIDISM/THYROIDITIS
5
HYPOTHYROIDISM
6
THYROIDITIS
7
DIABETES MELLITUS
8
Other Events of Special Interest
Category/class of OEOSI
Order in the output
MYASTHENIC SYNDROME
1
DEMYELINATION EVENT
2
GUILLAIN-BARRE SYNDROME
3
PANCREATITIS EVENT
4
UVEITIS EVENT
5
ENCEPHALITIS EVENT
6
MYOCARDITIS EVENT
7
MYOSITIS EVENT
8
RHABDOMYOLYSIS EVENT
9
GRAFT VERSUS HOST DISEASE
10
CA224 OTHER MENINGITIS
11
CA224 TROPONIN
12
13.9.1 Pregnancy
Every effort should be made to prevent pregnancy throughout the entire duration of 
participation in this study.  All patients of reproductive potential involved in the study 
      
 
 
        
 
 

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are required to use effective methods of contraception during the study and for 24 
weeks after the last combination treatment of nivolumab and relatlimab.  Female 
patients will be instructed to notify the Investigator as soon as possible if they 
discover they are pregnant; male patients will be instructed to notify the Investigator 
immediately if they discover that their sexual partner is pregnant.  
If, following initiation of the investigational product, it is subsequently discovered that 
a study participant is pregnant or may have been pregnant at the time of 
investigational product exposure, including during at least 5 half-lives after product 
administration, the investigational product will be permanently discontinued in an 
appropriate manner (e.g., dose tapering if necessary for participant). 
The investigator must immediately notify Worldwide.Safety@bms.com of this event 
and complete one of the following forms within 24 hours of awareness of the event 
via either the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in 
accordance with SAE reporting procedures. 
Protocol-required procedures for study discontinuation and follow-up must be 
performed on the participant.
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on 
the CIOMS, MedWatch, BMS Pregnancy Surveillance Form, or approved site SAE 
form.  A BMS Pregnancy Surveillance Form may be provided upon request.
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 order for Sponsor or designee to collect any pregnancy 
surveillance information from the female partner, the female partner must sign an 
informed consent form for disclosure of this information. 
13.9.2 Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or 
not these procedures are required by the protocol, should also be recorded as a 
non-serious or serious AE, as appropriate, and reported accordingly. 
      
 
 
        
 
 

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14
UNANTICIPATED PROBLEMS
14.1 Definition of Unanticipated Problems
The Office for Human Research Protections (OHRP) considers unanticipated 
problems involving risks to participants or others to include, in general, any incident, 
experience, or outcome that meets all of the following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
Institutional Review Board (IRB)-approved research protocol and informed 
consent document; and (b) the characteristics of the participant population 
being studied;
•
Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and
•
Suggests that the research places participants or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized.
14.2 Unanticipated Problem Reporting
The Sponsor-Investigator will report unanticipated problems (UPs) to the reviewing 
Institutional Review Board (IRB). 
14.3 Reporting Unanticipated Problems to Participants
Not Applicable 
      
 
 
        
 
 

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15
DATA REPORTING
15.1 Data submission
Electronic case report forms for study data entry will be developed by staff at the 
University of Miami using Velos, a HIPAA AND 21 CFR part 11 compliant database. 
Only investigators and assigned research staff will have access to study data. The 
electronic case report forms will be available to sponsor, IRB or regulatory 
authorities in event of an audit 
15.2 Data and Safety Monitoring
The research team will continuously monitor study accruals, toxicities, and response 
to treatment. The Sylvester Comprehensive Cancer Center’s (SCCC) Data and 
Safety Monitoring Committee (DSMC) will monitor this clinical trial according to the 
Cancer Center’s data and safety monitoring (DSM) plan to assure the well-being of 
patients enrolled on Investigator-Initiated Trials that do not have an outside 
monitoring review.  In its oversight capacity, the DSMC bears responsibility for 
suspending or terminating this study.  The activities of this committee includes 
ongoing review of accrual, periodic review of response adverse events including 
SAEs, important medical events, significant revisions or amendments to the 
protocol, and approval of cohort/dose escalations. The DSMC also reviews reports 
from internal audits of protocol compliance and data integrity conducted by the 
University of Miami, Office of Research Compliance Assessment. If the DSMC 
and/or the PI have concerns about unexpected safety issues, the study will be 
stopped and will not resume until the issues are resolved. The DSMC will review 
reports from all audits, site visits, or study reviews pertaining to this clinical trial and 
take appropriate action.  The guidelines appearing in this section are offered for 
DSMC consideration in assessing adverse events and response to study treatment.  
The SCCC DSM Plan to which this study is subject can also be found at 
www.sylvester.org.
15.3 Early Stopping Guidelines
We propose the following guidelines for the Sylvester Data and Safety monitoring 
Committee (DSMC) in its review of accumulating data on toxicity and feasibility of 
study treatment. The proposed guidelines were developed using Bayesian methods, 
which can be applied at any stage of enrollment without advance specification of the 
number of interim analyses to be performed, or the number of patients evaluable for 
toxicity, or response, at the time such assessments are made.
Under the Bayesian method, we assign a prior probability (level of belief at the start 
of the trial) to a range of possible values for the true toxicity rate, and likewise for the 
true feasibility rate. As data on treated patients become available, each of these 
probability distributions is revised and the resulting posterior probability becomes the 
basis for recommending either early termination or continuation of the study. In the 
sections that follow, we provide specific stopping guidelines based on posterior 
      
 
 
        
 
 

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probabilities for monitoring toxicity and efficacy over the course of this trial. 
Underlying assumptions for the prior distributions are also presented.
15.4 Early Stopping Due to Safety
The following early stopping guidelines, which are based on a Bayesian method, will 
be applied to ensure safety of this trial. Safety monitoring will be based on the 
occurrence of treatment related (possible, probable, or definite) grade 3 or higher 
toxicity occurring during study treatment. We suggest a stopping rule guideline for 
safety as a posterior probability of a rate of grade 3  or higher toxicity exceeding 20% 
as 90% or higher. Table 4 shows specific instances where this guideline is met. 
Posterior probabilities used to derive the preceding table are calculated under a prior 
beta distribution with parameters 1 = 0.2 and 2 = 1.8, which corresponds to an 
expected rate of 10% based on prior information roughly equivalent to having studied 
2 patients. Furthermore, this prior distribution assigns a small a priori chance (17.5%) 
to the possibility that the true rate of unacceptable toxicity is 20% or greater.
Table 4. Stopping Rules for Safety
Number of Patients 
with 
Treatment 
Related 
Grade 3+ toxicity 
Total 
patients 
Evaluated
Observed rate
3
3 to 5
>60%
4
6 to 9
>44.4% 
5
10 to 12
>41.7%
6
13 to 16
>37.5%
7
17 to 20
>35%
8
21 to 24
>33.3%
9
24 to 27
>33.3%
15.5 Early Stopping Due to a Lack of Efficacy
Early stopping due to a lack of efficacy is built in study design since we use Simon 
two-stage design.
      
 
 
        
 
 

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16
STATISTICAL METHODS
16.1 Statistical Hypothesis
The primary hypothesis is that the ORR in patients treated with the combination of 
nivolumab and BMS-986016 is significantly higher than 20%. With the null 
hypothesis that the ORR of 5% or lower is considered not clinically significant.
16.2 Sample Size Determination
Based on Simon two-stage minimax design, 13 patients will be enrolled in Stage 1 
and evaluated for response. If none of the 13 patients respond (CR or PR), the study 
will be stopped for futility. Otherwise, the study will proceed to Stage 2 and enroll 
additional 14 patients for a total of 27 patients. The null hypothesis will be rejected if 
4 or more responses are observed among 27 patients. This design achieves 5% 
type I error and 80% power when the true ORR is 20%
16.3 Statistical Analyses
Demographic and disease characteristics will be summarized using descriptive 
statistics. Counts and percentages will be used to summarize the distribution of 
categorical variables. Median, range, mean, and standard deviation will be used for 
continuous variables. Continuous variables will be tested using Student’s t-test and/or 
Mann-Whitney U test. All statistical tests will be two-sided and p<0.05 will be 
considered as statistical significance.
The full analysis set will consist of all patients enrolled. The modified full analysis set  
will consist of all enrolled patients, except patients withdrawn prior to the first efficacy 
measurement (at Cycle 2). The per-protocol analysis set will consist of all patients 
from the FU analysis set without any major protocol violations. The safety analysis 
set will consist of all patients who get treatment regardless of completion of 
treatment. The safety analysis set will serve as the main analysis set for safety 
assessments. The modified full analysis set will serve as the main analysis set for 
efficacy assessments. The efficacy assessment will also be performed on the per-
protocol and full analysis sets.
Response rate will be estimated along with corresponding 95% confidence interval 
using Fisher’s exact method. Tumor response (CR, PR, SD, or PD) will be defined 
according to RECIST v1.1 guideline. Objective response rate (ORR) will be the 
proportion of patients with a confirmed CR or PR and disease control rate (DCR) is 
calculated by the proportion of patients with confirmed CR, PR, or SD.
Progression-free survival (PFS) is defined as the time from the date of enrollment to 
the date that objective progression disease is documented or death due to any cause, 
whichever occurs first. Overall survival (OS) is defined as the time from the date of 
enrollment to the date of death. Duration of response is defined as the time from the 
date of first documented response (CR or PR) until date of documented progression 
or death in the absence of disease progression.
For PFS and OS, Kaplan-Meier method will be used to estimate survival rates for pre-
specified time points along with 95% confidence intervals.
      
 
 
        
 
 

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Safety analysis will be include detailed tabulations of adverse events by type, grade 
and treatment attribution. 
16.3.1 Exploratory Analyses
The exploratory endpoint is tumor-infiltrating immune cells to identify LAG3 
checkpoint marker. V(D)J analysis will be conducted. Based on biopsy samples from 
pre-and post-treatment and blood samples at multiple time points, scRNA-seq and 
single-cell V(D)J profiling will be conducted
      
 
 
        
 
 

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17
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
17.1 Informed Consent Process
17.1.1 Consent/Assent and other Informational Documents Provided to 
Participants
Consent forms describing in detail the study intervention, study procedures, and 
risks are given to the participant and written documentation of informed consent is 
required prior to starting intervention/administering study intervention.  
17.1.2 Consent Procedures and Documentation
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Consent forms will be Institutional Review Board (IRB)-approved and the participant 
will be asked to read and review the document. We anticipate to enroll non-English 
speaking participants, specifically Spanish-speaking participants. Consent forms will 
be translated to Spanish. The investigator will explain the research study to the 
participant and answer any questions that may arise. A verbal explanation will be 
provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research 
participants.  The consent process will take place in a private clinic room. 
Participants will be given as much time as needed for them to be comfortable with 
participating in this study.  Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants should 
have the opportunity to discuss the study with their family or surrogates or think 
about it prior to agreeing to participate. The participant will sign and date the 
informed consent document prior to any procedures being done specifically for the 
study. Participants must be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the informed 
consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document 
(including the date), and the form signed, before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected 
by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study.
For subjects not qualified or able to give legal consent, consent must be obtained 
from their legally authorized representative (LAR).
The rights and welfare of the participants will be protected by emphasizing to them 
that they will not be penalized or lose any benefits and the quality of their medical 
care will not be adversely affected if they decline to participate in this study or leave 
the study early. 
      
 
 
        
 
 

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17.2 Study Discontinuation and Closure
This study may be temporarily suspended or prematurely terminated if there is 
sufficient reasonable cause.  Written notification, documenting the reason for study 
suspension or termination, will be provided by the suspending or terminating party to 
study participants, investigators, funding agency, the Investigational New Drug (IND) 
sponsor and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Sponsor-Investigator will promptly inform study participants, the 
Institutional Review Board (IRB), and the Investigational Drug Sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.
 
Circumstances that may warrant termination or suspension include, but are not 
limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data 
quality are addressed, and satisfy the Investigational Drug Sponsor, IRB and/or 
Food and Drug Administration (FDA).
17.3 Confidentiality and Privacy
Information collected as part of this study will be destroyed or de-identified at the 
earliest opportunity. Information collected will not be reused or disclosed to any other 
person or entity, except as required by law, for authorized oversight of the research 
study or for other research for which the use or disclosure of PHI is permissible. 
Specimens obtained for this research will be de-identified and coded with the link 
between code and the subject’s identity maintained separately from the data. 
Research data may be sent to the investigational drug sponsor, Bristol Myers 
Squibb. Data sent will be coded/de-identified. Information may be sent via email, fax, 
Fedex, UPS, USPS, courier, or via a study-specific electronic data capture system. 
Procedures to protect confidentiality of information being sent are the following: de-
identifying/coding reports, utilizing cover sheets for faxes, sending emails via secure 
transmittal, password-protected files, and utilizing delivery confirmation/tracking for 
items shipped via courier. Specimens will not be sent to external entities. This study 
will access electronic medical record or other protected health information without 
obtaining a signed HIPAA authorization from the subject to identify potential subjects 
for recruitment and to obtain study data. 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the Sponsor-Investigator and their interventions. This 
confidentiality is extended to cover testing of biological samples and genetic tests in 
      
 
 
        
 
 

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addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to 
any unauthorized third party without prior written approval of the Sponsor-
Investigator. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the Sponsor-Investigator, 
representatives of the Institutional Review Board (IRB), regulatory agencies or 
pharmaceutical company supplying study product may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants 
in this study. The Sponsor-Investigator will permit access to such records.
The study participant’s contact information will be securely stored in the University of 
Miami’s password-protected electronic devices and University of Miami approved 
cloud-based storage systems for internal use during the study. At the end of the 
study, all records will continue to be kept in a secure location for as long a period as 
dictated by the reviewing IRB, Institutional policies, or Investigational Drug Sponsor 
requirements.
Electronic case report forms for study data entry will be developed by staff at the 
University of Miami using Velos, a HIPAA AND 21 CFR part 11 compliant database. 
Only Investigators and assigned research staff will have access to study data. 
17.4 Future Use of Stored Specimens and Data
Data collected for this study will be analyzed and stored at the University of Miami 
on Velos. 
With the participant’s approval and as approved by local Institutional Review Boards 
(IRBs), biological samples will be stored at the University of Miami per institutional 
regulations. These samples could be used to research the causes of the condition 
being studied as part of this protocol or may be stored indefinitely to for research as 
new knowledge or technology becomes available.  The laboratory storing the 
biological specimens will also be provided with a code-link that will allow linking the 
biological specimens with the phenotypic data from each participant, maintaining the 
blinding of the identity of the participant. The principal investigator and other 
designated study staff will have access to the code sheet including sub-
investigators, clinical coordinators, data coordinators, clinical manager, and 
regulatory staff. 
During the conduct of the study, an individual participant can choose to withdraw 
consent to have biological specimens stored for future research. However, 
      
 
 
        
 
 

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withdrawal of consent with regard to biospecimen storage may not be possible after 
the study is completed. 
When the study is completed, access to study data and/or samples will be provided 
through Velos and the laboratory storing the biological specimens. 
17.5 Study Auditing and Monitoring
This study will be monitored (as applicable) and may be audited according to the 
University of Miami requirements.  See also 
http://research.med.miami.edu/clinical-research/crors/monitoring
Following the monitoring plan, the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements. 
17.5.1 Trial Monitoring, Auditing, and Inspecting
The investigator will permit trial-related monitoring, quality audits, and 
inspections by, government regulatory authorities, of all trial-related 
documents (e.g., source documents, regulatory documents, data collection 
instruments, case report forms).  The investigator will ensure the capability for 
inspections of applicable trial-related facilities.  The investigator will ensure 
that the trial monitor or any other compliance or QA reviewer is given access 
to all trial-related documents and trial-related facilities.  
Participation as an investigator in this trial implies the acceptance of potential 
inspection by government regulatory authorities. 
17.6 Quality Assurance and Quality Control
In addition to the Clinical Monitoring component of this protocol, Quality Assurance 
(QA) will be implemented to assess compliance with GCP and applicable regulatory 
requirements.  Data or documentation audited shall be assessed for compliance to 
the protocol, accuracy in relation to source documents and compliance to applicable 
regulations.
17.7 Data Handling and Record Keeping
17.7.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the Sponsor-Investigator. The Sponsor-Investigator is responsible for 
ensuring the accuracy, completeness, legibility, and timeliness of the data reported.
All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  
      
 
 
        
 
 

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Data for electronic CRFs will be entered into Velos. A CRF is required for every 
patient who received any amount of study treatment.  The investigator will ensure 
that the CRF’s are accurate, complete, legible and timely. Patients for whom 
documentation is inadequate to determine eligibility will generally be deemed 
ineligible. Data recorded in the electronic case report form (eCRF) derived from 
source documents should be consistent with the data recorded on the source 
documents. 
Clinical data (including adverse events (AEs), concomitant medications, and 
expected adverse reactions data) and clinical laboratory data will be entered into 
Velos, a HIPAA AND 21 CFR Part 11-compliant data capture system provided by 
the University of Miami. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents.
17.7.2 Study Records Retention
All records and documents relating to research studies and participants must be kept 
confidential to the extent permitted by law; however, records and documents shall be 
available in a timely manner to the University authorized employees or other agents 
authorized by the University including IRB members and HSRO staff and 
appropriate governmental agencies including but not limited to DHHS, OHRP and 
the FDA.
Although principal investigators are responsible for the creation and maintenance of 
research records and documents, such records and documents (including data 
collected pursuant to research) are the property of the University. Until the temporal 
requirements for record/document retention are met, investigators or others may not 
remove or destroy research records or documents (or copies of such records or 
documents) without written permission from the Vice Provost of Research. This 
permission requirement extends to investigators leaving the University even if they 
plan to continue the research at another institution.
With certain exceptions, investigators must retain complete records and documents 
(including the consent documents) from their study for the duration of that study and 
for a minimum period of three (3) years following closure of a study. Exceptions to 
this 3-year minimum retention period are:
a. HIPAA REQUIREMENTS: if a study involves the collection of identifiable 
health information, records must be retained for a minimum of six (6) years 
following study closure. This retention period is consistent with the HIPAA 
Privacy Rule under which subjects may ask investigators for an accounting of 
all uses and  disclosures of their study information for a period of 6  years 
after their participation is completed (c.f. 45 CFR 164.528)
b. FDA REQUIREMENTS FOR A STUDY INVOLVING AN INVESTIGATIONAL 
DRUG UNDER AN IND (c.f. 21 CFR 312.62): if a study involves the use of an 
      
 
 
        
 
 

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investigational drug under an IND, principal investigators must retain study 
records and documents until at least the later of the following dates:
a. 2-years following the date of a marketing application is approved for 
the drug for the indication for which it was being investigated; or
b. 2-years after the investigation is discontinued and the FDA is notified if 
no marketing application is to be filed or, if the application is not 
approved for such indication; or 
c. 3-years after IRB approval of the closure of the study
c. FDA REQUIREMENTS FOR A STUDY INVOLVING AN INVESTIGATIONAL 
DEVICE UNDER AN IDE (c.f. 21 CFR 812.140): if a study involves an 
investigational device under an IDE, principal investigators must retain study 
records and documents until at least the later of the following dates:
a. 2-years following the date on which the investigation is terminated or 
completed; or
b. 2-years following the date that the records are no longer required for 
purposes of supporting a premarket approval application or a notice of 
completion of a product development protocol; or
c. 3-years after IRB approval of the closure of the study. 
NOTE-The FDA two-year requirements may occur during the applicable retention 
period or it may occur afterward and be additional to that period.
d. VA REQUIREMENTS: if a study engages the VA, investigators must retina 
research records and documents for a minimum of five (5) years after IRB 
approval of study closure. This retention period is consistent with the VA’s 
Records Control Schedule (RCS 10-1).
e. ICH-GCP REQUIREMENTS: trial documents must be retained as specified in 
Essential Documents for the Conduct of a Clinical Trial and as required by the 
applicable regulatory requirement(s). Measures must be taken to prevent 
accidental or premature destruction of these documents.
Records must be retained longer than the times specified above as other 
requirements may apply such as may be forthcoming from sponsors in executed 
contracts, institutional entities or extramural funding agencies.
If your Human Research is funded by an investigational drug sponsor, contact the 
investigational drug sponsor before disposing of Human Research records. The 
protocol and clinical trial agreement/contract will also contain terms for records 
retention. 
17.8 Compliance with Protocol
The investigator/institution should conduct the trial in compliance with the protocol 
agreed to by the investigational drug sponsor and, if required, by the regulatory 
authorities and which was given approval opinion by the IRB. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the investigational drug sponsor and prior review and 
documented approval opinion from the IRB of an amendment, except where 
      
 
 
        
 
 

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necessary to eliminate an immediate hazard to trial subjects, or when the changes 
involves only logistical or administrative aspects of the trial (e.g. change in monitors, 
change of telephone numbers). 
The investigator, or designee, should document and explain any deviation from the 
approved protocol.
The investigator may implement a deviation from, or change of, the protocol to 
eliminate an immediate hazard to trial subjects without prior IRB approval opinion. 
As soon as possible, the implemented deviation or change, the reasons for it, and if 
appropriate, the proposed protocol amendments should be submitted:
a. To the IRB for review and approval opinion;
b. To the investigational drug sponsor for agreement, if required, 
c. To the regulatory authorities
17.9 Publication and Data Sharing 
All information provided regarding the trial, as well as all information 
collected/documented during the course of the trial, will be regarded as confidential.  
The financial disclosure information will be completed prior to trial participation from 
all PIs and Sub-Investigators who are involved in the trial and named on the FDA 
1572 form.
BMS will review of all publications 30-45 days prior to submission to any congresses 
and/or journals as per contract agreement. 
The Sponsor-Investigator will register the trial on www.clinicaltrials.gov.  In addition, 
Sponsor-Investigator will publish the results of the trial
17.10
Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by 
the pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of 
persons who have a role in the design, conduct, analysis, publication, or any aspect 
of this trial will be disclosed and managed. Furthermore, persons who have a 
perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  
The study leadership in conjunction with the University of Miami has established 
policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities 
of interest.
      
 
 
        
 
 

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18
REFERENCES
1.
Khoja, L., Atenafu, E.G., Suciu, S. et al., Meta-analysis in metastatic uveal 
melanoma to determine progression free and overall survival benchmarks: an 
international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol. 
, 2019. 30: p. 1370-1380.
2.
Algazi, A.P., Tsai, K.K., Shoushtari, A.N. et al. , Clinical outcomes in 
metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer, 
2016(21): p. 3344-3353.
3.
Pelster, M.G., S.K., Bassett, R., et al. , Phase II study of ipilimumab and 
nivolumab (ipo/nivo) in metastatic uveal melanoma.  . Journal of Clinical 
Oncology, 2019. 37(15): p. 9522.
4.
Baitsch, L., Baumgaertner, P., Devêvre, E., et al. , Lukas Baitsch,1 Petra 
Baumgaertner,1 Estelle Devêvre,1 J Clin Invest., 2011. 121: p. 2350-2360.
5.
Woo, S.R., Turnis, M.E., Goldberg, M.V., et al.  , Immune inhibitory molecules 
LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral 
immune escape. Cancer Res., 2012. 72(4): p. 917-27.
6.
Durante, M.A., Rodriguez, D.A., Kurtenbach, S. et al. , Single-cell analysis 
reveals new evolutionary complexity in uveal melanoma. Nature 
Communications, 2020. 11: p. 496.
7.
Karlsson, J., Nilsson, L.M., Forsberg, E.M.V., et al. , Molecular profiling of 
driver events and tumor-infiltrating lymphocytes in metastatic uveal 
melanoma. BioRxiv., 2019.
8.
Sharpe, A.H., Wherry, E.J., Ahmed, R., et al. , The function of programmed 
cell death 1 and its ligands in regulating autoimmunity and infection.Nat 
Immunol 2007;. 8(3): p. 239-45.
9.
Nonclinical Study Report: Medarex Study No. MDX1106-028-R. Binding and 
blocking characteristics of chimeric anti-mouse PD-1 antibody, 4H2. . Bristol-
Myers Squibb Company 2007.
10.
Nonclinical Study Report: Medarex Study No. MDX1106-025-R. In vitro 
characterization of a fully human anti-PD-1 monoclonal antibody. . Bristol-
Myers Squibb Company, 2007. Document Control No. 930046580.
11.
Velu , V., Titanji, K., Zhu, B., et al. , Enhancing SIV-specific immunity in vivo 
by PD-1 blockade. . Nature Communications, 2009;. 458: p. 206-10.
12.
Nonclinical Study Report: Medarex Study No. MDX1106-032-R. Effects of 
anti-PD-1 administration on staged MC38 tumors in mice. Bristol-Myers 
Squibb Company, 2006: p. Document Control No. 930046566.
13.
Nonclinical Study Report: Medarex Study No. MDX1106-023-R. Effect of anti-
PD-1 monoclonal antibody administration on unstaged MC38 tumor growth 
rates in mice. . Bristol-Myers Squibb Company, 2006: p. Document Control 
No. 930046542.
14.
Wang, C., Thudium, K.B., Han, M., et al., In vitro characterization of the anti-
PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human 
primates. . Cancer Immunol Res 2014. 2: p. 846-856.
15.
Nonclinical Study Report: Study No. DN12123; BMS-986016 and BMS-
936558: Four-week intravenous combination toxicity study in monkeys with a 
      
 
 
        
 
 

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6-week recovery. . Bristol-Myers Squibb Company, 2013. : p. Document 
Control No. 930070016.
16.
Habicht, A., Dada, S., Jurewicz, M., et al. , A link between PDL1 and T 
regulatory cells in fetomaternal tolerance. . J Immunol 2007. 179: p. 5211-9.
17.
Clinical Study Report: Study No. CA209004. A Phase 1b, Open-Label, 
Multicenter, Multidose, Dose-Escalation Study of MDX-1106 (BMS936558) in 
Combination with Ipilimumab (BMS-734016) in Subjects with Unresectable 
Stage III or Stage IV Malignant Melanoma. . Bristol Myers Squibb Company, 
2014: p. Document Control No. 930082868.
18.
Woo, S.R., Turnis, M.E., Goldberg, M.V., et al., Immune inhibitory molecules 
LAG 3 and PD-1 synergistically regulate T-cell function to promote tumoral 
immune escape. . Cancer Res 2012. 72: p. 917-27.
19.
SEB activation of human PBMC with BMS-986016, alone or in combination 
with nivolumab or ipilimumab (Study BDX-1408-246). Bristol-Myers Squibb 
Company, 2013: p. Document Control No. 930071253.
20.
Wherry, E.J., Ha, S.J., Kaech, S.M., et al. , Molecular signature of CD8+ T 
cell exhaustion during chronic viral infection [published erratum appear in 
Immunity 2007;27:824]. . Immunity 2007. 27: p. 670-84.
21.
Antitumor activity of anti-LAG-3 antibody alone and in combination with anti-
PD-1 antibody in a MC38 colon adenocarcinoma tumor model (Study BDC-
1408-253). . Bristol-Myers Squibb Company, 2013: p. Document Control No. 
930071267.
22.
Ascierto, P.A., Melero, I., Bhatia, S., et al. , J Clin Oncology. J Clin Oncology, 
2017. 35(15).
23.
Hong, D.S., Schoffski, P., Calvo,A., et al. , Phase I/II study of LAG525 ± 
spartalizumab (PDR001) in patients (pts) with advanced malignancies. J Clin 
Oncology, 2018. 36(15).
24.
Institute, N.C. NCI Drug Dictionary; Relatlimab. 6 April, 2020 [cited 2020 6 
April]; Webpage]. Available from: 
https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-lag-3-
monoclonal-antibody-bms-986016.
      
 
 
        
 
 

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APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING 
REQUIREMENTS
For all AEs that meet criteria for expedited reporting, the Sponsor-Investigator (SI) is 
obligated to pursue and provide follow-up reporting information until the event has 
resolved or until an acceptable medical endpoint has been reached (i.e. for the 
duration specified in the protocol), or the patient is lost to follow-up.
The SI and all applicable research study team members should become familiar with 
the safety profile of the investigational agent(s) and/or intervention at the start of the 
study and for the duration of the research, e.g. by reviewing the Investigator’s 
Brochure (IB) and any Safety Reports released, by the Sponsor as applicable.  
A. FDA Expedited Reporting
a. Sponsor-Investigators i.e. IND Holders, have additional reporting 
requirements to the FDA and other committees, and should consult the 
applicable regulations and agency guidelines for these requirements.  
b. Since this protocol involves the use of FDA IND agent(s), completion of 
the FDA MedWatch 3500A Reporting Form is required for Sponsor-
Investigators.  The Form can be obtained electronically at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/
UCM048334.pdf
i. All serious, unexpected (unanticipated) and suspected adverse 
events must be directly reported to the FDA within 15 calendar 
days of being made known to the Principal Investigator (PI).  
ii. All fatal or life-threatening AEs must be directly reported to the 
FDA within 7 calendar days of being made known to the SI.
c. For more information regarding reporting to the FDA, please refer to the 
FDA website for REPORTING GUIDELINES:  
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm
B. IRB Expedited Reporting
a. All Investigators should also be aware of local Institutional requirements 
for AE reporting.  For more information regarding the IRB policy, please 
refer to the UM HSRO’s Investigator Manual: 
http://hsro.med.miami.edu/documents/HRP-103 -
_INVESTIGATOR_MANUAL_4.11.2014.docx and the UM HSRO SOP 
on New Information (HRP-024) 
https://eprost.med.miami.edu/eProst/Doc/0/HLJ5OTJVQEH419E0I6QPT
3B199/HRP-024%20-%20SOP%20-%20New%20Information.docx
b. All AEs that are serious, unanticipated and possibly related will be 
reported to the IRB within ten (10) working days of being made known to 
the SI.  
c. Events that are more frequent than anticipated or more severe than 
expected must be reported to the IRB within ten (10) working days of 
being made known to the SI.
      
 
 
        
 
 

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d. All unanticipated deaths must be reported to the IRB within 24 hours of 
being made known to the SI.
C. Bristol Myers Squibb Expedited Reporting, as applicable 
a. In addition to the mandatory MedWatch 3500A Form, the Sponsor-
Investigator is also required to comply with all reporting requirements as 
supplied by Bristol Myers Squibb. Refer to Section 13.3 Non-Serious 
Adverse Event, 13.6 Serious Adverse Event Reporting 13.7 Adverse 
Event Collection and Reporting Information. 
      
 
 
        
 
 

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APPENDIX B: PERFORMANCE STATUS SCALES
As published in Am J Clin Oncol: Oken MM, Creech RH, Tormey DC, Horton J, 
Davis TE, McFadden ET, Carbone PP. Toxicity and Response Criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. The 
Eastern Cooperative Oncology Group, Robert Comis, MD, Group Chair. 
      
 
 
        
 
 

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APPENDIX C: BIOMARKER, CORRELATIVE AND SPECIAL 
STUDIES
Samples will be processed and stored at <insert lab>
1. Email notification
Jose Lutzky (PI) should be contacted via email to notify him of all specimen 
submissions for storage.  
PI (Dr.Lutzky): jxl810@med.miami.edu to
Laboratory Collaborator: harbour@med.miami.edu 
2. Specimen Collection
Refer to Section 11.0 Correlative Studies
3. Future Use of Specimens and Data
Refer to Section 17.4 Future Use of Stored Specimens and Data
4. Storage and analysis for tumor and blood will be conducted at:
The laboratory of J. William Harbour
Department of Ophthalmology
1501 NW 10th Ave
Biomedical Research Building
Room 832, Suite H-I