A Phase 1/2 First-in-Human Study of BMS-986258 Alone and in Combination With Nivolumab in Advanced Malignant Tumors
Phase: PHASE1
Conditions: Advanced Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 1/2 First-in-human Study of BMS-986258 Alone and in Combination with Nivolumab 
in Advanced Malignant Tumors 
 
NCT Number: NCT03446040 
Document Date (Date in which document was last revised): 16 Jun 2021 
 
 
 

Page:
1
Protocol Number:
CA031002
IND Number:
137385
EUDRACT Number:
2019-000442-35
Date:
01-Dec-2017
Revised Date:
16-Jun-2021
CLINICAL PROTOCOL CA031002
A Phase 1/2 First-in-human Study of BMS-986258 Alone and in Combination with Nivolumab 
in Advanced Malignant Tumors
Protocol Amendment 07
Medical Monitor
Clinical Scientist
Parque Científico Tecnológico Cartuja 93
Centro de Empresas, Pabellón de Italia 
C/Isaac Newton 4, E-41092 
Sevilla, Spain
Parque Científico Tecnológico Cartuja 93
Centro de Empresas, Pabellón de Italia 
C/Isaac Newton 4, E-41092 
Sevilla, Spain
Telephone (office): 
Telephone (office): 
Mobile: 
Mobile: 
24-hr Emergency Telephone Number
USA: 1-866-470-2267
International: +1-248-844-7390
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
Protocol Amendment No.: 07
Date: 16-Jun-2021
2
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 
07
16-Jun-2021
Included the option for participants in cohort A1 who received subcutaneous 
BMS-986258 on Cycle 1 Day 1 to be subsequently treated with intravenous 
BMS-986258 in combination with nivolumab (standard dose of 480 mg) at 
the dose of BMS-986258 that has been shown to be safe and tolerable in the 
dose escalation.
Deleted the requirement for imaging results prior to enrollment in 
participants with anti-PD-(L)1-resistant RCC, CRC, NSCLC, and SCCHN in 
Part C, Part A NSCLC PD, and Part B NSCLC PD cohorts.
Clarified the definition of the end of treatment (EOT) visit.
Protocol 
Amendment 
06
23-Dec-2020
Included a new BMS-986258 formulation 
. 
Additional corrections in numbering of exclusion criterion 3, male 
contraception, 
 were included. 
 
 for inclusion in NSCLC PD cohorts. 
Candidates to NSCLC PD cohorts will be allowed to be enrolled in dose 
escalation cohorts (Part A and B) if the 
 is not fulfilled.
Revised 
Protocol 05
22-Oct-2020
Defined initial dose for Part A1 of the study, BMS-986258 at 1200 mg co-
administered subcutaneously with recombinant human hyaluronidase PH20 
(rHuPH20), at Cycle 1 Day 1. All subsequent doses of BMS-986258 will be 
administered as monotherapy IV, Q4W twice per cycle, for up to twelve 8-
week cycles (96 weeks). Instructions and infusion rate for SC administration. 
Inclusion of SARS-CoV-2 language and EPE v6 updates. Additional 
editorial changes and minor clarifications.
Revised 
Protocol 04
27-Apr-2020
Defined
 dose levels (1600 mg and 2400 mg) in Part A 
(monotherapy) and 
 dose level (1600 mg) in Part B (combination 
with nivolumab 480 mg).
Reduced the number of NSCLC PD cohorts in Part B.
Updated imaging and biopsy language for clarity.
Updated text throughout to bring in line with current BMS standards.
Incorporated Administrative Letter 01.
Revised 
Protocol 03
14-Mar-2019
Added pharmacodynamic (PD) cohorts of participants with non-small cell 
lung cancer (NSCLC), selected for 
, to Parts A and B, 
changed the planned highest dose level of BMS-986258 from 800 mg to 
1200 mg for both monotherapy (Part A and A1) and combination therapy 
(Part B) 
. See Key Changes 
table
Administrative 
Letter 01
02-Nov-2018
Removed the unit of dose strength of rHupH20 from the protocol. 
Revised 
Protocol 02
12-Jun-2018
Added subcutaneous dosing cohort; see Key Changes table 
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BMS-986258
Anti-TIM-3 mAb
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Document
Date of Issue
Summary of Change
Revised 
Protocol 01
08-Jan-2018
See Key Changes table
Original 
Protocol
01-Dec-2017
Not applicable
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BMS-986258
Anti-TIM-3 mAb
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07:
The rationale for this amendment was to include the option for participants in cohort A1 who have 
received subcutaneous BMS-986258 on Cycle 1 Day 1 to be subsequently treated with intravenous 
BMS-986258 in combination with nivolumab (standard dose of 480 mg) at the dose of BMS-
986258 that has been shown to be safe and tolerable in the dose escalation.
In addition, in the inclusion criteria for participants with anti-PD-(L)1-resistant tumors, the 
documentation of the radiological progression from prior anti-PD-(L)1-containing regimen by 
submission of available scans before and after anti-PD-(L)1 treatment has been deleted from 
eligibility criteria.
The definition of end of treatment (EOT) visit has been further clarified.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
Section 1 - Synopsis
Revised the synopsis to incorporate all 
changes described below
Updated to align with study 
protocol changes
 
Section 5.1.4.1 -Safety 
Follow-up Period;
Clarified definition of EOT visit
Defined EOT visit as the visit in 
which the participant receives the 
last dose of study treatment
Section 3.3.3 - BMS-986258 
Starting Dose for Part A1 
(Monotherapy SC);
Section 5.1.3 - Treatment 
Period;
Section 5.4.2 - Rationale for 
Subcutaneous Administration 
of BMS-986258 (Part A1);
Section 7.1 - Treatments 
Administered
Added the option for participants in cohort 
A1 to switch to combination therapy after 
receiving subcutaneous BMS-986258 on 
Cycle 1 Day 1
To give participants in cohort A1 
the option to be treated in 
combination with nivolumab at 
the maximum tolerable dose of 
BMS-986258 observed in Part B
Section 3.3.6 - Safety 
Monitoring on Study 
Therapy
Added clarification that non-live COVID-
19 vaccination is considered a simple 
concomitant medication within the study
To align with current BMS 
COVID-19 guidelines
Section 4 - Objectives and 
Endpoints
Revised 
 
To align with current BMS 
COVID-19 guidelines
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BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
 
Section 5 - Study Design;
Section 9.5 -
Pharmacokinetics;
 
 
 
 
 
 
Table 9.5-3, 
Updated to align with study 
protocol changes
Section 6.1- Inclusion 
Criteria 
Deleted documentation of the radiological 
progression from prior anti-PD-(L)1-
containing regimen by submission of 
available scans before and after anti-PD-
(L)1 treatment from inclusion criteria 
2i(i[3]) and 2i(i[4]) (participants with anti-
PD-[L]1-resistant RCC, CRC, NSCLC, and 
SCCHN in Part C, Part A NSCLC PD, and 
Part B NSCLC PD cohorts only)
Submission of imaging results 
from treatments prior to the 
clinical study is unfeasible
Section 6.2 - Exclusion 
Criteria
Clarified exclusion criteria 3e(xiv) related 
to previous receipt of SARS-CoV-2 
vaccines
To align with current BMS 
COVID-19 guidelines
Section 7.3 - Blinding
Deleted text related to obtaining treatment 
assignment codes
Not relevant to open-label studies
Section 7.7.1- Prohibited 
and/or Restricted Treatments;
Updated and clarified text related to receipt 
of authorized or approved SARS-CoV-2 
vaccines while continuing on study
 
 
 
To align with current BMS
COVID-19 guidelines
Table 9.5-1: Pharmacokinetic 
Parameters
Corrected abbreviations and definitions for 
AI_AUC and T-HALFeff_AUC
Corrected for consistency
Section 10.3 - Statistical 
Analyses
Clarified that results will be presented by 
study part; participants who cross over from 
the SC cohort (A1) to IV monotherapy or 
combination treatment will be tabulated 
separately
To clarify statistical analysis of 
participants in cohort A1 who 
subsequently receive combination 
therapy
Appendix 2 - Study 
Governance Considerations
Added text regarding monitoring details and 
dissemination of clinical study data
Updated for consistency with 
current BMS protocol standards 
and policies
Entire document
Made additional corrections and editorial or 
formatting changes where appropriate
Added to provide clarity
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.2 Background ....................................................................................................... 
 
3.2.1 BMS-986258 ............................................................................................ 
 
 
 
 
 
 
 
3.2.2 Nivolumab ................................................................................................ 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
3.3.1 Recombinant Human Hyaluronidase PH20............................................. 
 
3.3.2 BMS-986258 Starting Dose for Part A (Monotherapy) ........................... 
 
3.3.3 BMS-986258 Starting Dose for Part A1 (Monotherapy SC) ................... 
 
3.3.4 BMS-986258 Starting Dose for Part B (Combination with Nivolumab) . 
 
3.3.5 Dose Escalation in Parts A and B............................................................ 
 
3.3.6 Safety Monitoring on Study Therapy ....................................................... 
 
3.3.7 Overall Benefit/Risk for Combination with Nivolumab ........................... 
 
3.3.8 Summary .................................................................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Pre-screening for PD Cohorts only (NSCLC) ......................................... 
 
5.1.2 Screening Period ...................................................................................... 
 
5.1.3 Treatment Period ..................................................................................... 
 
5.1.3.1 BMS-986258 Monotherapy Dose Escalation (Part A) (Including 
NSCLC PD Cohorts) and Subcutaneous Dose (Part A1) ..................... 
 
5.1.3.2 BMS-986258 in Combination with Nivolumab Dose Escalation and 
NSCLC PD Cohorts (Part B) ................................................................ 
 
5.1.3.3 BMS-986258 in Combination with Nivolumab Expansion Cohorts 
(Part C) ................................................................................................. 
 
5.1.4 Follow-up ................................................................................................. 
 
5.1.4.1 Safety Follow-up Period ................................................................. 
 
5.1.4.2 Survival Follow-up.......................................................................... 
 
5.1.5 Data Monitoring Committee and Other External Committees ................ 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.4.1 Rationale for the Monotherapy Dose Escalation (Part A) ...................... 
 
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CA031002
Anti-TIM-3 mAb
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5.4.2 Rationale for Subcutaneous Administration of BMS-986258 (Part A1) .. 
 
5.4.3 Rationale for Dose Escalation Phase Design .......................................... 
 
 
 .......................................... 
 
5.4.5 Rationale for the Combination of BMS-986258 with Nivolumab ............ 
 
5.4.6 Rationale for 2-Year Duration of Treatment ........................................... 
 
5.4.7 Rationale for Tumor Selection for Expansion (Part C) ........................... 
 
5.4.8 Rationale for Treatment Beyond Progression ......................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 Rationale for BMS-986258 Starting Dose ............................................... 
 
5.5.2 Rationale for Dose Selection and Dosing Schedule ................................ 
 
5.5.2.1 BMS-986258 ................................................................................... 
 
5.5.2.2 Nivolumab ....................................................................................... 
 
5.5.2.3 Rationale for 30-Minute Dose Administration of Nivolumab ......... 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Dose-Limiting Toxicities .......................................................................... 
 
7.1.1.1 Hepatic Dose-Limiting Toxicity ...................................................... 
 
7.1.1.2 Hematologic Dose-Limiting Toxicity .............................................. 
 
7.1.1.3 Dermatologic Dose-Limiting Toxicity ............................................ 
 
7.1.1.4 Other Dose-Limiting Toxicities....................................................... 
 
7.1.2 Management Algorithms for Immuno-Oncology Agents ......................... 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Dose Delays Due to Toxicity.................................................................... 
 
7.4.2 Criteria to Resume Treatment .................................................................. 
 
7.4.3 Management of Drug-related Infusion Reactions.................................... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability/Bioequivalence/Biocomparability 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.2.1 Vaccinations .................................................................................... 
 
7.7.2.2 Imaging Restriction and Precautions ............................................. 
 
7.7.3 Permitted Therapy ................................................................................... 
 
7.7.3.1 Radiotherapy ................................................................................... 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
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CA031002
Anti-TIM-3 mAb
Protocol Amendment No.: 07
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8.1 Discontinuation From Study Treatment ........................................................... 
 
8.1.1 Temporary Discontinuation ..................................................................... 
 
8.1.2 Rechallenge .............................................................................................. 
 
8.1.3 Treatment Beyond Progression ................................................................ 
 
8.1.3.1 Discontinuation Due to Further Progression (Confirmed 
Progression) .......................................................................................... 
 
8.1.4 Exceptions to Permanent Discontinuation Criteria ................................. 
 
8.1.5 Post-Study Treatment Follow-up ............................................................. 
 
8.2 Discontinuation From the Study ....................................................................... 
 
8.3 Lost to Follow-up .............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Imaging Assessment for the Study............................................................ 
 
9.1.1.1 Methods of Assessment ................................................................... 
 
9.1.1.2 Imaging and Clinical Assessment ................................................... 
 
9.2 Adverse Events ................................................................................................. 
 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug Induced Liver Injury ....................................................... 
 
9.2.8 Immune-mediated Adverse Events ........................................................... 
 
9.2.9 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
 ................................................................................. 
 
9.4.2 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.3 Imaging Safety Assessment ...................................................................... 
 
9.4.4 Physical Examinations ............................................................................. 
 
9.4.5 Vital Signs ................................................................................................ 
 
9.5 Pharmacokinetics .............................................................................................. 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.7.1 ADME Sampling ...................................................................................... 
 
 
 
 
 
 
 
 
 
 
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Clinical Protocol
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CA031002
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9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.1.1 Dose Escalation ..................................................................................... 
 
10.1.2 Cohort Expansion .................................................................................. 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.3 Pharmacokinetic Analyses for BMS-986258 and Nivolumab ................ 
 
10.3.4 Immunogenicity ...................................................................................... 
 
 
 
 
 
10.3.7 Other Analyses ....................................................................................... 
 
10.3.8 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
 
APPENDIX 6 EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ................................................................................... 
 
APPENDIX 7 NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ................................................................................................ 
 
APPENDIX 8 MANAGEMENT ALGORITHMS ....................................................... 
 
 ..................................................... 
 
 
 
 
 
APPENDIX 11 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
 
APPENDIX 12 REFERENCES .................................................................................... 
 
 
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BMS-986258
CA031002
Anti-TIM-3 mAb
Protocol Amendment No.: 07
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CA031002
BMS-986258
Anti-TIM-3 mAb
1
SYNOPSIS
Protocol Title: A Phase 1/2 First-in-human Study of BMS-986258 Alone and in Combination 
with Nivolumab in Advanced Malignant Tumors
Study Phase: 1/2
Rationale: Patients with metastatic or refractory solid tumors have very poor prognosis. The 
unmet need resides in the lack of effective treatments to deliver long-term survival, hence the need 
to test compounds that have novel mechanisms of action in clinical studies. T-cell immunoglobulin 
and mucin-domain containing-3 (TIM-3) is expressed mostly on monocytes, macrophages, 
dendritic cells, and natural killer cells, as well as in endothelial cells; little expression of TIM-3 is 
detected in peripheral T cells in the majority of normal healthy donors or cancer patients, but it 
can be induced upon T-cell activation. Functional anti-TIM-3 monoclonal antibodies (mAbs), 
including BMS-986258 and the mouse surrogate anti-TIM-3 antibodies, all bind to the 
phosphatidylserine (PS)-binding loops of TIM-3, suggesting that PS might be a functional ligand 
of TIM-3 either by itself or associated with another unidentified molecule in dampening T cell 
responses. TIM-3 expression marks dysfunctional or exhausted cluster of differentiation 8 positive 
(CD8+) T cells in several cancer types. In tumor infiltrating lymphocytes (TIL) from patients with 
advanced metastatic melanoma, non-small cell lung cancer (NSCLC), and follicular B cell non-
Hodgkin lymphoma, in vitro TIM-3 blockade improved T-cell responses with TIM-3/programmed 
cell death-1 (PD-1) co-blockade showing even greater responses than single agents. TIM-3 might 
also work as a mechanism of resistance to anti-PD-1 therapy, as TIM-3 expression was found to 
be upregulated in 2 lung cancer patients who developed secondary resistance to anti-PD-1 mAb 
treatment. Thus, an antagonistic antibody such as BMS-986258 that blocks TIM-3-mediated 
inhibitory signals in T cells and, perhaps, in other immune subsets as well, might provide 
therapeutic benefit to cancer patients. 
Study Population:
Participants must be at least 18 years old and have histologic confirmation of a solid tumor that is 
advanced (metastatic, recurrent, and/or unresectable) with measurable disease per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. The tumor types to be evaluated in 
participants are NSCLC, renal cell carcinoma (RCC), colorectal cancer (CRC), triple negative 
breast cancer (TNBC), and squamous cell carcinoma of the head and neck (SCCHN).
 
 
 
 
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
Objectives and Endpoints:
Objectives
Endpoints
Primary
To assess the safety, tolerability, and to determine MTD or 
MAAD and RP2D of BMS-986258 administered as 
monotherapy and in combination with nivolumab in 
participants with select advanced solid tumors.
Incidence of AEs, SAEs, AEs meeting protocol-
defined DLT criteria, AEs leading to 
discontinuation, and death.
Secondary
1.
To assess the preliminary anti-tumor activity of BMS-
986258 as monotherapy and in combination with 
nivolumab in advanced solid tumors.
2.
To explore the PK of BMS-986258 when administered 
IV as monotherapy and in combination with nivolumab.
3.
To characterize the immunogenicity of BMS-986258 as 
monotherapy and in combination with nivolumab.
1.
ORR, mDOR, and PFS rate at 6, 9, and 12 
months.
2.
Summary measures of PK parameters of 
BMS-986258 after monotherapy and 
combination treatment.
3.
Incidence of ADA to BMS-986258.
Abbreviations: ADA, anti-drug antibody; AE, adverse event; BMS, Bristol-Myers Squibb;
 
 DLT, dose-limiting 
toxicity; 
; IV, intravenous; MAAD, maximum administered dose; mDOR, median duration 
of response; MTD, maximum tolerated dose; 
; ORR: overall response rate; 
; PFS, progression-free survival; PK, pharmacokinetics; 
 
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
; RP2D, recommended Phase 2 dose; SAE, serious adverse event; 
 
Overall Design:
This is a Phase 1/2, open-label, non-randomized study of BMS-986258, administered as a single 
agent and in combination with nivolumab, in participants with select advanced solid tumors. The 
study is comprised of 4 parts: Part A (dose escalation of BMS-986258 monotherapy), Part A1 
(subcutaneous [SC] BMS-986258 monotherapy), Part B (dose escalation of BMS-986258 in 
combination with nivolumab), and then Part C (BMS-986258 in combination with nivolumab 
cohort expansion). Data obtained from the analysis of the SC dose(s) in Part A1 may be used to 
inform route of administration and dose selection in Part C. 
All participants will complete up to 4 study periods: Screening 
, Treatment for up 
to 12 cycles (56 days/cycle), Safety Follow-up (100 days), and Survival Follow-up 
 
. The duration of the study will be approximately 4 years. 
Pre-screening for participants in Part A and B NSCLC PD cohorts will be completed prior to the 
screening period. All on-study images will be submitted to a central imaging vendor for collection.
At the Sponsor’s discretion, scans may undergo blinded independent central review. Sites should 
be trained prior to scanning the first study participant. Image acquisition guidelines and submission 
process will be outlined in the CA031002 Imaging Manual to be provided by the core lab.
Number of Participants: 
The approximate number of participants will be up to 
 as shown below. 

Part A Monotherapy Escalation: The total sample size is up to approximately 
 participants
including 
 to assess the maximum tolerated dose (MTD)/ maximum administered dose 
(MAAD) and an additional 
 in NSCLC PD cohorts. 

Part A1: Subcutaneous (SC) Dose: The total sample size is up to approximately 
 participants 
to evaluate up to 
.
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
Part B Combination Escalation: The total sample size is up to approximately 
 participants
including 
 participants to assess the MTD/MAAD in combination and 
 in 
NSCLC PD 
cohorts. 

Part C Cohort Expansion: Approximately up to 
 participants will be treated in each of the 5
tumor cohorts (up to a total of 
 across tumors).
Treatment Arms and Duration:

The Dose Escalation Phase, where the dose level of BMS-986258 administered intravenously 
(IV) as monotherapy (Part A) or in combination with nivolumab (Part B) will be escalated to 
determine the MTD or MAAD.

Part A, BMS-986258 Monotherapy Dose Escalation: Dosing Q4W up to twelve 8-week 
cycles, administered as monotherapy; escalations will be based on dose-limiting toxicities, 
using a Bayesian Logistic Regression Model (BLRM) employing the escalation with 
overdose control principle.

Part A1 will be independent from the other treatment arms where BMS-986258 will be co-
administered SC with recombinant human hyaluronidase PH20 (rHuPH20) for the first 
dose in Cycle 1. All subsequent doses of BMS-986258 will be administered as 
monotherapy IV, Q4W twice per cycle, for up to twelve 8-week cycles (96 weeks). 
Alternatively, participants in cohort A1 who have received SC BMS-986258 on Cycle 1 
Day 1 will be offered the option to receive subsequent IV combination therapy of BMS-
986258 with nivolumab (480 mg) at the highest dose of BMS-986258 that has been shown 
to be safe and tolerable in the dose escalation (Part B). Treatment will be given Q4W twice 
per cycle, for up to twelve 8-week cycles (96 weeks). The dose selected for Part A1 will 
not exceed a dose determined to be safe and tolerable in Part A. Once initiated Part A1 may
be run in parallel with Part A and B.

Part B, BMS-986258 in Combination with Nivolumab Dose Escalation: Dosing Q4W, 
administered as combination up to twelve 8-week cycles, with escalation decisions based 
on dose-limiting toxicities, using a BLRM copula employing the escalation with overdose 
control principle.

During dose escalation, all the eligible participants will be initially assigned to Part A until 
the decision is made to escalate to the third dose cohort. Subsequently, treatment in Part B 
will be initiated, and dose escalation in the 2 parts will occur in parallel. 

Expansion Phase (Part C): Dosing Q4W, administered as combination up to twelve 8-week 
cycles. The dose(s) selected for Part C will not exceed the MTD (or MAAD if no MTD is 
determined) in Part B, and may incorporate assessment of other data including toxicities, PK, 
and PD data from Parts A and B.
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Study Treatment: 
Study Drug for CA031002
Medication 
Potency 
IP/Non-IP 
BMS-986258
IP
BMS-986258
IP
Nivolumab
10 mg/mL
IP
ENHANZE® Drug Product 
(rHuPH20)a
1 mg/mL
IP
Abbreviations: IP: investigational product; rHuPH20, recombinant human hyaluronidase PH20.
a ENHANZE® (rHuPH20) is referred to as rHuPH20 in the protocol
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Pre-Screening for PD Cohort only (NSCLC)
Participants in Parts A and B NSCLC PD cohorts only must have tumor-associated
 
 as measured by
a 
 
 prior to completion of the remaining screening procedures. A 
participant is considered enrolled only when a main protocol-specific informed consent is signed. 
If allowed by institutional practices, sites are required to use a pre-screening consent for the 
 
 staining to evaluate 
 from biopsy samples. Participants must have a 
lesion that can be biopsied at an acceptable clinical risk as judged by the Investigator, in order to 
be eligible for the NSCLC PD cohorts. 
Participants in Part A and B NSCLC PD cohorts will be allowed to sign the main ICF and continue 
with other screening procedures while the 
 result is available for the determination of 
participant eligibility in NSCLC PD cohorts.
Screening: The screening period will be
 and begins by signing the main protocol 
informed consent form. Participants meeting all eligibility criteria will be enrolled in the study 
using an Interactive Response Technology according to the part and treatment arm availability.
Treatment: The dosing regimen of BMS-986258 is Q4W. 
 
 Refer to Section 5.1 and 
 of the protocol. All participants will 
be treated for up to twelve 8-week treatment cycles, totaling 96 weeks. Continuous safety 
evaluation and tumor assessment (every 8 weeks) will guide the decision to treat a participant with 
additional cycles of study therapy if the participant has confirmed clinical benefit. 
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
In Part A (BMS-986258 Monotherapy Escalation), BMS-986258 will be administered Q4W. 
BMS-986258 will be infused according to dosing and infusion times in Table 7.1-1. Shorter 
infusion times may be used for initial dose panels and longer infusion times will be used for 
the higher dose panels. In Part A1 (BMS-986258 SC for first dose), BMS-986258 will be co-
administered with rHuPH20 for the first dose of BMS-986258 in Cycle 1. All subsequent doses 
will be administered as monotherapy IV Q4W. Alternatively, participants in cohort A1 who 
have received SC BMS-986258 on Cycle 1 Day 1 will be offered the option to receive
subsequent IV combination therapy of BMS-986258 with nivolumab (480 mg) at the highest 
dose of BMS-986258 that has been shown to be safe and tolerable in the dose escalation (Part 
B). Treatment will be given Q4W twice per cycle, for up to twelve 8-week cycles (96 weeks). 
. Please refer to the Pharmacy 
Manual for dose-specific infusion times and sites of SC administration. BMS-986258 will 
require a 
 observation period following the completion of the infusion for the first 2 
doses for each participant.

In Part B (BMS-986258 in Combination with Nivolumab Escalation) and Part C (BMS-986258 
in Combination with Nivolumab Cohort Expansion), nivolumab will be administered Q4W 
and will be infused over 30 minutes. When both BMS-986258 and nivolumab are given in 
combination, nivolumab will be given first, over 30 minutes, followed by a 
 
observation period then BMS-986258, over approximately 
. BMS-986258 infusion 
will begin at least 
 after completion of the infusion of nivolumab. BMS-986258 
infusions will require a 
 observation period following the completion of the infusion 
for the first 2 doses for each participant. Shorter infusion times for BMS-986258 may be used 
for initial dose panels and longer infusion times 
 will be 
used for the higher dose panels. 
 
. Please refer to the Pharmacy Manual for dose-specific infusion times and 
administration details for nivolumab and BMS-986258.

Tumor progression and response endpoints will be assessed using RECIST v1.1 criteria for 
solid tumors.
Follow-up:

Safety Follow-up Period:

Upon completion of study therapy (or up to a maximum of 96 weeks, if applicable), or 
once the participant has received the last administration of any study treatment (ie, 
at end of treatment), all participants will enter a safety follow-up period for 100 days.

For participants who complete all scheduled cycles of therapy, the end of treatment (EOT)
visit will be the same visit as the last scheduled and completed on-treatment visit and will 
be the start of the safety follow-up period. For participants who do not complete all 
scheduled cycles of therapy, the EOT visit will be the most recent on-treatment visit (with 
all available safety and response data) and will not need to be repeated. Accordingly, for 
these participants, this visit will be considered the start of the safety follow-up period.

Survival Follow-up Period:

In parallel with the safety follow-up period, all participants will continue on the survival 
follow-up period. Participants will be followed up for survival at each Safety Follow-up 
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visit and then by telephone 
, loss to 
follow-up, withdrawal of consent, or conclusion of the study, whichever comes first. 
Subsequent therapies will also be recorded in this survival follow-up period. 
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3
INTRODUCTION
T-cell immunoglobulin (Ig) and mucin-domain containing-3 (TIM-3) is a protein that in humans 
is encoded by the hepatitis A virus cellular receptor 2 (HAVCR2) gene and works as an inhibitory 
receptor that suppresses activation and functional responses in T cells. TIM-3 is often co-expressed 
with programmed cell death 1 (PD-1) in cluster of differentiation 8 (CD8)+ T cells in different 
types of cancer. BMS-986258 is an antagonistic antibody to TIM-3 and its use as monotherapy or 
in combination with nivolumab will be explored in the CA031002 study, a Phase 1/2, first-in-
human (FIH), ascending multiple-dose study, in humans with advanced/metastatic solid tumors –
non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), colorectal cancer (CRC), triple 
negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN). This 
study will evaluate the safety profile, tolerability, pharmacokinetics (PK), and pharmacodynamics 
(PD) of intravenous (IV) doses of BMS-986258 administered every 4 weeks (Q4W) as 
monotherapy and in combination with nivolumab in advanced solid tumors and is expected to 
determine the maximum tolerated dose (MTD)/maximum administered dose (MAAD) or an 
alternate dose(s) of BMS-986258 to be used in future trials. In addition, the study will evaluate the 
preliminary efficacy of BMS-986258 in combination with nivolumab in the following disease-
restricted populations, as follows: RCC participants who received and progressed on or after anti-
PD-1 therapy (combined or not with other immuno-oncology [I-O] agents); microsatellite 
instability-high (MSI-H) CRC participants who received and progressed on or after-anti-PD-1 
therapy, and microsatellite stability (MSS) CRC participants; NSCLC participants who received 
and progressed on or after-anti-PD-1 therapy; SCCHN subjects who received and progressed on 
or after anti-PD-1 therapy; and participants with recurrent or metastatic TNBC.
3.1
Study Rationale
Patients with metastatic or refractory solid tumors have very poor prognosis.1 Despite advances in 
multimodal therapy, increases in overall survival (OS) in this patient population have been limited. 
The unmet need resides in the lack of effective treatments to deliver long-term survival, hence the 
need to test compounds that have novel mechanisms of action in clinical studies.
The idea of harnessing the immune system to battle cancer is not new; in fact, it dates back to the 
19th century with William Coley and his bacterial inoculations of several types of tumor, starting 
with sarcoma.2 One hundred and twenty years later, immunotherapy was named breakthrough of 
the year by the Science Journal in 2013, not so much for the number of patients who had been 
successfully treated at that point, but for “a sense of paradigms shifting.”3 Immuno-oncology 
cancer drugs are able to alter the unfavorable balance between positive (co-stimulatory) and 
negative (co-inhibitory) T-cell surface molecules exploited by the tumors to escape immune 
surveillance.4 The treatment focus, then, changes from targeting tumor cells to counteracting the 
resistance mechanisms developed by tumors, therefore enabling the endogenous immune system 
to reject tumors.
The most extensively studied immune-modulating molecules are agents blocking checkpoint 
molecules, such as PD-1 and cytotoxic T lymphocyte–associated antigen 4 (CTLA-4). Inhibition 
of these negative regulatory receptors, referred to as immune checkpoint blockade, results in the 
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enhanced activation of T-cell responses and potent antitumor activity in preclinical models. Trials 
with CTLA-4 blockade provided the first clinical evidence of improvement in OS with immune 
modulatory anticancer therapy in patients with metastatic melanoma. 5 , 6 Shortly after that, 
objective responses were obtained for NSCLC, melanoma, and RCC with anti-PD-1 antibody.7
Moreover, metastatic melanoma patients treated with the combination of ipilimumab and an anti-
PD-1 antibody (nivolumab) achieved an unprecedented 53% response rate and prolonged 
responses,8 which demonstrated the potential of combination therapy. More recently, the benefit 
of combination therapy was also demonstrated in RCC.9
TIM-3 is a 
. 
TIM-3 is expressed mostly on monocytes, macrophages, dendritic cells (DC) and natural killer 
(NK) cells, as well as in endothelial cells; little expression of TIM-3 is detected in peripheral T
cells in the majority of normal healthy donors or cancer patients, but it can be induced upon T-cell 
activation.10,11,12 Multiple ligands have been proposed for TIM-3 and include the following: 
galectin-9, phosphatidylserine (PS), high mobility group B1, and carcinoembryonic antigen-
related cell adhesion molecule 1. 13 Functional anti-TIM-3 monoclonal antibodies (mAbs), 
including BMS-986258 and the mouse surrogate anti-TIM-3 antibodies, all bind to the PS-binding 
loops of TIM-3, suggesting that PS might be a functional ligand of TIM-3 either by itself or 
associated with another unidentified molecule in dampening T-cell responses (internal BMS data).
During chronic viral infections in mouse and humans, TIM-3 is expressed on dysfunctional or 
exhausted CD8+ T cells. Co-blockade of TIM-3 and PD-1 pathways results in greater restoration 
of T-cell responses in chronic viral infections than restoration of T-cell responses by PD-1 
blockade alone.14,15,16,17 TIM-3 expression also marks dysfunctional or exhausted CD8+ T cells 
in several cancer types. In tumor-infiltrating lymphocytes (TIL) from patients with advanced 
metastatic melanoma,18 NSCLC19 and follicular B cell non-Hodgkin lymphoma,20 in vitro TIM-3 
blockade improved T-cell responses with TIM-3/PD-1 co-blockade showing even greater 
responses than single agents. TIM-3 might also work as a mechanism of resistance to anti-PD-1 
therapy, as TIM-3 expression was found to be upregulated in 2 lung cancer patients who developed 
secondary resistance to anti-PD-1 mAb treatment.21
Thus, an antagonistic antibody such as BMS-986258 that blocks TIM-3-mediated inhibitory 
signals in T cells and, perhaps, in other immune subsets as well, might provide therapeutic benefit 
to cancer patients. Moreover, based on recent emerging clinical evidence of increased response 
rates with combination therapies, the association of BMS-986258 to anti-PD-1 may lead to greater 
depth of response and OS in advanced or metastatic solid tumors.
3.2
Background
A detailed description of BMS-986258 chemistry, pharmacology, and toxicology is provided in 
the BMS-986258 Investigator’s Brochure (IB).12
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3.2.1
BMS-986258
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3.2.2
Nivolumab
Nivolumab is a fully human, IgG4 (kappa) isotype mAb that binds to PD-1 with nanomolar affinity 
(dissociation constant, 3.06 nM) and a high degree of specificity. Nivolumab blocks binding of 
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PD-1 to its ligands programmed death ligand 1 (PD-L1) and programmed death ligand 2. 
Nonclinical in vitro testing of nivolumab demonstrated that binding to PD-1 results in enhanced 
T-cell proliferation and release of IFN-γ in vitro in mixed lymphocyte reaction (MLR) and 
cytomegalovirus (CMV) assays.
The nonclinical safety of nivolumab was evaluated in a comprehensive toxicology program in 
mice and monkeys and was submitted as part of Biologics License Application 125527.30 Details 
of the in vitro and in vivo nonclinical pharmacology studies conducted to support the development 
of nivolumab can be found in Section 4.1 of the nivolumab Investigator’s Brochure (IB).31
While nivolumab was well tolerated in cynomolgus monkeys, there is a potential for enhanced 
toxicity when combined with other immunostimulatory agents. However, nonclinical studies with
nivolumab did not predict clinically relevant adverse effects (eg, no evidence of immune-mediated 
adverse effects was observed in nonclinical toxicology studies with nivolumab). Therefore, 
combination nonclinical toxicology studies with BMS-986258 and nivolumab have not been 
conducted and are not required by the International Council for Harmonisation S9 Note for 
Guidance on Nonclinical Evaluation for Anticancer Pharmaceuticals. 32 The safety of the 
combination will be carefully monitored in this clinical trial.
The overall safety experience with nivolumab, as either monotherapy or in combination with other 
therapeutics, is based on experience in approximately 23,507 participants (see nivolumab IB).31
Nivolumab has been approved by the United States (US) Food and Drug Administration (FDA) 
for the treatment of patients with unresectable or metastatic melanoma (as a single agent and in 
combination with ipilimumab), metastatic NSCLC after progression on or after platinum-based 
chemotherapy, metastatic SCLC after platinum-based chemotherapy, advanced RCC previously 
treated with anti-angiogenic therapy, recurrent or metastatic squamous cell carcinoma of the head 
and neck with disease progression on or after a platinum-based therapy, classical Hodgkin 
lymphoma that has relapsed or progressed, advanced or metastatic urothelial carcinoma with 
disease progression on or after a platinum-based therapy, hepatocellular carcinoma (HCC) as 
single agent or in combination with ipilimumab that has previously been treated with sorafenib, 
MSI-H CRC that has progressed after chemotherapy in combination with ipilimumab and 
unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) after 
prior fluoropyrimidine- and platinum-based chemotherapy.31
For nivolumab monotherapy, the safety profile is similar across tumor types. The only exception 
is pulmonary inflammation adverse events (AEs), which may be numerically greater in participants 
with NSCLC. In NSCLC patients, it can be difficult to distinguish between nivolumab-related and 
unrelated causes of pulmonary symptoms and radiographic changes. There is no relationship 
between the incidence, severity, or causality of AEs and the nivolumab dose level. Additional 
details on the safety profile of nivolumab, including results from other clinical studies, are 
summarized in the nivolumab IB.31
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3.3
Benefit/Risk Assessment
As of the reporting cut-off date of 12-Sep-2019, 25 participants have been treated with various 
doses of BMS-986258 as monotherapy (n = 3 at 8 mg, n = 3 at 24 mg, n = 4 at 72 mg, n = 4 at 200 
mg, n = 4 at 480 mg, n = 4 at 800 mg, and n = 3 at 1200 mg). As of the data cutoff date of 12-Sep-
2019, based on 25 participants treated with BMS-986258 IV monotherapy in doses 8 to 1200 mg, 
the majority of AEs observed were 
 in severity. 
 treatment-related 
AEs were reported.
 
 no dose-limiting toxicities (DLTs) were observed. Therefore, BMS-986258 administered as 
monotherapy is considered to have a manageable safety profile in doses up to 1200 mg IV.12
Additionally, there are preliminary data on 4 participants who have received at least 1 cycle of 
BMS-986258 480 mg IV combined to nivolumab 480 mg; none of them presented a DLT during 
the observation period of 28 days. At this time, no efficacy data are available. There is limited
prior human experience with BMS-986258; therefore, clinical benefit in participants with 
advanced solid tumors has not been established, but the initial data support its continued 
development. 
Extensive details on the safety profile of nivolumab are available in the IB and will not be repeated 
herein.
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical trials with no MTD 
reached at any dose tested up to 10 mg/kg. Most AEs were low-grade 
 with relatively 
few related 
 AEs. There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level. A pattern of immune-related AE (irAE) has 
been defined, for which management algorithms have been developed; these are provided in 
Appendix 8. Most high-grade events were manageable with the use of corticosteroids or hormone 
replacement therapy (endocrinopathies) as instructed in these algorithms. Additional details on the 
safety profile of nivolumab, including results from other clinical studies, are also available in the 
nivolumab IB.31
Other TIM-3 inhibitors that have entered human trials, both as monotherapy and in combination 
with other immunotherapy drugs include MGB453 from Novartis, TSR-022 from Tesaro, and 
LY3321367 from Eli Lilly. Safety and efficacy data have been presented for TSR-022, showing 
safe dose escalation up to 10 mg/kg in participants with solid tumors and AEs consistent with other 
checkpoint inhibitors.33 In follow-up presentation,34 efficacy data were disclosed for NSCLC 
participants that had progressed on or after anti-PD-(L)1 treatment and then received dual TIM-3 
and PD-1 blockade. Although data were reported for a small number of participants, it was 
suggested that responses were more frequent in participants treated with higher dose and in those 
who expressed PD-(L)1 1%. Novartis reported results from a Phase 1/2 study of MBG453 as 
monotherapy or combined to an anti-PD-1 antibody in patients with solid tumors, in which
MGB453 was escalated up to 1200 mg Q4W as monotherapy or in combination. AEs were mainly 
G1-2, constitutional symptoms, and no Grade 4 AEs were reported in more than 2% of participants. 
Overall response rate (ORR) of 4.7% and disease control rate of 44.2% were reported across all 
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different indications for the MBG453 combination therapy. The recommended Phase 2 dose
(RP2D) of MBG453 was declared as 800 mg Q4W and Phase 2 studies are ongoing in participants 
with melanoma or NSCLC resistant to anti-PD-(L)1 therapy. 35 MBG453 is also under 
development for participants with acute myeloid leukemia (AML) or high-risk myelodysplastic 
syndrome (MDS), in combination with decitabine; Phase 1 results showed favorable efficacy in 
newly diagnosed AML and high-risk MDS.36 A Phase 1a/1b study of LY3321367 as monotherapy 
or in combination with an anti-PD-L1 antibody, which enrolled 41 participants with solid tumors, 
investigated doses of LY3321367 up to 1200 mg every 2 weeks (Q2W). Results showed a 
favorable toxicity profile, with mostly Grade 1-2 treatment-emergent AEs and no DLTs. One 
participant with small cell lung cancer treated in the monotherapy arm showed a partial response 
(PR) in a post-PD-1 setting.37
In addition to the initial safety data observed for BMS-986258 in the current study, and the safety 
data reported by other companies for other TIM-3 inhibitors that demonstrated a safe profile as 
monotherapy or in combination with anti-PD-(L)1 agents, the evaluation of risk for this study is 
based on information from in vitro studies on human cell lines and from nonclinical studies in 
monkeys.
3.3.1
Recombinant Human Hyaluronidase PH20
Recombinant Human Hyaluronidase PH20 (rHuPH20) is a recombinant form of hyaluronidase, a 
human enzyme that increases the dispersion and absorption of co-administered therapeutics by 
locally depolymerizing interstitial hyaluronan in the SC space, thereby decreasing the viscosity of 
SC extracellular matrix. This facilitates administration of greater fluid volumes via the SC route 
and potentially allows more antibody to reach the systemic circulation as compared to SC 
administration without rHuPH20. The half-life of rHuPH20 in skin is < 30 minutes and hyaluronan 
in the SC space is restored via normal bodily processes within 24 to 48 hours.38 Additional details 
are provided in version 08 of the rHuPH20 IB.39
3.3.2
BMS-986258 Starting Dose for Part A (Monotherapy)
The FIH dose for this study has been carefully selected based on a review of all available 
nonclinical data (see Section 5.4.2). To balance the potential for possible therapeutic benefit and 
need for reasonable safety in a cancer patient population, the starting dose of 8 mg 
 
Q4W was selected. This dose is 
 the MRSD 
 based on a 
 HNSTD/NOAEL and the projected human exposures (AUCs) at 
 
 are 
 than the exposures observed in cynomolgus monkeys at the 
HNSTD/NOAEL 
).40 Furthermore, BMS-986258 is a blocking 
antibody with no Fc mediated effector function and no in vitro human PBMC activation or 
cytokine release, suggesting very low potential for adverse PBMC activation or cytokine release 
in humans.
3.3.3
BMS-986258 Starting Dose for Part A1 (Monotherapy SC)
Treatment in Part A1 (SC dose[s] BMS-986258 with rHuPH20) will be initiated after a dose level
of BMS-986258 has been cleared for safety in Part A (IV monotherapy). The starting dose of 
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BMS-986258 administered in Part A1 will not exceed IV doses of BMS-986258 that have 
demonstrated to be safe in the monotherapy dose escalation arm (Part A). The SC dose(s) of BMS-
986258 for Part A1 will be selected taking into consideration preliminary safety and available PK 
and PD data from the initial cohorts and 
 may be evaluated. Once a dose has 
been determined to be safe and tolerable from Part A, Part A1 may be initiated independently of 
Parts B and C, using all available safety and PK data and may be run in parallel with Parts A and 
B. 
The first cohort in Part A1 has a goal of obtaining preliminary data on feasibility of SC 
administration of BMS-986258 and preliminary bioavailability. The highest dose that has been 
demonstrated to be safe and tolerable in Part A to date is 1200 mg Q4W; therefore, this is the dose 
that will be tested in the first cohort in Part A1. Participants in this cohort will receive their first 
dose of BMS-986258 1200 mg in combination with rHuPH20 as an SC injection. All subsequent 
doses will be administered as monotherapy 1200 mg IV, Q4W until EOT. Alternatively, 
participants in cohort A1 who have received SC BMS-986258 on Cycle 1 Day 1 will be offered 
the option to receive subsequent IV combination therapy of BMS-986258 with nivolumab (480 
mg) at the highest dose of BMS-986258 that has been shown to be safe and tolerable in the dose 
escalation (Part B). Treatment will be given Q4W twice per cycle, for up to twelve 8-week cycles 
(96 weeks). A second cohort may be opened upon analysis of the totality of data from Parts A and 
B, and the preliminary data from the first cohort in Part A1.
Data obtained from the analysis of the SC dose(s) in Part A1 may be used to inform route of 
administration and dose selection in Part C.
3.3.4
BMS-986258 Starting Dose for Part B (Combination with Nivolumab)
The starting dose of BMS-986258 in Part B (combination with nivolumab) was selected to be 480 
mg IV Q4W. Part B was initiated only after both 800 mg Q4W and 1200 mg Q4W cohorts were 
determined to be safe in Part A. In participants treated with BMS-986258 in Part A, no drug-related 
serious adverse effects were observed up to the highest tested dose of 1200 mg Q4W. The choice 
of 480 mg as the starting dose for Part B was also supported by preliminary PK and biomarker 
data. Preliminary PK results from Part A demonstrated that PK was linear and dose proportional 
at doses 200 mg Q4W and higher (internal BMS data). Preliminary biomarker data showed 
sustained optimal peripheral RO throughout the dosing period at doses 72 mg Q4W and higher. 
Preliminary data also show dose-dependent increases in total soluble TIM-3 that appear to plateau 
at doses 480 mg Q4W and higher (internal data at BMS). Thus, given the totality of safety and 
preferred PK and biomarker characteristics of BMS-986258, 480 mg IV Q4W was considered as 
potentially therapeutic, and therefore was chosen as the starting dose in Part B. At no point will 
the dose of BMS-986258 administered in combination with nivolumab in Part B exceed doses of 
BMS-986258 that have been demonstrated previously to be safe in the monotherapy dose 
escalation arm (Part A), nor at any point during Part B escalation will the BMS-986258 dose 
exceed the highest dose determined to be tolerated in Part A.
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3.3.5
Dose Escalation in Parts A and B
Bayesian Logistic Regression Model (BLRM) with overdose control (escalation with overdose 
control [EWOC]) principle will be employed to limit the risk of exposing participants to an unsafe 
or toxic dose. In addition, following the completion of 
 
 will be made in conjunction with the data available on all previously dosed 
participants (including clinical and laboratory safety assessments, PK, and PD data); escalation by 
more than 
 will not be permitted; and determination to escalate will be made after 
discussion and agreement between investigators and the Medical Monitor.
3.3.6
Safety Monitoring on Study Therapy
In the absence of a pre-clinically defined safety signal, safety monitoring, by way of complete 
blood counts and chemistry (including liver enzyme) tests will be carried out prior to 
administration of study therapy, every 2 weeks for the first cycle and every 4 weeks thereafter. In 
addition, complete physical examinations (PEs) will be conducted on Day 1 of each new cycle, 
along with Q4W symptom-directed targeted PEs prior to each administration of study treatment.
Because preclinical data show that mAbs have no effect on human ether-a-go-go-related gene 
(hERG) channel activity in the in vitro hERG assay, the potential for BMS-986258 to alter cardiac 
re-polarization will only be studied as part of this FIH trial with pre- and post-ECG studies on 
Cycle 1 Day 1 and Cycle 3 Day 1 of Part A. A single ECG will be required at other visits as 
specified
 Nevertheless, participants with corrected QT 
(QTc) interval prolongation at baseline will be excluded and medications known to cause 
prolonged QT will be prohibited.
The mandated biopsies pose limited risk to the participant, which include discomfort, pain, and 
bleeding. Biopsies should be performed at minimal acceptable clinical risk as judged by the 
Investigator and not in a target lesion or a lesion in an area treated with prior radiation therapy. 
Tissue must be a core needle biopsy, excisional biopsy, or incisional biopsy. Fine needle biopsies 
are not considered adequate for biomarker analysis. Biopsies of bone lesions that do not have a 
soft tissue component are also not acceptable. Participants who do not have accessible tumor 
lesions in order to provide a fresh pre-treatment tumor biopsy are eligible. Participants in Parts A 
and B NSCLC PD cohorts whose pre-treatment biopsy yields inadequate tissue quantity or quality 
will not be eligible for NSCLC PD cohorts, but they can be enrolled in dose escalation (Part A and 
B) cohorts. Section 9.8.4 gives additional guidance on lesions that are appropriate for a research 
biopsy. Because of the need for development, investigation of selection using biomarkers for 
participants treated with BMS-986258, the limited risk of a research biopsy in low-risk participants 
is considered appropriate in a Phase 1 research setting.
As noted in the nonclinical studies in Section 3.2.1.3, BMS-986258 repeatedly administered to 
cynomolgus monkeys did not induce infusion-related or anaphylactoid reactions. However, 
because of the as yet unknown potential of infusion reactions with the administration of 
BMS-986258 in humans, although the first 25 participants treated with BMS-986258 monotherapy 
in doses ranging from 8 to 1200 mg did not present with infusion-related reactions, all participants
receiving the first 2 doses of BMS-986258 monotherapy or in combination with nivolumab will 
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be closely monitored until 
 post infusion for potential infusion reactions that could occur 
after either first administration or from repeat dosing of a novel mAb. In addition, the 
administration of BMS-986258 as monotherapy or in combination with nivolumab will occur at 
sites with medical monitoring and capability to manage infusion reaction or anaphylaxis.
Frequent safety assessments will be utilized by the investigators and Sponsor to determine whether 
dose modification, additional safety measures, or termination of the study is required at any time. 
In addition, AEs and SAEs will be reviewed regularly by the Medical Monitor/Study Director and 
the Pharmacovigilance group to look for trends and potential safety signals. Treatment of AEs will 
follow Institutional guidelines and recommended management algorithms as listed in the 
nivolumab prescribing information30 and nivolumab IB31 and provided as appendices to the 
protocol.
It is unknown if treatment with BMS-986258 or BMS-986258 in combination with nivolumab 
increases the risk for contracting symptomatic SARS-CoV-2 infection or increases the severity or 
duration of symptoms. This unknown risk must be considered when enrolling a subject.
No additional safety monitoring or routine screening tests for all participants will be implemented 
because of the SARS-CoV-2 pandemic. However, eligibility for this trial may be impacted in 
participants with a recent episode of SARS-CoV-2 infection (please refer to Section 6.2 Exclusion 
Criteria). 
 
 
Non-live COVID-19 vaccination is considered a simple concomitant medication within the study. 
However, the efficacy and safety of non-live vaccines (including non-live COVID-19 vaccines) in 
participants receiving BMS-986258 or BMS-986258 in combination with nivolumab is unknown.
3.3.7
Overall Benefit/Risk for Combination with Nivolumab
Nivolumab has demonstrated clinical activity in subjects with advanced NSCLC, RCC, melanoma,
and lymphomas as well as other tumors. Nivolumab has demonstrated a manageable safety profile; 
the overall safety experience with nivolumab, as monotherapy or in combination with other 
therapeutics, is based on experience in approximately 23,507 subjects treated to date.31 There is 
no pattern in the incidence, severity, or causality of AEs to nivolumab dose level. The most 
common AEs included fatigue, rash, pruritus, diarrhea, and nausea. Side effects of nivolumab 
therapy may include those associated with immune-mediated activation, such as pneumonitis, 
thyroiditis, and transaminitis. To mitigate risk from serious immune-mediated AE (IMAEs), 
subject management algorithms for nivolumab-related AEs from prior collective nivolumab 
experience have been included (Appendix 8). For nivolumab monotherapy, the safety profile is 
similar across tumor types. The only exception is pulmonary inflammation AEs, which may be 
numerically greater in subjects with NSCLC because, in some cases, it can be difficult to 
distinguish between nivolumab-related and unrelated causes of pulmonary symptoms and 
radiographic changes. 
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The combination of nivolumab and BMS-986258 has potential for clinical benefit in participants
who were refractory to or progressed after anti-PD-(L)1 therapy. TIM-3 is frequently co-expressed 
with PD-1 in TILs, and patients with the highest co-expression of PD-1 and TIM-3 generally have 
the highest frequencies of PD-1+ and TIM-3+ CD8 T cells. Furthermore, TIM-3 expression was 
found to be upregulated in 2 lung cancer patients who developed secondary resistance to anti-PD-
1 mAb treatment.21 Therefore, it is plausible that TIM-3 may have a role in resistance to anti-PD-
1 blockade, and the association of both therapies is able to overcome resistance.
In general, the combination of nivolumab with other therapeutic agents results in a safety profile 
with similar types of AEs as either agent alone, but in some cases, with a greater frequency. In 
several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics such 
as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being explored. 
Most studies are ongoing and, as such, the safety profile of nivolumab combinations continues to 
evolve. Because BMS-986258 is a novel anti-TIM-3 antibody with potentially additive action with 
nivolumab and the 2 checkpoints are frequently co-expressed by T cells, augmented and/or 
unanticipated irAEs may occur. On the other hand, this potentially additive action justifies the 
exploration of the 2 drugs in combination, since clinical activity may be higher with BMS-986258 
in combination with nivolumab compared to either drug administered as monotherapy.
3.3.8
Summary
An urgent need exists for new therapies for subjects with advanced cancer that have progressed 
after or not responded to other treatments. The lack of a safety signal in pre-clinical toxicology 
studies, the emerging role of combination immune-modulating therapies in producing deep and 
durable responses in a variety of tumor types, and the careful consideration for safety in designing 
this study support the exploration of BMS-986258 as monotherapy or in combination with 
nivolumab in participants with advanced solid tumors who have few treatment options.
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4
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the safety, tolerability, and to determine MTD or 
MAAD and RP2D of BMS-986258 administered as 
monotherapy and in combination with nivolumab in 
participants with select advanced solid tumors.
Incidence of AEs, SAEs, AEs meeting protocol-
defined DLT criteria, AEs leading to 
discontinuation, and death.
Secondary
1.
To assess the preliminary anti-tumor activity of 
BMS-986258 as monotherapy and in combination with 
nivolumab in advanced solid tumors.
2.
To explore the PK of BMS-986258 when administered 
IV as monotherapy and in combination with nivolumab.
3.
To characterize the immunogenicity of BMS-986258 as 
monotherapy and in combination with nivolumab.
1.
ORR, mDOR, and PFS rate at 6, 9, and 12 
months.
2.
Summary measures of PK parameters of 
BMS-986258 after monotherapy and 
combination treatment.
3.
Incidence of ADA to BMS-986258.
Abbreviations: ADA, anti-drug antibody; AE, adverse event; BMS, Bristol-Myers Squibb;
 
; DLT, dose-limiting 
toxicity; 
; IV, intravenous; MAAD, maximum administered dose; mDOR, median duration 
of response; MTD, maximum tolerated dose; 
; ORR, overall response rate; OS,
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overall survival; PFS, progression-free survival; PK, pharmacokinetics; 
 
; RP2D, recommended Phase 2 dose; SAE, serious adverse event;
; SC, subcutaneous; 
 
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 1/2, open-label, non-randomized study of BMS-986258, administered as a single 
agent and in combination with nivolumab, in participants with select advanced solid tumors:
NSCLC, RCC, CRC, TNBC, and SCCHN. The study comprises 4 parts: Part A (dose escalation 
of BMS-986258 monotherapy), Part A1 (SC BMS-986258 monotherapy), Part B (dose escalation 
of BMS-986258 in combination with nivolumab) where the dose is escalated to determine the 
MTD, and Part C (BMS-986258 in combination with nivolumab cohort expansion), where the 
cohort of participants is expanded to gather additional safety, tolerability, preliminary efficacy, 
PK, and PD information regarding BMS-986258 in combination with nivolumab. Data obtained 
from the analysis of the SC dose(s) in Part A1 may be used to inform route of administration and 
dose selection in Part C.
 
 
 
 
 Treatment in Part A1 (SC 
dose[s] BMS-986258 with rHuPH20) will be initiated independent of the Treatment Arms B and 
C but only after a dose level of BMS-986258 in Part A has cleared the DLT period.
 
 
 
 
 After preliminary evaluation of safety and PK data from these 
 
 re-escalating doses of BMS-986258 may be initiated. 
 
 
 
 
. All participants will complete up to 
4 study periods: Screening 
, Treatment (12 cycles, 56 days/cycle), Safety Follow-
up (100 days), and Survival Follow-up 
 
. The duration of the study will be approximately 4 years. Pre-screening for participants 
in Part A and B NSCLC PD cohorts will be completed prior to the screening period.
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5.1.1
Pre-screening for PD Cohorts only (NSCLC)
Participants in Part A and B NSCLC PD cohorts only must have tumor-associated 
 
 as measured by a 
 prior to 
completion of the remaining screening procedures. A participant is considered enrolled only when 
a main protocol-specific informed consent is signed. If allowed by institutional practices, sites are 
required to use a pre-screening consent for the 
 staining to evaluate 
 from biopsy samples. Participants must have a lesion that can be biopsied at an acceptable 
clinical risk as judged by the Investigator in order to be eligible for the NSCLC PD cohorts. 
Participants in Parts A and B NSCLC PD cohorts whose pre-treatment biopsy yields inadequate 
tissue quantity or quality will not be eligible for NSCLC PD cohorts, but they can be enrolled in 
dose escalation (Part A and B) cohorts.
Participants in Part A and B NSCLC PD cohorts will be able to sign the main ICF and continue 
with other screening procedures while the 
 result is available for the determination of 
participant eligibility in NSCLC PD cohorts. 
5.1.2
Screening Period
The screening period will be up to 
 and begins by signing of the main protocol informed 
consent form (ICF). The screening assessments are shown in Table 2-2. 
If a participant exceeds the 
 screening period due to a study-related procedure 
(eg, scheduling of a tumor biopsy or waiting for a study-related laboratory value), the participant 
must be re-consented but does not require a new patient identification number. In this situation, 
the fewest number of procedures from the initial screening should be repeated to qualify the 
participant, while maintaining participant safety and eligibility. Within a given disease type, 
participants meeting all eligibility criteria will be enrolled in the study using an Interactive 
Response Technology (IRT) according to the part and treatment arm availability.
5.1.3
Treatment Period
The dosing regimen of BMS-986258 is Q4W. 
 
 Refer to Section 5.1 and 
. All participants will be treated for up to 96 weeks. 
The treatment period will consist of up to 12 treatment cycles (each cycle is 8 weeks in length).
Following each treatment cycle, the decision to treat a participant with additional cycles of study 
therapy (up to a maximum of 12 cycles) will be based on response assessment at the end of each 
cycle. Continuous safety evaluation and tumor assessment (every 8 weeks [Q8W]) will guide the 
decision to treat a participant with additional cycles of study therapy if the participant has 
confirmed clinical benefit (up to a maximum of 96 weeks) for all study parts. 
Study visits will be performed every 2 weeks for the first 8 weeks following the first dose of study 
treatment for the BMS-986258 Monotherapy Escalation (Part A), BMS-986258 with rHuPH20 SC 
for first dose (Part A1), and BMS-986258 in Combination with Nivolumab (Part B). Study visits 
at Cycle 2 and beyond will be every 4 weeks. During Cycles 1 and 3 of the treatment period, 
additional study visits to collect samples for intensive PK, ADA, 
are 
required. See Section 9.5
for further details. In Part C (BMS-986258 in 
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Combination with nivolumab Cohort Expansion), study visits will be performed every 2 weeks for 
the first cycle. Study visits at Cycle 2 and beyond will be every 4 weeks.
In Part A (BMS-986258 Monotherapy Escalation), BMS-986258 will be administered Q4W. 
BMS-986258 will be infused according to dosing and infusion times in Table 7.1-1. Shorter
infusion times may be used for initial dose panels and longer infusion times will be used for the 
higher dose panels. 
In Part A1 (BMS-986258 SC for first dose), BMS-986258 will be co-administered with rHuPH20
for the first dose of BMS-986258 in Cycle 1. All subsequent doses will be administered as 
monotherapy IV Q4W. Alternatively, participants in cohort A1 who have received SC BMS-
986258 on Cycle 1 Day 1 will be offered the option to receive subsequent IV combination therapy 
of BMS-986258 with nivolumab (480 mg) at the highest dose of BMS-986258 that has been shown 
to be safe and tolerable in the dose escalation (Part B). Treatment will be given Q4W twice per 
cycle, for up to twelve 8-week cycles (96 weeks). 
 
BMS-986258 SC should be administered in the abdomen or alternatively in the thigh. ENHANZE®
Drug Product (rHuPH20) should not be injected into or around an infected or acutely inflamed 
area because of the danger of spreading a localized infection. Clinical judgment should be used in 
determining the best site for SC drug administration. Please refer to the Pharmacy Manual for 
dose-specific infusion times and sites of SC administration. BMS-986258 will require a 
observation period following the completion of the infusion for the first 2 doses for each 
participant. 
In Part B (BMS-986258 in Combination with Nivolumab Escalation) and Part C (BMS-986258 in 
Combination with Nivolumab Cohort Expansion), nivolumab will be administered Q4W and will 
be infused over 30 minutes. When both BMS-986258 and nivolumab are given in combination, 
nivolumab will be given first, over 30 minutes, followed by a 
 observation period then 
BMS-986258, over approximately 
. BMS-986258 infusion will begin 
 
 after completion of the infusion of nivolumab. BMS-986258 infusions will require  
 observation period following the completion of the infusion for the first 2 doses for 
each participant. Shorter infusion times for BMS-986258 may be used for initial dose panels and 
longer infusion times 
 will be used for the higher dose panels. 
. Please refer to the 
Pharmacy Manual for dose-specific infusion times and administration details for nivolumab and 
BMS-986258.
During dose escalation, all eligible participants will be assigned to Part A until the decision is 
made to escalate to the third dose cohort. Subsequently, treatment in Part B may be initiated, and 
dose escalation in the 2 parts will occur in parallel. The dose(s) of BMS-986258 for Part A1 will 
be selected based on preliminary safety and available PK and PD data. Once a dose has been 
determined to be safe and tolerable from Part A, Part A1 can be initiated independently, using all 
available safety and PK data and may be run in parallel with Parts A and B. The dose(s) of 
BMS-986258 monotherapy or in combination with nivolumab for Part A and B NSCLC PD 
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cohorts will be selected based on preliminary safety and available PK and PD data. The doses 
selected for Part C will not exceed the MTD (or MAAD if no MTD is determined) in Part B, but 
may incorporate assessment of other data including toxicities and PK, PD data from Parts A and 
B, as well as feasibility and bioavailability (BA) of SC administration from Part A1.
Sentinel Participant:
During the dose escalation phase in Part A, Part A1, and Part B, a staggered dosing (sentinel 
participant) approach will be used. In Part A and Part A1, the first participant to be dosed at Cycle 1
Day 1 of the first dose level will be observed for 5 days before additional participants (ie, 
Participant 2 onward in that cohort) receive study treatments in the same dose level. In Part B, the 
first participant to be dosed at Cycle 1 Day 1 of each dose level will be observed for 5 days before 
additional participants (ie, Participant 2 onward in that cohort) receive study treatments in the same 
dose level.
Initially, 3 participants will be enrolled at the start of each cohort, in accordance with the sentinel 
participant approach cited above. However, to allow for any unforeseen discontinuations (such as 
disease progression) before the 4-week DLT period (28 days) is completed, an extra participant 
may be enrolled in each dose escalation cohort. Therefore, there may be a total of 4 participants 
(3 + 1) at the start of each cohort, provided that the fourth participant is able to start dosing within 
approximately 1 week of the third participant in the same dose escalation cohort. Additional 
information on DLTs can be found in Section 7.1.1. 
5.1.3.1
BMS-986258 Monotherapy Dose Escalation (Part A) (Including NSCLC 
PD Cohorts) and Subcutaneous Dose (Part A1)
Approximately 
 participants are expected to be treated during the BMS-986258 Monotherapy 
Dose Escalation (Part A) of the study guided by BLRM for the primary objective. Additionally, 
approximately 
 participants are expected to be treated in the  NSCLC PD cohorts in Part A
 
per dose level in order to have at least 
 evaluable participants with baseline and on treatment 
biopsies considered as adequate tissue sample); and approximately 
 participants are planned to 
be treated in SC cohort(s) (Part A1). Therefore, a total of 
participants are expected to be treated 
in Parts A and A1. Refer to Section 10 for additional details. 
In dose escalation, each participant will be administered IV doses of BMS-986258 in planned dose 
levels of 8, 24, 72, 200, 480, 800, 1200, 1600, and 2400 mg Q4W twice per cycle, for up to 12 
cycles (96 weeks) of study therapy. 
 monotherapy dose cohorts may be 
 in the escalation phase 
based upon the BLRM analysis and clinical evaluation of all available safety and PK/PD data.
Participants enrolled in the NSCLC PD cohorts will receive a dose level that has already been 
cleared for safety within the corresponding dose escalation cohort.
Prior to declaring the MTD, and in consultation with investigators, the Sponsor has the option to 
expand any dose level previously established to be tolerable in order to obtain 
 
 to those defined in the protocol. Planned dose 
levels may be modified, or 
 added, based upon the BLRM analysis and 
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clinical evaluation of all available safety and PK/PD data. Once the tolerability (during the DLT 
evaluation) of a dose level has been established, additional participants may be added at that dose 
level to better characterize the safety, PK, and PD profiles.
The dose escalation phase of the study will evaluate the safety and tolerability of BMS-986258,
administered as monotherapy based on DLTs, using a BLRM (for the BMS-986258 Monotherapy
Dose Escalation [Part A]). During the Monotherapy Dose Escalation phase, approximately 
3 participants will be treated at each dose level. Cohort tolerability assessment and subsequent 
dose recommendation will occur when at least 2 evaluable participants within a cohort have 
completed the 4-week DLT period. Any toxicities that occur beyond the DLT period will be 
considered in making dose level decisions and/or dose level modifications. Additional information 
on DLTs can be found in Section 7.1.1.
If the potential DLT occurring in the third evaluable participant regarding any specific dose level 
does not influence the dose recommendation by BLRM, the next dose level may proceed without 
waiting for the third participant to complete the corresponding DLT observation period, after 
discussion and agreement between the Sponsor and investigators. Continuous reassessment of dose 
recommendation, by BLRM in the BMS-986258 Monotherapy Escalation (Part A) will be carried 
out for each dose level. Planned dose levels for dose escalation are provided in Section 5.5.
Approximately up to 
 participants are expected to be treated in the BMS-986258 monotherapy 
SC cohort(s) (Part A1). Refer to Section 10 for additional details. For each participant in Part A1, 
BMS-986258 will be co-administered SC with rHuPH20 for the first dose in Cycle 1. All 
subsequent doses of BMS-986258 will be administered as monotherapy IV, Q4W twice per cycle, 
for up to twelve 8-week cycles (96 weeks). Alternatively, participants in cohort A1 who have 
received SC BMS-986258 on Cycle 1 Day 1 will be offered the option to receive subsequent IV 
combination therapy of BMS-986258 with nivolumab (480 mg) at the highest dose of BMS-
986258 that has been shown to be safe and tolerable in the dose escalation (Part B). Treatment will 
be given Q4W twice per cycle, for up to twelve 8-week cycles (96 weeks). 
The dose selected for Part A1 will not exceed a dose determined to be safe and tolerable in Part A.
5.1.3.2
BMS-986258 in Combination with Nivolumab Dose Escalation and 
NSCLC PD Cohorts (Part B)
Approximately
participants are expected to be treated during the BMS-986258 combination 
with Nivolumab Dose Escalation (Part B) of the study guided by BLRM-copula for the primary 
objective. Additionally, approximately 
 participants are expected to be treated in the NSCLC 
PD cohorts in Part B, with approximately up to 
 participants per cohort, in order to obtain 
 
participants with evaluable biopsies per cohort. Refer to Section 10 for additional details.
Therefore, a total of 
 participants are expected to be treated in Part B.
Based on preliminary safety, PK, and PD from Part A, the starting dose of BMS-986258 in Part B 
may be higher than the starting dose from Part A. Each dose level in Part B, including the starting 
dose, will only be opened after at least  higher dose levels in Part A have demonstrated tolerability 
during the DLT observation period. 
 
. Each participant may be administered IV doses of 
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BMS-986258 in planned dose levels of 8, 24, 72, 200, 480, 800, 1200 and 1600 mg combined with
480 mg of nivolumab Q4W (twice per cycle), for up to twelve 8-week cycles of study therapy 
(96 weeks) unless criteria for study drug discontinuation are met earlier (see Protocol Section 8).
 during escalation based 
upon the BLRM analysis and clinical evaluation of all available safety and PK/PD data. 
Participants enrolled in the PD cohorts will receive a dose level that has already been cleared for 
safety within the corresponding dose escalation cohort. Upon completion of study therapy, all 
participants will enter the Safety Follow-up period.
The combination dose escalation phase (Part B) of the study will evaluate the safety and tolerability 
of BMS-986258, given in combination with nivolumab, based on DLTs, using a BLRM-copula. 
During the combination dose escalation phase, approximately  participants will be treated at each 
dose level. Cohort tolerability assessment and subsequent dose recommendation will occur when 
at least  evaluable participants within a cohort have completed a 4-week DLT period. Any 
toxicities that occur beyond the DLT period will be considered in making dose level decisions 
and/or dose level modifications. Additional information on DLTs can be found in Section 7.1.1.
If the potential DLT occurring in the third evaluable participant regarding a/any specific dose level 
does not influence the dose recommendation the BLRM-copula, the next dose level may proceed 
without waiting for the third participant to complete the corresponding DLT observation period, 
after discussion and agreement between the Sponsor and investigators. Continuous re-assessment 
of dose recommendation, BLRM-copula in the Safety Evaluation of Combination Doses of 
BMS-986258 with Nivolumab (Part B), will be carried out for each dose level. Planned dose levels 
for dose escalation are provided in Section 5.5. 
Planned dose levels may be modified, or 
 dose levels added, based upon the 
BLRM-copula analysis for combination and clinical evaluation of all available safety and PK/PD 
data. Once the tolerability (during the DLT evaluation) of a dose level has been established, 
additional participants may be added at that dose level to better characterize the safety, PK, and 
PD profiles.
5.1.3.3
BMS-986258 in Combination with Nivolumab Expansion Cohorts
(Part C)
The purpose of the BMS-986258 cohort expansion is to gather preliminary efficacy information 
in specific patient populations regarding BMS-986258 in combination with nivolumab.
In the BMS-986258 cohort expansion in combination (Part C), the preliminary efficacy of 
BMS-986258 in combination with nivolumab may be explored in selected populations with RCC, 
NSCLC, CRC, TNBC, and SCCHN. Please refer to Section 5.4.7 and Section 6 Study Population 
for additional details.
Treatment in Part C will be initiated when the RP2D, MTD, or MAAD for BMS-986258 in 
combination with nivolumab has been determined based on evaluation of the totality of available 
clinical safety, PK, PD, and modeling data from Parts A, A1, and B, including information from 
the NSCLC PD cohorts. The dose(s) selected for Part C will not exceed the MTD or MAAD 
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determined in Parts A and B. Part C may begin while Part B continues to 
 
. 
Participants with stable disease (SD), partial response (PR), or complete response (CR) at the end 
of a given cycle will continue to the next treatment cycle. Participants will be allowed to continue 
study treatment until the first occurrence of any of the following:

Confirmed progressive disease defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 (Appendix 5) unless participants meet criteria for treatment beyond 
progression (Section 8.1.3).

Clinical deterioration suggesting that no further benefit from treatment is likely.

Intolerability to therapy.

Participant meets criteria for discontinuation of study treatment as shown in Section 8.1.

Completion of the maximum number of cycles (12 cycles).
Continuous evaluation of toxicity events in the BMS-986258 cohort expansions will be performed 
throughout enrollment for all expansion cohorts. If, at any time, the aggregate rate of 
treatment-related toxicities meeting DLT criteria exceeds 
 across all participants treated in 
cohort expansions, the findings will be discussed and further enrollment will be interrupted. 
Depending on the nature and grade of the toxicity, and after assessing the benefit/risk ratio, a new 
dose for all cohorts may be initiated at a previously tested lower dose level or at a dose level 
 to previously tested lower dose levels.
5.1.4
Follow-up
5.1.4.1
Safety Follow-up Period
Upon completion of study therapy (or up to a maximum of 96 weeks, if applicable), or once the 
participant has received the last administration of any study treatment (ie, at EOT), all 
participants will enter a safety follow-up period.
For participants who complete all scheduled cycles of therapy, the EOT visit will be the same visit 
as the last scheduled and completed on-treatment visit and will be the start of the safety follow-up 
period. For participants who do not complete all scheduled cycles of therapy, the EOT visit will 
be the most recent on-treatment visit (with all available safety and response data) and will not need 
to be repeated. Accordingly, for these participants, this visit will be considered the start of the 
safety follow-up period.
After the EOT visit, all participants will be evaluated for any new AEs for at least 100 days after 
the last dose of study treatment. 
 
 All participants 
will be required to complete the 3 clinical safety follow-up visits, regardless of whether new 
anti-cancer therapy is started, except those participants who withdraw consent for study 
participation.
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5.1.4.2
Survival Follow-up
In parallel with the safety follow-up period, all participants will continue on the survival follow-
up period. Participants will be followed up for survival at each Safety Follow-up visit and then by 
telephone 
 
. The duration of this follow-up is up to 
 
following the last dose of study treatment, although a longer follow-up period could be considered 
in selected cases if an efficacy signal is apparent. Tumor assessment scans, for participants who 
have ongoing clinical benefit beyond the 
 period following the end of treatment, may 
continue to be collected as part of standard-of-care treatment upon agreement between the Sponsor 
and Investigator. Subsequent therapies will also be recorded in this survival follow-up period. 
5.1.5
Data Monitoring Committee and Other External Committees
BMS has in place a multi-layered process for ensuring patient safety through close collaboration 
of study site investigators, the BMS study team, and the BMS Global Pharmacovigilance and 
Epidemiology (GPVE)-led Medical Surveillance Team (MST). This collaborative process 
constitutes the Data Safety Monitoring Plan for the study as detailed below:
Study safety is evaluated continuously by representatives of BMS GPVE, who operate 
independently from the clinical team and monitor safety across all BMS protocols. AEs are 
monitored continuously by GPVE. Signal detection is performed at least monthly and ad hoc 
throughout the study by the MST composed, at a minimum, of the GPVE medical safety 
assessment physician (Chairman of the MST) and GPVE single case review physician, the study 
medical monitor(s), the study biostatistician, and epidemiologist. The MST monitors actual or
potential issues related to patient safety that could result in a significant change in the medical 
benefit/risk balance associated with the use of study drugs. Furthermore, investigators will be kept 
updated of important safety information, such as DLTs, during teleconferences between 
investigators and the BMS clinical team that will be held at least every 2 weeks during dose 
escalation and at least monthly during cohort expansion. If appropriate, select safety issues may 
be escalated to a senior level, multidisciplinary, BMS-wide Medical Review Group for further 
evaluation and action.
To support safety oversight, BMS has established ongoing processes for collection, review, 
analysis, and submission of individual AE reports and their aggregate analyses. Because this is an 
open-label study, the BMS medical monitor and the investigators will have access to all data 
necessary for safety evaluation.
All participants in this study represent individuals with high unmet medical need, as the prognosis 
for advanced/metastatic solid tumors is generally very poor.
BMS has elected not to use a Data Monitoring Committee for this study. In addition to the 
comprehensive safety-monitoring plan outlined above, the following key points were considered 
for this decision:

This is an open-label study.
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
The eligibility criteria exclude participants with disease characteristics that could predispose 
to higher risk of morbidity.

Exclusion of participants with known autoimmunity also applies as they could be at risk for 
exacerbation of their condition by the administration of therapies that relieve immune 
suppression such as BMS-986258 and nivolumab.

Participants will be observed frequently for clinical evaluation and blood counts during dose 
escalation.

Well-defined discontinuation criteria are established in the protocol for individual participants
for both safety and treatment futility with clear criteria for treatment discontinuation, dose 
delay, and toxicity management.

For the combination therapy with nivolumab, management algorithms for immune-related 
events are well established based on the clinical experiences from the over 23,500 subjects 
who were exposed to nivolumab as either monotherapy or in combination with other agents, 
in the past as well as in ongoing studies.
5.2
Number of Participants
The approximate number of participants will be up to 
 as shown below.
Part A Monotherapy Escalation: The total sample size is up to approximately 
 participants
including 
 to assess the MTD/MAAD and an additional 
 in  NSCLC PD cohorts.
Part A1: SC Dose: The total sample size is up to approximately 
 participants to evaluate up to 
dose levels.
Part B Combination Escalation: The total sample size is up to approximately 
 participants, 
including 
participants to assess the MTD/MAAD in combination and 
 in 
NSCLC PD 
cohorts.
Part C Cohort Expansion: Approximately up to 
 participants will be treated in each of the 5 
tumor cohorts (up to a total of 
 across tumors). 
5.3
End of Study Definition
The start of the study is defined as the first visit for the first participant screened. Similarly, the 
end of the study is defined as the last visit or scheduled procedure shown in the Schedule of 
Activities (
) for the last participant. Primary study completion is defined as the final 
date on which data for the primary endpoint are expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
BMS-986258 will be evaluated in participants with RCC, CRC, NSCLC, SCCHN, and TNBC. 
These indications were chosen based on prevalence of TIM-3 expression on immune cells in the 
tumor microenvironment (internal data at BMS).
 
 
 
. TIM-3 expression marks exhausted T 
cells, therefore it is expected that TIM-3 blockade will promote T-cell activation, proliferation, 
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effector function, and survival. TIM-3 expression in tumor samples will be assessed 
retrospectively in this study. 
The study design includes the following:

Pre-Screening for 
 (Part A and B NSCLC PD cohorts 
only) 

 Screening period

Treatment period of up to twelve 8-week cycles, totaling 96 weeks

Dose escalation phases in monotherapy and combination with nivolumab

Cohort expansion phase

Safety follow-up period of 100 days

Survival follow-up period of 
The rationale for the individual elements of the study design is given below.
5.4.1
Rationale for the Monotherapy Dose Escalation (Part A)
BMS-986258 has never been tested in humans; however, the experiments described above suggest 
a role for BMS-986258 as monotherapy in advanced solid tumors. This study will evaluate the 
safety profile, tolerability, preliminary efficacy, PK, and PD of IV doses of BMS-986258 
administered Q4W, and in combination with nivolumab (Q4W) in participants with select 
advanced solid tumors. Part A will provide data for BMS-986258 as monotherapy that may be 
used in future studies in association with drugs other than nivolumab.
5.4.2
Rationale for Subcutaneous Administration of BMS-986258 (Part A1)
rHuPH20 is a recombinant form of hyaluronidase, a human enzyme that degrades hyaluronan, an 
extracellular matrix component that poses a barrier to large injection volume and fluid flow at the 
SC injection site, therefore, decreasing the viscosity of SC extracellular matrix, and enabling a 
rapid delivery of large volume of study drug. It improves the SC absorption rate, thus it has the 
potential to improve bioavailability. 
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rHuPH20 has dose-dependent, usually local, mild, transient and reversible side effects. rHuPH20 
has a local half-life < 30 minutes and systemic half-life < 5 minutes. Additional details are provided 
in version 08 of the rHuPH20 IB.38
Part A1 will be conducted to obtain preliminary data on the PK profile of BMS-986258 when 
administered SC combined with rHuPH20 in comparison to IV administered BMS-986258. This 
SC cohort will initiate after IV dose(s) and schedule(s) have been shown to be safe in Part A.
SC administration has the potential to reduce infusion time and provide greater convenience and 
comfort for oncology patients. Co-administration of rHuPH20 (a tissue permeability enhancer) 
may further enable to overcome barriers of SC drug delivery especially for large mAbs with 
regards to time and volume to be administered. As of 15-Nov-2019, rHuPH20 has been 
administered to 1592 participants in 30 clinical studies conducted under the US rHuPH20 IND. In 
these studies, individual doses have ranged from 15 to 96,000 U rHuPH20. Across all studies, SC 
injections of rHuPH20 were generally well tolerated in healthy subjects, dehydrated pediatric 
subjects, hospice and palliative care subjects, subjects with type 1 and 2 diabetes, and subjects 
with RA. Subcutaneous injections of rHuPH20 alone or in combination with lactated Ringer’s, 
normal saline, co-injected drugs (morphine, ceftriaxone, insulin, and insulin analogs), or biologic 
products (IgG and adalimumab) have been well tolerated in all clinical trials. Adverse events were 
generally mild, transient injection site reactions, including erythema, pain, bruising, pruritus, 
burning, tenderness, edema, induration, irritation, paresthesia, numbness, and rash. Moderate 
injection site reactions, which have occurred less frequently, include burning, erythema, pain, and 
numbness. Mild-to-moderate headache was also commonly reported. Adverse events in these trials 
have otherwise generally reflected the adverse reaction profiles of the co-administered drug or 
have been associated with the rapid introduction of a relatively large volume of fluid in the SC 
space. 
A large safety database exists for approved products coformulated with rHuPH20 SC is available, 
including Herceptin®SC, HYQVIA®, and RITUXAN HYCELA™/MabThera® SC/Rituxan®.39
Public data presented to the FDA to support coadministration of rituximab (1400 mg and 1600 
mg) and rHuPH20, summarizing data from randomized PK bridging trials in patients with 
follicular lymphoma, CLL, or DLBCL (SparkThera, SABRINA, SAWYER, MabEase, PrefMab) 
show: (1) comparable Ctrough and overall exposure; (2) comparable safety, aside from 
administration site reactions; and (3) comparable efficacy (ORR, CRR, PFS, EFS, and OS in 
various studies) for SC versus IV routes. Injection site reactions (discomfort, erythema) were 
increased following SC administration, occurring in 1.9% - 25.9% of subjects; these were 
generally mild and did not limit therapy. Importantly, patient preference and patient-reported 
outcomes were evaluated in a randomized crossover trial (PrefMab) of 743 previously untreated
patients with DLBCL or FL receiving R-CHOP, R-CVP, or R-Bendamustine to SC versus IV
administration. Over 80% of patients preferred SC administration, due to
reduced time for 
administration and greater comfort.40
Studies have shown that the BA of mAbs following SC administration approximates 70% (50% to 
80%), with lower Cmax and a delayed time of maximum observed concentration (Tmax) compared 
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to IV. The doses evaluated in these studies ranged from 2 to 1400 mg administered with or without 
rHuPH20.38,41,42,43 Drugs administered with rHuPH20 provide an added advantage of faster Tmax 
as compared to when administered without rHuPh20. The PK of BMS-986258 is expected to 
follow a similar profile as other IgG mAbs and hence the BA is expected to be approximately 70% 
in the dose range planned in Part A when administered SC.
Overall, these data suggest that SC administration of BMS-986258 with rHuPH20, at a dose 
previously shown to be safe intravenously, should be feasible and tolerable. 
 
 
 
 
 
For each participant in Part A1, 1200 mg of BMS-986258 will be co-administered with rHuPH20
SC for the first dose in Cycle 1. All subsequent doses of BMS-986258 will be administered as 
monotherapy 1200 mg IV, Q4W twice per cycle, for up to twelve 8-week cycles (96 weeks).
Alternatively, participants in cohort A1 who have received SC BMS-986258 on Cycle 1 Day 1 
will be offered the option to receive subsequent IV combination therapy of BMS-986258 with 
nivolumab (480 mg) at the highest dose of BMS-986258 that has been shown to be safe and 
tolerable in the dose escalation (Part B). Treatment will be given Q4W twice per cycle, for up to 
twelve 8-week cycles (96 weeks). The dose selected for Part A1 is based on the safety and 
tolerability observed in Part A. Based on the expected bioavailability of 
 for SC administered 
mAbs, the 1200 mg SC dose is expected to produce exposures similar to IV 800 mg Q4W, which 
has been found to be within the range of linear PK. Dose-dependent increases in soluble TIM-3 
were observed in Part A, and preliminary data suggest that target engagement is suboptimal at 
doses below 800 mg IV Q4W. Thus, given the totality of safety and PK and biomarker 
characteristics of BMS-986258 IV, 1200 mg SC Q4W is considered as potentially therapeutic, and 
therefore was chosen as starting dose in Part A1. Additional cohorts at higher doses may be tested 
depending on the safety and PK data of the dose at 1200 mg level. 
5.4.3
Rationale for Dose Escalation Phase Design
The BLRM with an overdose control principle escalation was selected as an appropriate design for 
this study. It offers more accuracy and efficiency in determining the true MTD compared to 
rule-based methods (such as 3 + 3 design) by incorporating external information from preclinical 
studies as well as historical clinical trials. The EWOC principle limits the risk of exposing 
participants in the next cohort to an unsafe or toxic dose. Hence, it ensures that safety is not 
compromised during dose escalation. Simulation results demonstrate that BLRM allows fast 
escalation when the expected toxicity is very low and with participants treated at sub-therapeutic 
doses, which is attributed to the adaptive Bayesian learning from previous doses. In addition, 
BLRM has greater applicability to the combination therapy setting compared to other model-based 
methods. After completing the monotherapy phases (Part A), the drug-associated dose-toxicity 
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profiles are characterized and incorporated as prior knowledge into the drug combination phase of 
the study (Part B) or used in future studies.
5.4.5
Rationale for the Combination of BMS-986258 with Nivolumab
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA-4, inducible costimulator (ICOS), and B and T-lymphocyte attenuator (BTLA).45 PD-1 
signaling has been shown to inhibit CD28-mediated upregulation of interleukin(IL)-2, IL-10, IL-
13, IFN-γ, and Bcl-xL. PD-1 expression has also been noted to inhibit T-cell activation and 
expansion of previously activated cells. Evidence for a negative regulatory role of PD-1 comes 
from studies of PD-1 deficient mice, which develop a variety of autoimmune phenotypes.46 These 
results suggest that PD-1 blockade has the potential to activate anti-self T-cell responses, but these 
responses are variable and dependent upon various host genetic factors. Thus, PD-1 deficiency or 
inhibition is not accompanied by a universal loss of tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (half-maximal effective
concentration [EC50] 0.39-2.62 nM) and inhibits the binding of PD-1 to its ligands PD-L1 and 
PD-L2 (IC50 1 nM). Nivolumab binds specifically to PD-1 and not to related members of the 
CD28 family such as CD28, ICOS, CTLA-4, and BTLA. Blockade of the PD-1 pathway by 
nivolumab results in a reproducible enhancement of both proliferation and IFN-γ release in the 
MLR. Using a CMV re-stimulation assay with human PBMC, the effect of nivolumab on antigen-
specific recall response indicates that nivolumab augmented IFN-γ secretion from CMV specific 
memory T cells in a dose-dependent manner versus isotype-matched control. In vivo blockade of 
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PD-1 by a murine analog of nivolumab enhances the anti-tumor immune response and results in 
tumor rejection in several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).47
The power of combining immune-oncology drugs to broaden responses has been demonstrated for 
metastatic melanoma48 and for RCC.9 Given that TIM-3 is frequently co-expressed with PD-1, 
and that patients that had the highest co-expression of PD-1 and TIM-3 were generally those with 
the highest frequencies of PD-1+ and TIM-3+ CD8 T cells, the combination of BMS-986258 and 
nivolumab may result in stronger clinical activity compared to either agent. In fact, in an evaluation 
of antitumor activity in staged CT26 syngeneic CRC model of treatment with anti-mouse TIM-3 
antibodies, both anti-TIM-3 and anti-PD-1, while neither surrogate antibody alone demonstrated 
efficacy, the combination of anti-TIM-3 and anti-PD-1 antibodies showed a greater effect in 
reducing median tumor volume than either antibody alone. In a human Th1 assay, BMS-986258 
was tested with nivolumab in co-culture using irradiated CHO-OKT3 cells co-expressing PD-L1 
(CHO-OKT3-PD-L1). While both PD-1 and anti-TIM-3 antibodies promoted Th1 cell 
proliferation as single agents, co-blockade of TIM-3 and PD-1 showed an additive effect. 
Prior experience with the combination of nivolumab and ipilimumab and the pre-clinical data 
utilizing the combination of BMS-986258 and nivolumab support the investigation of this 
combination in the clinic.
5.4.6
Rationale for 2-Year Duration of Treatment
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long-term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 participants with NSCLC), specified a maximum treatment duration of 2 years. 
Among 16 participants with NSCLC who discontinued nivolumab after completing 2 years of 
treatment, 12 participants were alive > 5 years and remained progression-free without any 
subsequent therapy. In the CA209003 NSCLC cohort, the OS curve begins to plateau after 2 years, 
with an OS rate of 25% at 2 years and 18% at 3 years.49These survival outcomes are similar to 
Phase 3 studies in previously treated NSCLC, in which nivolumab treatment was continued until 
progression or unacceptable toxicity (2-year OS rates of 23% and 29%, and 3-year OS rates of 
16% to 18% for squamous and non-squamous NSCLC, respectively).50
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
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progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached versus 10.3 months, respectively; hazard ratio (HR) 
= 0.42 (95% confidence interval [CI], 0.25 to 0.71). With a median follow-up of 14.9 months post-
randomization, there also was a trend for patients on continued treatment to live longer (OS HR = 
0.63 [95% CI: 0.33, 1.20]). Of note, the PFS curves in both groups plateau approximately 1 year 
after randomization (ie, 2 years after treatment initiation), suggesting that there may be minimal 
benefit in extending treatment beyond a total of 2 years.51
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond 2 years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer-term treatment. Therefore, in 
study CA031002, treatment with BMS-986258 and nivolumab will be administered for up to 2 
years. Participants may receive a total of 12 cycles, which corresponds to approximately 96 weeks. 
5.4.7
Rationale for Tumor Selection for Expansion (Part C)
Five tumor types were chosen for the study. The following specific populations may be chosen for 
Part C: 

RCC participants who received and progressed on or after anti-PD-1 therapy as monotherapy 
or in combination with other I-O agents)

MSI-H CRC participants who received and progressed on or after-anti-PD-1 therapy, and MSS 
CRC participants

NSCLC participants who received and progressed on or after-anti-PD-1 therapy

SCCHN participants who received and progressed on or after anti-PD-1 therapy 

Recurrent or metastatic TNBC participants
The precise indications that will be evaluated in these tumor types were defined based on current 
results (or lack of) with immune-oncology agents, but also on the premise that TIM-3 and PD-1 
are frequently co-expressed and TIM-3 may arise as a mechanism of resistance for anti-PD-1 
therapy.
Given its inherent immunogenic characteristics, RCC was among the first tumor types to be 
studied in the context of immunotherapy. High-dose IL-2 was approved in 1992 for the treatment 
of RCC and remained an important treatment option for 2 decades.52 More recent discoveries of 
molecular and immunological alterations led to the approval of nivolumab for previously treated 
advanced RCC, based on an ORR of 25% in comparison with 5% for everolimus.53 Recently 
published results demonstrated response rates of around 40% with the combination of nivolumab 
and ipilimumab for patients with metastatic RCC.51 Progress is being made, but despite recent 
advances, most patients with advanced RCC will succumb to their disease.
The current standard treatment for patients with metastatic CRC is fluorouracil-based 
chemotherapy regimens combined with agents targeting angiogenesis or epidermal growth factor 
receptor (EGFR).54 Based on results from the Phase 2 CheckMate-142 trial, nivolumab was 
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approved for the treatment of patients with MSI-H or mismatch repair-deficient (MMR-D)
metastatic CRC55 but MSI-H patients correspond to 5% of the patient population with metastatic 
CRC. MSS colon cancers, which make up the majority of the tumors, do not respond to anti-PD-
1 monotherapy. TIM-3 is expressed in the immune infiltrate in CRC; therefore, BMS-986258 may 
be active in this indication.
Lung cancer is the leading cause of cancer death in the US. In 2017, an estimated 222,510 new 
cases are expected to be diagnosed, and 155,870 deaths are estimated to occur because of the 
disease, making it the leading cause of death due to cancer.56 Most lung cancers (∼80%) are 
NSCLC57; of these patients, more than 65% present with locally advanced or metastatic disease.58
Patients with metastatic NSCLC have a median survival of approximately 10 months and a 5-year 
survival rate of less than 5%.54 Treatment options are pembrolizumab with chemotherapy in first 
line, chemotherapy-based, and anaplastic lymphoma kinase (ALK) and EGFR inhibitors for 
patients that carry these mutations. Nivolumab was approved for the management of previously 
treated advanced squamous and non-squamous NSCLC after there was demonstrable survival 
difference compared to chemotherapy.59 TIM-3 has been demonstrated to be upregulated in 
patients that develop secondary resistance to anti-PD-1 therapy, therefore participants in this 
situation may benefit from treatment with BMS-986258.
The incidence and primary site of head and neck cancers present large geographic variability, 
likely caused by the ethnic and genetic differences among populations, but also related to 
differences in the prevalence of risk factors like tobacco and alcohol consumption. Human 
papillomavirus (HPV) infection plays an increasingly prominent role as a causative agent for head 
and neck cancer. HPV-associated head and neck cancers occur primarily in the oropharynx (tonsils 
and base of tongue), account for the younger age of patients with oropharyngeal squamous cell 
carcinoma and define a subset of patients with improved treatment outcome. However, the use of 
HPV status in clinical decision making remains investigational at this time, and treatment is the 
same as for patients without an HPV-associated tumor.60,61,62,63,64,65,66 Radiation and platinum-
based chemotherapy remain the backbone of treatment for advanced cases. Nivolumab was 
approved for recurrent or metastatic SCCHN based on increased OS when compared to standard 
treatment.67 The combination of BMS-986258 and nivolumab may be able to rescue patients that 
progress after anti-PD-1 therapy.
TNBCs are usually more aggressive and harder to treat than hormone receptor-positive tumors; 
they are associated with a higher risk of early relapse and metastasis after surgery, chemotherapy,
and/or radiotherapy.68 The lack of estrogen receptor, progesterone receptor, and human EGFR 2 
expression precludes the use of targeted therapies in advanced stages, and the only approved 
systemic treatment option is chemotherapy with or without bevacizumab. 69 In patients with 
advanced TNBC, responses to chemotherapy occur but are often of short duration and prognosis 
is poor. No I-O agent is approved for TNBC. However, some findings support the investigation: 
the elevated numbers of TAM in breast cancer and its negative association to clinical evolution70; 
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TILs work as a prognostic factor for disease-free survival and OS in TNBC patients71; and data in 
mouse models that suggest that major TIL populations in breast tumors express TIM-3.72
5.4.8
Rationale for Treatment Beyond Progression
Immunotherapeutic agents produce atypical clinical response patterns that are not usually observed 
in conventional chemotherapy. Accumulating clinical evidence indicates some participants treated 
with immune system stimulating agents may develop disease progression by the conventional 
response criteria before demonstrating clinical objective responses and/or SD.
Two distinct non-conventional patterns have been reported: 1) a reduction in target tumor burden 
despite the appearance of new lesion(s), and 2) a transient increase in target tumor burden in an 
initial phase, followed by subsequent tumor shrinkage.
This phenomenon was observed in the Phase 2 study of nivolumab, CA209003 in solid tumor 
patients. Two hypotheses explain this phenomenon. First, enhanced inflammation within tumors 
could lead to an increase in tumor size, which would appear as enlarged index lesions and as newly 
visible small non-index lesions. Over time, both the malignant and inflammatory portions of the 
mass may then decrease leading to overt signs of clinical improvement. Alternatively, in some 
individuals, the kinetics of tumor growth may initially outpace anti-tumor immune activity. With 
sufficient time, the anti-tumor activity will dominate and become clinically apparent. Therefore, it 
is important to avoid premature discontinuation of the study drug that might induce a non-
conventional response pattern in some patients.
5.5
Justification for Dose
5.5.1
Rationale for BMS-986258 Starting Dose
A flat dose of 8 mg 
 IV once Q4W was selected to render possible 
therapeutic benefit to patients while maintaining adequate safety. At the 
 Q4W starting 
dose, the anticipated steady-state trough concentration (Cminss) of 0.90 μg/mL approximates the 
90% maximal effective concentration (EC90) determined from in vitro TIL function assay to 
ensure adequate target coverage for possible therapeutic effects to patients. In addition, the starting 
dose is 
 the MRSD
 based on a 
 HNSTD/NOAEL and the 
projected human exposures (AUCs) at 
 (AUC = 
) are 
 than 
the exposures observed in cynomolgus monkeys at the HNSTD/NOAEL (AUC = 
). Furthermore, BMS-986258 is a blocking antibody with no Fc mediated 
effector function with no in vitro human PBMC activation or cytokine release, suggesting very 
low potential for adverse PBMC activation or cytokine release in humans. 
5.5.2
Rationale for Dose Selection and Dosing Schedule
5.5.2.1
BMS-986258
In the Monotherapy Dose Escalation (Part A), SC Monotherapy (Part A1), Combination with 
Nivolumab Dose Escalation (Part B), and the Cohort Expansion - Combination (Part C), 
BMS-986258 will be administered Q4W. This dosing frequency is supported by the projected 
human T-HALF for BMS-986258 of 
. In addition, this dosing regimen complements the 
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Q4W schedule of nivolumab, planned for Part B and C, thereby simplifying study logistics for 
both participants and investigators. Doses up to 
 have been tested in a definitive 
(GLP-compliant) pre-clinical 1-month IV toxicity study with good tolerance. Therefore, proposed 
doses of BMS-986258 to be tested in this study will be 8, 24, 72, 200, 480, 800, 1200, 1600, and 
2400 mg IV Q4W as monotherapy and 8, 24, 72, 200, 480, 800, 1200, and 1600 mg IV Q4W in 
combination with nivolumab 480 mg IV Q4W.
5.5.2.2
Nivolumab
The nivolumab dose of 480 mg Q4W was selected for this study based on clinical data and 
modeling and simulation approaches using population PK (PPK) and exposure-response (ER) 
analyses examining relationships between nivolumab exposures and efficacy (eg, OS and overall 
response) and safety responses, using data from studies in multiple tumor types (melanoma, 
NSCLC, and RCC) with body weight-normalized dosing (mg/kg). A flat dose is expected to reduce 
prescription dosing errors, shorten pharmacy preparation time, and improve ease of administration. 
Extending the dosing interval to 4 weeks provides numerous benefits to patients, as they would 
have increased flexibility between clinical visits. The PPK analyses have shown that exposure to 
nivolumab increased dose proportionally over the dose range of 0.1 mg/kg to 10 mg/kg 
administered Q2W, and no clinically meaningful differences in PK across ethnicities and tumor 
types were observed. Nivolumab clearance and volume of distribution were found to increase as 
body weight increases but less than proportionally with increasing weight, indicating that 
milligram-per-kilogram dosing represents an over-adjustment for the effect of body weight on 
nivolumab PK. 
Using the PPK and ER models, nivolumab exposures and probabilities of efficacy responses and 
risks of AEs were predicted following nivolumab 480 mg Q4W and were comparable to those 
following nivolumab 3 mg/kg Q2W. The overall distributions of average nivolumab steady-state 
exposures were comparable following administration with either nivolumab 3 mg/kg Q2W or 
nivolumab 480 mg Q4W over a wide range of body-weight ranges. Nivolumab 480 mg Q4W is 
predicted to result in approximately 43% greater steady-state peak concentrations (Cmaxss) 
compared to nivolumab 3 mg/kg Q2W; however, these exposures are predicted to be lower than 
the exposure ranges observed at doses up to nivolumab 10 mg/kg Q2W used in the nivolumab 
clinical program. Although the Cmaxss of nivolumab is expected to be greater following 
nivolumab 480 mg Q4W compared to nivolumab 3 mg/kg Q2W, the predicted Cmaxss following 
nivolumab 480 mg Q4W is well below the median Cmaxss achieved following administration of 
nivolumab 10 mg/kg Q2W, a safe and tolerable dose level. 
Exposure-safety analysis demonstrated that the exposure margins for safety are maintained 
following nivolumab 480 mg Q4W, and the predicted risks of discontinuations due to AEs or 
death, AE Grade 3+, and IMAEs Grade 2+ are predicted to be similar following nivolumab 480 
mg Q4W relative to nivolumab 3 mg/kg Q2W across tumor types. Safety analyses using available 
data following nivolumab 3 mg/kg Q2W and 10 mg/kg Q2W administration indicated that there 
were no differences in AE profiles across body-weight groups. Finally, initial evidence 
demonstrates that, following administration of nivolumab 480 mg Q4W, nivolumab has been well 
tolerated.
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Nivolumab 480 mg Q4W is predicted to have approximately 16% lower Cminss compared to 
nivolumab 3 mg/kg Q2W. While these exposures are predicted to be lower, they are on the flat 
part of the ER curves and are not predicted to affect efficacy. Exposure-efficacy analyses of 
multiple PK measures and efficacy endpoints (eg, OS and overall response) indicated that, 
following administration of nivolumab 480 mg Q4W, efficacy is predicted to be similar to that 
following administration of nivolumab 3 mg/kg Q2W across multiple tumor types. Based on these 
data, nivolumab 480 mg Q4W is expected to have similar efficacy and safety profiles to nivolumab 
240 mg Q2W or nivolumab 3 mg/kg Q2W. 
Of note, as an immunoglobulin G4 mAb, nivolumab does not interact directly with cytochrome 
P450 (CYP) enzyme systems. Systemic cytokine modulation data indicated that there were no 
meaningful changes in cytokines known to have indirect effects on CYP enzymes across all dose 
levels of nivolumab (0.3, 2, and 10 mg/kg) during the course of treatment. Therefore, it is unlikely 
that nivolumab administered at 480 mg Q4W will affect the systemic exposures of BMS-986258.
5.5.2.3
Rationale for 30-Minute Dose Administration of Nivolumab
Long infusion times place a burden on participants and treatment centers. Using shorter infusion 
times of 30-minute duration in participants will diminish the burden provided there is no change 
in safety profile. Nivolumab is currently approved for IV administration over 60 minutes. Clinical 
studies show that nivolumab has been administered safely over 60 minutes at doses ranging up to 
10 mg/kg over a long treatment duration. For example, in Study CA209010 (a Phase 2, 
randomized, double-blinded, dose-ranging study of nivolumab in participants with 
advanced/metastatic, clear cell RCC, N = 167), a dose association was observed for infusion site 
reactions and hypersensitivity reactions (5.1% at 0.3 mg/kg, 3.7% at 2 mg/kg, and 18.5% at 
10 mg/kg).68 All the events were Grade 1/2 and were manageable.
The impact of infusion time on nivolumab safety was assessed in a substudy conducted as part of 
an ongoing community based trial (ie, CheckMate 153) in patients with previously treated 
advanced or metastatic NSCLC.73 In the substudy, 322 patients received nivolumab 3 mg/kg IV 
Q2W as a 30-minute infusion, and 355 patients received the same nivolumab regimen as a 
60-minute infusion.
Overall, the safety profiles between the 30- and 60-minute infusion groups were similar. Any grade 
treatment-related AEs were reported in 53% and 51% of patients given 30- or 60-minute infusions, 
respectively. Grade 3 to 4 treatment-related AEs were reported in 12% of patients in each infusion 
group. Among select AEs of any cause, Grade 3 to 4 events were comparable between infusion 
groups in the pulmonary (3% and 2%), hepatic (2% and 3%), and gastrointestinal (2% and 2%) 
categories. Hypersensitivity/infusion reactions of any cause were reported in 8 (2%) and 5 (1%) 
patients administered 30- and 60-minute infusions, respectively. The incidence of Grade 3 to 4 
hypersensitivity/infusion reactions was < 1% in each infusion group. Hypersensitivity/infusion 
reactions were managed either through dosing interruptions (8 patients given 30-minute infusions 
and 3 patients given 60-minute infusions), discontinuations (1 patient given a 30-minute infusion 
and 2 patients given 60-minute infusions), or administration of systemic corticosteroids (3 patients 
given 30-minute infusions and 1 patient given a 60-minute infusion). In addition, PPK modelling 
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demonstrated similar predicted Cmax after the first nivolumab dose and at steady state in both 
infusion groups, suggesting that a 30-minute infusion does not pose an increased safety risk due 
to an increase in nivolumab Cmax.
In conclusion, nivolumab can be safely administered as a 30-minute infusion, with a low incidence 
of infusion-related AEs. Given these findings, 30-minute infusion is being implemented across the 
nivolumab development programs, including the FIH study CA031002.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The participant must sign the ICF prior to the performance of any study-related procedures 
that are not considered part of standard of care.
b) The participant must sign the consent for pretreatment and on treatment tumor biopsy 
samples at acceptable clinical risk, as judged by the Investigator. 
2) Type of Participant and Target Disease Characteristics
a) Participants must be at least 18 years old and have histologic confirmation of one of the 5 
tumors described below (metastatic, recurrent, and/or unresectable), with measurable 
disease per RECIST v1.1 (Appendix 5).
b) Eastern Cooperative Oncology Group Performance Status of 0 or 1 (Appendix 6).
c) Participants with controlled brain metastases are eligible. Controlled brain metastases are 
defined as no radiographic progression for at least 4 weeks following radiation and/or 
surgical treatment (or 4 weeks of observation if no intervention is clinically indicated), and 
no longer taking steroids for at least 2 weeks prior to first dose of study treatment, and with 
no new or progressive neurological signs and symptoms.
d) Participants with RCC:
i)
Advanced or metastatic RCC with a clear cell component.
ii) Participants must have received at least 1 but not more than 2 prior anti-angiogenic 
therapy regimens (including but not limited to sunitinib, sorafenib, pazopanib, axitinib, 
tivozanib, and bevacizumab) in the advanced or metastatic setting. Prior cytokine 
therapy (eg, IL-2, IFN-γ), vaccine therapy, or treatment with cytotoxics is allowed.
iii) Participants must have received no more than 3 total prior systemic treatment regimens 
in the advanced or metastatic setting and must have evidence of progression on or after 
the last treatment regimen received and within 6 months prior to study enrollment.
iv) Participants must have received and progressed on or after anti-PD-(L)1 therapy, if 
available, for enrollment. Other I-O agents previously used in association with anti-
PD-(L)1 therapy are allowed.
v) Not applicable per Protocol Revision 04. See inclusion criterion 2, d, iv.
vi) Participants in Part C only must have been resistant to anti-PD-(L)1 therapy. Refer to 
inclusion criteria 2) i) for the definition of anti-PD-(L)1 resistance.
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e) Participants with CRC
i)
Histologically confirmed CRC that is metastatic or recurrent.
ii) Participants with MSS CRC must have received and then progressed on or after, or 
have been intolerant or refractory to, at least 1 standard systemic therapy for metastatic 
and/or unresectable disease (or have progressed within 6 months of adjuvant therapy), 
including oxaliplatin and irinotecan.
Participants must have known microsatellite instability or mismatch repair status. V-
Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, and B-Raf proto-oncogene status, 
if known, should be documented; if unknown, participants must consent to allow their 
submitted archived tumor tissue sample (block or unstained slides) to be tested, in 
addition to the required fresh tumor biopsies.
iii) Participants who have received prior anti-angiogenic therapy (eg, bevacizumab) and/or 
anti-EGFR therapy (eg, cetuximab or panitumumab) are eligible.
iv) Participants with MSI-H or MMR-D status must have received and progressed on or 
after anti-PD-(L)1 therapy, if available, for enrollment.
v) Participants in Part C only, with MSI-H or MMR-D status, must have been resistant to 
anti-PD-(L)1 therapy. Refer to inclusion criteria 2) i) for the definition of anti-PD-(L)1 
resistance.
f)
Participants with NSCLC
i)
Histologically confirmed NSCLC meeting stage criteria for Stage IIIB, Stage IV, or 
recurrent disease.
ii) Participants must have recurrent or progressive disease during or after platinum 
doublet-based chemotherapy for advanced or metastatic disease.
OR 
Must have recurrent or progressive disease within 6 months after completing platinum-
based chemotherapy for local disease.
iii) Status for actionable mutations (eg, EGFR, ALK, ROS1, RET, etc.) must be known 
[when testing is available as per country/region standard of care practices]; participants 
with actionable mutations must have received and progressed on, have been intolerant 
to, or not be a candidate for, standard tyrosine kinase inhibitors [as available per 
country/region standard of care practices].
iv) Participants must have received and progressed on or after anti-PD-(L)1 therapy, if 
available, for enrollment.
v) Participants in Part A and B NSCLC PD cohorts and Part C only must have been 
resistant to anti-PD-(L)1 therapy. Refer to inclusion criteria 2) i) for the definition of 
anti-PD-(L)1 resistance.
g) Participants with SCCHN
i)
Histologically confirmed, recurrent, or metastatic SCCHN (oral cavity, pharynx, 
larynx) and not amenable to local therapy with curative intent.
ii) Participants who progressed on or after, or were intolerant to, a platinum-containing 
regimen.
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iii) Prior curative radiation therapy must have been completed at least 4 weeks prior to first 
study drug administration. Prior focal palliative radiotherapy must have been 
completed at least 2 weeks before study drug administration.
iv) Documentation of p16 is sufficient to determine HPV status of tumor for SCCHN of 
the oropharynx. Note: If results are not available, then a sample (tissue on microscopic 
slides, tissue block, or a fresh tissue biopsy in formalin) should be sent to the central 
laboratory for analysis.
v) Participants must have received and progressed on or after anti-PD-(L)1 therapy, if 
available, for enrollment. 
vi) Participants in Part C only must have been resistant to anti-PD-(L)1 therapy. Refer to 
inclusion criteria 2) i) for the definition of anti-PD-(L)1 resistance.
h) Participants with TNBC
i)
Males and females with histologically confirmed TNBC as defined by American 
Society of Clinical Oncology/College of American Pathologists guidelines74.
ii) Participants must have received and progressed on or after, or have been intolerant or 
refractory to, at least 1 standard chemotherapy regimen containing anthracycline and 
taxane; in addition, the participant must have received at least 1 regimen for the 
treatment of metastatic or locally advanced disease.
i)
Participants with anti-PD-(L)1 resistant RCC, CRC, NSCLC, and SCCHN, participating 
in Part C, Part A NSCLC PD, and Part B NSCLC PD cohorts only.
i)
Participants must have received prior anti-PD-1/PD-L1 therapy and have radiologically 
or clinically documented disease progression or recurring disease on or within 3 months 
following last dose of anti-PD 1/PD-L1 therapy for their advanced (metastatic and/or 
unresectable) cancer and have been considered for all other potentially efficacious 
therapies prior to enrollment.
(1) One intervening systemic therapy is allowed between anti PD-(L)1 therapy and 
enrollment.
(2) Anti-PD-(L)1 therapies may have been received in sequential or combination 
regimens.
(3) Required documentation includes start and stop dates of prior anti-PD-(L)1 therapy 
and a progression date no more than 3 months after the last dose of anti-PD-(L)1 
therapy. 
(4) At screening, the Investigator should document on the electronic case report form 
(eCRF) the progression date and criteria used in determining disease progression 
from prior anti-PD-(L)1 therapy (eg, RECIST v1.1, irRC, irRECIST, and/or 
iRECIST).
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3) Physical and Laboratory Findings
a) Adequate hematologic function for participants as defined by the following:
i)
Neutrophils 1500/L (use of growth factors to achieve this level is not permitted 
within 2 weeks prior to screening laboratories).
ii) Platelets 80 × 103/L (transfusion to achieve this level is not permitted within 
2 weeks prior to screening laboratories).
iii) Hemoglobin 8 g/dL (transfusion to achieve this level is not permitted within 2 weeks 
prior to screening laboratories).
b) Adequate hepatic function
i)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 3 × upper 
limit of normal (ULN).
ii) Total bilirubin 1.5 × ULN (except participants with Gilbert’s syndrome who must 
have normal direct bilirubin).
c) Clinically stable thyroid function per Investigator assessment.
d) Serum creatinine 1.5 × ULN or creatinine clearance (CrCl) 40 mL/min (measured using 
the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) × weight in kg × 0.85
72 × serum creatinine in mg/dL
Male CrCl = (140 - age in years) × weight in kg × 1.00
72 × serum creatinine in mg/dL
e) Ability to comply with treatment, PK and PD sample collection, and required study follow-
up periods.
4) Age and Reproductive Status
a) Males and females ages 18 years, or age of majority, or older at time of consent.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin) within 24 hours prior to the start of study treatment. An extension up to 72 
hours prior to the start of study treatment is permissible in situations where results cannot 
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be obtained within the standard 24-hour window. Additional requirements for pregnancy 
testing during and after study intervention are located in 
 Schedule of Activities.
c) WOCBP must agree to follow instructions for method(s) of contraception (Appendix 4) 
and as described below and included in the ICF. WOCBP are permitted to use hormonal 
contraception methods (as described in Appendix 4).
d) WOCBP who are continuously not heterosexually active are also exempt from 
contraceptive requirements but should still undergo pregnancy testing as described in this 
section.
e) Not applicable per Protocol Amendment 06. Males who are sexually active with WOCBP 
must agree to follow instructions for method(s) of contraception and fetal protection 
(Appendix 4) during BMS-986258 monotherapy or in combination treatment with study 
treatment BMS-986258 and nivolumab, for a total of 90 days post-treatment completion 
(duration of sperm turnover). In addition, male participants must be willing to refrain from 
sperm donation during this time.
f)
Not applicable per Protocol Revision 05. Azoospermic males are exempt from 
contraceptive requirements unless the potential exists for fetal toxicity due to study drug 
being present in seminal fluid, even if the participant has undergone a successful vasectomy 
or if the partner is pregnant.
g) Women who are not of childbearing potential are exempt from contraceptive requirements.
h) Women participants must have documented proof that they are not of childbearing 
potential.
i)
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
j)
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least one of the following conditions applies:
(1) Is not a WOCBP.
OR
(2) Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with low user dependency, as described in Appendix 
4 during the intervention period and for at least 5 months and agrees not to donate 
eggs (ova, oocytes) for the purpose of reproduction for the same time period.
Investigators shall counsel WOCBP on the importance of pregnancy prevention, the implications 
of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of 
study drug to a developing fetus.
6.2
Exclusion Criteria
1) Medical Conditions
a) Women who are pregnant or breastfeeding.
2) Prior/Concomitant Therapy
a) Cytotoxic agents, unless at least 4 weeks have elapsed from last dose of prior anti-cancer 
therapy and initiation of study therapy.
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b) Non-cytotoxic agents, unless at least 4 weeks or 5 half-lives (whichever is shorter) have 
elapsed from the last dose of prior anti-cancer therapy and the initiation of study therapy. 
c) Prior immune therapy treatments, unless at least 4 weeks or 5 half-lives (whichever is 
shorter) have elapsed from the last dose of immune therapy and initiation of study therapy.
d) Prior participation in an anti-TIM-3 clinical study.
e) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 2 
weeks prior to randomization/treatment. Refer to Section 7.7.1 for prohibited therapies.
f)
Prior radiation therapy within 2 weeks prior to first study treatment. Participants must have 
recovered (ie, Grade ≤1 or at baseline) from radiation-related toxicities prior to first study 
treatment.
3) Medical History and Concurrent Diseases
a) Participants with concomitant second malignancies (except adequately treated 
nonmelanomatous skin cancers or in situ bladder, breast, or cervical cancers) are excluded 
unless a complete remission was achieved at least 2 years prior to study entry, and no 
additional therapy is required or anticipated to be required during the study period.
i)
In addition, in Part C, participants with concurrent malignancies that do not require 
treatment and are clinically stable and anticipated to be followed in an active 
surveillance manner for the next 12 months are eligible. Treatment should not be 
required at timing of consent and not be expected to be needed not only for the 
concurrent malignancy, but also for complications caused by it. The Investigator should 
inform the participant that the study treatment is not intended and not expected to be 
considered as treatment for the concurrent malignancy.
b) Participants with other active malignancy requiring concurrent intervention.
c) Prior organ or tissue allograft.
d) Toxicity (except for alopecia) related to prior anti-cancer therapy and/or surgery, unless 
the toxicity is either resolved, returned to baseline or Grade 1, or deemed irreversible.
i)
Any active neuropathy > Grade 2 (National Cancer Institute [NCI] common 
Terminology Criteria for Adverse Events [CTCAE] v4.03)
e) Participants with the following:
i)
Active, known, or suspected autoimmune disease.
(1) Participants with well-controlled asthma and/or mild allergic rhinitis (seasonal 
allergies) are eligible.
(2) Participants with the following disease conditions are also eligible:
(a) Vitiligo.
(b) Type 1 diabetes mellitus on stable conditions under insulin treatment.
(c) Residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement.
(d) Euthyroid participants with a history of Grave’s disease (participants with 
suspected autoimmune thyroid disorders must be negative for thyroglobulin and 
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thyroid peroxidase antibodies and thyroid stimulating Ig prior to the first dose 
of study drug).
(e) Psoriasis not requiring systemic treatment, or conditions not expected to recur 
in the absence of an external trigger are permitted to enroll.
ii) History of life-threatening toxicity related to prior immune therapy (eg, anti-CTLA-4 
or anti-PD-(L)1 treatment or any other antibody or drug specifically targeting T cell 
co-stimulation or immune checkpoint pathways) except those that are unlikely to 
re-occur with standard countermeasures (eg, hormone replacement after adrenal crisis).
iii) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive 
medications within 30 days of treatment assignment. Inhaled or topical steroids, and 
adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted 
in the absence of active autoimmune disease.
iv) Uncontrolled or significant cardiovascular disease including, but not limited, to any of 
the following:
(1) Myocardial infarction or stroke/transient ischemic attack within the past 6 months
(2) Uncontrolled angina within the past 3 months
(3) Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes)
(4) History of other clinically significant heart disease (eg, cardiomyopathy, congestive 
heart failure with New York Heart Association functional classification III to IV 
[Appendix 7])
(5) Cardiovascular disease-related requirement for daily supplemental oxygen therapy
(6) QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation 
> 480 msec, except for right bundle branch block
(7) History of myocarditis, regardless of etiology
v) History of or with active interstitial lung disease
vi) History of chronic hepatitis as evidenced by the following:
(1) Positive test for hepatitis B surface antigen
(2) Positive test for qualitative hepatitis C viral load by polymerase chain reaction 
(PCR)
(3) Participants with positive hepatitis C antibody and negative quantitative hepatitis C 
by PCR are eligible. History of resolved hepatitis A virus infection is not an 
exclusion criterion.
(4) Additional testing or substitute testing per institutional guidelines to rule out 
infection is permitted.
vii)Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal 
therapy 7 days prior to the first dose of study drug (except for viral infections that are 
presumed to be associated with the underlying tumor type required for study entry).
viii)
Human immunodeficiency virus (HIV) or known acquired immunodeficiency 
syndrome:
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(1) For Parts A, A1, and B, known history of testing positive for HIV or known 
acquired immunodeficiency syndrome constitutes an exclusion criterion.
Note: Testing for HIV must be performed at sites where mandated by local 
requirements.
(2) For Part C, HIV infection does not constitute an exclusion criterion if the following 
conditions are satisfied:
(a) Subject is in use of an antiretroviral therapy regimen for > 4 weeks.
(b) HIV viral load is undetectable or below the lower limit of detection as per local 
testing standards.
(c) CD4+ T-cell counts >= 350 cells/mL, up to 4 weeks prior to enrollment.
(d) Subject has no history of AIDS-defining opportunistic infections.
ix) Any major surgery within 4 weeks of the first dose of study drug. Participants must 
have recovered from the effects of major surgery or significant traumatic injury at least 
14 days before the first dose of study drug.
x) Receipt of non-oncology vaccines containing live virus for prevention of infectious 
diseases within 4 weeks prior to first dose of study drug.
(1) The use of inactivated seasonal influenza vaccines (eg, Fluzonewill be permitted 
on study without restriction.
xi) Receipt of packed red blood cells or platelet transfusion within 2 weeks of the first dose 
of study drug unless agreed by the Medical Monitor.
xii)Any known or underlying medical, psychiatric condition, and/or social reason that, in 
the opinion of the Investigator or Sponsor, could make the administration of study drug 
hazardous to the participants or could adversely affect the ability of the participant to 
comply with or tolerate the study.
xiii)
Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic 
infections or 20 days for severe/critical illness prior to Cycle 1 Day 1. 
(1) Acute symptoms must have resolved and based on investigator assessment in 
consultation with the Medical Monitor, there are no sequelae that would place the 
participant at a higher risk of receiving study treatment.
xiv)
Previous SARS-CoV-2 vaccine within 14 days of Cycle 1 Day 1. For vaccines 
requiring more than one dose, the full series (eg, both doses of a two-dose series) should 
be completed prior to Cycle 1 Day 1 when feasible and when a delay in Cycle 1 Day 1
would not put the study participant at risk.
xv) Symptomatic central nervous system (CNS) metastases. Participants are eligible if 
CNS metastases are asymptomatic and do not require immediate treatment or have been 
treated and participants have neurologically returned to baseline (except for residual 
signs or symptoms related to the CNS treatment). In addition, participants must have 
been either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent) for at least 2 weeks prior to treatment assignment. In case 
of past or suspect CNS metastases, imaging performed 
 prior to treatment
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assignment must document radiographic stability of CNS lesions and be performed 
after completion of any CNS-directed therapy.
xvi)
Leptomeningeal metastases.
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components.
b) History of severe hypersensitivity reaction to any mAb.
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances and only in countries where local regulations permit, a participant who has 
been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
Bristol-Myers Squibb (BMS) approval is required).
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria and confirmed prior to Cycle 1 Day 1.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently treated in the study/included in the analysis population. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials publishing requirements, as applicable, and to 
respond to queries from regulatory authorities. Minimal information includes date of consent, 
demography, screen failure details, eligibility criteria, and any serious AEs. If re-enrolled, the 
participant must be reconsented.
6.4.1
Retesting During Screening or Lead-In Period
This study permits the re-enrollment of a participant that has discontinued the study as a 
pretreatment failure (eg, participant has not been treated). If re-enrolled, the participant must be 
re-consented. 
Retesting of laboratory parameters and/or other assessments within any single Screening or Lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Treatment is the value by which study inclusion will be assessed, 
as it represents the participant’s most current clinical state.
Laboratory parameters and/or assessments that are included in
may be repeated in an 
effort to find all possible well-qualified participants. Consultation with the Medical Monitor may 
be needed to identify whether repeat testing of any particular parameter is clinically relevant.
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Testing for asymptomatic SARS-CoV-2 infection by reverse transcription polymerase chain 
reaction (RT-PCR) or viral antigen is not required. However, some participants may develop 
suspected or confirmed symptomatic SARS-CoV-2 infection or be discovered to have 
asymptomatic SARS-CoV-2 infection during the screening period. In such cases, participants may 
be considered eligible for the study after meeting all inclusion/exclusion criteria related to active 
infection, and after meeting the following criteria:

At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive RT-PCR or viral antigen test result

At least 24 hours have passed since last fever without the use of fever-reducing medications

Acute symptoms (eg, cough, shortness of breath) have resolved 

In the opinion of the investigator, there are no SARS-CoV-2 infection sequelae that may place 
the participant at a higher risk of receiving investigational treatment
In the instance of a SARS-CoV-2 infection during screening, the screening period may be extended 
beyond the protocol-specified timeframe with Medical Monitor approval.

Any screening tests already performed which could potentially be affected by the SARS-CoV-
2 infection or its complications on an individual basis and agreed upon with the Medical 
Monitor (eg, safety labs, oxygen saturation, chest CT scan) should be repeated.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

BMS-986258 

Nivolumab

ENHANZEDrug Product (rHuPH20)
An IP, also known as IMP in some regions, is defined as a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical study, including products 
already with a marketing authorization but used or assembled (formulated or packaged) differently 
than the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form.
Drugs used in this open-label study qualify as IPs. Their description and storage information are 
described in Table 7-1. Please refer to the Pharmacy Manual for additional information.
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Table 7-1:
Study Treatments for CA031002
Product 
Description/Class 
and Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage 
Conditions
(per label)
BMS-986258
IP
Open Label
Kit
Refer to 
Product label
BMS-986258
IP
Open Label
Kit
Refer to 
Product label
Nivolumab
100 mg/vial
(10 mg/mL)
IP
Open Label
Kit
Refer to 
Product label
ENHANZEDrug 
Product (rHuPH20)a
1 mg/mL
IP
Open Label
Vial and 
various 
packaging 
configurations
Refer to the 
label on 
container or 
package insert
Abbreviations: IP, Investigational Product; IMP, Investigational Medicinal Product; rHuPH20, recombinant human 
hyaluronidase PH20
a ENHANZE® (rHuPH20) is referred as rHuPH20 in the protocol
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
IPs.
7.1
Treatments Administered
The selection and timing of dose (Table 7.1-1) for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit Dose 
Strength(s)/Dosage 
Level(s)
Dosage Formulation
Frequency of 
Administration
Route of 
Administration
Infusion 
Time
BMS-986258
8, 24, and 72 mga,b
Q4W
IV
See noteb
200, 480, and 800 mgb
Q4W
IV
1200 mgb
Q4W
IV
1600 mgb
Q4W
IV
2400 mgb
Q4W
IV
Nivolumab
480 mgb
Q4W
IV
30 minutes
BMS-986258 + 
ENHANZEDrug 
Product (rHuPH20)
1200 mg
Once
SC
Abbreviations: IV, intravenously; Q4, every 4 weeks; rHuPH20, recombinant human hyaluronidase PH20; SC,
subcutaneous.
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a
b For study drugs preparation and infusion times, please refer to the Pharmacy Manual.
Intravenous (IV) BMS-986258:
Participants in Part A, Part A1 (after the first dose), and NSCLC PD cohorts will receive IV BMS-
986258 as monotherapy at doses ranging from 8 mg to 2400 mg. After the first dose, participants 
in cohort A1 will be offered the option to receive subsequent IV BMS-986258 in combination with 
nivolumab (480 mg) at the highest dose of BMS-986258 that has been shown to be safe and 
tolerable in the dose escalation (Part B). Treatment will be given Q4W twice per cycle, for up to 
twelve 8-week cycles (96 weeks).
There will be no dose escalations or reductions of BMS-986258 allowed. For Q4W dosing cycles, 
participants may be dosed within a ±3-day window.
BMS-986258 will be administered through an IV line. For details in study drug preparation and 
administration, refer to Pharmacy Manual. 
Subcutaneous (SC) BMS-986258:
Participants in Part A1 will receive BMS-986258 plus rHuPH20 as an SC injection. BMS-986258 
+ rHuPH20 will be administered subcutaneously 
 via a syringe pump (refer to 
Pharmacy Manual) on Cycle 1 Day1. 
Nivolumab:
Participants in Part A1 who have received combination therapy and participants in Part B, Part B 
NSCLC PD, and Part C cohorts should receive nivolumab at a dose of 480 mg as a 30-minute 
infusion on Day 1 of each treatment cycle every 4 weeks until progression, unacceptable toxicity, 
withdrawal of consent, completion of 
 of treatment, or the study ends, whichever occurs 
first. Participants should begin study treatment within 3 calendar days of treatment assignment.
There will be no dose escalations or reductions of nivolumab allowed. For Q4W dosing cycles, 
participants may be dosed within a ±3-day window. Premedications are not recommended for the 
first dose of nivolumab.
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.4.3.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed. Nivolumab 
injection will be administered as an IV infusion over approximately 30 minutes.
7.1.1
Dose-Limiting Toxicities
For the purpose of guiding decisions regarding dose escalation in Parts A and B, DLTs will be 
defined based on the incidence, intensity, and duration of AEs for which no clear alternative cause 
is identified. The DLT period will start on the first day of Cycle 1 and end at Day 28 (therefore, 
4 weeks) in Parts A and B. The severity of AEs will be graded according to NCI CTCAE v4.03.
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For the purpose of participant management, DLTs that occur at any time, whether during dose 
escalation (Part A or B), SC dose(s) (Part A1), or cohort expansion (Part C), will result in study 
drug being held pending evaluation of the event being related to study drug, in accordance with 
Section 7.4.
A participant is considered DLT evaluable if receiving 1 dose of BMS-986258 in Part A or 1 dose 
of BMS-986258 and nivolumab 480 mg in Part B and completing the DLT observation period.
Participants who withdraw from the study during the 4-week DLT evaluation period for reasons 
other than a DLT may be replaced with a new participant at the same dose level. The incidence of 
DLT(s) during the 4-week DLT evaluation period will be used in dose escalation decisions and to 
define the MTD/RP2D in monotherapy and in combination with nivolumab. AEs occurring after 
the 4-week DLT period will be considered for the purposes of defining the RP2D upon agreement 
between the Sponsor and Investigators. Participants experiencing a DLT will not be retreated with 
study drug and will enter the safety follow-up period of the study. 
7.1.1.1
Hepatic Dose-Limiting Toxicity
Any one of the following study drug-related events will be considered a hepatic DLT:
7.1.1.2
Hematologic Dose-Limiting Toxicity
Any of the following events will be considered a DLT:
7.1.1.3
Dermatologic Dose-Limiting Toxicity
Any of the following events will be considered a DLT:
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7.1.1.4
Other Dose-Limiting Toxicities
Any of the following events will be considered a DLT:
7.1.2
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology agents are associated with irAEs that can differ in severity and duration from 
AEs caused by other therapeutic classes. BMS-986258 and nivolumab are considered I-O agents 
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in this protocol. Early recognition and management of irAEs associated with I-O agents may 
mitigate severe toxicity. Management algorithms have been developed from extensive experience 
with nivolumab to assist investigators in assessing and managing the following groups of irAEs:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathies

Skin

Neurological

Myocarditis
The clinical nature of AEs noted with BMS-986258 will determine the role of the algorithms for 
use in toxicities related to its use in this study. The algorithms recommended for the management 
of irAEs in this protocol are in Appendix 8.
7.2
Method of Treatment Assignment
During the screening visit, the investigative site will call into the enrollment option of the IRT
designated by BMS for assignment of a 5-digit participant number that will be unique across all 
sites. Enrolled participants, including those not dosed, will be assigned sequential participant
numbers starting with 
. The patient identification 
number (PID) will ultimately be comprised of the site number and participant number. For 
example, the first participant screened (ie, enrolled) at site number  will have a PID of 
 
. Once it is determined that the participant meets the eligibility criteria following the 
screening visit, the investigative site will call the IRT to assign the participant into the open dose 
panel. 
Participants will not be replaced if they are discontinued from the study secondary to an AE unless 
the AE can be determined to be unrelated to treatment. 
During dose escalation, all participants will be assigned to Part A until the decision is made to 
escalate to the third dose cohort. Subsequently, treatment in Part B will be initiated, and dose 
escalation in the 2 parts will occur in parallel. In addition, Part A1 can be initiated independently, 
using all available safety and PK data and may be run in parallel with Parts A and B. Treatment 
assignments for participants eligible for Part A, Part A1, and Part B will alternate between the 
3 parts, with consecutively treated participants assigned to different parts through IRT whenever 
possible and according to the corresponding inclusion criteria. If there are no openings available 
in the part to which the subject would be assigned by this algorithm, then the subject will be 
assigned to the next open part/cohort.
In addition, participants enrolled in monotherapy or combination PD cohorts will be assigned to 
dose levels that are already established as safe based on data coming from the corresponding dose 
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escalation cohort. The participants assigned in Part A and B NSCLC PD cohorts will need to pass 
eligibility for selection based on 
 at baseline (see Section 5.1 and Inclusion 
Criteria Section 6.1).
7.3
Blinding
This is an open-label, non-randomized study. The specific treatment to be taken by a participant 
will be assigned using an IRT. The site will contact the Interactive Response System prior to the 
start of study treatment administration for each participant. The site will record the treatment 
assignment on the applicable case report form (CRF).
7.4
Dosage Modification
Intra-participant dose escalation/reduction of BMS-986258 or nivolumab is not permitted in this 
study in order to allow better evaluation of the safety and efficacy at individual dose levels and 
schedules. No dose reductions of BMS-986258 or nivolumab will be allowed.
7.4.1
Dose Delays Due to Toxicity
Participants who experience the following must have all study drug(s) withheld:

Potential DLTs, until DLT relatedness is defined.

Select AEs and laboratory abnormalities:

AE, laboratory abnormality, or concurrent illness that, in the judgment of the Investigator, 
warrants delaying study drug administration.

Confirmed SARS-CoV-2 infection.
Criteria for participants who are required to permanently discontinue both study drugs are listed 
in Section 8.1. Participants not meeting guidelines for permanent discontinuation will be permitted 
to resume therapy based on the criteria specified below in Section 7.4.2. Participants eligible to 
resume study therapy will resume study therapy at the nominal treatment visit following their last 
received study medication dose.
The end of cycle tumor assessments, such as computed tomography (CT), magnetic resonance 
imaging (MRI), or positron emission tomography (PET), will continue on a Q8W schedule relative 
to the participant’s first dose, regardless of any treatment delay incurred.
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7.4.2
Criteria to Resume Treatment
Subsequent dosing with study therapy may resume once drug-related non-DLT AEs resolve to 
Grade 1 or baseline. Participants experiencing AEs not meeting criteria for permanent 
discontinuation as outlined in Section 8.1 may resume treatment with study medication under the 
following criteria:
Participants may resume treatment with study drug when the drug-related AE(s) resolve to Grade 1 
or baseline value, with the following exceptions:

Participants may resume treatment in the presence of Grade 2 fatigue

Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity

Participants with Grade 2 uveitis, episcleritis, iritis, eye pain, or blurred vision not meeting 
DLT criteria (Section 7.1.1.4) must resolve to baseline prior to resuming study therapy

For participants with Grade 2 AST, ALT, or total bilirubin elevations, dosing may resume 
when laboratory values return to baseline, and management with corticosteroids, if needed, is 
complete

Participants with combined Grade 2 AST/ALT and total bilirubin values meeting DLT criteria 
(Section 7.1.1.1) should have treatment permanently discontinued

Participants with confirmed SARS-CoV-2 infection may resume treatment after 1) at least 10 
days (20 days for severe/critical illness) have passed since symptoms first appeared or positive 
RT-PCR viral antigen test result, 2) resolution of acute symptoms (including at least 24 hours 
has passed since last fever without fever reducing medications), 3) evaluation by the 
Investigator with confirmation that there are no sequelae that would place the participant at a 
higher risk of receiving investigational treatment, and 4) consultation by the Medical Monitor. 
For suspected cases, treatment may also resume if SARS-CoV-2 infection is ruled-out and 
other criteria to resume treatment are met.
Prior to re-initiating on-study treatment in a participant with a dosing delay lasting 8 weeks
due to SARS-CoV-2 infection, the Medical Monitor/designee must be consulted.
7.4.3
Management of Drug-related Infusion Reactions
For Grade 3 or 4 symptoms (severe reaction, Grade 3: prolonged [eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]; Grade 4: life-threatening; pressor or ventilatory support indicated):

Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and 
treat the participant as follows: recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for SC administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly 
for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV 
(or equivalent), as needed. Participant should be monitored until the Investigator is comfortable 
that the symptoms will not recur. Study drug will be permanently discontinued except for a 
Grade 3 infusion reaction that returns to Grade 1 in less than 6 hours. Investigators should 
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follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor participant until recovery of the symptoms.

In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, 
oral antihistamine or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the Investigator to ensure that IP is only dispensed to study participants. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and BMS should be contacted immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration, and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
For study drugs not provided by BMS and obtained commercially by the site, storage should be in 
accordance with the product label.
Please refer to the current version of the IBs and/or Pharmacy Manual for complete preparation, 
storage, and handling information.

Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2 and the Pharmacy Manual.
7.5.1
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
Not applicable.
7.6
Treatment Compliance
Not applicable.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):

Immunosuppressive agents
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
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.2 and
Section 7.7.2)

Any concurrent anti-neoplastic therapy (eg, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy)

Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.

Administration of investigational SARS-CoV-2 vaccines is not allowed during the study. 
Participants may receive authorized or approved SARS-CoV-2 vaccines while continuing on 
study treatment at the discretion of the investigator.

Treatment of active SARS-CoV-2 infections or high-risk exposures, including use of 
investigational therapies, is allowed and should be discussed with the Medical Monitor.
No concomitant medications (prescription, over-the-counter, or herbal) are to be administered 
during study unless they are prescribed for treatment of specific clinical events. Any concomitant 
therapies must be recorded on the CRF.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization or treatment assignment are excluded. Inhaled or topical steroids, and adrenal 
replacement steroid doses 10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease.
For participants who need to undergo elective surgery (not tumor related) during the study, it is 
recommended to hold study drug(s) for at least 2 weeks before and 2 weeks after surgery, or until 
the subject recovers from the procedure, whichever is longer. Prior to resuming study drug 
treatment, surgically-related AEs should resolve to Grade 1 or baseline and participants must 
meet relevant eligibility criteria as determined by the BMS Medical Monitor in discussion with 
the Investigator. The BMS Medical Monitor must be consulted prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 8 weeks after the last dose.
7.7.2.1
Vaccinations
Any vaccination containing attenuated or inactivated virus may be permitted if clinically indicated. 
However, this must be discussed and documented with the BMS Medical Monitor prior to 
administration and may require a study drug washout period prior to and after administration of 
the vaccine. Inactivated influenza vaccination will be permitted on study without restriction. Any 
vaccination containing live virus, including live SARS-CoV-2 vaccines, is prohibited.
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7.7.2.2
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history, and renal status), the appropriate imaging modality and contrast 
regimen for each participant. Imaging contraindications and contrast risks should be considered in 
this assessment. Participants with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie,
estimated glomerular filtration rate 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this participant population. In addition, participants are excluded from MRI if they 
have metallic implants, pacemakers, etc.
The ultimate decision to perform MRI in an individual participant in this study rests with the site 
radiologist, the Investigator, and the standards set by the local Ethics Committee.
7.7.3
Permitted Therapy
Participants are permitted the use of the following treatments:

Topical, ocular, intra-articular, intra-nasal, and inhalational corticosteroids

Adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent

A brief (less than 1 week) course of corticosteroids for prophylaxis (eg, contrast dye allergy) 
or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by a contact allergen)
7.7.3.1
Radiotherapy
Palliative and supportive care for disease-related symptoms may be offered to all participants on 
the trial; however, investigators should consult with the BMS Medical Monitor prior to initiating
palliative radiation in participants who have not yet completed the DLT evaluation interval (Parts
A and B).
The potential for overlapping toxicities with radiotherapy and BMS-986258 administered as 
monotherapy or in combination with nivolumab is currently not known. Therefore, palliative 
radiotherapy is not recommended while receiving any of these drugs, alone or in combination. If 
palliative radiotherapy in short courses and for isolated fields is required to control symptoms not 
clearly related to disease progression, then drug administration should be withheld, if possible, for 
at least 1 week before radiation and for at least 1 week after its completion. Participants should be 
closely monitored for any potential toxicity during and after receiving radiotherapy. Prior to 
resuming study drug treatment, radiotherapy-related AEs should resolve to Grade 1 or baseline 
and participants must meet relevant eligibility criteria as determined by the BMS Medical Monitor 
in discussion with the Investigator. The BMS Medical Monitor must be consulted prior to 
re-initiating treatment in a subject with a dosing interruption lasting > 8 weeks after the last dose.
Details of palliative radiotherapy should be documented in the source records and eCRF. Details 
in the source records should include: dates of treatment, anatomical site, dose administered and 
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fractionation schedule, and AEs. Symptoms requiring palliative radiotherapy should be evaluated 
for objective evidence of disease progression. Participants receiving palliative radiation of target 
lesions will have the evaluation of best overall response (BOR) just prior to radiotherapy but such 
participants will no longer be evaluable for determination of response subsequent to the date 
palliative radiation occurs.
7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS-supplied study treatment up to the maximum duration of 12 cycles as 
specified in Section 7.1. Study treatment will be provided via an extension of the study, a rollover 
study requiring approval by responsible health authority and ethics committee, or through another 
mechanism at the discretion of BMS.
BMS reserves the right to terminate access to BMS-supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of BMS-986258 is 
terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
study objectives; c) the participant can obtain medication from a government-sponsored or private 
health program. In all cases, BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation From Study Treatment
Participants MUST discontinue IP (and non-IP at the discretion of the Investigator) for any of the 
following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information.

Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
Investigator, indicates that continued participation in the study is not in the best interest of the 
participant.

Documented disease progression as defined by RECIST v1.1 (Appendix 5) unless participants 
meet criteria for treatment beyond progression (Section 8.1.3).

Clinical deterioration while receiving active study therapy that, in the opinion of the 
Investigator, indicates that continued participation in the study is not in the best interest of the 
participant.

Any drug-related AE occurring at any time that meets DLT criteria as outlined in Section 7.1.1
will require permanent discontinuation. Exceptions to permanent discontinuation are listed in 
Section 7.4.2.

Inability to comply with protocol.

Discretion of the Investigator.

Pregnancy.
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
Termination of the study by BMS.

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.

Individual participants with confirmed CR will be given the option to discontinue study therapy 
on a case-by-case basis after specific consultation and agreement between the Investigator and 
BMS Medical Monitor in settings where benefit/risk justifies discontinuation of study therapy.
Any event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions:

Dosing delays for prolonged steroid tapers to manage drug-related AEs are allowed. 

Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related reasons 
may be allowed if approved by the BMS Medical Monitor. 
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of BMS-986258. Although there is overlap among the discontinuation 
criteria, if a participant in any of the combination arms meets criteria for discontinuation and the 
Investigator is unable to determine whether the event is related to both or one study drug, the 
participant should discontinue both nivolumab and BMS-986258 and be taken off the treatment 
phase of the study. An exception to the discontinuation of BMS-986258 can be made in the case 
of a nivolumab-related hypersensitivity or infusion reaction.
Specifically, for hypersensitivity or infusion-related reactions, because nivolumab is administered 
first, if a participant presents with a reaction before the administration of BMS-986258 has started, 
treatment with BMS-986258 may continue after the hypersensitivity or infusion-related reactions 
have been resolved. For other IMAEs, when signs or symptoms have developed after 
administration of both study drugs, if discontinuation criteria are met, both study drugs should be 
discontinued.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the Investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a female participant becomes pregnant during a 
clinical trial, the study treatment must be discontinued immediately. Please call the BMS Medical 
Monitor within 24 hours of awareness of the pregnancy. If the Investigator determines a possible 
favorable benefit/risk ratio that warrants continuation of study treatment, a discussion between the 
Investigator and the BMS Medical Monitor/designee must occur. Refer to Section 9.2.5 
Pregnancy.
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All participants who discontinue study treatment should comply with protocol-specified follow-
up procedures 
. The only exception to this requirement is when a participant
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (eg, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate CRF page.
8.1.1
Temporary Discontinuation
Not applicable.
8.1.2
Rechallenge
Not applicable.
8.1.3
Treatment Beyond Progression
As described in Section 5.4.8, accumulating evidence indicates that a minority of patients with 
tumors treated with immunotherapy may derive clinical benefit despite initial evidence of 
progressive disease. The decision to continue treatment beyond investigator-assessed progression 
according to RECIST v. 1.1 should be discussed with the BMS Medical Monitor and documented 
in the study records. Participants with progressive disease may be permitted to continue study 
therapy provided the following criteria are met:

Subject is deriving clinical benefit as assessed by the Investigator.

Disease progression is not rapid as assessed by the Investigator.

Subject continues to meet relevant eligibility criteria as determined by the BMS Medical 
Monitor in discussion with the Investigator.

Subject tolerates study treatment.

Subject has stable performance status.

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, central nervous system metastases). 

Participant provides written informed consent prior to receiving any additional nivolumab or 
BMS-986258 treatment, using an ICF describing any reasonably foreseeable risks or 
discomforts, or other alternative treatment options. 
The assessment of clinical benefit should take into account whether the participant is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. If the Investigator 
feels that the participant continues to achieve clinical benefit by continuing treatment with the 
study treatments, the participant should remain on the trial and continue to receive monitoring 
according to the Schedule of Activities 
. All decisions to continue treatment beyond 
initial progression must be discussed with the BMS Medical Monitor, and an assessment of the 
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benefit/risk of continuing with study therapy must be documented in the study records (see 
Appendix 2).
For the participants who continue BMS-986258 (as a monotherapy or in combination with 
nivolumab) study therapy beyond progression, further progression is defined as an additional 10% 
increase in tumor burden with a minimum 5 mm absolute increase from time of initial PD. This 
includes an increase in the sum of diameters of all target lesions and/or the diameters of new 
measurable lesions compared to the time of initial PD. Nivolumab treatment should be 
discontinued permanently upon documentation of further progression.
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes that must have a short axis of at least 15 mm). 
Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes that must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions that become measurable, these new lesions must demonstrate an absolute increase of 
at least 5 mm.
8.1.3.1
Discontinuation Due to Further Progression (Confirmed Progression)
Participants that meet the above criteria and continue on study therapy beyond initial progressive 
disease must discontinue BMS-986258 (and nivolumab, if part of the combination cohorts) upon 
the next documented event of progressive disease. A follow-up efficacy assessment should be 
performed at the next scheduled evaluation 8 weeks later (but no sooner than 4 weeks later) to 
determine whether there is continued progressive disease.
Subjects should discontinue study therapy upon further evidence of further progression, defined 
as an additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions). The tumor burden volume from time of 
initial progression should be used as the reference baseline for comparison with the post-
progression assessment. Any new lesion considered non-measurable at the time of initial 
progression may become measurable and therefore must be included in the tumor burden 
measurement as follows:
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm).
For statistical analyses that include the investigator-assessed progression date, participants who 
continue treatment beyond initial investigator-assessed, RECIST v1.1-defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event.
Subjects should continue to receive monitoring according to Study Assessments and Procedures 
described in Section 9. Radiographic assessment by CT (preferred) or MRI described in Section 
9.1.1 is required when participants continue post-progression treatment. For participants that 
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discontinue post-progression treatment with study therapy, no additional radiographic assessments 
will be required.
8.1.4
Exceptions to Permanent Discontinuation Criteria
Any drug-related AE occurring at any time that meets DLT criteria as outlined in Section 7.1.1
will require permanent discontinuation, with the exception of the following:
Any event that leads to a delay in dosing for BMS-986258 monotherapy or BMS-986258 in 
combination with nivolumab, lasting > 8 weeks from the previous dose, requires discontinuation, 
with the exception of the following:

Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are allowed. 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks from the 
previous dose, the BMS Medical Monitor must be consulted. Tumor assessments should 
continue as per protocol even if dosing is delayed. Periodic study visits to assess safety and 
laboratory studies should also continue every 8 weeks, or more frequently if clinically 
indicated, during such dosing delays.

Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related reasons 
may not require discontinuation, if approved by the BMS Medical Monitor. Prior to 
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re-initiating treatment in a participant with a dosing delay lasting > 8 weeks, the BMS Medical 
Monitor must be consulted.

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing.
All participants who discontinue IP should comply with protocol-specified follow-up procedures 
. The only exception to this requirement is when a participant withdraws 
consent for all study procedures including post-treatment study follow-up or loses the ability to 
consent freely (eg, imprisonment, involuntarily incarceration for the treatment of either a 
psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate CRF page.
8.1.5
Post-Study Treatment Follow-up
In this study, safety and efficacy are key endpoints of the study. Post-study follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed (in this study or a 
rollover study) for collection of outcome and/or survival follow-up data as required and in line 
with Section 5 and
until death or the conclusion of the study.
8.2
Discontinuation From the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants should notify the Investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
Investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post-treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
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8.3
Lost to Follow-up

All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the Investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 

The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.

If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the Investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities
. 

Protocol waivers or exemptions are not allowed.

All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.

Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected 
drug-induced liver enzyme evaluations) will be monitored during the follow-up phase via on 
site/local labs until all study treatment-related toxicities resolve, return to baseline, or are 
deemed irreversible.
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
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, 
cough, and fever) consistent with possible pulmonary AEs, the participant should be 
immediately evaluated to rule out pulmonary toxicity, according to the suspected pulmonary 
toxicity management algorithm in Appendix 8.

Some of the assessments referred to in this section may not be captured as data in the eCRF. 
They are intended to be used as safety monitoring by the treating physician. Additional testing 
or assessments may be performed as clinically necessary or where required by institutional or 
local regulations.
9.1
Efficacy Assessments
Data for the tumor assessments specified in this protocol should be submitted to BMS. Additional 
assessments may be performed as part of standard of care; however, data for these assessments 
should remain in the subject’s medical record and should not be provided to BMS unless 
specifically requested by the Sponsor. The Sponsor can request scans for review at any time during 
or after the study.
9.1.1
Imaging Assessment for the Study
All on-study images will be submitted to a central imaging vendor for collection. At the Sponsor’s 
discretion, scans may undergo blinded independent central review. Sites should be trained prior to 
scanning the first study participant. Image acquisition guidelines and submission process will be 
outlined in the CA031002 Imaging Manual to be provided by the core lab. 
Screening images should be acquired 
. On-study images should be acquired 
from the date of first dose.
Tumor assessments at other time points may be performed if clinically indicated and should be 
submitted to the central imaging vendor. Unscheduled CT/MRI should be submitted to central 
imaging vendor. X-rays and bone scans that clearly demonstrate interval progression of disease 
(eg, most commonly as unequivocal lesions that are unmistakably new since the prior CT/MRI)
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should be submitted to central imaging vendor. Otherwise, they do not need to be submitted 
centrally.
9.1.1.1
Methods of Assessment
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known/suspected sites of 
disease should be performed for tumor assessments. For participants with SCCHN, a CT or MRI 
of the neck is required. For participants with TNBC without measurable lesions outside of the 
breast, contrast-enhanced MRI of the breasts should also be performed. Images should be acquired 
with slice thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should 
be made to image each participant using an identical acquisition protocol on the same scanner for 
all imaging time points. Tumor measurements should be made by the same investigator or 
radiologist for each assessment whenever possible. Change in tumor measurements and tumor 
response to guide ongoing study treatment decisions will be assessed by the Investigator using the 
RECIST v1.1 criteria.
Should a participant have contraindication for CT IV contrast, a non-contrast CT of the chest and 
a contrast-enhanced MRI of the neck, abdomen, pelvis, and other known/suspected sites of disease 
should be obtained.
Should a participant have contraindication for both MRI and CT intravenous contrasts, a non-
contrast CT of the chest and a non-contrast MRI of the neck, abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT IV contrast, a non-contrast CT of the neck, chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable.
Use of CT component of a PET-CT scanner: Combined modality scanning such as with PET-CT 
is increasingly used in clinical care and is a modality/technology that is in rapid evolution; 
therefore, the recommendations outlined here may change rather quickly with time. At present, 
low dose or attenuation correction CT portions of a combined PET-CT are of limited use in 
anatomically based efficacy assessments and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast-enhanced CT scans for anatomically-based RECIST 
measurements. However, if a site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST v1.1 measurements. Note, however, that the PET portion of 
the CT introduces additional data, which may bias an investigator if it is not routinely or serially 
performed.
Bone scan or PET scan is not adequate for assessment of RECIST v1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain 
non-target organs, those non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when CR is identified in target disease or when progression in 
bone is suspected.
Bone scans may be collected per local standards, as clinically indicated. 
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MRI of the brain (without and with contrast) should be acquired as outlined in 
 (Schedule 
of Activities). CT of the brain (without and with contrast) can be performed if MRI is 
contraindicated.
9.1.1.2
Imaging and Clinical Assessment 
Tumor assessments should continue on the protocol-defined imaging schedule regardless if dosing 
is delayed or discontinued. Changes in tumor measurements and tumor responses will be assessed 
by the same investigator or designee using RECIST v1.1 criteria. Investigators will report the 
number and size of new lesions that appear while on study. The time point of tumor assessments 
will be reported on the eCRF based on the investigator’s assessment using RECIST v1.1 criteria 
(see Appendix 5 for specifics of RECIST v1.1 criteria to be used in this study). Assessments of 
PR and CR must be confirmed at least 4 weeks (28 days) after initial response. A BOR of SD 
requires a minimum of 49 days on study from date of first dose.
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Section 7.1 in the IB12 represents the Reference Safety Information to determine expectedness of 
SAEs for expedited reporting. After the participant signs the Pre-Screen ICF for 
, all 
SAEs related to the biopsy must be collected and followed until resolution or stabilization. After 
the participant signs the main ICF to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures.
After the Pre-Screen ICF is signed:

Only SAEs related to the screening biopsy will be collected and followed until resolution or 
stabilization.

All related SAEs will be recorded and reported to Sponsor or designee within 24 hours, as 
indicated in Appendix 3.

The Investigator will submit any updated SAE data to the Sponsor within 24 hours of this being 
available.
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After the Main ICF is signed:

All SAEs related to the screening biopsy will be followed until resolution or stabilization.

All SAEs must be collected from the time of signing the consent, including those thought to 
be associated with protocol-specified procedures and within 100 days of discontinuation of 
dosing except in cases where a study participant has started a new anti-neoplastic therapy. Any 
SAE occurring after the start of a new anti-neoplastic therapy that is suspected to be related to 
study treatment by the Investigator will be reported.

For participants assigned to treatment and never treated with study drug, SAEs should be 
collected for 30 days from the date of treatment assignment.

The Investigator must report any SAE that occurs after these time periods and that is believed
to be related to study drug or protocol-specified procedure (eg, follow-up).

Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.

All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 

The Investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of updated information being available.

All AEs (SAEs or non-serious AEs), including those associated with SARS-CoV-2 infection, 
must be collected from time of consent.

All AEs (SAEs or non-serious AEs), including those associated with SARS-CoV-2 infection, 
must be collected continuously during the treatment period and for a minimum of 100 days 
following discontinuation of study treatment. 
Every AE must be assessed by the Investigator with regard to whether it is considered immune
mediated. For events that are potentially immune mediated, additional information will be 
collected on the participant’s CRF.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the Investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the Investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgment in 
the context of known AEs, when appropriate for the program or protocol.
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9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AEs (SAEs and non-serious AEs) associated with 
confirmed or suspected SARS-CoV-2 infection will be followed until resolution, the condition 
stabilizes, the event is otherwise explained, the event is deemed irreversible, the participant is lost 
to follow-up (as defined in Section 8.3), or for suspected cases, until SARS-CoV-2 infection is 
ruled-out.
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the Investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious 
Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least for 
5 half-lives after study product administration, the Investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to the BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3.
Study treatment will be permanently discontinued in an appropriate manner. Please call the BMS 
Medical Monitor within 24 hours of awareness of the pregnancy.
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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 Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE.

Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted.

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug-induced liver injury is defined as: 
1) Aminotransferases (AT) (ALT or AST) elevation > 3 times ULN
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
The key responsibilities for investigators during DILI assessment include (1) early detection, 
medical evaluation (including the exclusion of other potential causes), and rapid laboratory 
confirmation of liver-related abnormalities and (2) BMS notification of DILI cases via SAE forms. 
Following the gathering and assessment of relevant clinical information, BMS is responsible for 
(1) timely evaluation and triaging of DILI cases, (2) expedited reporting of DILI cases, and (3) 
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expanded review of DILI cases including a detailed assessment of all available clinical 
information, investigations, and biochemical data.
Investigators are expected to monitor ongoing routine and ad hoc hepatic laboratory test results to 
rapidly determine whether a participant meets DILI criteria. They are expected to promptly notify 
BMS of all DILI cases. Drug-induced liver injury cases may be identified by abnormal liver 
biochemistry values, whether or not they are accompanied by liver-related signs and/or symptoms.
In both cases, expedited confirmation with repeat laboratory testing should occur within 3 business 
days using a Hepatic Laboratory Panel (ALT, AST, total bilirubin, and ALP). Any participant with 
an abnormal Hepatic Laboratory Panel that meets DILI criteria is a candidate for study treatment 
discontinuation. Any confirmed DILI events must be reported (along with a description of the 
clinical findings) to BMS as an SAE within 24 hours of confirmation.
An extensive clinical history, examination, and appropriate investigations should be obtained to 
exclude cholestatic and other apparent causes that may explain the observed abnormalities in liver 
function and/or hepatic signs and symptoms. Other apparent causes include, non-exhaustively and 
by way of example only, the following: infectious diseases (such as active hepatitis A, B, and C), 
congenital diseases (such as Gilbert’s syndrome), neoplastic diseases, autoimmune diseases (such 
as primary biliary cirrhosis), and the use of concomitant hepatotoxic medications (such as 
antibiotics, the oral contraceptive pill, and herbal medicines). All investigations to exclude 
potential causes of liver function abnormalities or hepatic signs and/or symptoms should be guided 
by relevant factors such as the participant’s age, gender, clinical history, and signs and symptoms.
9.2.8
Immune-mediated Adverse Events
Immune-mediated AEs are AEs consistent with an immune-mediated mechanism or immune-
mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) 
have been ruled out. Immune-mediated AEs can include events with an alternate etiology, which 
were exacerbated by the induction of autoimmunity. Information supporting the assessment will 
be collected on the participant’s CRF.
9.2.9
Other Safety Considerations
Any significant worsening noted during interim or final PEs, ECG, x-ray filming, any other 
potential safety assessment required or not required by protocol should also be recorded as a 
nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (see Appendix 3).
For this study, any dose of study drug greater than the assigned dose and considered excessive and 
medically important by the Investigator will be considered an overdose.
In the event of an overdose, the Investigator should:
1) Contact the Medical Monitor immediately.
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2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities until BMS-986258 
can no longer be detected systemically. 
3) Obtain a serum sample for PK if requested by the Medical Monitor (determined on a 
case-by-case basis).
4) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications secondary to an overdose will be made by 
the Investigator in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities
.
9.4.2
Clinical Safety Laboratory Assessments

Investigators must document their review of each laboratory safety report.

A local laboratory will perform the analyses and will provide reference ranges for these tests. 
Results of clinical laboratory tests performed on Day -1 must be available prior to dosing.

The laboratory tests that will be performed for study participants are shown in Table 9.4.2-1. 

Results of all laboratory tests required by this protocol must be provided to the Sponsor, 
recorded either on the laboratory pages of the CRF or by another mechanism as agreed upon 
between the Investigator and BMS (eg, provided electronically). If the units of a test result 
differ from those printed on the CRF, the recorded laboratory values must specify the correct 
units. Any abnormal laboratory test result considered clinically significant by the Investigator 
must be recorded on the appropriate AE page of the CRF.
Table 9.4.2-1:
Clinical Laboratory Assessments
Hematology
Hemoglobin and hematocrit
Total leukocyte count, including differential
Platelet count
Prothrombin time, activated partial thromboplastin time, and international normalized ratio (at screening only)
Coagulation (screening only)
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Table 9.4.2-1:
Clinical Laboratory Assessments
Serum Chemistry
Aspartate aminotransferase 
Alanine aminotransferase 
Total bilirubin
Direct bilirubin (reflex only)a
Alkaline phosphatase
Lactate dehydrogenase 
Creatinine
Creatine kinase/ Creatine phosphokinase
C-reactive protein
Blood urea nitrogen or urea
Uric acid 
Glucose
Lipase
Amylase
Gamma glutamyl transferase (reflex only)b
Thyroid stimulating hormone
Free T3 and T4 (screening and reflex only)c
Total protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatinine clearance (Cockcroft-Gault method)
(screening only)
Troponin
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive on the dipstick
Serology
Serum for hepatitis C Ab, hepatitis B surface antigen, HIV-1 and HIV-2 Ab (at screening, and as mandated by 
local requirement)
Other Analyses
Pregnancy test (WOCBP only: screening, predose, discharge).
FSH (screening only and women only)
a Reflex testing to be performed only if total bilirubin is abnormal.
b Reflex testing to be performed only if liver function test is abnormal. 
c Reflex testing to be performed only if TSH is abnormal.
9.4.3
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
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9.4.4
Physical Examinations
Refer to the Schedule of Activities for timing of assessments 
9.4.5
Vital Signs
Refer to the Schedule of Activities for timing of assessments 
.
9.5
Pharmacokinetics
The PK of BMS-986258 and nivolumab will be derived, if feasible, from serum concentrations 
versus time data in monotherapy and in combination with nivolumab. The PK parameters that will 
be assessed following serial PK collection are shown in Table 9.5-1. Sparse nivolumab 
concentration-time data will be collected and may be used in an integrated PPK or ER analysis 
along with data from other nivolumab studies, which would be the subject of a separate report. 
 
 
Individual participant PK parameter values will be derived by non-compartmental methods by a 
validated PK analysis program. Actual times will be used for the analyses.
Table 9.5-1:
Pharmacokinetic Parameters
Abbreviation
Definition
Parameters to be Reported Separately in Cycle 1 for Parts A, A1, and B
Cmax
Maximum observed serum concentration
Tmax
Time of maximum observed serum concentration
AUC(0-T)
Area under the serum concentration-time curve from time zero to time of last 
quantifiable concentration
Ctau
Concentration at the end of the dosing interval
AUC(TAU)
Area under the concentration-time curve in one dosing interval
Parameters that May Potentially be Assessed Following the Dose Administration in Cycle 3 for Parts A and 
B
CLT 
Total body clearance
Css-avg
Average concentration over a dosing interval (AUC[TAU]/tau)
AI_AUC
AUC accumulation index; ratio of AUC(TAU) at steady state to AUC(TAU) after the 
first dose
T-HALFeff_AUC
Effective elimination half-life that explains the degree of accumulation observed
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Table 9.5-1:
Pharmacokinetic Parameters
Table 9.5-2, Table 9.5-3, Table 9.5-4, and Table 9.5-5 list the sampling schedule to be followed 
for the assessment of the PK and immunogenicity of BMS-986258 and nivolumab. All time points 
are relative to the start of BMS-986258 administration. Pre-dose samples should be taken within 
30 minutes before the start of any dose administration. End-of-infusion samples should be taken 
just prior to the end of infusion (preferably within 2 minutes). On-treatment PK samples are 
intended to be drawn relative to actual dosing days. If it is known that a dose is going to be delayed, 
then the pre-dose sample should be collected just prior to the delayed dose. Treatment assignments 
will be released to the bioanalytical laboratory, as needed, in order to minimize unnecessary 
analysis of samples.
Table 9.5-2:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-
986258 Q4W in Monotherapy Dose Escalation (Part A)
Study Day of Sample Collection
(1 Cycle = 8 Weeks)
Event
Time (Relative to 
BMS- 986258 
Dose)
Hour:Min
PK Serum 
Samples 
for
BMS-986258
ADA Samples 
for
BMS-986258
Cycle 1 Day 1
Predosea
00:00
X
X
Cycle 1 Day 1
EOIb
EOIb
X
Cycle 1 Day 1
04.00
X
Cycle 1 Day 2
24:00
X
Cycle 1 Day 3-Day 5
48:00-96:00
X
Cycle 1 Day 8
168:00
X
Cycle 1 Day 15
336:00
X
Cycle 1 Day 22
504:00
X
Cycle 1 Day 29
Predosea
00:00
X
X
Cycle 1 Day 29
EOIb
EOIb
X
Cycle 2 Day 1
Predosea
00:00
X
X
Cycle 2 Day 29
Predosea
00:00
X
X
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Table 9.5-2:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-
986258 Q4W in Monotherapy Dose Escalation (Part A)
Study Day of Sample Collection
(1 Cycle = 8 Weeks)
Event
Time (Relative to 
BMS- 986258 
Dose)
Hour:Min
PK Serum 
Samples 
for
BMS-986258
ADA Samples 
for
BMS-986258
Cycle 3 Day 1
Predosea
00:00
X
X
Cycle 3 Day 1
EOIb
EOIb
X
Cycle 3 Day 1
04.00
X
Cycle 3 Day 2
24:00
X
Cycle 3 Day 3-Day 5
48:00-96:00
X
Cycle 3 Day 8
168:00
X
Cycle 3 Day 15
336:00
X
Cycle 3 Day 22
504:00
X
Cycle 3 Day 29
Predosea
00:00
X
X
Cycle 5 and every other cycle (i.e., 
cycle 7, 9, ..) Day 1
Predosea
00:00
X
X
EOT
00:00
X
X
30 day follow up
X
X
60 day follow up
X
X
100 day follow up
X
X
Abbreviations: ADA, anti-drug antibody; EOI, end of infusion; EOT, end of treatment; PK, pharmacokinetics.
a Predose: All predose samples should be taken within 30 minutes prior to the start of any treatments.
b The EOI occurs when the entire BMS-986258 dose in the infusion bag is administered to the patient. If diluent is 
used to flush the dose remaining in the infusion line, then the EOI will occur when there is no dose is remaining in 
the infusion line after a flush. A PK sample should be taken immediately prior to the EOI (preferably within 2 
minutes prior to the EOI). If the EOI is delayed to beyond the nominal infusion duration (30 minutes), the collection 
of this sample should also be delayed accordingly. EOI samples may not be collected from the same IV access as 
the drug was administered.
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Table 9.5-3:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-
986258 Q4W in Subcutaneous PK Sub-study (Part A1)
Study Day of 
Sample 
Collection 
(1 Cycle = 8 
Weeks)
Event
Time 
(Relative to 
BMS-986258 
Dose)
Hour:Min
PK Serum 
Samples 
for
BMS-
986258
ADA 
Samples for
BMS-
986258
Subcutaneous Administration
Cycle 1 Day 1
Predoseb
00:00
X
X
Cycle 1 Day 2
24:00
X
Cycle 1 Day 4-
Cycle 1 Day 5
72:00-96:00
X
Cycle 1 Day 8
168:00
X
Cycle 1 Day 15
336:00
X
Cycle 1 Day 22
504:00
X
Intravenous Administration
Cycle 1 Day 29
Predoseb
00:00
X
X
Cycle 1 Day 29
EOIc
EOIc
X
Cycle 1 Day 31-
Cycle 1 Day 33
48:00- 96:00
X
Cycle 1 Day 36
168:00
X
Cycle 1 Day 43
336:00
X
Cycle 1 Day 50
504:00
X
Cycle 2 Day 1
Predosea
00:00
X
X
Cycle 2 Day 29
Predosea
00:00
X
X
Cycle 3 Day 1
Predosea
00:00
X
X
Cycle 3 Day 1
EOIc
EOIc
X
Cycle 3 Day 29
Predosea
00:00
X
X
Cycle 5 and every 
other cycle (i.e., 
cycle 7, 9, ..) 
Day 1
Predosea
00:00
X
X
EOT
00:00
X
X
30 day follow up
X
X
60 day follow up
X
X
100 day follow up
X
X
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Abbreviations: ADA, anti-drug antibody; EOI, end of infusion; EOT, end of treatment; IV, intravenous; PK,
pharmacokinetics; Q4W, every 4 weeks.
 
b Predose: All predose samples should be taken within 30 minutes prior to the start of any treatments.
c The EOI occurs when the entire BMS-986258 dose in the infusion bag is administered to the patient. If diluent is 
used to flush the dose remaining in the infusion line, then the EOI will occur when there is no dose is remaining in 
the infusion line after a flush. A PK sample should be taken immediately prior to the EOI (preferably within 2 
minutes prior to the EOI). If the EOI is delayed to beyond the nominal infusion duration (30 minutes), the collection 
of this sample should also be delayed accordingly. EOI samples may not be collected from the same IV access as 
the drug was administered.
Table 9.5-4:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-
986258 Q4W in Combination with Nivolumab Q4W in Dose 
Escalation (Part B)
Study Day of 
Sample 
Collection
(1 Cycle = 8 
Weeks)
Event
Time 
(Relative To 
BMS-986258 
Dose)
Hour:Min
PK Serum 
Samples for
BMS-986258
ADA
Samples for
BMS-
986258
Cycle 1 Day 1
Predosea
00:00
X
X
Cycle 1 Day 1
EOIb
EOIb
X
Cycle 1 Day 1
04.00
X
Cycle 1 Day 2
24:00
X
Cycle 1 Day 3-
Day 5
48:00-96:00
X
Cycle 1 Day 8
168:00
X
Cycle 1 Day 15
336:00
X
Cycle 1 Day 22
504:00
X
Cycle 1 Day 29
Predosea
00:00
X
X
Cycle 1 Day 29
EOIb
EOIb
X
X
Cycle 2 Day 1
Predosea
00:00
X
X
Cycle 2 Day 29
Predosea
00:00
X
X
Cycle 3 Day 1
Predosea
00:00
X
X
Cycle 3 Day 1
EOIb
EOIb
X
Cycle 3 Day 1
04.00
X
Cycle 3 Day 2
24:00
X
Cycle 3 Day 3-
Day 5
48:00-96:00
X
Cycle 3 Day 8
168:00
X
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Table 9.5-4:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-
986258 Q4W in Combination with Nivolumab Q4W in Dose 
Escalation (Part B)
Study Day of 
Sample 
Collection
(1 Cycle = 8 
Weeks)
Event
Time 
(Relative To 
BMS-986258 
Dose)
Hour:Min
PK Serum 
Samples for
BMS-986258
 
 
 
ADA
Samples for
BMS-
986258
Cycle 3 Day 15
336:00
X
Cycle 3 Day 22
504:00
X
Cycle 3 Day 29
Predosea
00:00
X
X
Cycle 5 and every 
other cycle (i.e., 
cycle 7, 9, ..) Day 
1
Predosea
00:00
X
X
EOT
X
X
30 day follow up
X
X
60 day follow up
X
X
100 day follow up
X
X
Abbreviations: ADA, anti-drug antibody; EOI, end of infusion; EOT, end of treatment; PK, pharmacokinetics.
a Predose: All predose samples should be taken within 30 minutes prior to the start of any treatments.
b The EOI occurs when the entire BMS-986258 dose in the infusion bag is administered to the patient. If diluent is 
used to flush the dose remaining in the infusion line, then the EOI will occur when there is no dose is remaining in 
the infusion line after a flush. A PK sample should be taken immediately prior to the EOI (preferably within 2 
minutes prior to the EOI). If the EOI is delayed to beyond the nominal infusion duration (30 minutes), the collection 
of this sample should also be delayed accordingly. EOI samples may not be collected from the same IV access as 
the drug was administered.
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Table 9.5-5:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-
986258 Q4W in Combination with Nivolumab Q4W in Dose 
Expansion (Part C)
Study Day of 
Sample Collection
(1 Cycle = 8 Weeks)
Event
Time 
(Relative To 
BMS-986258 
Dose)
Hour:Min
PK Serum 
Samples for
BMS-986258
 
 
 
ADA
Samples 
for
BMS-
986258
Cycle 1 Day 1
Predosea
00:00
X
X
Cycle 1 Day 1
EOIb
EOIb
X
Cycle 1 Day 29
Predosea
00:00
X
X
Cycle 1 Day 29
EOIb
EOIb
X
Cycle 2 Day 1
Predosea
00:00
X
X
Cycle 2 Day 29
Predosea
00:00
X
X
Cycle 3 Day 1
Predosea
00:00
X
X
Cycle 3 Day 29
Predosea
00:00
X
X
Cycle 5 and every 
other cycle (i.e., 
cycle 7, 9, ..) Day 1
Predosea
00:00
X
X
EOT
X
X
30 day follow up
X
X
60 day follow up
X
X
100 day follow up
X
X
Abbreviations: ADA, anti-drug antibody; EOI, end of infusion; EOT, end of treatment; PK, pharmacokinetics.
a Predose: All predose samples should be taken within 30 minutes prior to the start of any treatments.
b The EOI occurs when the entire BMS-986258 dose in the infusion bag is administered to the patient. If diluent is 
used to flush the dose remaining in the infusion line, then the EOI will occur when there is no dose is remaining in 
the infusion line after a flush. A PK sample should be taken immediately prior to the EOI (preferably within 2 
minutes prior to the EOI). If the EOI is delayed to beyond the nominal infusion duration (30 minutes), the collection 
of this sample should also be delayed accordingly. EOI samples may not be collected from the same IV access as 
the drug was administered.
9.6
Pharmacodynamics
For details about biomarkers, please see Section 9.8.
9.7
Pharmacogenomics
Not applicable.
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9.7.1
ADME Sampling
Not applicable.
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
10.1.1
Dose Escalation
During the dose escalation phase, an adaptive dose escalation scheme (BLRM for monotherapy 
and BLRM-copula for combination therapy) employing the EWOC principle will be used. The 
method is fully adaptive, makes use of all the information available at the time of each dose 
assignment, not just data from the current dose level, and directly addresses the ethical need to 
control the probability of overdosing. 
 
 
 
 
 
 The operating characteristics of BLRM for monotherapy escalation and BLRM-
copula for combination therapy escalation were studied in various scenarios through simulations 
in 
.
The maximum number of participants treated will be 
for dose escalation Part A (BMS-986258
monotherapy) and
for Part B (BMS-986258 in combination with nivolumab).
Approximately  participants will be treated at the starting dose levels of BMS-986258 or 
BMS-986258 in combination with nivolumab. While the BLRM/BLRM-copula will use DLT 
information from the DLT period only, clinical assessment will take into consideration the totality 
of available data including PK/PD from all treated participants encompassing monotherapy and 
combination therapy, in assigning a dose level for the next cohort of  participants. At least 
DLT-evaluable participants will be treated at the MTD. At most 
DLT-evaluable participants 
will be treated at each dose level. Additional participants may be treated at or any dose level below 
the estimated MTD for further evaluation of safety, PK, or PD parameters as required for a total 
of up to 
 across doses for monotherapy and 
for combination therapy.
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The model-recommended MTD is the dose that satisfies the following 3 conditions:
The final recommended MTD/RP2D will be based on the recommendation from the 
BLRM/BLRM-copula and overall clinical assessment of all available safety, PK, PD and efficacy 
data. Lower doses of BMS-986258 may be tested if none of the planned doses are found to be 
tolerable as monotherapy or in combination with nivolumab. Such decisions will be made after 
discussion and agreement between the Investigators and the BMS Medical Monitor.
Sample size calculations for the SC study (Part A1) are based on width of the confidence interval 
for the geometric mean ratio (GMR) of exposure measures for SC and IV dosing. For each dose 
to be tested in Part A1, the PK parameters are assumed to be distributed log-normally, 
 
 
 
 To account for potential 
missing data, approximately 
subjects will be treated for each dose to be tested in Part A1.
In addition, up to 
 participants will be enrolled in each of the Part A and B NSCLC PD cohorts 
in monotherapy and combination, with the goal of obtaining at least 
 participants with evaluable 
pairs of screening and on-treatment biopsies, in order to evaluate PD changes in NSCLC tumors 
with minimum 
.
For example, assuming a 
 intra-participant standard deviation, about 
 participants per dose 
level will be needed to estimate the change from baseline with the above precision; However, in 
order to account for non-evaluable biopsy samples or lack of repeat biopsy due to early dropouts, 
about 
 more participants would be needed (eg, in order to have 
 evaluable participants, up 
to 
will need to be treated per dose level).
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10.1.2
Cohort Expansion
The purpose of cohort expansion is to gather additional safety, tolerability, preliminary efficacy, 
PK, and PD information regarding BMS-986258 in combination with nivolumab. However, the 
sample size is strictly based on efficacy, specifically on the target ORR relative to historic response 
rate.
Part C will be an expansion phase for BMS-986258 in combination with nivolumab and may 
include participants with RCC, CRC, NSCLC, SCCHN, and TNBC. Enrolled participants with 
RCC, SCCHN, NSCLC and CRC MSI-H will be relapsed or refractory to prior PD-(L)1 treatment. 
Participants with a diagnosis of RCC, CRC, NSCLC, and SCCHN may be selected 
 
. Each disease cohort expansion will be handled independently and there 
will be no multiplicity adjustment. Up to 
 participants may be treated per expansion cohort (for 
a total of 
 in Part C overall) to allow for 
 if needed per tumor cohort,
although a total of up to 
 participants need to be treated across tumor cohorts based on the 
sample size assumptions and characteristics in the 2-stage design shown below. 
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10.2
Populations for Analyses
For purposes of analysis, the following populations are defined in Table 10.2-1 below:
Table 10.2-1:
Population for Analyses
Population
Description
Enrolled 
All participants who sign informed consent and are registered into the IRT.
Treated
All participants who take at least 1 dose of study treatment.
Response-evaluable
All treated participants with measurable disease at baseline and one of the following: 
(a) at least 1 post-baseline tumor assessment, (b) clinical progression, (c) death.
Pharmacokinetic
All treated participants who have concentration-time data.
Immunogenicity
All treated participants who have baseline and at least 1 post baseline pre-infusion 
immunogenicity assessment.
Abbreviations: IRT, Interactive Response Technology.
10.3
Statistical Analyses
The Statistical Analysis Plan will be developed and finalized before database lock and will 
describe the selection of participants to be included in the analyses. Below is a summary of planned 
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statistical analyses. Results will be presented by study part; data for participants who cross over 
from the SC cohort (A1) to IV monotherapy or combination treatment will be tabulated separately.
10.3.1
Efficacy Analyses
The primary efficacy analyses (Table 10.3.1-1) will be performed on the treated population for the 
final analysis. Efficacy analyses based on the response-evaluable population may be performed 
for interim analyses when the minimum follow-up period is less than sufficient to warrant adequate 
interpretation of the result. Details of the censoring scheme on time-to-event endpoints such as 
DOR, PFS, and OS rate will be described in the Statistical Analysis Plan.
Table 10.3.1-1:
Efficacy - Statistical Analyses
Endpoint
Statistical Analysis Methods
ORR is defined as the proportion of population of interest 
whose BOR is either CR or PR per RECIST v1.1
BOR for a participant will be assessed per RECIST v1.1.
Estimate of ORR and corresponding 2-sided exact 
95% CI 
 by 
treatment for each tumor type.
Median DOR 
DOR for a participant with a BOR of CR or PR is defined 
as the time between the date of first response and the date 
of the first objectively documented tumor progression per 
RECIST v1.1 or death, whichever occurs first.
Median duration of response using the Kaplan-
Meier method and corresponding 2-sided 95% CI 
 
 by treatment for each 
tumor type.
PFS rate at 6, 9, and 12 months
PFS for a participant is defined as the time from the first 
dosing date to the date of first objectively documented 
disease progression or death due to any cause, whichever 
occurs first. 
Estimate by the Kaplan-Meier method and 
corresponding 95% CI will be derived 
 
 for each tumor 
type.
Abbreviations: BOR, best overall response; CI, confidence interval; CR, complete response; DOR, duration of 
response; ORR, overall response rate; PFS, progression free survival; PR, partial response; RECIST, Response 
Evaluation Criteria In Solid Tumors.
10.3.2
Safety Analyses
All safety analyses will be performed on the treated population.
Endpoint
Statistical Analysis Methods

Incidence of AEs, SAEs, AEs 
meeting protocol defined DLT 
criteria, AEs leading to
discontinuation, and death
DLT rate by dose level, frequency distribution of treated participants with 
AE using the worst CTC grade. Participants will only be counted (1) once at 
the PT level, (2) once at the system organ class level, and (3) once in the 
‘total participant’ row at their worst CTC grade, regardless of system organ 
class or PT.
Laboratory abnormalities
Laboratory values will be graded 
according to CTCAE v4.03.
Laboratory shift table using the worst CTC grade on treatment per participant
Abbreviations: AE, adverse event; CTC, common terminology criteria; CTCAE, common terminology criteria for 
adverse events; DLTs, dose-limiting toxicities; PT, preferred term; SAE, serious adverse event.
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10.3.3
Pharmacokinetic Analyses for BMS-986258 and Nivolumab
Parameters will be reported separately in Parts A, A1, and B in Cycle 1.
Endpoint
Statistical Analysis Methods
BMS-986258
Parameters and Plots to Be Reported Separately for Cycle 1 in Parts A, A1, and B 
Cmax, AUC(0-T), AUC(TAU), Ctau 
Summary statistics: geometric means and 
coefficients of variation
Tmax
Summary statistics: medians and ranges
Parameters that May potentially be Assessed Following the Dose Administration for Cycle 3 in Parts A and 
B
CLT, Css-avg, AI_AUC, and T-HALFeff_AUC 
Summary statistics: geometric means
and 
coefficients of variation
Cmax, AUC(TAU)
Scatter plots versus dose for each cycle 
measured; dose proportionality based on a power 
model and a CI around the power coefficient
Abbreviations: AI_AUC, accumulation index ratio of AUC at steady state to that after the first dose; AUC(0-T), area 
under the concentration-time curve from time zero to the time of the last quantifiable concentration; AUC(TAU), area 
under the concentration-time curve in one dosing interval; 
; CI, confidence 
interval; CLT, total body clearance; Cmax, maximum observed concentration; Css-avg, average concentration over a 
dosing interval (AUC(TAU)/tau); Ctau, observed concentration at the end of a dosing interval; 
 
; T-HALFeff_AUC, effective elimination half-life that explains the degree of 
accumulation observed for a specific exposure measure; Tmax, time of maximum observed concentration.
Summary statistics will be tabulated for each PK parameter, if feasible, and wherever applicable, 
by treatment and dosing regimen. PK time-concentration data may be pooled with data from other 
studies for PPK analysis, which will be presented in a separate report.
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10.3.4
Immunogenicity
Endpoint
Statistical Analysis Methods

Incidence of ADA to BMS-986258

 
Baseline ADA-positive participant is defined as a participant 
who has an ADA-detected sample at baseline.a ADA-positive 
participant is a participant with at least 1 ADA-positive sample 
relative to baseline after initiation of the treatment
Frequency distribution of BMS-986258 
baseline ADA-positive participants and ADA-
positive participants after initiation of the 
monotherapy and combination treatment
 
 
Abbreviations: ADA, anti-drug antibody.
a Baseline sample is the last sample before initiation of the treatment.
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10.3.7
Other Analyses
Other exploratory analyses will be described in detail in the Statistical Analysis Plan finalized 
before database lock. Summary of OS rate 
 will be analyzed similarly to PFS rate. 
10.3.8
Interim Analyses 
The expansion phase of this study employs a 2-stage design framework. Therefore, there will be 
an interim analysis planned when an adequate number of treated participants have available tumor 
data. Additional interim analyses may also be performed for administrative purposes or 
publications. No formal inferences requiring any adjustment to statistical significance level will 
be performed.
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11
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31 Nivolumab BMS-936558 Investigator Brochure Version 19. Bristol-Myers Squibb Company, 
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34 Davar D et al. A phase 1 study of TSR-022, an anti-TIM-3 monoclonal antibody, in 
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37 Harding JJ, Patnaik A, Moreno V, et al. A phase Ia/Ib study of an anti-TIM-3 antibody 
(LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): 
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38 Ismael G, Hegg R, Muehlbauer S, et al. Subcutaneous versus intravenous administration of
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(HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 
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39 Recombinant Human Hyaluronidase PH20 (rHuPH20) Investigator's Brochure, Version 8.0.
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40 Biologics license application (BLA) 761064, rituximab/hyaluronidase injection for 
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41 Davda JP, Dodds MG, Gibbs MA, Wisdom W, Gibbs J. A model-based meta-analysis of 
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42 https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
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Drug Metab Dispos 2014;42:1881–9.
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45 Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
2000;192:1027-34.
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its ligands in regulating autoimmunity and infection. Nat Immunol 2007;8:239-45.
47 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20.
48 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369(2):122-33.
49 Brahmer J, et al. Five-year follow-up from the CA209-003 study of nivolumab in previously 
treated advanced non-small cell lung cancer: clinical characteristics of long-term survivors. 
Oral presentation presented at: American Association for Cancer Research (AACR) Annual 
Meeting; April 1-5, 2017; Washington, DC, USA.
50 Felip E et al. Three-year follow-up from Checkmate 017/057: Nivolumab versus docetaxel in 
patients with previously treated advanced non-small lung cancer (NSCLC). Poster discussion 
presentation at the European Society of Medical Oncology Annual Meeting. 2017 Sep 8-12; 
Madrid, Spain. Poster 1301PD.
51 Spigel DR, et al. Randomized results of continuous vs 1-year fixed-duration in patients with 
advanced non-small cell lung cancer. Oral presentation at the European Society of Medical 
Oncology Annual Meeting. 2017 Sep 8-12; Madrid, Spain. Abstract 1297O.
52 Hanzly M, Aboumohamed A, Yarlagadda N, et al. High-dose interleukin-2 therapy for 
metastatic renal cell carcinoma: a contemporary experience. Urology 2014;83:1129-34.
53 Motzer RJ, Escudier B, McDermott DF, et. al. Nivolumab versus everolimus in advanced 
renal-cell carcinoma. N Engl J Med 2015;373:1803-13.
54 National comprehensive cancer network. NCCN Guidelines v. 2.2017. Available on URL:
https://www.nccn.org/professionals/physician_gls/recently_updated.asp. Accessed on 16-Oct-
2017.
55 Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA 
mismatch DNA repair-deficient or microsatellite instability-high colorectal cancer 
(CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18:1182-91.
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57 Devesa SS, Bray F, Vizcaino AP, Parkin DM. International lung cancer trends by histologic 
type: male:female differences diminishing and adenocarcinoma rates rising. Int J Cancer 
2005;117:294–9.
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58 Morgensztern D, Ng SH, Gao F, Govindan R. Trends in stage distribution for patients with 
non-small cell lung cancer: a National Cancer Database survey. J Thorac Oncol 2010;5:29–33.
59 Brahmer J, Reckamp KL, Bass P et al. Nivolumab versus docetaxel in advanced squamous-
cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.
60 Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet 
2008;371:1695-709.
61 Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment 
for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. 
MACH-NC collaborative group. Meta-analysis of chemotherapy on head and neck cancer. 
Lancet 2000;355:949-55.
62 Siegel R, Naishadham D, Jemal A. Cancer statistics, 20131. CACancer J Clin 2013;63:11-30.
63 Pignon JP, le Maitre A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis 
of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 
17,346 patients. Radiother Oncol 2009;92:4-14.
64 Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation 
therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable 
squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8.
65 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous cell 
carcinoma of the head and neck. N Engl J Med 2006;354:567-78.
66 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally 
advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and 
relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21-8.
67 Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma 
of the head and neck. N Engl J Med 2016;375:1856-67.
68 Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J 
Med 2010;363:1938-48.
69 NCCN Clinical Practice Guidelines in Oncology. v.2.2017; Available on URL: www.nccn.org.
70 Obeid E, Nanda R, Fu YX, Olopade OI. The role of tumor-associated macrophages in breast 
cancer progression (review). Int J Oncol 2013;43:5-12.
71 Mao Y, Qu Q, Chen X, et al. The prognostic value of tumor-infiltrating lymphocytes in breast 
cancer: a systematic review and meta-analysis. PLoS One 2016;11:e0152500.
72 Sakuishi K, Apetoh L, Sullivan JM, et al. Targeting TIM-3 and PD-1 pathways to reverse T 
cell exhaustion and restore anti-tumor immunity. J Exp Med 2010;207:2187–94.
73 Waterhouse D, Horn L, Reynolds C, et al. Safety Profile of Nivolumab Administered as 30-
Minute Infusion: Analysis of Data from CheckMate 153. ASCO poster #3059.
74 Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth 
factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of 
American Pathologists clinical practice guideline update. J Clin Oncol 2013;31:3997-4013.
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75 Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 
1982;38:143-151.
76 Kramar A, Potvin D, Hill C. Multistage design for phase II clinical trials: statistical issues in 
cancer research. Br J Cancer 1996;74:1317-20.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ADA
anti-drug antibody
AE
adverse event
AI
accumulation index
AI_AUC
AUC accumulation index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve (exposure)
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
BA
bioavailability
BCR
B-cell receptor
BLRM
Bayesian Logistic Regression Model
BMS
Bristol-Myers Squibb
BOR
best overall response
BTLA
B and T-lymphocyte attenuator
C
cycle
Cav-gss
steady-state exposures
CD8
cluster of differentiation 8
CD28
cluster of differentiation 28
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Term
Definition
CHO-OKT3
Chinese hamster ovary cells stably expressing a single-chain variable 
fragment of anti-CD3 antibody
CI
confidence interval
CLT
total body clearance
Cmax
maximum observed concentration
Cmaxss
steady-state peak concentrations
Cminss
steady-state trough concentrations
CMV
cytomegalovirus
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
case report form
Css-avg
average steady-state concentration
CT
computed tomography
CTLA-4
cytotoxic T lymphocyte–associated antigen 4
Ctau
concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CTC
common terminology criteria
CTCAE
common terminology criteria for adverse events
CYP
cytochrome P450
DC
dendritic cells
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
EC50
half-maximal effective concentration
EC90
90% maximal effective concentration
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Term
Definition
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor 2
EOI
end of infusion
EOT
end of treatment
ER
exposure response
EWOC
escalation with overdose control
Fc
fraction crystallizable
FDA
Food and Drug Administration
FIH
first in human
FSH
follicle stimulating hormone
GLP
Good Laboratory Practices
GMR
geometric mean ratio
GPVE
Global Pharmacovigilance and Epidemiology
HAVCR2
hepatitis A virus cellular receptor 2
hERG
human ether-a-go-go-related gene
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
HPV
human papillomavirus
HR
hazard ratio
IB
investigator’s brochure
ICF
informed consent form
ICOS
inducible costimulator
IFN-
interferon gamma
Ig
immunoglobulin
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Term
Definition
IgG
immunoglobulin G
IL
interleukin
IMAEs
immune-mediated AEs
IMP
Investigational Medicinal Product
I-O
immuno-oncology
IP
investigational product
irAE
immune-related adverse event
IRT
interactive response technology
IV
intravenous
mAb
monoclonal antibody
MAAD
maximum administered dose
mDOR
median duration of response
MDS
myelodysplastic syndrome
MLR
mixed lymphocyte reaction
MMR
mismatch repair
MMR-D
mismatch repair-deficient
MRI
magnetic resonance imaging
MRSD
maximum recommended starting dose
MSI-H
microsatellite instability high
MSS
microsatellite stable
MST
Medical Surveillance Team
MTD
maximum tolerated dose
N
number of subjects or observations
NCI
National Cancer Institute
NK
natural killer
NOAEL
non-observed-adverse-effect
NSCLC
non-small cell lung cancer
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Term
Definition
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
pharmacodynamics
PD-1
programmed cell death 1
PD-L1
programmed death ligand 1
PD-L2
programmed death ligand 2
PET
positron emission tomography
PFS
progression-free survival
PID
patient identification number
PK
pharmacokinetics
PPK
population pharmacokinetic
PR
partial response
PS
phosphatidylserine 
PT
preferred term
Q2W
every 2 weeks
Q4W
every 4 weeks
Q8W 
every 8 weeks
QTc
corrected QT interval
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RCC
renal cell carcinoma
RECIST
response evaluation criteria in solid tumors
RO
receptor occupancy
RP2D
recommended Phase 2 dose 
rHuPH20
recombinant human hyaluronidase Ph20
RT-PCR
reverse transcription polymerase chain reaction
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Term
Definition
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
T-HALF
apparent elimination half-life
T-HALFeff_AUC
effective elimination half-life that explains the degree of accumulation 
observed
TIL
tumor-infiltrating lymphocyte
TIM-3
T-cell immunoglobulin and mucin domain-3
Tmax, TMAX
time of maximum observed concentration
TNBC
triple negative breast cancer
ULN
upper limit of normal
US
United States
USP
United States Pharmacopeia
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:

Good Clinical Practice (GCP), 

as defined by the International Council on Harmonisation (ICH)

in accordance with the ethical principles underlying European Union Directive 2001/20/EC

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 

applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP (occurring in any country) in connection 
with the study or the protocol, which is likely to affect, to a significant degree, the safety or 
physical or mental integrity of 1 or more subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and 
other information (eg, expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
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applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to:

IRB/IEC for 

Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
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
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.

Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
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STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage 
area

amount currently in storage area

label identification number or batch 
number

amount dispensed to and returned by each 
participant, including unique participant 
identifiers

amount transferred to another area/site for 
dispensing or storage

non-study disposition (e.g., lost, wasted) 

amount destroyed at study site, if 
applicable

amount returned to BMS

retain samples for 
bioavailability/bioequivalence, if 
applicable 

dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study treatment integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
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CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals.
MONITORING
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
Certain CRF pages and/or electronic files may serve as the source documents:
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In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee.
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety,
or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
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It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

Participant recruitment (eg, among the top quartile of enrollers)

Regional representation (eg, among top quartile of enrollers from a specified region or country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
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forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
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 study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in 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 (e.g., 
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 (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see Section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.

The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form.

The required method for SAE data reporting is through the eCRF.

The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
When paper forms are used, the original paper forms are to remain on site

Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their judgment
in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the time point where the IMP or any active major metabolites 
has decreased to a concentration that is no longer considered to be relevant for human 
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teratogenicity or fetotoxicity. This should be evaluated in context of safety margins from the no-
observed adverse effect level (NOAEL) or the time required for 5 half-lives of the IMP to pass.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
Any birth control method used must be highly effective with a failure rate less than 1% per year. 
WOCBP must use an adequate method(s) to avoid pregnancy for the duration of this study and for 
up to 5 months after the last dose of study drugs. Local laws and regulations may require use of 
alternative and/or additional contraception methods.
Highly Effective 
Methods of 
Contraception
Progestogen only hormonal contraception associated with inhibition of 
ovulation
Hormonal methods of contraception including oral contraceptive pills 
(combination of estrogen and progesterone), vaginal ring, injectables, 
implants, transdermal and intrauterine hormone-releasing system (IUS)
Bilateral tubal ligation
Vasectomized Partner
Intrauterine devices (IUD) 
Complete abstinence
Unacceptable 
Methods for 
Contraception
Vaginal sponge with spermicide
Progestin only pills
Cervical cap with spermicide
Diaphragm with spermicide
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
Withdrawal (coitus interruptus)
Spermicide only
Lactation amenorrhea method (LAM)
Male condoms with or without spermicide for partners of female 
subjects, as the only method of contraception
Female condoms
A male and a female condom must not be used together
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COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 5
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or 2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be 15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis 10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with 10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.3
Special Considerations Regarding Lesion Measurability
1.3.1
Bone Lesions

Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.

Blastic bone lesions are non-measurable.
1.4
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.

Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
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small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.

Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 

Non-CR/Non-PD: Persistence of one or more non-target lesion(s)

Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
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disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore, the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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2) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response, PR, partial response, SD, stable disease, PD, progressive disease and NE, inevaluable
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Table 2.3.2-2:
Time Point Response
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR, complete response, PD, progressive disease and NE, inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study). If the subject is not on-study for 
at least this amount of time, any tumor assessment indicating stable disease before this time period 
will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
CR, complete response, PR, partial response, SD, stable disease, PD, progressive disease, and NE, inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a 
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
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APPENDIX 6
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS
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APPENDIX 7
NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION
Heart failure is usually classified according to the severity of the patient’s symptoms. The table 
below describes the most commonly used classification system, the New York Heart Association 
(NYHA) functional classification. It places patients in 1 of 4 categories based on how much they 
are limited during physical activity.
Class
Patient Symptoms
I
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of 
breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, or dyspnea 
(shortness of breath).
III
Marked limitation of physical activity. Comfortable at rest. Less 
than ordinary activity causes fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort. 
Symptoms of heart failure at rest. If any physical activity is 
undertaken, discomfort increases.
Class
Objective Assessment
A
No objective evidence of cardiovascular disease. No symptoms 
and no limitation in ordinary physical activity.
B
Objective evidence of minimal cardiovascular disease. Mild 
symptoms and slight limitation during ordinary activity. 
Comfortable at rest.
C
Objective evidence of moderately severe cardiovascular disease. 
Marked limitation in activity due to symptoms, even during 
less-than-ordinary activity. Comfortable only at rest.
D
Objective evidence of severe cardiovascular disease. Severe 
limitations. Experiences symptoms even while at rest.
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APPENDIX 8
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 11
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 06, 23-Dec-2020
The rationale for this amendment was to include:

New BMS-986258 formulation 
. 

Additional corrections in numbering of exclusion criterion 3, male contraception, and in 
the 
 were included. 

. 

 for inclusion in NSCLC PD cohorts. Candidates to NSCLC 
PD cohorts will be allowed to be enrolled in dose escalation cohorts (Part A and B) if the 
 is not fulfilled.
BMS document titling nomenclature has been updated to align with Transcelerate guidance, 
therefore Revised Protocols are now titled as Amendments.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & Title
Description of Change
Brief Rationale
Title Page
Added Clinical Scientist contact detail 
information
Editorial change
Section 1-Synopsis
The synopsis has been modified to 
incorporate all changes described below.
Updated to align with study 
protocol changes.
Section 5-Study Design
Reduced the 
To facilitate the recruitment in the 
in Parts A and B NSCLC PD 
cohorts
Section 5.1.1-Pre-screening 
for PD Cohorts only 
(NSCLC)
Reduced the 
Allowed participants to be enrolled in dose 
escalation cohorts (Part A and B) if not 
eligible for NSCLC PD cohorts, and 
therefore, continue with screening 
procedures while waiting for 
 
result
To facilitate the recruitment in the 
in Parts A and B NSCLC PD 
cohorts and in dose escalation 
(Part A and B) cohorts
Section 5.4.4-Rationale for 
Design of the NSCLC 
Pharmacodynamic Cohorts in 
Reduced the 
To align it with the current 
 
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & Title
Description of Change
Brief Rationale
Parts A and B and for Patient 
Selection Strategy
Section 6.1-Inclusion Criteria
Updated inclusion 1)b, 2)a, 
Inclusion criterion 4)e is not applicable
To align with the current
 
 and with the current 
Monoclonal antibodies are not 
genotoxic and do not concentrate 
in seminal fluid at concentrations 
sufficient to cause fetal 
toxicity. For these reasons, in 
studies involving monoclonal 
antibodies, there are no 
contraception requirements for 
male participants or WOCBP 
partners of male participants.
Section 6.2-Exclusion 
Criteria
Renumbered Exclusion criterion 3
To align exclusion criteria 
numbering with the previous 
protocol version.
Section 7-Treatment
Included additional formulation and 
strength of BMS-986258 in Table 7-1 Study 
Treatments
Added to provide most current 
formulation for BMS-986258
Section 8.1-Discontinuation 
from Study Treatment
Removed sentence concerning pregnancy in 
the partner of male participant
Monoclonal antibodies are not 
genotoxic and do not concentrate 
in seminal fluid at concentrations 
sufficient to cause fetal 
toxicity. For these reasons, in 
studies involving monoclonal 
antibodies, there are no 
contraception requirements for 
male participants or WOCBP 
partners of male participants
Section 9.2.5-Pregnancy
Removed information related to female 
partner’s pregnancy of a male study 
participant
Monoclonal antibodies are not 
genotoxic and do not concentrate 
in seminal fluid at concentrations 
sufficient to cause fetal 
toxicity. For these reasons, in 
studies involving monoclonal 
antibodies, there are no 
contraception requirements for 
male participants or WOCBP 
partners of male participants.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & Title
Description of Change
Brief Rationale
Appendix 4-Women of 
childbearing potential 
definitions and methods of 
contraception
Updated contraception guidance for female 
participants of childbearing potential table 
and removed information related to 
contraception guidance for male 
participants with partner(s) of childbearing 
potential
Monoclonal antibodies are not 
genotoxic and do not concentrate 
in seminal fluid at concentrations 
sufficient to cause fetal 
toxicity. For these reasons, in 
studies involving monoclonal 
antibodies, there are no 
contraception requirements for 
male participants or WOCBP 
partners of male participants.
Entire document
Additional editorial or formatting changes, 
where appropriate.  
Added to provide clarity.
Overall Rationale for Revised Protocol 05, 22-Oct-2020
The rationale for this revision was to define dose for subcutaneous (SC) administration so that Part 
A1, SC investigation, of the study could be opened. 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated name and address of Medical 
Monitor/Study Director.
Editorial change.
Section 1-Synopsis
The synopsis has been modified to 
incorporate all applicable changes described 
below.
Updated to align with study 
protocol changes.
 
, 3.2.2-Nivolumab
Added additional paragraph on nonclinical 
toxicology and updated nivolumab 
background.
Updated to reflect updated latest 
version of the Nivolumab IB.
Section 3.3.3-BMS-986258 
Starting Dose for Part A1 
(Monotherapy SC)
Added additional paragraph for starting 
dose and treatment for Part A1.
Added to include the rationale for 
the starting dose of BMS-986258 
Protocol Amendment No.: 07
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & Title
Description of Change
Brief Rationale
monotherapy, administered 
subcutaneously. 
Section 3.3.6-Safety 
Monitoring
Added additional paragraph on SARS-CoV-
2 safety monitoring.
Added to clarify information of 
safety monitoring regarding 
SARS-CoV-2 infection.
Section 5.1-Overall design
Updated
 to include new dose. 
Added 
 for Part A1.
Added to align with study 
protocol changes and to 
subcutaneous administration.
Section 5.4.2- Rationale for 
Subcutaneous Administration 
of BMS-986258 (Part A1)
Added paragraph on rHuPH20 rationale for 
subcutaneous administration and additional 
safety information. Added paragraph on 
detailed dosing and timing information for 
rHuPH20.
Added to provide additional 
background information on 
rHuPH20 characteristics,  
mechanism of action and results 
of its combination with other 
compounds.
Section 6.1-Inclusion criteria
Updated inclusion criteria 2) f) iii); 
 3) 
a) i) ii) and iii); and 4) a), b), c), e) with 
additional language. Removed inclusion 
criteria 4)f). Added inclusion criteria 
4)g),h), i), and j). modified language in 
paragraph below 4)j).
Changes added to provide clarity 
about targeted treatments that the 
participants must have received 
prior to the clinical trial, 
according to mutations related to 
their disease and to align with 
EPE v6.
Section 6.2-Exclusion criteria
Added new exclusion criteria 2) f); 3) a) b), 
g) xiii) and xiv). Updated language in 
3)g)iii). Updated numbering.
Added to align with EPEv6 
updates and SARS-CoV-2 
language and to provide clarity.
Section 6.4.1-Restesting 
During Screening or Lead-In 
Period
Added language for SARS-CoV-2 infection.
To allow participants to be 
rescreened if they present 
suspected or confirmed SARS-
CoV-2 infection.
Section 7.1-Treatments 
Administered
Updated Table 7.1-1 to include new BMS-
986258 dose and rHuPH20 dose and 
infusion times. Added additional paragraphs 
on both IV and SC dosing requirements. 
Removed additional detail on nivolumab 
infusion procedures.
Added to provide additional 
information on IV and SC BMS-
986258 administration aligned 
with study protocol changes and 
to provide clarity.
Section 7.4.1-Dose Delays 
Due to Toxicity
Added confirmed SARS-CoV-2 infection as 
AE requiring study drug(s) withheld.
Addition of standard language for 
BMS protocol with respect to 
SARS-CoV-2.
Section 7.4.2-Criteria to 
Resume Treatment
Added guidance for resuming treatment 
after SARS-CoV-2 infection.
Addition of standard language for 
BMS protocol with respect to 
SARS-CoV-2.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & Title
Description of Change
Brief Rationale
Section 7.7.1 Prohibited 
and/or Restricted Treatments
Added language for SARS-CoV-2 
infections and vaccines.
Addition of standard language for 
BMS protocol with respect to 
SARS-CoV-2.
Section 9.2.1- Time Period 
and Frequency for Collecting 
AE and SAE Information, 
Section 9.2.3-Follow-up of 
AEs and SAEs
Added language for SARS-CoV-2 AE 
collection and AE monitoring.
Addition of standard language for 
BMS protocol with respect to
SARS-CoV-2.
Section 9.5-Pharmacokinetic 
Parameters
Updated Table 9.5-1 definition headings. 
Updated table footnote b definition and 
timing for EOI in Table 9.5-2. Updated 
table footnote b definition and timing for 
EOI in Table 9.5-3 
 
 
 
 
 
 
Added to clarify PK and 
immunogenicity sampling BMS-
986258 Q4W in dose escalation.
Section 10.3.3-
Pharmacokinetic Analyses 
for BMS-986258 and 
Nivolumab
Added additional information on the 
parameters and posts under endpoints and 
statistical analysis methods. Added 
clarification language.
Added to provide clarity.
Appendix 4-Women of 
childbearing potential 
definitions and methods of 
contraception
Updated language under contraception 
guidance.
Updated to align with EPEv6 
updates.
Entire document
Additional editorial or formatting changes, 
where appropriate.  
Added to provide clarity.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
Overall Rationale for Revised Protocol 04, 27-Apr-2020
Because no safety signals were identified at the maximal dose level (1200 mg) and the available 
PK and PD data are supportive, the decision was made to further escalate doses of BMS-986258 
by defining 
 dose levels (1600 mg and 2400 mg) in Part A (monotherapy) and  
 dose level (1600 mg) in Part B (combination with nivolumab 480 mg). This decision 
was based on the assessment of clinical safety for 
 participants who have been treated in this 
study (CA031002) with either BMS-986258 monotherapy up to 1200 mg IV every 4 weeks (Q4W) 
or BMS-986258 480 mg IV Q4W in combination with nivolumab 480 mg IV Q4W as of the data 
cutoff of 
 and non-clinical toxicity data that supports the proposed maximum IV dose 
of 2400 mg Q4W.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Global
Removed reference to “Part B (all 
participants)” in regards to prospective 
selection based on 
 
in screening biopsies.
Only participants in Part A and 
Part B NSCLC PD cohorts will be 
prospectively selected for 
 
 in screening 
biopsies. Participants enrolled in 
escalation cohorts in Part B will 
not be prospectively selected.
Global
Added new proposed doses to be tested: 
1600 mg (Part A and B) and 2400 mg (Part 
A).
Safety data supports dose 
escalation up to 2400 mg (see 
overall rationale above).
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
3.1.1, Rationale for 
Subcutaneous Administration 
of BMS-986258
Deleted section.
Rationale added to Section 5.4.2.
3.3, Benefit/Risk Assessment
Updated section with initial safety data 
observed for BMS-986258 in the current 
study, nivolumab-related safety data from 
the Investigator Brochure, and the safety 
data reported by other companies for other 
TIM-3 inhibitors.
Inform evaluation of benefit-risk 
for this study.
3.3.4, BMS-986258 Starting 
Dose for Pat B (Combination 
with Nivolumab)
Updated section text as starting dose for 
Part B was selected to be 480 mg BMS-
986258 Q4W in combination with 480 mg 
nivolumab Q4W. 
Data from Part A and preliminary 
PK and biomarker data supports 
initiation at 480 mg BMS-986258 
Q4W in combination with 480 mg 
nivolumab Q4W.
3.3.6, Safety Monitoring on 
Study Therapy

Updated pretreatment tumor biopsy 
participant eligibility language.

Added text highlighting there were no 
infusion-related reactions in 
monotherapy doses of 8 to 1200 mg.

Updated language for clarity.

Text provides supporting 
information for the addition 
of new dose levels to Part A 
and Part B.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
5.1.3, Treatment Period
Updated the infusion time to read “up to 
approximately 
.”
Dose increases to 1600 and 2400 
mg will use longer infusion times.
5.1.3.1, BMS-986258 
Monotherapy Dose 
Escalation (Part A) 
(including NSCLC PD 
cohorts) and Subcutaneous 
Dose (Part A1)
Updated number of participants to be 
treated.
Added 2 new dose levels to Part 
A.
5.1.3.2, BMS-986258 in 
Combination with 
Nivolumab Dose Escalation 
and PD Cohorts (Part B)
Updated number of participants to be 
treated.
Added 
 and 
reduced number of NSCLC PD 
cohorts in Part B.
5.1.3.3, BMS-986258 in 
Combination with 
Nivolumab Expansion 
Cohorts (Part C)
Included RP2D in the following sentence: 
“Treatment in Part C will be initiated when 
the RP2D, MTD, or MAD for BMS-986258 
in combination with nivolumab...”
Updated language for clarity.
5.1.4.2, Survival Follow up
Updated to be consistent with changes to 
Survival Follow-up period in 
Updated language for clarity.
5.2, Number of Participants
Updated number of participants.
Added 
 to 
Part A and Part B and reduced 
number of NSCLC PD cohorts in 
Part B.
5.4.2, Rationale for 
Subcutaneous Administration 
of BMS-986258 (Part A1)
Replaced previous text with text from 
Section 3.1.1 and new text has been updated 
to reflect current data.
Updated text to reduce 
redundancy of data and to add 
supporting information.
6.1, Inclusion Criteria; 2) 
Type of Participant and 
Target Disease 
Characteristics; d); v)
Removed inclusion criteria
duplicate of 2), d), iv)
6.1, Inclusion Criteria; 2) 
Type of Participant and 
Target Disease 
Characteristics; i); 4)
Updated text to indicate at screening that 
the date of and criteria used to determine 
disease progression should be documented 
on eCRF. Additionally, submission of 
available scans to support the information 
recorded in the eCRF may be required at the 
Sponsor’s discretion.
Updated language for clarity.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
6.1, Inclusion Criteria; 4) 
Age and Reproductive 
Status; c)
Added the following sentence: WOCBP 
participants must agree not to donate eggs 
(ova, oocytes) for the purpose of 
reproduction for the same time period.
Updated language for clarity.
6.2, Exclusion Criteria; 2) 
Prior/Concomitant Therapy
Added the following exclusion criterion: e) 
Treatment with botanical preparations (eg 
herbal supplements or traditional Chinese 
medicines) intended for general health 
support or to treat the disease under study 
within 2 weeks prior to 
randomization/treatment. Refer to Section 
7.7.1 for prohibited therapies.
Update to current BMS standards.
6.2, Exclusion Criteria; 5) 
Other Exclusion Criteria; a)
Updated to be consistent with Section 8.1.
Update for consistency.
6.3, Lifestyle Restrictions
6.4, Screen Failures
6.4.1, Retesting During
Screening or Lead-In Period
Text updated to reflect the current BMS 
required language for each of these sections.
Update to current BMS standards.
7.1, Treatments Administered
Added subsection for nivolumab dosing and 
infusion information
Updated to current nivolumab 
standards.
Table 7.1-1: Selection and 
Timing of Dose
Updated doses for BMS-986258 to include 
1600 and 2400 mg and updated rHuPH20 
dose to 
.
Added 
dose levels to 
Part A and Part B.
7.1.2, Management 
Algorithms for Immuno-
Oncology Agents
Myocarditis added to list of Management 
Algorithms. Algorithm was added to 
Appendix 8.
Update to current nivolumab 
standards.
7.4.1, Dose Delays Due to 
Toxicity
Added the following Dose Delay criteria:
Update to current nivolumab 
standards.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
7.7.1, Prohibited and/or 
Restricted Treatments
Added the following: Any botanical 
preparation (eg herbal supplements or 
traditional Chinese medicines) intended to 
treat the disease under study or provide 
supportive care. Use of marijuana and its 
derivatives for treatment of symptoms 
related to cancer or cancer treatment are 
permitted if obtained by medical 
prescription or if its use (even without a 
medical prescription) has been legalized 
locally.
Update to current BMS standards.
8.1, Discontinuation from 
Study Treatment
Added the following: Note: Under specific 
circumstances and only in countries where 
local regulations permit, a participant who 
has been imprisoned may be permitted to 
continue as a participant. Strict conditions 
apply and BMS approval is required.
Update to current BMS standards.
8.1.3, Treatment Beyond 
Progression
Added definition of further progression for 
participants who continue nivolumab study 
therapy beyond progression.
Update to current nivolumab 
standards. 
9.1.1, Imaging Assessment 
for the Study
Updated text to reflect that all images will 
be submitted to a central imaging vendor 
and scans may undergo blinded independent 
central review at the Sponsor’s discretion.
Added the following paragraph: 
Unscheduled CT/MRI should be submitted 
to central imaging vendor. X-rays and bone 
scans that clearly demonstrate interval 
progression of disease, for example most 
commonly as unequivocal lesions that are 
unmistakably new since the prior CT/MRI, 
should be submitted to central imaging 
vendor. Otherwise, they do not need to be 
submitted centrally.
Updated language for clarity.
9.1.1.1, Methods of 
Assessment
Added the following paragraph: MRI of 
brain (without and with contrast) should be 
acquired as outlined in 
 (Schedule 
of Activities). CT of the brain (without and 
with contrast) can be performed if MRI is 
contraindicated.
Updated language for clarity.
9.1.1.2, Imaging and Clinical 
Assessment
Replaced text.
Update to current BMS standards.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
9.2.1, Time Period and 
Frequency for Collecting AE 
and SAE Information

Clarified that SAEs will be collected 
for 30 days for participants assigned to 
treatment but never treated after the 
main ICF is signed.

Added timing for collection of all 
nonserious adverse events.

Added text stating that Investigators 
must assess all adverse events as to 
whether it is considered immune-
mediated. 
Updated language for clarity and 
to current BMS standards.
9.2.2, Method of Detecting 
AEs and SAEs
Text updated to reflect the current BMS 
required language.
Update to current BMS standards.
9.2.5, Pregnancy
For cases where study drug can be present 
in seminal fluid, updated text to read that if 
sexual activity has occurred between a male 
participant and a pregnant partner without 
the use of a condom during or for at least 5 
half-lives of study treatments plus 90 days 
(duration of sperm turnover) defined as 220 
days after the end of treatment in the male 
participant, then it should be reported even 
if male participant has had a vasectomy.
Update to current BMS standards.
9.2.7, Potential Drug Induced 
Liver Injury (DILI)
Deleted paragraph stating specific criteria 
for identifying potential DILI have not been 
identified.
DILI is defined in text.
9.3, Overdose
Change the following sentence to say 
“study drug” instead of “BMS-986258”
For this study, any dose of study drug 
greater than the assigned dose and 
considered excessive and medically 
important by the Investigator will be 
considered an overdose.
To include other treatments 
received by participants.
9.5, Pharmacokinetics
Updated the infusion time to read “up to 
approximately
” in footnote b in 
Table 9.5-2, Table 9.5-3, Table 9.5-4, and 
Table 9.5-5.
Dose increases to 1600 and 2400 
mg will use longer infusion times.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
10.1.1, Dose Escalation
Updated number of participants.
Added 
 dose levels to 
Part A and Part B and reduced 
number of NSCLC PD cohorts in 
Part B.
Appendix 4 Women Of 
Childbearing Potential 
Definitions And Methods Of 
Contraception
Added definition for end of relevant 
systemic exposure
Changed the number of days for use of 
effective methods of contraception for 
female partners of male participants and for 
male participants with pregnant or 
breastfeeding partners from 160 to 220 
days.
Update to current BMS standards.
Appendix 8 Management 
Algorithms
Updated treatment algorithms and added 
myocarditis algorithm.
Update to current nivolumab 
standards.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
Overall Rationale for Revised Protocol 03, 14-Mar-2019
The purpose of the revised protocol is to:
Also includes Administrative Letter 01 which removed the unit of dose strength of rHuPH20 from 
the protocol.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 3.3 Benefit/Risk 
Assessment
Added updated information on 
efficacy and safety data for NSCLC 
participants that had progressed on 
or after anti-PD(L)1 treatment and 
then received dual TIM-3 and PD-1 
blockade.
To provide the latest efficacy and 
safety data.
Section 3.3.6 Safety Monitoring on 
Study Therapy
Biopsies should be performed at 
minimal clinical risk and provided 
requirements for the biopsy. 
To ensure participant safety.
Section 5.1 Overall Study Design 
and other applicable sub-sections; 
 
 
 
Added language for PD cohorts, 
pre-screening period for NSCLC PD 
cohorts only, and 
 
To align the text and study 
schematics with the addition of the 
NSCLC PD cohorts.
Section 5.1.1 Pre-screening for PD 
Cohort only (NSCLC)
Added section describing that 
participants in PD NSCLC cohorts 
will be required to pre-screen for 
 status
To align the text with the addition of 
the NSCLC PD cohorts.
Section 5.1.3.1 BMS-986258 
Monotherapy Dose Escalation 
(Part A) (including PD cohorts) 
and Subcutaneous Dose (Part A1); 
Section 5.1.3.2 BMS-986258 in 
Combination with Nivolumab 
Dose Escalation and PD Cohorts 
(Part B) Table 7.1-1 Selection and 
Planned highest dose level of BMS-
986258 for monotherapy and 
combination therapy are changed 
from 800 mg to 1200 mg
Doses up to 
 QW have 
been tested in a definitive (GLP-
compliant) pre-clinical 1-month IV 
toxicity study with good tolerance. 
Escalation up to 1200mg will be 
based on safety, PK and PD data 
from the initially proposed cohorts.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Timing of Dose; Section 5.5.2.1 
BMS-986258
Section 5.4 Scientific Rationale for 
Study Design
Language added for the PD cohorts
To align the text with the addition of 
the NSCLC PD cohorts.
Section 5.4.4 Rationale for 
Pharmacodynamic cohorts selected 
based on 
Rationale added for the PD cohorts
Previous clinical studies with 
nivolumab monotherapy have 
shown that patients with TIM-3 
expression on 
 
 may have higher response 
rates than those with indeterminate 
expression.
Section 6.1 Inclusion Criteria 1) b) 
Signed Written Informed Consent
Added text regarding acceptable 
risk to the participant for the biopsy.
To protects the participant’s safety 
during biopsy procedure.
2) Type of Participant and Target 
Disease Characteristics
Participants with RCC, CRC, 
NSCLC, SCCHN: Removed: Anti-
PD(L)1 therapy naive participants 
may be eligible for Part B
To align the inclusion criteria 
throughout the protocol to be able to 
better compare data between 
monotherapy and combination 
cohorts.
Participants with NSCLC: added 
language for PD cohorts and for 
pre-treatment 
 
status
To understand the drug effect in a 
more specific population of 
participants.
Guidelines for participants with 
anti-PD-1/anti-PD-L1 
refractory/resistant RCC, CRC, 
NSCLC, and SCCHN
To more clearly define PD-(L)1 
resistant populations.
4) Age and Reproductive Status f) 
and Section 9.2.5 Pregnancy
Clarified that azoospermic males are 
exempt from contraceptive 
requirements unless the potential 
exists for fetal toxicity due to study 
drug being present in seminal fluid, 
even if the participant has 
undergone a successful vasectomy 
or if the partner is pregnant.
To align with BMS standards for 
contraception.
Section 6.2 Exclusion Criteria 
Medical History e) iv) (4) 
Removed pericarditis or significant 
pericardial effusion as an exclusion 
criteria
To correct unnecessary exclusion 
criteria.
Table 7.1-1 Selection and Timing 
of Dose
Added 1200 mg dosage level for 
BMS-986258
 
 
.. 
Escalation up to 1200mg will be 
based on safety, PK and PD data 
from the initially proposed cohorts.
Section 7.3 Blinding
Added text to allow randomization 
codes to be released prior to 
database lock
To facilitate the bioanalytical 
analysis of pharmacokinetic and 
immunogenicity samples.
Protocol Amendment No.: 07
Date: 16-Jun-2021
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Clinical Protocol
CA031002
BMS-986258
Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Appendix 3 ADVERSE EVENTS 
AND SERIOUS ADVERSE 
EVENTS: DEFINITIONS AND 
PROCEDURES FOR 
RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING
Entire appendix was replaced.
To align with the latest BMS 
standards.
Appendix 4 WOMEN OF 
CHILDBEARING POTENTIAL 
DEFINITIONS AND METHODS 
OF CONTRACEPTION
Updated the methods of 
contraception and requirements for 
male contraception with partners of 
childbearing potential.
To align with the latest BMS 
standards.
Overall Rationale for Revised Protocol 02, 12-Jun-2018:
The purpose of the revised protocol is to add a cohort (PartA1), to 
 subcutaneous (SC) 
administration of BMS-986258 using ENHANZEDrug Product (rHuPH20). Both Q4W and (SC) 
administration offer potential convenience and improved compliance to patients. Revised 
Protocol 02 adds Part A1 to the study design and seeks to confirm feasibility of Q4W dosing by 
SC route of administration of BMS-986258. Additionally microbiome analysis has been added to 
 the potential influence of the gut microbiome on cancer treatment outcomes. Sections in 
the synopsis have been updated to align with the protocol section changes listed below.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & 
Title
Description of Change
Brief Rationale
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.1.1, 
Rationale for 
Subcutaneous 
Administration of 
BMS-986258 (Part 
A1)
Added the rationale for adding 
Part A1 SC dosing of 
BMS-986258.
SC dosing objective has been added 
to Part A1 of this study to assess an 
alternative approach to dosing.
Section  3.3.1, 
Recombinant 
Human 
Hyaluronidase PH-
20 rHuPH20 
Added information about the 
pharmacology of new study 
drug - Recombinant Human 
Hyaluronidase PH-20 
(rHuPH20).
rHuPH20 will be co-administered 
with BMS-986258 SC
Section  3.3.3, 
BMS-986258 
Starting Dose for 
Part A1 
(Monotherapy SC)
Added Part A1 to the section 
describing the dose and timing 
of dosing in relation to the other 
parts of the study. 
SC dosing objective has been added 
to Part A1 of this study to assess an 
alternative approach to dosing.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.1, Overall 
Design: 
 
Section 5.1.2, 
Treatment Period: 
Section 5.1.2.1, 
BMS-986258 
Monotherapy Dose 
Escalation (Part A) 
and Subcutaneous 
Dose (Part A1); 
Section 7.1.1, Dose 
Limiting Toxicities, 
7.2, Method of 
Treatment 
Assignment
Sections added or modified 
based on addition of 
 relating to 
BMS-986258 SC dosing in Part 
A1.
 has 
been added as Part A1 of this study to
assess an 
 to 
BMS-986258 dosing.
Section 5.2, 
Number of 
Participants
Updated to include Part A1 
participants; up to 
approximately 
 participants in 
to evaluate up to two dose 
levels.
Additional subjects added 
 
.
Section 5.4.2, 
Rationale for 
Subcutaneous Dose 
Cohort (Part A1)
Section added based on 
 
 relating 
to bioavailability of 
subcutaneous dosing in Part A1. 
 has 
been added as Part A1 of this study to 
assess an alternative approach to 
dosing.
Section 5.5.2, 
Rationale for Dose 
Selection and 
Dosing Schedule
Added the rationale for 
subcutaneous administration of 
BMS-986258.
 has 
been added as Part A1 of this study to 
assess an alternative approach to 
dosing.
Section 6.1, 
Inclusion Criteria 
h) ii)
Included Part A1 where 
applicable in tumor types. In 
addition, for SCCHN modified 
the criteria for previous 
therapies 
h), ii)
Participants must have 
received and progressed on or 
after, or have been intolerant or 
refractory to, at least 1 standard 
chemotherapy regimen 
Clarified which tumor type inclusion 
criteria was applicable for Part A1.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & 
Title
Description of Change
Brief Rationale
containing anthracycline and 
taxane; in addition the 
participant must have received 
at least 1 regimen for the 
treatment of metastatic or 
locally advanced disease.
Section 7, 
Treatment: Section 
Added ENHANZEDrug 
Product (rHuPH20) as study 
treatment to tables and text and 
updated treatment assignments 
based 
 
 for 
subcutaneous dosing in Part A1.
To support the 
 
 has been added to this 
study.
Section 7.7.3 
Permitted Therapy
Revised the duration of 
corticosteroid treatment from 
less than 3 weeks to less than 1 
week for prophylaxis or for 
treatment of non-autoimmune 
conditions
Correction of original text to align 
with clinical practice.
Section 9.1.1.1 
Methods of 
Assessment 
For participants with SCCHN, a 
CT or MRI of the neck is 
required.
Imaging requirement for SCCHN 
participants.
Section 9.2.1 Time 
Period and 
Frequency for 
Collecting AE and 
SAE Information
Text revised to clarify timing of 
start of SAE and AE collection.
To clarify timing to start collection of 
SAE from signing of consent and AE 
collection from the start of study 
treatment.
Table 9.2.8-1 
Preferred Terms 
Included in 
Analysis of IMAEs 
to Support 
Removed the table and text 
listing specific preferred terms 
for immune mediated adverse 
events. 
The list of immune mediated adverse 
events is ever changing and it is not 
practical to provide the list in the 
protocol. 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & 
Title
Description of Change
Brief Rationale
Warnings and 
Precautions
Section 9.3 
Overdose
Text revised to clarify that 
overdoses that meet the 
regulatory definition of an SAE 
will be reported.
To align with the updated Appendix 
#3 “Adverse Events and Serious 
Adverse Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow up and 
Reporting”.
Section 9.5, 
Pharmacokinetics: 
Table 9.5-3, 
Pharmacokinetic 
Sampling Schedule 
for BMS-986258 
Q4W in 
Monotherapy 
Subcutaneous PK 
Sub-study (Part A1)
Table for pharmacokinetic 
sampling was added to include 
Part A1.
To support the 
 
 that has been added to this 
study.
Section 10.1.1, 
Dose Escalation: 
Section 10.3.1 
Efficacy Analysis
Section updated to include Part 
A1 sample size calculation and 
summary statistics.
To support the 
 
 that has been added to this 
study.
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Anti-TIM-3 mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & 
Title
Description of Change
Brief Rationale
Appendix 3 
Adverse Events 
And Serious 
Adverse Events: 
Definitions And 
Procedures For 
Recording, 
Evaluating, Follow 
Up And Reporting
Defines what AE events meet or 
do not meet the AE definition. 
Provides the definition of an 
SAE. Pregnancy and drug 
induced liver injury must follow 
same transmission timing and 
processes as used for SAEs
Appendix was updated to provide 
definitions and to align with 
Transcelerate Protocol Model 
Document.
Appendix 5 Recist 
1.1 Criteria
Appendix was updated. New 
title is: “Response Evaluation 
Criteria In Solid Tumors 
Guidelines (Version 1.1) With 
BMS Modifications”.
To be in alignment with the current 
RECIST Guidelines and BMS 
criteria.
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Anti-TIM-3 mAb
Overall Rationale for Revised Protocol 01, 08-Jan-2018:
The revised protocol clarifies some exclusion criteria, dose limiting criteria and criteria for 
discontinuation as described in the Summary of Key Changes table. Applies to all participants
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 6.3: 
Exclusion 
Criteria
Exclusion criteria 6.2.e.v  was 
updated to state that participants 
with active interstitial lung disease 
will be excluded
Not only history of, but active 
interstitial lung disease represent a 
potential risk factor for development 
of pneumonitis with the use of IO 
drugs
Section 8.1: 
Discontinuation 
from Study 
Treatment
Clarified that an exception to the 
discontinuation of BMS-986258 
can be made in the case of a 
nivolumab-related 
hypersensitivity/infusion reaction. 
Because nivolumab is administered 
first, if a participant presents with a 
reaction before the administration of 
BMS-986258 has started, treatment 
with BMS-986258 may continue after 
the hypersensitivity or infusion 
related reactions have been resolved.
All
Minor formatting and typographical 
corrections
Minor, therefore have not been 
summarized
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Anti-TIM-3 mAb
APPENDIX 12
REFERENCES
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
2
Babb J, Rogatko A, Zacks S. Cancer Phase I clinical trials: efficient dose escalation with 
overdose control. Stat Med 1998;17:1103-20.
3
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to Phase 
I cancer trials. Stat Med 2008;27:2420-39.
4
Neuenschwander B, Capkun-Niggli G, Branson M, et al. Summarizing historical information 
on controls in clinical trials. Clin Trials 2010;7:5-18.
5
Yin G, Yuan Y. Bayesian dose finding in oncology for drug combinations by copula 
regression. J R Stat Soc Ser C Appl Stat 2009;58(2):211-24.
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