A Phase 1/2 First-in-Human Study of BMS-986249 Alone and in Combination With Nivolumab in Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 1/2 First-in-Human Study of BMS-986249 Alone and in Combination with Nivolumab 
in Advanced Solid Tumors 
NCT Number: NCT03369223 
Document Date (Date in which document was last revised): 14 Mar 2023 

Page:
1
Protocol Number:
CA030001
IND Number:
136442
EUDRACT Number:
2018-000416-21
Date:
10-Oct-2017
Revised Date:
14-Mar-2023
Clinical Protocol CA030001
A Phase 1/2 First-in-Human Study of BMS-986249 Alone and in Combination with Nivolumab 
in Advanced Solid Tumors
Protocol Amendment 09
Incorporates Administrative Letter 07
Medical Monitoring Contact Information
Clinical Trial Physician - Medical Monitor
Bristol Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648 USA
Telephone 
Email: 
Clinical Scientist
Bristol Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648 USA
Telephone 
Email: 
24-hr Emergency Telephone Number
USA: +1-866-470-2267
International: +1-248-844-7390
Bristol Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
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this document without due authorization from BMS is requested to return it to BMS or 
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Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Protocol Amendment No.: 09
Date: 14-Mar-2023
2
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).
© 2023 Bristol-Myers Squibb Company
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Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Protocol Amendment No.: 09
Date: 14-Mar-2023
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 09
14-Mar-2023
The overall rationale for this protocol amendment is to remove exploratory 
endpoints (modified RECIST version 1.1 for immune-based therapeutics 
[iRECIST] and severe acute respiratory syndrome coronavirus 2 [SARS-
CoV-2]); to introduce the option of also supplying sites with 10-mL vials 
containing 50 mg of ipilimumab; to decrease participant and site burden by 
reducing pharmacokinetic (PK), anti-drug antibody (ADA), and biomarker 
sample collections; and to add clarifying language.
Administrative 
Letter 07
29-Sep-2022
Updated study personnel.
Protocol 
Amendment 08
22-Feb-2022
The primary reasons for Protocol Amendment 08 are to update and/or clarify 
the inclusion criteria to align with the current disease state and treatment 
landscape based on investigator feedback for Part 2.
Administrative 
Letter 06
09-Nov-2021
Updated study personnel.
Administrative 
Letter 05
17-May-2021
Addresses typographical errors for clarification purposes.
Revised 
Protocol 07
15-Nov-2020
This is a revised protocol to modify the treatment arms in the Part 2A 
Expansion Phase and define the Part 2B Expansion Phase. The Part 2A 
Expansion Phase will now include concurrent evaluation of 3 treatment arms 
in a randomized setting in melanoma (2 different dose regimens of BMS-
986249 in combination with nivolumab and 1 standard-of-care reference arm) 
rather than the previously defined 5 treatment arms. The Part 2B Expansion 
Phase will evaluate a single-dose regimen of BMS-986248 in combination 
with nivolumab in 3 tumor-specific cohorts. This revision also includes global 
changes to reduce redundancies and increase readability, incorporates updated 
learnings for BMS-986249, nivolumab, and ipilimumab, and adds language 
around COVID-19.
Revised 
Protocol 06
05-Aug-2019
This is a revised protocol that defines the selected BMS-986249 + nivolumab 
doses and schedules for Part 2A Arms A - C, updates modified intermediate 
dose levels in Part 1B, and incorporates other minor clarifying edits.
Revised 
Protocol 05
01-May-2019
This is a revised protocol to explicitly mention encephalitis as an example of 
a possible neurological adverse event, updates management algorithms for 
immuno-oncology agents, updates PD-L1 stratification criteria for Part 2A, 
clarifies screening biopsy criteria for Part 2A, and incorporates other 
clarifying modifications.
Revised 
Protocol 04
01-Mar-2019
This is a revised protocol to define the Part 2A Expansion Phase, which 
includes concurrent evaluation of three different dose regimens of BMS-
986249 in combination with nivolumab in relation to two standard of care 
reference arms in a randomized setting in melanoma. This protocol revision 
also updates DLT criteria, updates inclusion/exclusion criteria, changes the 
on-treatment biopsy timing, and provides clarifications around planned dose 
level modifications/intermediate dose levels, and incorporates other clarifying 
modifications.
Administrative 
Letter 04
01-Feb-2019
Part 1B combination dose escalation
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Anti-CTLA-4 Probody mAb
Protocol Amendment No.: 09
Date: 14-Mar-2023
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Administrative 
Letter 03
31-Oct-2018
Dose level modification
Revised 
Protocol 03
25-May-2018
Change dose-limiting toxicity evaluation period, change Parts 1A and 1B 
treatment assignments, provide a window for clinic visits, incorporate 
Administrative Letter 01, and minor typographical updates were made for 
consistency and clarity.
Administrative 
Letter 02
14-May-2018
Euderact number added
Admnistrative 
Letter 01
14-Mar-2018
To rectify incorrect imaging requirements for new bone lesions in prostate 
cancer subjects captured in the Prostrate Cancer Clinical Trials Working 
Group 3.
Revised 
Protocol 02
24-Jan-2018
Expand Part 1B tumor types, clarify the change in frequency of scans up to 
Week 48 versus thereafter, add co-administration of BMS-986249 + 
nivolumab in Part 1B, update 2 year treatment duration, add PCWG3 for 
prostate cancer, and minor typographical updates were made for consistency 
and clarity of the words participants, patients, and subjects.
Revised 
Protocol 01
20-Nov-2017
Includes responses to FDA questions about bladder and breast cancer 
population inclusion criteria, DLT criteria including ocular events, 
discontinuation from study treatment, clarification of expression of some 
tumor markers, updated imaging, biopsy and infusion time language.
Original
10-Oct-2017
Not applicable
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BMS-986249
Anti-CTLA-4 Probody mAb
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 09:
The overall rationale for this protocol amendment is to remove exploratory endpoints (modified 
RECIST version 1.1 for immune-based therapeutics [iRECIST] and severe acute respiratory 
syndrome coronavirus 2 [SARS-CoV-2]); to introduce the option of also supplying sites with 
10-mL vials containing 50 mg of ipilimumab; to decrease participant and site burden by reducing 
pharmacokinetic (PK), anti-drug antibody (ADA), and biomarker sample collections; and to add 
clarifying language.
The revisions are not considered substantial, as the primary and secondary endpoints as well as
patient safety and the benefit/risk assessment remain unchanged in the trial.
The Protocol Synopsis has been updated to align with the changes in the table below.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 09
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated Medical Monitor and 
Clinical Scientist contact information.
Updated with the most 
current contact 
information.
Section 2: Schedule of 
Activities
Table 2-1: Screening 
Schedule of Activities for 
All Study Parts
Table 2-2: On Treatment -
Schedule of Activities for 
Q4W Treatment
Administration in Part 1A, 
Part 1B, Part 2A Arm E, 
Part 2A Arm F, and the 
Nivolumab Maintenance 
Phase of Part 2A Arms A 
and D
Table 2-3: On Treatment -
Schedule of Activities for 
Part 2A Arm A and Arm 
D Combination Therapy 
Phase
Table 2-4: On-treatment 
Schedule of Activities for 
Part 2A Arm B and Arm 
C, and Part 2B
Revised adverse event (AE) and 
serious AE (SAE) monitoring 
language to indicate that for all study 
participants, safety reporting of AEs 
and SAEs should take place from the 
date of informed consent through 
100 days post end of treatment.
AE language was made 
consistent throughout the 
protocol:
For all study participants, 
safety reporting of AEs and 
SAEs should take place 
from the date of informed 
consent through 100 days 
post end of treatment.
This was implicit in prior 
versions of the protocol 
and clarified in this 
version.
Protocol Amendment No.: 09
Date: 14-Mar-2023
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 09
Section Number & Title
Description of Change
Brief Rationale
Table 2-5: Follow-up 
Procedural Outline for All 
Study Parts
Section 5.1.5.1: Safety 
Follow-up Period
Section 9.2.1: Time 
Period and Frequency for 
Collecting AE and SAE 
Information
Section 9.4: Safety
Section 2: Schedule of 
Activities
Table 2-2: On Treatment -
Schedule of Activities for 
Q4W Treatment 
Administration in Part 1A, 
Part 1B, Part 2A Arm E, 
Part 2A Arm F, and the 
Nivolumab Maintenance 
Phase of Part 2A Arms A 
and D
Table 2-3: On Treatment -
Schedule of Activities for 
Part 2A Arm A and Arm 
D Combination Therapy 
Phase
Table 2-4: On-treatment 
Schedule of Activities for 
Part 2A Arm B and Arm 
C, and Part 2B
Table 2-5: Follow-up 
Procedural Outline for All 
Study Parts;
Section 9.4: Safety
Removed on-treatment and follow-up
SARS-CoV-2 serology assessments.
Added statement indicating that 
testing for coronavirus disease 2019
(COVID-19) to inform decisions 
about clinical care during the study 
should follow local standard practice.
Allowing sites to test for 
COVID-19 per local 
standard practice to help 
inform decisions about 
clinical care during the 
study will decrease 
participant and site burden.
Section 2: Schedule of 
Activities
Table 2-5: Follow-up 
Procedural Outline for All 
Study Parts
Updated language about the duration 
of the follow-up period from “a total 
of 2 years” to “up to 100 days 
following the end of treatment.”
Revised language to reflect 
removal of long-term
survival follow up since 
further formal overall 
survival (OS) analyses will 
not be conducted. 
Protocol Amendment No.: 09
Date: 14-Mar-2023
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 09
Section Number & Title
Description of Change
Brief Rationale
Section 5.1.5.2: Imaging 
Follow-up Period
Section 5.1.5.3: Survival 
Follow-up Period
Updated survival follow up period 
from approximately 2 years to up to
100 days following the end of 
treatment.
Updated imaging follow up period 
from approximately 2 years to up to
100 days following the end of 
treatment 
Section 3.2.1.6: Clinical 
Safety Summary
Removed statement that dose 
escalation is currently ongoing.
Dose escalation is 
complete.
Section 4: Objectives and 
Endpoints
Table 4-2: Objectives and 
Endpoints: The Dose 
Expansion Phase in 
Melanoma (Part 2A)
Table 4-3: Objectives and 
Endpoints: The Dose 
Expansion Phase in 
Additional Tumors (Part 
2B)
Removed the exploratory objective to 
assess the impact of SARS-CoV-2 
serologic status on participants 
receiving BMS-986249 and to 
support health authority requests.
Based on low incidence of 
COVID-19 /
COVID-19-related disease
reported among study 
participants, exploratory 
assessment of impact of 
SARS-CoV-2 on study 
participants is unfeasible.
Removing further 
collection will reduce 
participant and site burden.
Section 9.8.1.6: Other 
Assessment
Removed section.
Removed section on 
SARS-CoV-2 serum
collection.
Section 4: Objectives and 
Endpoints
Table 4-1: Objectives and 
Endpoints: The Dose 
Escalation Phase (Part 1)
Table 4-2: Objectives and 
Endpoints: The Dose 
Expansion Phase in 
Melanoma (Part 2A)
Table 4-3: Objectives and 
Endpoints: The Dose 
Expansion Phase in 
Additional Tumors (Part 
2B)
Removed the exploratory objectives
of objective response rate (ORR), 
duration of response (DOR), and 
progression-free survival (PFS) per 
iRECIST by blinded independent 
central review (BICR) assessments 
for efficacy evaluation of 
BMS-986249 in combination with 
nivolumab and for ipilimumab in 
combination with nivolumab.
Updated to align with
current Bristol-Myers 
Squibb Company (BMS)
efficacy assessment
standards.
Protocol Amendment No.: 09
Date: 14-Mar-2023
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BMS-986249
Anti-CTLA-4 Probody mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 09
Section Number & Title
Description of Change
Brief Rationale
Section 9.1: Efficacy 
Assessments
Section 4: Objectives and 
Endpoints
Table 4-1: Objectives and 
Endpoints: The Dose 
Escalation Phase (Part 1)
Table 4-2: Objectives and 
Endpoints: The Dose 
Expansion Phase in 
Melanoma (Part 2A)
Table 4-3: Objectives and 
Endpoints: The Dose 
Expansion Phase in 
Additional Tumors (Part 
2B)
Section 9.8: Biomarkers
Removed mention of tumor
expressed and tumor-specific 
proteases.
Tumor-specific proteases 
biomarker analysis is no 
longer in scope for this 
study.
Section 4: Objectives and 
Endpoints
Added estimand framework language 
for primary objectives and endpoints 
for Parts 2A and 2B.
Align with BMS statistical 
analyses plan. Added 
estimand framework to 
clarify which event will be 
included in the primary 
endpoint of safety analysis 
in case of occurrence of 
intercurrent event like 
subsequent therapy.
Section 5.1.5.1: Safety 
Follow-up Period
Revised language regarding the 
timing for follow-up visits and 
evaluation of any new AEs after the
end of treatment (EOT) visit.
Added clarifying language.
Section 5.1.5.2: Imaging 
Follow-up Period
Stated that the initiation of another 
anti-cancer treatment will indicate the 
end of the Imaging Follow-up Period.
Imaging follow up will end at the 
conclusion of the safety follow up 
period.
Added clarifying language.
Section 5.1: Overall 
Design
Changed description of overall 
duration of study from 
“approximately 4 years” to “up to 
2.5 years.”
Added clarifying language.
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 09
Section Number & Title
Description of Change
Brief Rationale
Section 7.3: Treatment 
Duration
Added Section 7.3.
Section 7.1: Treatments 
Administered
Table 7.1-1: Study 
Treatments for CA030001
Added row for 50 mg/vial (5 mg/mL) 
ipilimumab solution for injection.
To provide an ipilimumab
vial option (50 mg/vial
5 mg/mL) that minimizes 
waste of drug product.
Section 7.7.3: Palliative 
Local Therapy
Revised language regarding 
evaluation of symptoms requiring 
palliative radiotherapy for objective 
evidence of disease progression.
Added clarifying language.
Section 9.5: 
Pharmacokinetics and 
Immunogenicity 
Assessments
Table 9.5-2: PK and ADA 
Sampling Schedule for 
BMS-986249 Q4W 
Monotherapy in Dose 
Escalation (Part 1A)
Table 9.5-3: PK and ADA 
Sampling Schedule for 
BMS-986249 Q4W in 
Combination with 
Nivolumab Q4W in Dose 
Escalation (Part 1B)
Table 9.5-4: PK and ADA 
Sampling Schedule for 
Part 2A Arm A
Table 9.5-5: PK and ADA 
Sampling Schedule for 
Part 2A Arm B and Arm 
C
Table 9.5-6: PK and ADA 
Sampling Schedule for 
Part 2A Arm D
Table 9.5-7: PK and ADA 
Sampling Schedule for 
Part 2A Arm E
Removed all PK and ADA samples 
after Cycle 3 Day 1 (C3D1), with the 
exception of occurrence of Grade 3+ 
infusion reactions.
Removed sample 
collection after C3D1 to 
reduce participant and site 
burden as available sample 
collections are sufficient 
for proposed analysis of
the secondary objective of 
PK characterization and the 
exploratory objective of 
ADA analysis. 
Removed footnote d in Table 9.5-4 
and Table 9.5-6.
Footnote was removed, as 
it only applied to the 
removed samples.
Protocol Amendment No.: 09
Date: 14-Mar-2023
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 09
Section Number & Title
Description of Change
Brief Rationale
Table 9.5-8: PK and ADA 
Sampling Schedule for 
Part 2A Arm F
Table 9.5-9: PK and ADA 
Sampling Schedule for 
Part 2B
Section 9.8.3: Biomarker 
Sampling Schedule
Table 9.8.3-1: Biomarker 
Sampling Schedule for All 
Study Parts
Removed whole blood (germline and 
T cell receptor), whole blood 
(PAXgene), blood 
(immunophenotyping), plasma, 
serum, and anti-SARS-CoV-2 
serology assessments 
 
.
Removed footnote b on 
anti-SARS-CoV-2 serology.
Removed sample 
collection after 
to 
reduce participant and site 
burden as available sample 
collections are sufficient 
for proposed analysis of 
the exploratory endpoint.
Section 10.2: Populations 
for Analyses
Table 10.2-1: Populations 
for Analyses
Section 10.3.1: Analyses
Removed definition of 
response-evaluable population for 
analysis.
Response-evaluable 
definition would not apply 
for the clinical study 
report. Removed for 
consistency and clarity.
Outlined the timing of primary 
analyses
Added clarifying language
Appendix 2
Added new section:
BMS Commitment to Diversity in 
Clinical Trials
Align with BMS 
commitment to diversity in 
clinical trials. 
Added new section:
Data Protection, Data Privacy, and 
Data Security
Align with BMS practice 
and comply with European 
Union Clinical Trials 
Regulation (EU-CTR)
requirement.
All
Minor formatting and typographical 
corrections.
Minor, therefore, have not 
been summarized.
Protocol Amendment No.: 09
Date: 14-Mar-2023
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 09: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 09 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.2 Background ....................................................................................................... 
 
3.2.1 BMS-986249 ............................................................................................ 
 
3.2.1.1 Generation of an Anti-human CTLA-4 Probody mAb .................... 
 
3.2.1.2 BMS-986249 Nonclinical Pharmacology ....................................... 
 
3.2.1.3 BMS-986249 Nonclinical Pharmacokinetics .................................. 
 
3.2.1.4 BMS-986249 Nonclinical Toxicology ............................................. 
 
3.2.1.5 BMS-986249 Clinical Pharmacokinetics ........................................ 
 
3.2.1.6 Clinical Safety Summary ................................................................. 
 
3.2.2 Nivolumab ................................................................................................ 
 
3.2.2.1 Clinical Pharmacokinetics of Nivolumab ....................................... 
 
3.2.3 Ipilimumab ............................................................................................... 
 
3.2.4 Nivolumab Combined with Ipilimumab ................................................... 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Screening Period ...................................................................................... 
 
5.1.2 Treatment Period ..................................................................................... 
 
5.1.2.1 BMS-986249 Monotherapy Escalation (Part 1A) ........................... 
 
5.1.2.2 Safety Evaluation of Combination Doses of BMS-986249 with 
Nivolumab (Part 1B) ............................................................................. 
 
5.1.2.3 Dose Escalation Decisions for the BMS-986249 Monotherapy 
Escalation (Part 1A) and the Safety Evaluation of Combination Doses 
of BMS-986249 with Nivolumab (Part 1B) ........................................... 
 
5.1.2.4 The BMS-986249 Cohort Expansion Combination Therapy (Part 2)
............................................................................................................... 
 
5.1.3 Treatment Beyond Progression ................................................................ 
 
5.1.4 Window Visits........................................................................................... 
 
5.1.5 Follow-up ................................................................................................. 
 
5.1.5.1 Safety Follow-up Period ................................................................. 
 
5.1.5.2 Imaging Follow-up Period .............................................................. 
 
5.1.5.3 Survival Follow-up Period .............................................................. 
 
5.1.6 Data Monitoring Committee and Other External Committees ................ 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
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Clinical Protocol
BMS-986249
CA030001
Anti-CTLA-4 Probody mAb
Protocol Amendment No.: 09
Date: 14-Mar-2023
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5.4 Scientific Rationale for Study Design .............................................................. 
 
5.4.1 Rationale for the BMS-986249 Monotherapy Dose Escalation (Part 1A) 
and the Safety Evaluation of Combination Doses of BMS-986249 with 
Nivolumab (Part 1B) Design ...................................................................... 
 
5.4.2 Rationale for the Combination of BMS-986249 and Nivolumab ............. 
 
5.4.3 Rationale for Tumor Selection for Part 1B .............................................. 
 
5.4.4 Rationale for Treatment Duration ........................................................... 
 
5.4.5 Rationale for Treatment Beyond Progression ......................................... 
 
5.4.6 Rationale for Selecting Melanoma in Part 2A Expansion ....................... 
 
5.4.7 Rationale for Part 2A Expansion Reference Arms .................................. 
 
5.4.7.1 Rationale for Ipilimumab and Nivolumab Combination Therapy as 
a Reference ............................................................................................ 
 
5.4.7.2 Rationale for Nivolumab Monotherapy as a Reference .................. 
 
5.4.8 Rationale for Part 2A Stratification by M-Staging and PD-L1 Status .... 
 
5.4.9 Rationale for Selecting HCC, CRPC, and TNBC in Part 2B Expansion . 
 
5.4.10 Rationale for Quality of Life Evaluation ............................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 BMS-986249 Rationale for Starting Dose in Humans ............................. 
 
5.5.1.1 Starting Dose Selection Supported by BMS-986249 Nonclinical 
Pharmacology ....................................................................................... 
 
5.5.1.2 Starting Dose Selection Supported by the HNSTD in Monkeys ...... 
 
5.5.1.3 Starting Dose Selection Based on Ipilimumab Clinical Safety Data
............................................................................................................... 
 
5.5.1.4 Rationale for Flat Dosing ............................................................... 
 
5.5.2 Rationale for Ipilimumab and Nivolumab 30-minute Infusions .............. 
 
5.5.3 Rationale for BMS-986249 and Nivolumab Co-administration .............. 
 
5.5.4 Rationale for Evaluating Different Dose Levels and Schedules of BMS-
986249 in Combination with Nivolumab in Part 2A .................................. 
 
5.5.5 Rationale for Q3W dosing of BMS-986249 and Nivolumab in Part 2A 
Arm A .......................................................................................................... 
 
5.5.6 Rationale for Dose Selection in Part 2B .................................................. 
 
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 Period ......................................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Schedule of Dose for Each Investigational Product ................................ 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Treatment Duration ........................................................................................... 
 
7.4 Blinding............................................................................................................. 
 
7.5 Dosage Modification ......................................................................................... 
 
7.5.1 Dose-limiting Toxicities ........................................................................... 
 
7.5.1.1 Gastrointestinal Dose-limiting Toxicity .......................................... 
 
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Clinical Protocol
BMS-986249
CA030001
Anti-CTLA-4 Probody mAb
Protocol Amendment No.: 09
Date: 14-Mar-2023
12
10.0
Approved
930119402
10.0
v
Approved
1.0
v

7.5.1.2 Hepatic Dose-limiting Toxicity ....................................................... 
 
7.5.1.3 Hematologic Dose-limiting Toxicity ............................................... 
 
7.5.1.4 Dermatologic Dose-limiting Toxicity ............................................. 
 
7.5.1.5 Other Dose-limiting Toxicities ........................................................ 
 
7.5.2 Management Algorithms for Immuno-oncology Agents .......................... 
 
7.5.3 Dose Delays Due To Toxicity .................................................................. 
 
7.5.3.1 Criteria to Resume Treatment ......................................................... 
 
7.5.4 Exceptions to Permanent Discontinuation Criteria ................................. 
 
7.5.5 Management of Drug-related Infusion Reactions.................................... 
 
7.6 Preparation/Handling/Storage/Accountability .................................................. 
 
7.6.1 Retained Samples for Bioavailability/Bioequivalence ............................. 
 
7.7 Treatment Compliance ...................................................................................... 
 
7.8 Concomitant Therapy........................................................................................ 
 
7.8.1 Prohibited and/or Restricted Treatments................................................. 
 
7.8.2 Permitted Therapy ................................................................................... 
 
7.8.3 Palliative Local Therapy .......................................................................... 
 
7.8.3.1 Imaging Restriction and Precautions ............................................. 
 
7.9 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Treatment Beyond Progression ................................................................ 
 
8.1.1.1 Discontinuation Due to Further Progression (Confirmed 
Progression) .......................................................................................... 
 
8.1.2 Post-treatment Study Follow-up .............................................................. 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.2.1 Individual Discontinuation Criteria ........................................................ 
 
8.3 Lost to Follow-up .............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Imaging Assessment for the Study............................................................ 
 
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 Immune-mediated Adverse Events ........................................................... 
 
9.2.8 Potential Drug-induced Liver Injury ....................................................... 
 
9.2.9 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Vital Signs ................................................................................................ 
 
9.4.3 Electrocardiograms ................................................................................. 
 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
 
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Clinical Protocol
BMS-986249
CA030001
Anti-CTLA-4 Probody mAb
Protocol Amendment No.: 09
Date: 14-Mar-2023
13
10.0
Approved
930119402
10.0
v
Approved
1.0
v

9.4.5 Imaging Safety Assessment ...................................................................... 
 
9.5 Pharmacokinetics and Immunogenicity Assessments ...................................... 
 
 ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.7.1 ADME Sampling ...................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Peripheral Blood Biomarkers .................................................................. 
 
9.8.1.1 Soluble Biomarkers ......................................................................... 
 
9.8.1.2 Immunophenotyping ........................................................................ 
 
9.8.1.3 T cell Repertoire Analysis ............................................................... 
 
9.8.1.4 Germline DNA Variants .................................................................. 
 
 ................................. 
 
9.8.2 Tumor Samples......................................................................................... 
 
9.8.2.1 Characterization of Tumor Immune Microenvironment ................. 
 
 
 
 
9.8.3 Biomarker Sampling Schedule ................................................................. 
 
9.8.4 Additional Research Collection ............................................................... 
 
9.9 Patient-reported Outcomes................................................................................ 
 
9.9.1 EORTC QLQ-C30 .................................................................................... 
 
9.9.2 EQ-5D-3L ................................................................................................ 
 
9.9.3 FACIT GP5 .............................................................................................. 
 
9.9.4 PRO-CTCAE ............................................................................................ 
 
9.10 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 Part 2A Cohort Expansion ..................................................................... 
 
10.1.2.1 Original Sample Size Calculation ................................................. 
 
10.1.2.2 Changes to Sample Size Assumptions for Revised Protocol 07 .... 
 
10.1.3 Part 2B Cohort Expansion ..................................................................... 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Analyses ................................................................................................. 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.3 Pharmacokinetic Analysis for BMS-986249 .......................................... 
 
10.3.4 Immunogenicity ...................................................................................... 
 
10.3.5 Biomarker Analyses ............................................................................... 
 
10.3.6 ECG Analyses ........................................................................................ 
 
10.3.7 Patient-Reported Outcome Analyses ..................................................... 
 
10.3.8 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
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Clinical Protocol
BMS-986249
CA030001
Anti-CTLA-4 Probody mAb
Protocol Amendment No.: 09
Date: 14-Mar-2023
14
10.0
Approved
930119402
10.0
v
Approved
1.0
v

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 RECIST 1.1 CRITERIA........................................................................ 
 
APPENDIX 6 PCWG3 GUIDELINES (WITH MODIFIED RECIST CRITERIA FOR 
SOFT TISSUE LESION ASSESSMENT) ............................................................. 
 
APPENDIX 7 EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ................................................................................... 
 
APPENDIX 8 NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ................................................................................................ 
 
APPENDIX 9 MANAGEMENT ALGORITHMS ....................................................... 
 
 ................................................... 
 
APPENDIX 11 AJCC MELANOMA STAGING ........................................................ 
 
APPENDIX 12 SCHEDULE OF ACTIVITIES AND PHARMACOKINETICS 
SAMPLING SCHEDULE FOR POTENTIAL ALTERNATIVE DOSE 
SCHEDULE IN FOR PART 1 CA030001 ............................................................. 
 
APPENDIX 13 CHILD-PUGH SCORE ...................................................................... 
 
APPENDIX 14 COUNTRY SPECIFIC REQUIREMENTS/DIFFERENCES ............ 
 
APPENDIX 15 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
 
 
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Clinical Protocol
BMS-986249
CA030001
Anti-CTLA-4 Probody mAb
Protocol Amendment No.: 09
Date: 14-Mar-2023
15
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
1
SYNOPSIS
Protocol Title: A Phase 1/2 First-in-Human Study of BMS-986249 Alone and in Combination 
with Nivolumab in Advanced Solid Tumors
Study Phase: 1/2
Rationale:
This is a Phase 1/2, first-in-human study of BMS-986249, an anti-cytotoxic T lymphocyte-
associated protein 4 (CTLA-4) Probody™(PROBODY is a trademark of CytomX Therapeutics, 
Inc.) monoclonal antibody (mAb) of ipilimumab, alone and in combination with nivolumab 
(anti-programmed cell death 1 [PD-1]), in participants with advanced solid tumors. Anti-CTLA-4 
(ipilimumab) and anti-PD-1 (nivolumab) are approved immunotherapies for the treatment of select 
malignancies. Ipilimumab is a mAb that targets the checkpoint receptor CTLA-4 to activate 
anti-tumor immunity. Ipilimumab was the first checkpoint inhibitor approved for the treatment of 
human cancer, and it was the first therapeutic to demonstrate a survival advantage in metastatic 
melanoma. While ipilimumab has been shown to activate anti-tumor immune responses alone and 
in combination with nivolumab, this activity is often accompanied by immune-related adverse 
events. BMS-986249 is an anti-CTLA-4 Probody mAb made by the addition of 44 amino acids to 
the N-terminus of both light chains of the human anti-CTLA-4 antibody (Ab) ipilimumab. 
BMS-986249 contains a masking peptide with a cleavable linker containing protease cleavable 
sites for specific enzymes that are more prevalent and/or active in tumors than in peripheral tissues. 
The proform of the Ab, or “Probody,” has reduced binding to the target and lower activity of the 
prodrug outside the tumor. When the linker is preferentially cleaved at the tumor site, the fully 
active form is released. Restricting activity in this manner is hypothesized to reduce the systemic 
autoimmune side effects normally seen after ipilimumab treatment while maintaining its full 
activity in the tumor microenvironment, resulting in an improved therapeutic index.
Study Population:
Participants must be at least 18 years old and have histologic or cytologic confirmation of a solid 
tumor that is advanced (metastatic, recurrent, and/or unresectable) with measurable disease per 
RECIST v1.1 (Appendix 5) or metastatic disease documented by either bone lesions on 
radionuclide bone scan and/or soft tissue lesions on CT/MRI per PCWG3 criteria for prostate
cancer (Appendix 6) and have at least 1 soft-tissue tumor lesion accessible for biopsy. For Part 2B 
participants with HCC, intermediate disease is allowed.
Objectives and Endpoints:
The objectives and endpoints for the primary, secondary, and exploratory analysis of this study are 
shown in Table 1-1 (Part 1), Table 1-2 (Part 2A), and Table 1-3 (Part 2B).
Protocol Amendment No.: 09
Date: 14-Mar-2023
16
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 1-1:
Objectives and Endpoints: The Dose Escalation Phase (Part 1)
Objectives
Endpoints
Primary
•
To characterize the safety, tolerability, and DLTs 
and to determine the MTD/RP2D of BMS-986249 
administered as monotherapy and in combination 
with nivolumab in participants with advanced solid 
tumors (Parts 1A and 1B)
•
Incidence of AEs, SAEs, AEs meeting 
protocol-defined DLT criteria, AEs leading to 
discontinuation, death, and laboratory 
abnormalities
Secondary
•
To characterize the PK of BMS-986249 when 
administered alone and in combination with 
nivolumab
•
Summary measures of PK parameters of 
BMS-986249
•
To assess the preliminary antitumor activity of 
BMS-986249 alone and in combination with 
nivolumab in advanced solid tumors (Parts 1A and 
1B) using RECIST v1.1 or PCWG3 (for prostate 
cancer)
•
ORR, DOR, PFS, and TTR per RECIST v1.1 or 
PCWG3 (for prostate cancer)
Exploratory
•
To explore the associations between PK of
BMS-986249 and nivolumab, safety, efficacy, and 
clinical biomarkers such as, but not limited to 
T-cell specific genes
•
Association measures between BMS-986249 PK 
levels, select outcomes, and biomarkers of interest
•
To characterize the immunogenicity of 
BMS-986249 and nivolumab
•
Incidence of ADA to nivolumab and BMS-986249
•
To assess the potential effect of BMS-986249 
when administered as monotherapy on the QTc 
interval
•
Summary measures of ECG parameters and 
changes in QTcF (ΔQTcF) from baseline
Abbreviations: ADA = anti-drug antibody; AE = adverse event; DLT = dose-limiting toxicity; DOR = duration of 
response; ECG = electrocardiogram; MTD = maximum tolerated dose; ORR = Objective Response Rate; PCWG3 = 
Prostate Cancer Working Group 3; PFS = progression-free survival; PK = pharmacokinetics; QTc = QT interval 
corrected; QTcF = QT interval corrected for heart rate using Fridericia’s formula; RECIST = Response Evaluation 
Criteria in Solid Tumors; RP2D = recommended Phase 2 dose of BMS-986249; SAE = serious adverse event; 
TTR = time to response.
Protocol Amendment No.: 09
Date: 14-Mar-2023
17
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 1-2:
Objectives and Endpoints: The Dose Expansion Phase in Melanoma 
(Part 2A)
Objectives
Endpoints
Primary
•
To evaluate the preliminary safety and tolerability 
of BMS-986249 in combination with nivolumab 
(Arm C and Arm F) relative to ipilimumab in 
combination with nivolumab (Arm D) in 
participants with previously untreated, 
unresectable or metastatic melanoma
•
Incidence of treatment-related Grade 3-5 AEs 
within 24 weeks
•
To evaluate the preliminary efficacy of 
BMS-986249 in combination with nivolumab 
(Arm C and Arm F) relative to historic nivolumab 
monotherapy data in participants with previously 
untreated, unresectable or metastatic melanoma
•
ORR as assessed by investigator using RECIST 
v1.1
Secondary
•
To assess the anti-tumor activity of BMS-986249 
in combination with nivolumab (Arm C and Arm 
F) and ipilimumab in combination with nivolumab 
(Arm D) in participants with previously untreated, 
unresectable or metastatic melanoma
•
ORR, DOR, PFS, and TTR as assessed by 
investigator using RECIST v1.1
•
To assess the safety and tolerability of BMS-
986249 in combination with nivolumab (Arm C
and Arm F), and ipilimumab in combination with 
nivolumab (Arm D) in participants with previously 
untreated, unresectable or metastatic melanoma
•
Incidence of AEs, SAEs, AEs leading to 
discontinuation, death, and laboratory 
abnormalities
•
To characterize the PK of BMS-986249 when 
administered in combination with nivolumab
•
Summary measures of PK parameters of 
BMS-986249 in combination with nivolumab
•
To evaluate time to deterioration (TTD) in Quality 
of Life (QoL) and physical functioning
•
TTD as defined by a minimally important decrease 
from baseline ≥10 points on the European 
Organisation for Research and Treatment of 
Cancer (EORTC) QLQ-C30 global health 
status/quality of life subscale (items 29 & 30) and 
Physical Functioning Scale (items 1 to 5)
Exploratory
Protocol Amendment No.: 09
Date: 14-Mar-2023
18
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 1-2:
Objectives and Endpoints: The Dose Expansion Phase in Melanoma 
(Part 2A)
Objectives
Endpoints
•
To explore the associations between PK of 
BMS-986249, ipilimumab and nivolumab, safety, 
efficacy, and clinical biomarkers such as, but not 
limited to T-cell specific genes 
•
Association measures between BMS-986249, 
ipilimumab, and nivolumab PK levels, select 
outcomes, and biomarkers of interest
•
To characterize the immunogenicity of 
BMS-986249, ipilimumab and nivolumab
•
Incidence of ADA to ipilimumab, nivolumab, and 
BMS-986249
•
To explore OS of BMS-986249 in combination 
with nivolumab (Arm C and Arm F) and 
ipilimumab in combination with nivolumab 
(Arm D)
•
OS rate at 1 and 2 years
•
To evaluate changes in QoL, health status, and 
patient-reported tolerability
•
Mean scores and post-baseline score changes for 
all EORTC QLQ-C30 subscales, EQ-5D-3L utility 
index and VAS, and n (%) of endorsing 
participants by arm and time point for FACIT GP5 
item and PRO-CTCAE items
Abbreviations: ADA = anti-drug antibody; AE = adverse event; DOR = duration of response; EORTC QLQ-C30 = 
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30; EQ-5D-3L = 
European Quality of Life – 5 Dimension – 3 Level Questionnaire; FACIT GP5 = Functional Assessment of Chronic 
Illness Therapy General Physical item 5; ORR = objective response rate; OS = overall survival; PFS = progression-
free survival; PK = pharmacokinetics; PRO-CTCAE = Patient-reported Outcomes version of the Common 
Terminology Criteria for Adverse Events; QoL - Quality of Life; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event; TTR = time to response; VAS = visual analogue scale.
Protocol Amendment No.: 09
Date: 14-Mar-2023
19
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 1-3:
Objectives and Endpoints: The Dose Expansion Phase in Additional 
Tumors (Part 2B)
Objectives
Endpoints
Primary
•
To evaluate the preliminary safety and tolerability of 
BMS-986249 in combination with nivolumab in 
participants with previously treated HCC, CRPC, and 
TNBC.
•
Incidence of treatment-related Grade 3-5 AEs 
within 24 weeks
Secondary
•
To assess the preliminary anti-tumor activity of 
BMS-986249 in combination with nivolumab in 
participants with previously treated HCC, CRPC, and 
TNBC
•
To characterize the safety and tolerability of BMS-
986249 in combination with nivolumab in participants 
with previously treated HCC, CRPC, and TNBC
•
To characterize the PK of BMS-986249 when 
administered in combination with nivolumab in 
participants with previously treated HCC, CRPC, and 
TNBC
•
ORR, DOR, PFS, and TTR as assessed by 
investigator per RECIST v1.1 or PCWG3 (for 
prostate cancer). PSA response rate for prostate 
cancer
•
Incidence of AEs, SAEs, AEs leading to 
discontinuation, death, and laboratory 
abnormalities 
•
Summary measures of PK parameters of 
BMS-986249 in combination with nivolumab
Exploratory
•
To explore the associations between PK of 
BMS-986249 and nivolumab, safety, efficacy, and 
clinical biomarkers such as, but not limited to T-cell 
specific genes
•
Association measures between BMS-986249 
and nivolumab PK levels, select outcomes, and 
biomarkers of interest
•
To characterize the immunogenicity of BMS-986249 
and nivolumab
•
Incidence of ADA to nivolumab and 
BMS-986249
•
To explore OS
•
To evaluate changes in QoL, health status, and patient 
reported tolerability
•
OS rate at 1 and 2 years
•
Mean scores and post-baseline score changes 
for all EORTC QLQ-C30 subscales, EQ-5D-3L 
utility index and VAS, and n (%) of endorsing 
participants by arm and time point for FACIT 
GP5 item and PRO-CTCAE items
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CRPC = castration-resistant prostate cancer; DOR = 
duration of response; EQ-5D-3L = European Quality of Life – 5 Dimension – 3 Level Questionnaire; EORTC QLQ-
C30= European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30; FACIT
Protocol Amendment No.: 09
Date: 14-Mar-2023
20
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
GP5 = functional assessment of chronic illness therapy general phycial item 5; HCC = hepatocellular carcinoma; ORR 
= Objective Response Rate; OS = overall survival; PCWG3 = Prostate Cancer Working Group 3; PFS = progression-
free survival; PK = pharmacokinetics; PRO-CTCAE = patient reported outcomes common terminology criteria for 
adverse events; PSA = prostate-specific antigen; QoL = quality of life; RECIST = Response Evaluation Criteria in 
Solid Tumors; SAE = serious adverse events; TNBC = triple-negative breast cancer; TTR = time to response; VAS = 
visual analogue scale.
Overall Design:
This is a Phase 1/2, open-label study of BMS-986249, administered as a single agent and in 
combination with nivolumab in participants with advanced solid tumors. The study is composed 
of 2 parts: dose escalation and dose expansion.
This study will evaluate the safety, tolerability, pharmacokinetic (PK), 
, and 
preliminary efficacy profile of BMS-986249 alone and in combination with nivolumab. In the 
Dose Escalation Phase (Part 1) various doses of BMS-986249 will be given alone (Part 1A) or in 
combination with nivolumab (Part 1B). The BMS-986249 Cohort Expansion Combination 
Therapy Phase (Part 2) will expand a specific patient population to assess the anti-tumor activity, 
safety, and tolerability of BMS-986249 in combination with nivolumab.
All participants will complete up to 3 study periods: Screening (up to 30 days), Treatment (up to 
2 years), and Follow-up (starting after end of treatment [EOT], and is comprised of Safety, 
Imaging, and Survival Follow-up). The duration of the study will approximately 2 years and 3 
months (treatment up to 2 years and Follow-up Period of 100 days post EOT).
At the Sponsor’s discretion, scans will be submitted to an imaging core laboratory and may be 
reviewed by blinded independent central review at a later date or at any time during the study.
Number of Participants: 
•
Part 1A Monotherapy Escalation: The total sample size is up to approximately 45 evaluable 
participants.
•
Part 1B Combination Escalation: The total sample size is up to approximately 60 evaluable 
participants.
•
Part 2A Expansion in Melanoma: The total sample size is up to approximately 200 evaluable 
participants with approximately 60 evaluable participants each treated in Arm C, Arm D, and 
Arm F, respectively. Prior to Revised Protocol 07, up to approximately 20 evaluable 
participants may have been enrolled across Arms A, B, and E, collectively.
•
Part 2B Additional Tumor Cohort Expansion: The total sample size is up to approximately 
120 evaluable participants with approximately 40 evaluable participants per tumor type cohort.
Treatment Arms:
•
Part 1: The Dose Escalation Phase, where the dose of BMS-986249 given alone (Part 1A) or 
in combination with nivolumab (Part 1B) will be escalated to determine the maximum tolerated
dose (MTD)/recommended Phase 2 dose.
Protocol Amendment No.: 09
Date: 14-Mar-2023
21
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
−
Part 1A, the BMS-986249 Monotherapy Dose Escalation, will escalate the dose of 
BMS-986249 to determine a safe and efficacious dose. The study will first evaluate the 
safety and tolerability of BMS-986249 monotherapy administered once every 4 weeks 
(Q4W) up to 2 years. Dose escalation will be based on dose-limiting toxicities using a 
Bayesian Logistic Regression Model employing the escalation with overdose control 
principle.
−
Part 1B, the Safety Evaluation of Combination Doses of BMS-986249 with nivolumab, 
will evaluate the safety and tolerability of BMS-986249 in combination with nivolumab. 
Part 1B will begin only when data (safety and PK) on BMS-986429 at 240 mg (equivalent 
to approximately 3 mg/kg) and 800 mg (equivalent to approximately 10 mg/kg) are 
available from the BMS-986249 Monotherapy Dose Escalation cohort (Part 1A). The dose 
of BMS-986429 will be escalated, whereas the dose of nivolumab is fixed at 480 mg Q4W. 
However, if an MTD is identified, then additional cohorts with lower doses of nivolumab
and then potential higher doses of BMS-986249 may be studied as outlined below and in 
the study design schematic (Figure 1-1). Alternative administration schedules of 
BMS-986249 (eg, every 8 weeks) may also be explored after clinical evaluation of 
available safety, PK, and 
 data. Alternative dose schedules will be 
initiated and documented by a note to file or administrative letter following discussions 
and agreement between the investigators and Medical Monitor (or designee). The goal for 
the combination dose escalation is to identify at least 2 dose combinations with nivolumab 
as follows: 
♦One combination with a high dose of BMS-986249 with nivolumab that has an 
acceptable safety profile and with anticipation of potentially increased efficacy over 
what has been observed with ipilimumab and nivolumab combination
♦A second dose combination with a lower BMS-986249 dose in combination with 
nivolumab that has a potentially optimal safety and tolerability profile that is improved 
over the ipilimumab and nivolumab combination yet may yield at least comparable 
efficacy
•
Part 2: The BMS-986249 Cohort Expansion Combination Therapy Phase will open upon an 
overall assessment of available preliminary safety, PK, and
data from 
Part 1A and Part 1B. The different dose levels selected for Part 2 will not exceed the highest 
dose level assessed and deemed tolerable in Part 1. Part 2 will expand a specific patient 
population to assess the anti-tumor activity of BMS-986249 in combination with nivolumab. 
Safety, tolerability, PK, 
, and patient-reported outcome information of 
BMS-986249 in combination with nivolumab will also be evaluated. 
−
The BMS-986249 in Combination with Nivolumab Randomized Cohort Expansion in 
Melanoma (Part 2A) will include participants with previously untreated, unresectable or 
metastatic melanoma. Part 2A participants will be stratified by programmed death ligand-
1 (PD-L1) status (≥1% tumor cell surface expression versus < 1% tumor cell 
expression/indeterminate) and American Joint Committee on Cancer M-stage Version 7
(M0/M1a/M1b versus M1c) and initially randomized 1:1:1:1:1 between 5 treatment arms:
♦Arm A: 240 mg BMS-986249 in combination with 360 mg nivolumab administered
intravenously (IV) every 3 weeks (Q3W) for 4 doses (Combination Therapy Phase) as 
Protocol Amendment No.: 09
Date: 14-Mar-2023
22
10.0
Approved
930119402
10.0
v
Approved
1.0
v

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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
a co-administration, followed by 480 mg nivolumab monotherapy administered IV 
over approximately 30 minutes Q4W (Maintenance Phase), which will begin 3 weeks 
after the last combination dose.
♦Arm B: 800 mg BMS-986249 administered IV Q8W in combination with 480 mg 
nivolumab administered IV Q4W. Co-administration will continue on cycles where 
both study treatments are scheduled, while nivolumab will be administered IV over 
approximately 30 minutes when scheduled as a monotherapy.
♦Arm C: 1,200 mg BMS-986249 administered IV Q8W in combination with 480 mg 
nivolumab administered IV Q4W. Co-administration will continue on cycles where 
both study treatments are scheduled, while nivolumab will be administered IV over
approximately 30 minutes when scheduled as a monotherapy.
♦Arm D: 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered IV 
Q3W for 4 doses (Combination Therapy Phase), followed by 480 mg nivolumab 
monotherapy administered IV over approximately 30 minutes Q4W (Maintenance 
Phase), which will begin 3 weeks after the last combination dose. Nivolumab and 
ipilimumab will be administered sequentially as 2 separate IV infusions. Nivolumab 
will be given first, over approximately 30 minutes, followed by ipilimumab over 
approximately 30 minutes, beginning approximately 30 minutes after completion of the 
infusion of nivolumab.
♦Arm E: 480 mg nivolumab monotherapy administered IV over approximately 
30 minutes Q4W.
•
Addendum Per Revised Protocol 07: Part 2A Arm A, Arm B, and Arm E are discontinued for 
further enrollment/randomization. The modification of enrollment/randomization in Part 2A is 
not a consequence of changes in the safety or tolerability profile or benefit/risk assessment of 
BMS-986249. Currently active participants in these arms will continue treatment as assigned 
and can remain on study until protocol-defined discontinuation criteria have been met. In 
accordance with Revised Protocol 07, participants in Part 2A will be randomized across the 
study approximately 1:1:1 between 3 treatment arms: 
−
Arm C: described above
−
Arm D: described above
−
Arm F: 600 mg BMS-986249 administered IV Q4W in combination with 480 mg 
nivolumab administered IV Q4W as a co-administration.
The BMS-986249 in Combination with Nivolumab Additional Tumor Cohort Expansion (Part 2B) 
will be comprised of signal seeking expansion cohorts including participants with previously 
treated 
advanced
or 
intermediate 
hepatocellular 
carcinoma 
(Cohort 
1), 
metastatic 
castration-resistant prostate cancer (Cohort 2), and unresectable locally advanced or metastatic 
triple-negative breast cancer (Cohort 3).
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Study Treatment:
Study Treatments for CA030001
Medication
Potency
IP/Non-IP
BMS-986249 Injection
40 mg/mL
IP
ipilimumab Injection
5 mg/mL
IP
nivolumab Injection
10 mg/mL
IP
Abbreviation: IP = investigational product.
The study design schematic is shown in Figure 1-1 (Part 1) and Figure 1-2 (Part 2). 
Figure 1-1:
Study Design Schematic - Part 1, the Dose Escalation Phase
Abbreviations: BMS = Bristol Myers Squibb; CRC = colorectal cancer; CRPC = castration-resistant prostate cancer; 
CTLA-4 = cytotoxic T lymphocyte-associated protein 4; DLT = dose-limiting toxicity; NSCLC = non-small cell 
lung cancer; PD-1 = programmed cell death protein 1; PD-L1 = programmed death ligand-1; Q4W = every 4 weeks; 
Q8W = every 8 weeks; RCC = renal cell carcinoma; SCLC = small cell lung cancer.
a Alternative dosing schedules (eg, Q8W) may occur after evaluation of available safety, PK, and 
 
data, and upon discussion and agreement between the investigators and Medical Monitor (or designee).
b Participants in the monotherapy arm must be anti-CTLA-4-naive. Prior anti-PD-1 or anti-PD-L1 exposure is 
allowed in the monotherapy arm, but at time of enrollment, participants must be at least 5 half-lives (approximately 
100 days) from last dose of PD-1/PD-L1 therapy. 
c Intra-participant dose escalation/reduction of BMS-986249 or nivolumab is not permitted.
d Part 1B will not start until demonstration of acceptable safety in at least 2 cohorts from Part 1A has occurred. 
Subsequently, treatment in both parts will occur in parallel.
e Part 1B participants with NSCLC will only be evaluated in a cohort once the DLT evaluation for that cohort has 
been completed.
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Figure 1-2:
Study Design Schematic - Part 2, the BMS-986249 Cohort Expansion 
Combination Therapy Phase
Abbreviations: AJCC = American Joint Committee on Cancer; CRPC = castration-resistant prostate cancer; HCC = 
hepatocellular carcinoma; IV = intravenous; PD-L1 = programmed death ligand-1; Q3W = every 3 weeks; Q4W = 
every 4 weeks; Q8W = every 8 weeks; TNBC = triple-negative breast cancer.
a Will only open upon evaluation of available data from Parts 1A and 1B.
b Per Revised Protocol 07, Part 2A Arm A, Arm B, and Arm E were closed to enrollment and are not displayed. 
Part 2A Arm A 240 mg BMS-986249 IV Q3W for 4 doses followed by nivolumab monotherapy Maintenance Phase 
of 480 mg nivolumab IV Q4W continuous. Part 2A Arm B, 800 mg BMS-986249 IV Q8W in combination with
480 mg nivolumab IV Q4W continuous. Part 2A Arm E, 480 mg nivolumab IV Q4W continuous.
Screening: The screening period will be up to 30 days and begins by establishing the participant’s 
initial eligibility and signing of the informed consent form. If a participant exceeds the 30-day 
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 and will require a new 
participant 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. For Part 2A participants awaiting PD-L1 results, the screening window may be 
extended past the 30-day period upon discussion with the Medical Monitor (or designee). 
However, if screening extends over a prolonged period, baseline procedures, such as tumor 
assessments and labs, may need to be repeated so that they fall within the acceptable 
protocol-specified window. Within a given disease type, 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 initial dosing regimen of BMS-986249 was selected as Q4W, with an additional
dosing regimen of Q8W subsequently explored. All participants will be treated for up to 2 calendar 
years. Continuous safety evaluation and tumor assessment occurring in Part 1, Part 2A, and Part 2B
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
will guide the decision to treat a participant with additional cycles of study therapy if the participant 
has confirmed clinical benefit.
•
In the BMS-986249 Monotherapy Escalation (Part 1A), BMS-986249 will initially be 
administered Q4W and infused initially over approximately 30 minutes for the 240 mg dose. 
Infusion times for subsequent dose concentrations will vary to adjust for the different drug 
protein concentrations.
•
For the Safety Evaluation of Combination doses of BMS-986249 with nivolumab (Part 1B),
both study treatments will be administered as a co-administration through the same IV bag.
Initial dosing will be Q4W co-administration of 240 mg BMS-986249 in combination with
480 mg nivolumab infused over approximately 120 minutes. Infusion times will vary with
subsequent co-administration doses to adjust for the different drug protein concentrations. If 
an alternative dosing schedule is evaluated, co-administration will continue on cycles where 
both study treatments are scheduled, while nivolumab will be administered IV over
approximately 30 minutes when scheduled as a monotherapy.
•
In the BMS-986249 in Combination with Nivolumab Randomized Cohort Expansion in 
Melanoma (Part 2A) cycle length and dose administration will vary with treatment arm.
•
In the BMS-986249 in Combination with Nivolumab Additional Tumor Cohort Expansion 
(Part 2B), participants will receive 1,200 mg BMS-986249 administered IV Q8W in 
combination with 480 mg nivolumab administered IV Q4W. Co-administration will continue 
on cycles where both study treatments are scheduled, while nivolumab will be administered 
IV over approximately 30 minutes when scheduled as a monotherapy.
•
Refer to the pharmacy manual for treatment administration, timing, and infusion details for 
BMS-986249, ipilimumab, and nivolumab.
•
BMS-986249 infusions, as a monotherapy or co-administration, will require a 60-minute 
observation period after the completion of the infusion for the first 3 doses for each participant.
•
Tumor progression and response endpoints will be assessed using RECIST v1.1 criteria for 
solid tumors or PCWG3 (for prostate).
Follow-up:
•
Safety Follow-up Period:
−
Upon completion of study therapy (or up to a maximum of 2 years, if applicable) or once 
the decision is made to discontinue the participant from treatment, that is, 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, follow-up study visits should occur at Days 30, 60, and 100 (±7 days) 
for all study participants. Safety reporting of AEs and SAEs should take place from date 
of informed consent through 100 days post EOT.
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Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
−
All participants should 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. 
•
Imaging Follow-up Period:
−
At the time of study treatment discontinuation, participants will continue to have radiologic 
and clinical tumor assessments. The duration of the Imaging Follow-up Period will be 100 
days post EOT or until death, or initiation of another anti-cancer treatment, whichever 
occurs first. Radiological assessments for participants who have ongoing clinical benefit 
may continue to be collected after participants complete the Survival Follow-up Period of 
the study. Participants who have disease progression after an initial course of study therapy 
will be evaluated beyond the EOT visit and will be allowed to receive other tumor-directed 
therapy as required. The initiation of another anti-cancer treatment will indicate the end of 
the Imaging Follow-up Period.
•
Survival Follow-up Period:
−
In parallel with the Safety Follow-up Period, all participants will start the Survival 
Follow-up Period. Since further formal OS analyses will not be conducted, the maximum 
study duration will be through 100 days post EOT. Participants who are in the follow-up 
period past 100 days after EOT should be discontinued from the study. Participants will be 
followed by telephone (from EOT) through 100 days post EOT or until death, loss to 
follow-up, withdrawal of consent, or conclusion of the study, whichever comes first. For 
Part 2 participants, EQ-5D-3L data will be collected by telephone or email during the 
Survival Follow-up Period. Participants will have both the Imaging Follow-up Period and 
Survival Follow-up Period occur simultaneously. The duration of this follow-up will be 
through 100 days post EOT. Subsequent therapies will also be recorded in this Survival 
Follow-up Period.
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Date: 14-Mar-2023
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Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
2
SCHEDULE OF ACTIVITIES
Study assessments and procedures are shown in Table 2-1, Table 2-2, Table 2-3, Table 2-4, and 
Table 2-5.
In limited instances, scheduled events (including events other than safety assessments) can occur 
outside of the indicated timeframes but the Sponsor should first be notified.
If a participant has a delay in study treatment administration for any reason, then assessments and 
laboratory tests (with the exception of any tests needed to ensure participant safety) should be 
correspondingly delayed with the exception of tumor assessments. Tumor assessments continue 
per protocol schedule regardless of any treatment delay incurred.
The pharmacokinetic (PK), 
, and safety profiles of BMS-986249 are being 
elucidated, modifications to the procedures (ie, reduction in PK, 
sampling, 
timing of procedures, dose schedules) currently outlined in Section 2 and Section 9 may be 
required. These modifications will not include the addition of new procedures and will be 
documented in a note to file or administrative letter.
In the event that multiple procedures are required at a single time point, the electrocardiogram 
(ECG) may be obtained up to 15 minutes earlier, vital signs may be obtained up to 10 minutes 
earlier or later, and clinical laboratory samples may be obtained up to 5 minutes earlier than the 
nominal time point, ensuring the PK samples can be collected on time.
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-1:
Screening Schedule of Activities for All Study Parts
Procedure
Screening
Visit (Days -30 to -1)
Notes
Eligibility Assessments
Informed Consent
X
Must be obtained prior to performing any screening procedures. A participant is 
considered enrolled only when a protocol-specific ICF is signed.
Contact IRT
X
After the participants meet all eligibility criteria, sites will use IRT for participant 
number assignment. Register in IRT to obtain participant number. Subsequent visits 
will be registered into the IRT system for drug supply. See Section 5.1.1. If the IRT 
system is not available, participants will be enrolled manually. The participant 
number will be created in the IRT system upon availability.
Inclusion/Exclusion Criteria
X
Must be confirmed prior to randomization/treatment assignment. See Section 6.1
and Section 6.2.
Medical History
X
All medical history relevant to the disease under study. Include any toxicities or 
allergies related to previous treatments.
Prior Cancer Therapies
X
Child-Pugh Score
X
For Part 2B participants with HCC only. Child-Pugh A score is required. See 
Appendix 13.
Safety Assessments
PE, Measurements, Vital Signs, 
and Performance Status
X
Height, weight, ECOG performance status of 0 or 1 (see Appendix 7), seated/supine 
blood pressure, heart rate, body temperature, respiratory rate, and oxygen saturation 
by pulse oximetry at rest. Blood pressure and heart rate should be measured after the 
participant has been resting quietly for at least 5 minutes. Must be collected within 
15 days prior to randomization/treatment assignment. If the screening PE is 
performed within 72 hours prior to dosing on Day 1, then a single examination may 
count as both the screening and predose evaluation.
Concomitant Medication 
Collection
X
Within 15 days prior to randomization/treatment assignment. Vaccine use within 
30 days prior to first study treatment.
ECG
X
ECGs should be recorded after the participant has been supine for at least 5 minutes 
and prior to blood draws. See Section 9.4.3.
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-1:
Screening Schedule of Activities for All Study Parts
Procedure
Screening
Visit (Days -30 to -1)
Notes
Clinical Laboratory 
Assessmentsa
X
On-site/local laboratory tests must be performed within 15 days prior to 
randomization/treatment assignment. See Section 9.4.4 and Table 9.4.4-1.
Urinalysis
X
Microscopic urine reflex only for urinalysis positive for blood/protein/leukocytes.
See Section 9.4.4 and Table 9.4.4-1.
Serology
X
Viral testing is to be completed within 30 days prior to randomization/treatment 
assignment.
All participants must have hepatitis C Ab, hepatitis B surface antigen, and HIV-1 
and HIV-2 Ab testing completed. To be performed onsite/locally per local standards.
Additional testing for viral hepatitis is required and must be completed at the central 
laboratory for HCC participants only and includes Epstein-Barr virus antibody, 
hepatitis B surface antibody, hepatitis B core antibody, hepatitis B DNA viral load 
(PCR), HCV RNA viral load (PCR), hepatitis D antibody (if chronic HBV 
infection). Local laboratory serology results can be used to assess eligibility if the 
central laboratory result is not available in time. See Section 9.4.4 and Table 9.4.4-1.
Pregnancy Test (WOCBP Only)
X
Serum or urine pregnancy test (minimum sensitivity equivalent units 25 IU/L or 
equivalent units of hCG) to be done at screening visit and repeated within 24 hours 
prior to first dose of study treatment.Serum pregnancy test may be taken on the first 
day of treatment, provided results are available prior to starting study therapy. If 
pregnancy test is taken within 24 hours of dosing (C1D1), a further pregnancy test is 
not required. See Section 9.4.4 and Table 9.4.4-1.
FSH
X
Women only, as needed to document postmenopausal status. Females under the age 
of 55 years must have a serum FSH level > 40 mIU/mL to confirm menopause. See
Section 9.4.4 and Table 9.4.4-1.
Serum Alpha-fetoprotein
X
Required for Part 2B participants with HCC only. To be performed onsite/locally 
with clinical laboratory assessments. See Section 9.4.4 and Table 9.4.4-1.
PSA
X
Required for Part 2B participants with prostate cancer only. To be performed by 
local lab prior to participant receiving their first dose of study treatment. See Section 
9.4.4 and Table 9.4.4-1.
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Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-1:
Screening Schedule of Activities for All Study Parts
Procedure
Screening
Visit (Days -30 to -1)
Notes
Testosterone
X
Required for Part 2B participants with prostate cancer only. To be performed by 
local lab prior to participant receiving their first dose of study treatment. See
Section 9.4.4 and Table 9.4.4-1.
Adverse Event Reporting
Assessment of Signs/Symptoms/
Clinical Complaints
X
SAE Assessment
X
For all study participants, safety reporting of AEs and SAEs should take place from 
date of informed consent through 100 days post EOT, including all AEs (SAEs or 
non-serious AEs) associated with SARS-CoV-2 infection.
Tumor Assessments
Body Imaging
X
Must be performed within 30 days prior to randomization/treatment assignment. See 
Section 9.1.1.
For participants with HCC, a triphasic CT/MRI of the liver is required.
For participants with TNBC without measurable lesions outside of the breast, 
contrast-enhanced MRI of the breasts should be performed.
Brain Imaging
X
MRI of the brain without and with contrast is required for participants with known 
or suspected brain metastases who have not had brain imaging within 30 days of 
anticipated first study treatment administration. See Section 9.1.1.
Other: Bone Scan
X
Required for participants with prostate cancer only (PCWG3 Assessment, see 
Appendix 6). Others only as clinically indicated per local standards. See
Section 9.1.1.
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Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-1:
Screening Schedule of Activities for All Study Parts
Procedure
Screening
Visit (Days -30 to -1)
Notes
Biomarker Assessment
Collection of Tumor Tissue
X
All study parts: Consent for tumor biopsy samples is mandatory for 
enrollment. Instructions for the collection and processing of all samples will be 
provided in the Laboratory Manual. Biopsy tissue should be obtained from core 
biopsy, punch biopsy, excisional biopsy, or surgical specimen. Bone lesion biopsies 
are unacceptable for analyses. See Section 9.8.2. 
Part 1: A fresh biopsy should be performed during screening with sufficient tumor 
tissue. Archived tumor specimens are optional in addition to fresh specimens.
Part 2A/Part 2B: A fresh biopsy should be performed during screening with 
sufficient tumor tissue. A fresh screening biopsy will not be required if archived 
tumor specimens fulfill all the following conditions: 1) obtained in the metastatic 
setting or from an unresectable site that has not been previously irradiated, 2) are not 
older than 3 months with no intervening systemic anti-cancer treatment between 
time of acquisition and enrollment, 3) are of sufficient quality and quantity (as 
instructed in the Laboratory Manual), and 4) are submitted prior to 
randomization/treatment assignment. If despite best efforts, the above-mentioned 
criteria cannot be met, a fresh biopsy should occur; however, submission of the 
archival tumor sample beyond the above criteria may be acceptable in some 
circumstances following discussion with Medical Monitor or designee. In order to 
be randomized in Part 2A, a participant must have quantifiable PD-L1 expression 
(≥1% or < 1% tumor cell membrane staining) or be classified as PD-L1 
indeterminate.
SARS-CoV-2 Serology
X
Serum collected to be used for potential future measurements of anti-SARS-CoV-2 
serology (anti-SARS-CoV-2 total or IgG). 
Abbreviations: Ab = antibody; AE = adverse event; C1D1 = Cycle 1 Day 1; CT = computed tomography; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FSH = follicle stimulating hormone; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; hCG = human 
chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; IRT = Interactive Response Technology; 
MRI = magnetic resonance imaging; PCR = polymerase chain reaction; PCWG3 = Prostate Cancer Working Group 3; PD-L1 = programmed death ligand-1; PE = 
physical examination; PSA = prostate-specific antigen; RNA = ribonucleic acid; SAE = serious adverse events; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 2; TNBC = triple-negative breast cancer; WOCBP = women of childbearing potential.
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Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-2:
On Treatment - Schedule of Activities for Q4W Treatment Administration in Part 1A, Part 1B, Part 
2A Arm E, Part 2A Arm F, and the Nivolumab Maintenance Phase of Part 2A Arms A and D
Procedure
Cycle 1
(28 Days in Length)
Cycle 2
(28 Days in Length)
Cycles 3a
and Beyond 
(Each Cycle 
28 Days in 
Length)
EOTb,c
Notes
D1
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 
days)
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 days)
Safety Assessments
Targeted PE, 
Measurements, and 
ECOG Performance 
Statusd
X
X
X
X
Weight and ECOG Performance 
Status (see Appendix 7).
Oxygen Saturation
X
X
X
Symptom Directed PE
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
Includes body temperature, 
respiratory rate, blood pressure 
and heart rate. 
ECGe
X
X
X
X
ECG collections apply to Parts
1A, 1B, and 2A.
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-2:
On Treatment - Schedule of Activities for Q4W Treatment Administration in Part 1A, Part 1B, Part 
2A Arm E, Part 2A Arm F, and the Nivolumab Maintenance Phase of Part 2A Arms A and D
Procedure
Cycle 1
(28 Days in Length)
Cycle 2
(28 Days in Length)
Cycles 3a
and Beyond 
(Each Cycle 
28 Days in 
Length)
EOTb,c
Notes
D1
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 
days)
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 days)
Clinical Laboratory 
Assessments
X
X
X
X
X
X
X
X
X
X
Perform onsite/local laboratory 
testing within 72 hours prior to 
each dose. For the first treatment 
visit, labs need not be repeated if 
they were performed within 
72 hours and the results are 
available and have been reviewed 
for eligibility. See Section 9.4.4
for the list of laboratory tests to 
be conducted. Coagulation 
assessment at screening only.
Urinalysis 
X
X
As clinically 
indicated; 
microscopic 
urine reflex 
only for 
urinalysis
positive for 
blood/ 
protein/ 
leukocyte 
esterase
X
Pregnancy Test 
(WOCBP only)f
X
X
X
X
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Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-2:
On Treatment - Schedule of Activities for Q4W Treatment Administration in Part 1A, Part 1B, Part 
2A Arm E, Part 2A Arm F, and the Nivolumab Maintenance Phase of Part 2A Arms A and D
Procedure
Cycle 1
(28 Days in Length)
Cycle 2
(28 Days in Length)
Cycles 3a
and Beyond 
(Each Cycle 
28 Days in 
Length)
EOTb,c
Notes
D1
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 
days)
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 days)
Adverse Event Reporting and Concomitant Medication Assessments
Monitor for Non-SAEs
For all study participants, safety reporting of all AEs including non SAEs and SAEs should 
take place from date of informed consent through 100 days post EOT. 
For all study participants, all AEs 
(SAEs or non-serious AEs), 
including those associated with 
SARS-CoV-2 infection, must be 
collected from date of informed 
consent through 100 days post 
EOT. See Appendix 3 and 
Section 9.2.
Monitor for SAEs
For all study participants, safety reporting of all AEs including SAEs and non SAEs should 
take place from date of informed consent through 100 days post EOT. 
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
X
PK Assessments
Serial Blood Sampling
See Section 9.5 and corresponding tables for the PK sampling schedule.
Refer to outlined protocol 
sections for all required 
collections.
Immunogenicity (ADA) 
Assessments
See Section 9.5 and corresponding tables for the immunogenicity sampling schedule.
Refer to outlined protocol 
sections for all required 
collections.
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Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-2:
On Treatment - Schedule of Activities for Q4W Treatment Administration in Part 1A, Part 1B, Part 
2A Arm E, Part 2A Arm F, and the Nivolumab Maintenance Phase of Part 2A Arms A and D
Procedure
Cycle 1
(28 Days in Length)
Cycle 2
(28 Days in Length)
Cycles 3a
and Beyond 
(Each Cycle 
28 Days in 
Length)
EOTb,c
Notes
D1
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 
days)
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 days)
Imaging Assessments
Body Imaging
Part 1: Tumor imaging assessments should occur Q8W starting from the first dose (±7 days) 
up until Week 48, and then continue Q12W (±7 days).
Part 2A: The first tumor imaging assessment should occur 12 weeks (±7 days) from first dose. 
Subsequent tumor imaging assessments should occur Q8W (±7 days) from the date of the first 
tumor imaging assessment until Week 52 then continue Q12W (±7 days) thereafter.
The same imaging modality is to 
be used for all assessments, per 
RECIST v1.1. See Appendix 5. 
Tumor assessment to be 
performed prior to initiating next 
cycle of treatment. See 
Section 9.1.1.
Brain Imaging
See Section 9.1.1. Participants with history of brain metastasis should have surveillance MRI 
performed approximately Q12W or sooner if clinically indicated. CT of the brain without and 
with contrast can be performed if MRI is contraindicated.
Other: Bone Scan
See Section 9.1.1. Required for participants with prostate cancer only (PCWG3 Assessment, 
see Appendix 6). For participants with prostate cancer, bone scans should occur Q8W starting 
from the first dose (±7 days) up until Week 48, and then continue Q12W (±7 days). Others 
only as clinically indicated per local standards.
Protocol Amendment No.: 09
Date: 14-Mar-2023
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930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-2:
On Treatment - Schedule of Activities for Q4W Treatment Administration in Part 1A, Part 1B, Part 
2A Arm E, Part 2A Arm F, and the Nivolumab Maintenance Phase of Part 2A Arms A and D
Procedure
Cycle 1
(28 Days in Length)
Cycle 2
(28 Days in Length)
Cycles 3a
and Beyond 
(Each Cycle 
28 Days in 
Length)
EOTb,c
Notes
D1
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 
days)
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 days)
Biomarker Assessments
See Sections 9.5, 9.8, and Table 
9.8.3-1. 
On-treatment Tumor 
Biopsy
Part 1: Mandatory tumor biopsies must be performed at 
; specimens may be collected 
within 3 days of the time point and must be obtained prior to administration of study 
treatments. Bone lesion biopsies are unacceptable for submission. See Table 9.8.3-1
Part 2A: The on-treatment biopsy will be collected on 
 for approximately the first 75
participants treated (about 25 participants per active Arm), and then collected per Investigator 
preference on 
for approximately the next 105 participants treated (about 35 
participants per active Arm). Specimens may be collected within 3 days of the time point.
Bone lesion biopsies are unacceptable for submission. See Section 9.8.2 and Table 9.8.3-1.
.
Required Post-Progression Tumor Biopsy
See Section 9.8.2.
Exploratory Biomarker Assessments
See Sections 9.5, 9.8, and Table 
9.8.3-1.
Clinical Treatment Supplies
Randomization
For Part 2A, randomization should occur no more than 7 business days prior to the first day of 
treatment on C1D1, unless otherwise agreed upon with the Medical Monitor (or designee).
Part 2A only. PD-L1 result is 
required for randomization.
BMS-986249 Planned 
Administration Q4W 
X
X
X
Study treatments to be supplied 
by BMS.
Protocol Amendment No.: 09
Date: 14-Mar-2023
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930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-2:
On Treatment - Schedule of Activities for Q4W Treatment Administration in Part 1A, Part 1B, Part 
2A Arm E, Part 2A Arm F, and the Nivolumab Maintenance Phase of Part 2A Arms A and D
Procedure
Cycle 1
(28 Days in Length)
Cycle 2
(28 Days in Length)
Cycles 3a
and Beyond 
(Each Cycle 
28 Days in 
Length)
EOTb,c
Notes
D1
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 
days)
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 days)
(Part 1A, Part 1B, and 
Part 2A Arm F)
Q8W treatments and requirements 
for Part 1A and Part 1B are 
outlined in Appendix 12.g
Nivolumab 
Administration Q4W 
(Part 1B, Part 2A Arm 
E, Arm F and the 
Maintenance Phase of 
Part 2A Arm A and 
Arm D) 
X
X
X
Study treatments to be supplied 
by BMS.
Patient-reported Outcomes
Patient-reported outcomes for 
Part 2A participants only. See 
Section 9.9.
EORTC QLQ-C30
X
X
X
X
For C1D1, performed after 
randomization but prior to first 
dose. All other cycles collected 
prior to dosing.
EQ-5D-3L
X
X
X
X
For C1D1, performed after 
randomization but prior to first 
dose. All other cycles collected 
prior to dosing.
FACIT GP5
X
X
X
X
X
X
X
X
X
X
For C1D1, performed after 
randomization but prior to first 
Protocol Amendment No.: 09
Date: 14-Mar-2023
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10.0
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930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-2:
On Treatment - Schedule of Activities for Q4W Treatment Administration in Part 1A, Part 1B, Part 
2A Arm E, Part 2A Arm F, and the Nivolumab Maintenance Phase of Part 2A Arms A and D
Procedure
Cycle 1
(28 Days in Length)
Cycle 2
(28 Days in Length)
Cycles 3a
and Beyond 
(Each Cycle 
28 Days in 
Length)
EOTb,c
Notes
D1
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 
days)
D8
(± 2 
days)
D15
(± 2 
days)
D22
(± 2 
days)
D1
(± 2 days)
dose. All other cycles collected 
prior to dosing.
PRO-CTCAE
X
X
X
X
X
X
X
X
X
X
For C1D1, performed after 
randomization but prior to first 
dose. All other cycles collected 
prior to dosing.
Abbreviations: ADA = anti-drug antibody; AE = adverse event; BMS = Bristol Myers Squibb; CT = computed tomography; CXDY = Cycle X Day Y, as an 
example; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire – Core 30; EOT = end of treatment; EQ-5D-3L = European Quality of Life – 5 Dimension – 3 Level 
Questionnaire; FACIT GP5 = Functional Assessment of Chronic Illness Therapy General Physical item 5; hCG = human chorionic gonadotropin; MRI = magnetic 
resonance imaging; PCWG3 = Prostate Cancer Working Group 3; PD-L1 = programmed death ligand-1; PE = physical examination; PK = pharmacokinetic; PRO-
CTCAE = Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W = 
every 12 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 2; WOCBP = women of childbearing potential.
a For Part 2A Arm A and Arm D, the first dose of nivolumab monotherapy maintenance will be C5 of treatment, hence Table 2-2 activities should start under 
column “Cycles 3 and beyond.” For Part 2A Arm A and Arm D, C5 nivolumab monotherapy maintenance begins 3 weeks after C4 of the combination dose, 
refer to Table 2-3. Part 2A Arm A and Arm D participants who do not complete all scheduled combination therapy cycles will not be eligible for the nivolumab 
monotherapy Maintenance Phase and should enter follow-up (Table 2-5).
b EOT is defined as the visit where the decision is made to discontinue the participant from treatment. Evaluations will be performed prior to study discharge, or 
for participants who are prematurely discontinued.
c For participants who complete all scheduled cycles of therapy, the EOT visit will be the same as the last scheduled and completed on-treatment visit (eg, C26D1) 
and 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); it does not need to be repeated and will be considered as the start of the Safety Follow-up Period.
Protocol Amendment No.: 09
Date: 14-Mar-2023
39
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
d For the first 3 infusions including BMS-986249 (C1D1, C2D1, and C3D1), vital signs will be obtained before the infusion and then every 15 minutes 
(± 5 minutes) until 60 minutes after completion of the infusion; oxygen saturation to also be performed in conjunction with vital signs monitoring on these days. 
For all infusions that do not include BMS-986249 and for all cycles after C3, vital signs and oxygen saturation are to be taken before the infusion and at the end 
of infusion. If any vital sign is abnormal (based upon clinician assessment) at the final check, the participant must be observed further for a period of time, as 
clinically indicated.
e ECGs should be recorded after the participant has been supine for at least 5 minutes and prior to blood draws. For Part 1A, triplicate ECGs are performed at 
predose and EOI on C1D1 and C4D1. Single predose safety ECGs to be performed for all other time points For Part 1B, single predose ECGs are performed for 
all time points and also at EOI for C1D1 and C4D1. For Part 2A, single predose ECGs at all time points. See Section 9.4.3.
f Serum/urine to be collected within 24 hours prior to dosing. Pregnancy test may be completed on the first day of treatment, provided the results are available 
before the start of study therapy. Serum or urine pregnancy test must be performed within 24 hours prior to administration of study treatment (urine pregnancy 
test: minimum sensitivity 25 IU/L or equivalent units of hCG).
g Refer to Appendix 12 (if applicable) for potential alternative schedules that may be explored in Part 1 following evaluation of preliminary safety, PK, and 
 data. Decisions to initiate exploration of these alternative dose schedules will be made after discussion and agreement between the 
Investigators and the Medical Monitor (or designee). Implementation of these alternative dose schedules will not include the addition of new procedures and 
will be documented in a note to file or administrative letter.
Protocol Amendment No.: 09
Date: 14-Mar-2023
40
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-3:
On Treatment - Schedule of Activities for Part 2A Arm A and Arm D Combination Therapy Phase
Procedure
Study Treatment Every 3 Weeks for 4 Cycles
EOTb,c
Notes
Cycle 1, 2, 3, 4 (each cycle 21 days in length)a,c
D1
D8
D15
(± 2 days)
(± 2 days)
Safety Assessments
PE, Weight, and ECOG 
Performance Status
X
X
Symptom Directed PE
X
X
Vital Signsd
X
X
X
X
Includes body temperature, respiratory 
rate, blood pressure and heart rate.
Oxygen Saturationd
X
ECG
X
X
ECGs should be recorded after the 
participant has been supine for at least 
5 minutes and prior to blood draws. 
Single safety ECGs to be done prior to 
each infusion for all treatment cycles.
Laboratory Tests
X
X
X
X
To be performed onsite/locally. There 
will be a 72-hour window for collection 
of laboratory tests on D1. If laboratory 
tests performed at screening are within 
72 hours of C1D1, then they can also be 
used for C1D1. Coagulation assessment 
at screening only. See Section 9.4.4 and 
Table 9.4.4-1.
Urinalysis
X
X
For C3 and C4, as clinically indicated; 
microscopic urine reflex only for 
urinalysis positive for blood/protein/ 
leukocyte esterase. See Section 9.4.4 and 
Table 9.4.4-1.
Pregnancy Test (WOCBP only)e
X
X
See Section 9.4.4 and Table 9.4.4-1.
Protocol Amendment No.: 09
Date: 14-Mar-2023
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10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-3:
On Treatment - Schedule of Activities for Part 2A Arm A and Arm D Combination Therapy Phase
Procedure
Study Treatment Every 3 Weeks for 4 Cycles
EOTb,c
Notes
Cycle 1, 2, 3, 4 (each cycle 21 days in length)a,c
D1
D8
D15
(± 2 days)
(± 2 days)
Adverse Event Reporting and Concomitant Medication Assessments
Monitor for Non-SAEs
For all study participants, safety reporting of all AEs (non SAEs and SAEs)
should take place from date of informed consent through 100 days post 
EOT. 
All AEs (SAEs or non-serious AEs), 
including those associated with 
SARS-CoV-2 infection must be collected 
from date of informed consent through 
100 days post EOT. See Appendix 3 and 
Section 9.2.
AE Assessment
For all study participants, safety reporting of all AEs (non SAEs and SAEs) 
should take place from date of informed consent through 100 days post 
EOT. 
Concomitant Medications 
X
X
X
X
PK Assessments
Serial Blood Sampling
See Section 9.5,Table 9.5-4 and Table 9.5-9 for the PK sampling schedule.
Refer to outlined protocol sections for all 
required collections.
Immunogenicity (ADA) 
Assessments
See Section 9.5, Table 9.5-4and Table 9.5-6 for the immunogenicity 
sampling schedule.
Refer to outlined protocol sections for all 
required collections.
Imaging Assessments
Body Imaging
The first tumor imaging assessment should occur 12 weeks (±7 days) from 
first dose. Subsequent tumor imaging assessments should occur Q8W (± 7 
days) from the date of the first tumor imaging assessment until Week 52 
then continue Q12W (±7 days) thereafter. See Section 9.1.1.
The same imaging modality is to be used 
for all assessments, per RECIST v1.1. See 
Appendix 5. Tumor assessment to be 
performed prior to initiating next cycle of 
treatment.
Brain Imaging
Participants with history of brain metastasis should have surveillance MRI 
performed approximatelyQ12W or sooner if clinically indicated. CT of the 
brain without and with contrast can be performed if MRI is contraindicated.
See Section 9.1.1.
Protocol Amendment No.: 09
Date: 14-Mar-2023
42
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-3:
On Treatment - Schedule of Activities for Part 2A Arm A and Arm D Combination Therapy Phase
Procedure
Study Treatment Every 3 Weeks for 4 Cycles
EOTb,c
Notes
Cycle 1, 2, 3, 4 (each cycle 21 days in length)a,c
D1
D8
D15
(± 2 days)
(± 2 days)
Other: Bone Scan
See Section 9.1.1.Only as clinically indicated per local standards.
Biomarker Assessments
See Sections 9.5 and 9.8, and Table 9.8.3-
1.
On-Treatment Tumor Biopsy
For Part 2A, the on-treatment biopsy will be collected on 
 for 
approximately the first 75 participants treated (about 25 participants per
active Arm), and then collected per Investigator preference on 
or 
for approximately the next 105 participants treated (about 35 
participants per active Arm).Specimens may be collected within 3 days of 
the time point. Bone lesion biopsies are unacceptable for submission. See 
Table 9.8.3-1.
Required Post-progression Tumor 
Biopsy
See Section 9.8.2.
Exploratory Biomarker Assessments
See Sections 9.5 and 9.8 and Table 9.8.3-
1 for all required collections.
Clinical Treatment Supplies
Randomization
Randomization should occur no more than 7 business days prior to the first 
day of treatment on C1D1, unless otherwise agreed upon with the Medical 
Monitor (or designee).
PD-L1 result is required for 
randomization.
BMS-986249 Administration 
Q3W (Part 2A Arm A
Combination Therapy Phase)
X
BMS-986249 to be supplied by BMS. 
BMS-986249 to be administered for up to 
a maximum of 4 doses.
Protocol Amendment No.: 09
Date: 14-Mar-2023
43
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-3:
On Treatment - Schedule of Activities for Part 2A Arm A and Arm D Combination Therapy Phase
Procedure
Study Treatment Every 3 Weeks for 4 Cycles
EOTb,c
Notes
Cycle 1, 2, 3, 4 (each cycle 21 days in length)a,c
D1
D8
D15
(± 2 days)
(± 2 days)
Ipilimumab Administration Q3W 
(Part 2A Arm D Combination 
Therapy Phase)
X
Ipilimumab to be supplied by BMS. 
Ipilimumab to be administered for up to a 
maximum of 4 doses.
Nivolumab Administration Q3W 
(Part 2A Arm A and Arm D 
Combination Therapy Phase)c
X
Nivolumab to be supplied by BMS. 
Patient-Reported Outcomes
See Section 9.9
EORTC QLQ-C30
X
X
For C1D1, performed after randomization 
but prior to first dose. All other cycles 
collected prior to dosing.
EQ-5D-3L
X
X
For C1D1, performed after randomization
but prior to first dose. All other cycles 
collected prior to dosing.
FACIT GP5
X
X
X
X
For C1D1, performed after randomization 
but prior to first dose. All other cycles 
collected prior to dosing.
PRO-CTCAE
X
X
X
X
For C1D1, performed after randomization 
but prior to first dose. All other cycles 
collected prior to dosing.
Abbreviations: ADA = anti-drug antibody; AE = adverse event; BMS = Bristol Myers Squibb; C= cycle; CT = computed tomography; CXDY = Cycle X Day Y,
as an example; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire – Core 30; EOT = end of treatment; EQ-5D-3L = European Quality of Life – 5 Dimension – 3 Level 
Questionnaire; FACIT GP5 = Functional Assessment of Chronic Illness Therapy General Physical item 5; hCG = human chorionic gonadotropin; MRI = magnetic 
resonance imaging; PD-L1 = programmed death ligand-1; PE = physical examination; PK = pharmacokinetic; PRO-CTCAE = Patient-Reported Outcomes version 
of the Common Terminology Criteria for Adverse Events; Q3W = every 3 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; RECIST = Response Evaluation 
Criteria in Solid Tumors; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WOCBP = women of childbearing 
potential.
Protocol Amendment No.: 09
Date: 14-Mar-2023
44
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930119402
10.0
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1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
a Participants may be treated no less than 19 days between doses.
b EOT is defined as the visit where the decision is made to discontinue the participant from treatment. Evaluations will be performed only for participants who 
are prematurely discontinued (eg, do not complete all 4 planned combination treatment cycles). The EOT visit will be the most recent on-treatment visit (with 
all available safety and response data); it does not need to be repeated and will be considered as the start of the Safety Follow-up Period.
c Participants who complete all 4 scheduled cycles of BMS-986249 or ipilimumab in combination with nivolumab therapy will move to the nivolumab 
monotherapy Maintenance Phase (Table 2-2), beginning 3 weeks after the Cycle 4 BMS-986249 or ipilimumab in combination with nivolumab dose. The first 
dose of nivolumab monotherapy maintenance will be C5 of treatment  (Table 2-2).
d For the first 3 infusions including BMS-986249 (C1D1, C2D1, and C3D1), vital signs will be obtained before the infusion and then every 15 minutes 
(± 5 minutes) until 60 minutes after completion of the infusion; oxygen saturation to also be performed in conjunction with vital signs monitoring on these days. 
For C4D1 and beyond, vital signs and oxygen saturation are to be taken before the infusion and at the end of infusion. If any vital sign is abnormal (based upon 
clinician assessment) at the final check, the participant must be observed further for a period of time, as clinically indicated.
e Serum/urine to be collected within 24 hours prior to dosing. Pregnancy test may be completed on the first day of treatment, provided the results are available 
before the start of study therapy. Serum or urine pregnancy test must be performed within 24 hours prior to administration of study treatment (urine pregnancy 
test: minimum sensitivity 25 IU/L or equivalent units of hCG).
Protocol Amendment No.: 09
Date: 14-Mar-2023
45
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-4:
On-treatment Schedule of Activities for Part 2A Arm B and Arm C, and Part 2B
Procedure
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOTa,b
Notes
(28 days in length)
(28 days in length)
(each cycle 28 
days in 
length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Safety Assessments
PE, Weight, and
ECOG Performance 
Status
X
X
X
X
Symptom-directed 
PE
X
X
X
X
X
X
Child-Pugh Score
X
X
X
X
For HCC participants 
only. See Appendix 13.
Vital Signsc
X
X
X
X
X
X
X
X
X
X
Includes body 
temperature, respiratory 
rate, blood pressure and 
heart rate.
Oxygen Saturationc
X
X
X
ECG
X
X
X
X
ECGs should be recorded 
after the participant has 
been supine for at least 5 
minutes and prior to blood 
draws. Single safety ECGs 
to be done prior to each 
infusion for all treatment 
cycles.
Protocol Amendment No.: 09
Date: 14-Mar-2023
46
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-4:
On-treatment Schedule of Activities for Part 2A Arm B and Arm C, and Part 2B
Procedure
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOTa,b
Notes
(28 days in length)
(28 days in length)
(each cycle 28 
days in 
length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Laboratory Tests
X
X
X
X
X
X
X
X
X
X
To be performed 
onsite/locally. There will 
be a 72-hour window for 
collection of laboratory 
tests on D1. If screening 
laboratory tests are within 
72 hours of C1D1, 
laboratory tests performed 
at screening can be used 
for C1D1. PT/INR and 
aPTT required on D1 for 
HCC and CRPC 
participants; for all others,
coagulation assessment at 
screening only. See 
Section 9.4.4 and Table 
9.4.4-1.
Urinalysis
X
X
As clinically 
indicated; 
microscopic 
urine reflex 
only for 
urinalysis 
positive for 
blood/ protein/ 
leukocyte 
esterase.
X
See Section 9.4.4 and
Table 9.4.4-1. There will 
be a 72-hour window for 
collection of laboratory 
tests on D1
Protocol Amendment No.: 09
Date: 14-Mar-2023
47
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-4:
On-treatment Schedule of Activities for Part 2A Arm B and Arm C, and Part 2B
Procedure
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOTa,b
Notes
(28 days in length)
(28 days in length)
(each cycle 28 
days in 
length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Alpha-fetoprotein
X
X
X
X
For HCC participants 
only. To be performed 
onsite/locally with 
laboratory tests. There will 
be a 72-hour window for 
collection of laboratory 
tests on D1. See Section 
9.4.1 and Table 9.4.4-1. 
Viral Markers
X
X
X
X
For HCC participants 
only. To be completed at 
central laboratory. For 
HCV infected; HCV 
RNA. For HBV infected; 
HBV DNA. There will be 
a 72-hour window for 
collection of laboratory 
tests on D1. See Section 
9.4.4 and Table 9.4.4-1.
PSA
X
X
X
X
For CRPC participants 
only. If screening PSA is
within 72 hours of C1D1, 
laboratory tests performed 
at screening can be used 
for C1D1. There will be a 
72-hour window for 
collection of laboratory 
tests on D1. Performed 
onsite/locally D1 of C1 to 
Protocol Amendment No.: 09
Date: 14-Mar-2023
48
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 2-4:
On-treatment Schedule of Activities for Part 2A Arm B and Arm C, and Part 2B
Procedure
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOTa,b
Notes
(28 days in length)
(28 days in length)
(each cycle 28 
days in 
length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
C5 (prior to treatment), 
then D1 of every odd-
numbered cycle (C7, C9, 
C11, etc). See Section 
9.4.4 and Table 9.4.4-1.
Testosterone
X
X
For CRPC participants 
only. Performed 
onsite/locally at start of 
C7, then every fourth 
cycle starting
with C11D1 until EOT
(C11D1, C15D1, C19D1, 
etc.). See Section 9.4.4
and Table 9.4.4-1.
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Anti-CTLA-4 Probody mAb
Table 2-4:
On-treatment Schedule of Activities for Part 2A Arm B and Arm C, and Part 2B
Procedure
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOTa,b
Notes
(28 days in length)
(28 days in length)
(each cycle 28 
days in 
length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Pregnancy Test
(WOCBP only)d
X
X
X 
X
See Section 9.4.4 and 
Table 9.4.4-1.
Adverse Event Reporting and Concomitant Medication Assessments
Monitor for Non-
SAEs
For all study participants, safety reporting for non SAEs should take place from date of 
informed consent through 100 days post EOT. 
For all participants, all 
AEs (SAEs or non-serious 
AEs), including those 
associated with 
SARS-CoV-2 infection, 
must be collected from the 
date of the participant’s 
written consent through 
100 days following EOT 
(Safety Follow up). See 
Appendix 3 and 
Section 9.2.
Monitor for SAEs
For all study participants, safety reporting of SAEs should take place from date of 
informed consent through 100 days post EOT. 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
Including antiviral therapy 
for HCC participants.
PK Assessments
Serial Blood 
Sampling
See Section 9.5, Table 9.5-5 and Table 9.5-9 for the PK sampling schedule.
Refer to outlined protocol 
sections for all required 
collections.
Immunogenicity 
(ADA) Assessments
See Section 9.5, Table 9.5-5 and Table 9.5-9 for the immunogenicity sampling schedule.
Refer to outlined protocol 
sections for all required 
collections.
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Anti-CTLA-4 Probody mAb
Table 2-4:
On-treatment Schedule of Activities for Part 2A Arm B and Arm C, and Part 2B
Procedure
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOTa,b
Notes
(28 days in length)
(28 days in length)
(each cycle 28 
days in 
length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Imaging Assessments
Body Imaging
See Section 9.1.1. Additional imaging may be performed as clinically indicated.
For Part 2A: The first tumor imaging assessment should occur 12 weeks (± 7 days) from first dose. 
Subsequent tumor imaging assessments should occur Q8W (±7 days) from the date of the first tumor 
imaging assessment until Week 52 then continue Q12W (±7 days) thereafter.
For Part 2B: Tumor imaging assessments should occur Q8W starting from the first dose (±7 days) up 
until Week 48, and then continue Q12W (±7 days) thereafter. For participants with HCC, a triphasic 
CT/MRI of the liver is required. For participants with TNBC without measurable lesions outside of the 
breast, contrast-enhanced MRI of the breasts should be performed along with body imaging.
The same imaging 
modality is to be used for 
all assessments, per 
RECIST v1.1. See 
Appendix 5. Tumor 
assessment to be 
performed prior to 
initiating next cycle of 
treatment.
Brain Imaging
See Section 9.1.1. Participants with history of brain metastasis should have surveillance MRI performed 
approximately Q12W or sooner if clinically indicated. CT of the brain without and with contrast can be 
performed if MRI is contraindicated.
Other: Bone Scan
See Section 9.1.1. For CRPC participants, should occur Q8W starting from the first dose (± 7 days) up 
until Week 48, and then continue Q12W (±7 days) or until disease progression is assessed by the 
investigator or treatment is discontinued (whichever occurs later). Evidence of progressive disease as 
per PCWG3 (Appendix 6). All other participants only as clinically indicated per local standards.
Biomarker Assessments
See Sections 9.5, 9.8, and 
Table 9.8.3-1 for all 
required collections
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Anti-CTLA-4 Probody mAb
Table 2-4:
On-treatment Schedule of Activities for Part 2A Arm B and Arm C, and Part 2B
Procedure
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOTa,b
Notes
(28 days in length)
(28 days in length)
(each cycle 28 
days in 
length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
On-treatment Tumor 
Biopsy
For Part 2A: The on-treatment biopsy will be collected on 
 for approximately the first 75
participants treated (about 25 participants per active Arm), and then collected per Investigator 
preference on 
or 
for approximately the next 105 participants treated (about 35 participants 
per active Arm).
For Part 2B: The on-treatment biopsy will be collected on 
. Specimens may be collected within 
3 days of the time point. Bone lesion biopsies are unacceptable for submission. See Table 9.8.3-1.
Required Post-
progression Tumor 
Biopsy
See Section 9.8.2
Exploratory Biomarker Assessments
See Sections 9.5, 9.8, and 
Table 9.8.3-1 for all 
required collections.
Clinical Treatment Supplies
Randomization
For Part 2A, randomization should occur no more than 7 business days prior to the first 
day of treatment on Cycle 1 Day 1, unless otherwise agreed upon with the Medical 
Monitor (or designee).
For Part 2A, PD-L1 result 
required for 
randomization. 
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Table 2-4:
On-treatment Schedule of Activities for Part 2A Arm B and Arm C, and Part 2B
Procedure
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOTa,b
Notes
(28 days in length)
(28 days in length)
(each cycle 28 
days in 
length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
BMS-986249 
Administration Q8W 
(Part 2A Arm B and 
Arm C, and Part 2B)
X
X
BMS-986249 to be 
supplied by BMS.
Every other 
cycle starting 
at C3 [eg, C3, 
C5, C7, etc]
Nivolumab 
Administration Q4W 
(Part 2A Arm B and 
Arm C, and Part 2B)
X
X
X
Nivolumab to be supplied 
by BMS.
Patient-Reported Outcomes
See Section 9.9
EORTC QLQ-C30
X
X
X
X
For C1D1, performed after 
randomization but prior to 
first dose. All other cycles 
collected prior to dosing.
EQ-5D-3L
X
X
X
X
For C1D1, performed after 
randomization but prior to 
first dose. All other cycles 
collected prior to dosing.
FACIT GP5
X
X
X
X
X
X
X
X
X
X
For C1D1, performed after 
randomization but prior to 
first dose. All other cycles 
collected prior to dosing.
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Anti-CTLA-4 Probody mAb
Table 2-4:
On-treatment Schedule of Activities for Part 2A Arm B and Arm C, and Part 2B
Procedure
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOTa,b
Notes
(28 days in length)
(28 days in length)
(each cycle 28 
days in 
length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
PRO-CTCAE
X
X
X
X
X
X
X
X
X
X
For C1D1, performed after 
randomization but prior to 
first dose. All other cycles 
collected prior to dosing.
Abbreviations: ADA = anti-drug antibody; AE = adverse event; aPTT =  activated partial thromboplastin time; BMS = Bristol Myers Squibb; C = cycle; 
CRPC = castration-resistant prostate cancer; CT = computed tomography; CXDY = Cycle X Day Y, as an example; D = day; DNA = deoxyribonucleic acid; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire – Core 30; EOT = end of treatment; EQ-5D-3L = European Quality of Life – 5 Dimension – 3 Level Questionnaire; FACIT GP5 = 
Functional Assessment of Chronic Illness Therapy General Physical item 5; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; hCG = human chorionic 
gonadotropin; HCV = hepatitis C virus; INR = international normalized ratio; MRI = magnetic resonance imaging; PCWG3 = Prostate Cancer Working Group 3; 
PD-L1 = programmed death ligand-1; PE = physical examination; PK = pharmacokinetic; PRO-CTCAE = Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events; PSA = prostate-specific antigen; PT = prothrombin time; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W = every 
12 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; TNBC = triple-negative breast cancer; WOCBP = women of childbearing potential.
a EOT is defined as the visit where the decision is made to discontinue the participant from treatment. Evaluations will be performed prior to study discharge, or 
for participants who are prematurely discontinued.
b For participants who complete all scheduled cycles of therapy, the EOT visit will be the same as the last scheduled and completed on-treatment visit (eg, C26D1) 
and 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); it does not need to be repeated and will be considered as the start of the Safety Follow-up Period.
c Vital signs will be obtained before the first 3 infusions including BMS-986249 (C1D1, C3D1, and C5D1) and then every 15 minutes (± 5 minutes) until 
60 minutes after completion of the infusion; oxygen saturation to also be performed in conjunction with vital signs monitoring on these days. For all cycles after 
C5 and for the nivolumab monotherapy infusions, vital signs and oxygen saturation are to be taken before the infusion and at the end of infusion. If any vital 
sign is abnormal (based upon clinician assessment) at the final check, the participant must be observed further for a period of time, as clinically indicated. 
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d Serum/urine to be collected within 24 hours prior to dosing. Pregnancy test may be completed on the first day of treatment, provided the results are available 
before the start of study therapy. Serum or urine pregnancy test must be performed within 24 hours prior to administration of study treatment (urine pregnancy 
test: minimum sensitivity 25 IU/L or equivalent units of hCG).
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Table 2-5:
Follow-up Procedural Outline for All Study Parts
Procedure
Safety Follow-up
Notes
Follow-up 1
30 Daysa
(± 7 Days) 
Follow-up 2
60 Daysa
(± 7 Days)
Follow-up 3
100 Daysa
(± 7 Days)
Imaging Follow-up
Survival Follow-up
Safety Assessments
PE and Vital Signs
X
X
X
Includes body temperature, 
seated/supine blood pressure, 
and heart rate.
Laboratory Tests
X
X
X
To be performed 
onsite/locally. Laboratory tests 
also as clinically indicated; 
PT/INR and aPTT required for 
HCC and CRPC participants;
for all others, coagulation 
assessment at screening only.
For details of laboratory 
assessments, see Section 9.4.4
and Table 9.4.4-1. 
Urinalysis
As clinically indicated. See Section 9.4.4.
Alpha-fetoprotein
X
X
X
For participants with HCC
only. To be performed 
onsite/locally with laboratory 
tests. See Section 9.4.4 and 
Table 9.4.4-1.
Pregnancy Test
X
X
X
For WOCBP, serum/urine 
pregnancy test is to be 
performed (urine pregnancy 
test: minimum sensitivity 
25 IU/L or equivalent units of 
hCG). See Section 9.2.5, 
Section 9.4.4 and Table 9.4.4-
1.
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Anti-CTLA-4 Probody mAb
Table 2-5:
Follow-up Procedural Outline for All Study Parts
Procedure
Safety Follow-up
Notes
Follow-up 1
30 Daysa
(± 7 Days) 
Follow-up 2
60 Daysa
(± 7 Days)
Follow-up 3
100 Daysa
(± 7 Days)
Imaging Follow-up
Survival Follow-up
Viral Markers
X
X
X
For participants with HCC 
only. To be completed at 
central laboratory. For HCV-
infected; HCV RNA. For 
HBV-infected; HBV DNA.
See Section 9.4.4 and Table 
9.4.4-1.
PSA
For participants with CRPC only. To be performed onsite/locally. PSA performed Q8W (± 7 days) in follow-up until radiographic 
progression or the start of subsequent systemic cancer therapy, whichever occurs later. PSA evaluation beyond radiographic 
progression or the start of subsequent systemic cancer therapy to confirm PSA response or PSA progression should be performed as 
needed.
Adverse Event Reporting and Concomitant Medication Assessments
Monitor for 
Non-SAEsb
X
X
X
For all study participants, 
safety reporting of AEs and 
SAEs should take place from 
date of informed consent 
through 100 days post EOT. 
Monitor for SAEsb
X
X
X
For all study participants, 
safety reporting of AEs and 
SAEs should take place from 
date of informed consent 
through 100 days post EOT.
Concomitant 
Medication 
Assessments
X
X
X
Including antiviral therapy for 
HCC participants.
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Table 2-5:
Follow-up Procedural Outline for All Study Parts
Procedure
Safety Follow-up
Notes
Follow-up 1
30 Daysa
(± 7 Days) 
Follow-up 2
60 Daysa
(± 7 Days)
Follow-up 3
100 Daysa
(± 7 Days)
Imaging Follow-up
Survival Follow-up
Sample Collection
See Section 9.5, and Table 
9.5-2 through Table 9.5-9 for 
the sample collection 
schedule.
Efficacy Assessments
Tumor/Response 
Assessments
Part 1: Tumor assessments should occur Q12W (± 7 days), starting from the date of the last on-treatment tumor assessment. 
Part 2A: The first tumor imaging assessment should occur 12 weeks (± 7 days) from first dose. Subsequent tumor imaging 
assessments should occur Q8W (±7 days) from the date of the first tumor imaging assessment until Week 52 then continue Q12W
(±7 days) thereafter.
For Part 2B: Tumor imaging assessments should occur Q8W starting from the first dose (±7 days) up until Week 48, and then 
continue Q12W (± 7 days). For participants with HCC, a triphasic CT/MRI of the liver is required. For participants with TNBC 
without measurable lesions outside of the breast, contrast-enhanced MRI of the breasts should be performed along with body 
imaging.
For all study parts: The duration of the Imaging Follow-up Period will be 100 days post EOT, or until initiation of another 
anti-cancer treatment, or death, whichever occurs first. See Section 9.1.1.
Brain Imaging
Participants with history of brain metastasis should have surveillance MRI performed approximately Q12W or sooner if clinically 
indicated. CT of the brain without and with contrast can be performed if MRI is contraindicated. See Section 9.1.1.
Other: Bone Scan
Required for participants with prostate cancer only (PCWG3 Assessment). Should occur Q8W starting from the first dose (±7 days) 
up until Week 48, and then continue Q12W (±7 days) until disease progression is assessed by the investigator. Others only as 
clinically indicated per local standards. See Section 9.1.1.
Subsequent 
Treatments 
(Anti-cancer)
X
X
X
X
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Table 2-5:
Follow-up Procedural Outline for All Study Parts
Procedure
Safety Follow-up
Notes
Follow-up 1
30 Daysa
(± 7 Days) 
Follow-up 2
60 Daysa
(± 7 Days)
Follow-up 3
100 Daysa
(± 7 Days)
Imaging Follow-up
Survival Follow-up
Assessment of 
Participant Survival 
Status
X
X
X
X
Participant status will be 
assessed by any documented 
clinic visit, email, or telephone 
contact through 100 days post 
EOT.
Patient-Reported Outcomes
Patient-reported outcomes for 
Part 2A and 2B participants 
only. See Section 9.9.
EORTC QLC-C30
X
X
X
EQ-5D-3L
X
X
X
X
Can be collected via telephone 
or email during assessment of 
participant survival status.
FACIT GP5
X
X
X
PRO-CTCAE
X
X
X
Abbreviations: ADA = anti-drug antibody; AE = adverse event; aPTT = activated partial thromboplastin time; CRPC = castration-resistant prostate cancer; 
CT = computed tomography; DNA = deoxyribonucleic acid; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire – Core 30; EOT = end of treatment; EQ-5D-3L = European Quality of Life – 5 Dimension – 3 Level Questionnaire; FACIT GP5 = Functional 
Assessment of Chronic Illness Therapy General Physical item 5; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; hCG = human chorionic gonadotropin; 
HCV = hepatitis C virus; INR = international normalized ratio; MRI = magnetic resonance imaging; PCWG3 = Prostate Cancer Working Group 3; PE = physical 
examination; PRO-CTCAE = Patient-reported Outcomes version of the Common Terminology Criteria for Adverse Events; PSA = prostate-specific antigen; PT = 
prothrombin time; Q8W = every 8 weeks; Q12W = every 12 weeks; RNA = ribonucleic acid; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; TNBC = triple-negative breast cancer; WOCBP = women of childbearing potential. 
a Follow-up visits at Days 30 (±7 days), 60 (±7 days), and 100 (±7 days) should occur relative to the last dose of study treatment or date of discontinuation, 
whichever is later.
b Participants will be followed for all SAEs, non-serious AEs of special interest (as defined in Section 9.2), and all AEs (SAEs and non-serious AEs) associated 
with confirmed or suspected SARS-CoV-2 infection 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.
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Anti-CTLA-4 Probody mAb
3
INTRODUCTION
Ipilimumab is a fully
human monoclonal antibody (mAb)
that
binds the negative 
immunoregulatory protein, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Treatment 
with ipilimumab as a monotherapy or in combination with nivolumab (an anti-programmed cell 
death protein 1) [PD-1] mAb) results in clinically meaningful anti-tumor activity in several 
malignancies; however, it is also associated with a high frequency of immune-related adverse 
events (irAEs). Strategies to reduce the frequency and severity of ipilimumab-associated irAEs 
while preserving anti-tumor activity could improve the benefit/risk of ipilimumab-containing 
treatment regimens.
3.1
Study Rationale
Anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab) are approved immunotherapies for the 
treatment of select malignancies. Ipilimumab was the first immunotherapy to show a survival 
advantage in late-stage metastatic melanoma and has also demonstrated a significant 25% 
reduction in risk of recurrence or death in the adjuvant treatment in melanoma. Blockade of 
CTLA-4 by ipilimumab has demonstrated anti-tumor activity in other malignancies, including lung 
cancer, prostate cancer, and renal cell carcinoma (RCC). Ipilimumab is also approved and in 
clinical development in combination with nivolumab. The combination was associated with a 
greater benefit in melanoma compared to each single agent and is currently under evaluation in 
several malignancies, including non-small cell lung cancer (NSCLC). The activation of a 
pre-existing but attenuated immune response to cancer by checkpoint blockade is associated with 
an adverse event (AE) profile that is inherent to immune activation. Ipilimumab treatment-related 
AEs (TRAEs) can involve multiple organ systems (digestive, skin, and endocrine) and can require 
cessation of drug and treatment with corticosteroids. The combination regimen is associated with 
an increased incidence of AEs compared to nivolumab monotherapy but a similar overall AE 
profile. Strategies to reduce the frequency and severity of ipilimumab-associated irAEs while 
preserving anti-tumor activity could improve the benefit-risk of ipilimumab-containing treatment 
regimens.
BMS-986249 is an anti-CTLA-4 Probody™(PROBODY is a trademark of CytomX Therapeutics, 
Inc.) mAb. The Probody is made by the addition of 44 amino acids to the N-terminus of both light 
chains of the human anti-CTLA-4 antibody (Ab) ipilimumab. BMS-986249 contains a masking 
peptide with a cleavable linker containing protease cleavable sites for specific enzymes that are 
more prevalent and/or active in tumors than in peripheral tissues. Probody therapeutics are prodrug 
forms of mAb-based therapeutics. Similar to prodrug strategies that have been successfully applied 
to small-molecule pharmaceuticals, the premise of the “Probody technology” is to create mAbs 
that are administered in a form that has significantly reduced ability to bind to a mAb’s cognate 
antigen and maintains this form while in circulation and when encountering normal healthy tissue. 
The Probody therapeutic is designed to be activated by proteolytic cleavage at specific sites in the 
Probody sequence upon encountering proteases predominantly present
in the tumor 
microenvironment. In this way, Probody therapeutics have the potential to minimize toxicities due 
to limited interaction of the administered (“prodrug”) form of the drug with its target in healthy 
tissues and to maintain efficacy due to interaction of protease-activated drug with its target in 
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tumors. By widening the therapeutic window, Probody therapeutics are expected to be most useful 
for therapies whose clinical utility is limited by significant on-target toxicities caused by antibody 
binding to targets outside of the tumor. This serves as the basis for BMS-986249, the Probody 
version of ipilimumab. 
The properties of BMS-986249 ipilimumab Probody mAb are summarized below:
•
Decreased binding to human CTLA-4 protein (masking efficiency [ME] of 50X)
•
Comparable binding to CTLA-4 protein after protease cleavage
•
At least equivalent anti-tumor activity to ipilimumab in mouse tumor models 
•
Decreased peripheral activity compared to ipilimumab based on activation of extratumoral 
regulatory T cells (Tregs)
Based on this unique mechanism of action, this study will evaluate the safety and preliminary 
efficacy of BMS-986249 alone and in combination with nivolumab. 
3.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of BMS-986249 is 
provided in the Investigator’s Brochure (IB).
3.2.1
BMS-986249
Developing a second generation anti-CTLA–4 Ab that reduces the risk of autoimmune side effects 
has the potential to greatly improve the benefit-risk profile of anti-CTLA–4 therapy by either 
improving the safety profile with maintenance of comparable efficacy and/or maintaining the 
safety but at a higher dose that drives increased efficacy. This is especially important given that 
the combination therapy of ipilimumab and nivolumab in participants with metastatic melanoma 
has demonstrated improved progression-free survival (PFS) compared to monotherapy with either 
Ab,1 but with an increase in Grade 3-4 AEs that have led to treatment discontinuations. 
Nevertheless, the added benefit has prompted testing of this combination in multiple tumor types 
such as RCC, NSCLC, small cell lung cancer (SCLC), colorectal cancer (CRC) (microsatellite 
instability high [MSI-H]), and glioblastoma multiforme. Tolerability of the combination may 
depend on tumor type and, in some cases, be improved by changes in the dose or regimen of the 
combination.2
The Probody approach developed by CytomX offers an appealing strategy to address the systemic 
toxicity associated with anti-CTLA–4 Ab therapy. This system takes advantage of the increased 
protease activity present in tumors to cleave a proform or “Probody” of an Ab and convert it into 
an active Ab. Probody generation requires the addition of a masking peptide with a cleavable linker 
containing protease sites for specific enzymes that are more prevalent and/or active in tumors. The 
specific mask is derived from an in vitro panning approach where peptides that block antigen 
recognition by the Ab are identified. The linker is preferentially cleaved enzymatically at the tumor 
site owing to increased protease activity in the tumor microenvironment relative to those activities 
in normal tissue (periphery). This preferential binding and activity should result in an improved 
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therapeutic index as compared to the parental ipilimumab, which can bind its target throughout the 
body. 
The Probody version of ipilimumab is shown in Figure 3.2.1-1. Briefly, the Probody mAb consists 
of the ipilimumab light chain with an amino terminal addition of a linker sequence containing 
matric metalloproteinase (MMP) and serine protease sites followed by a flexible serine-glycine 
linker before a masking peptide that binds to the antigen binding domain of the Ab. If the Probody 
mAb can maintain activity at the tumor site and reduce peripheral systemic exposure to drug, this 
should result in an improved therapeutic index as compared to ipilimumab. This hypothesis does 
rely on the assumption that the anti-tumor activity of ipilimumab is only mediated by target binding 
at the tumor site or the tumor draining lymph node and does not require binding to CTLA-4 on T 
cells in peripheral lymphoid organs. A second assumption is that peripheral and not tumor target 
binding leads to the AEs seen after ipilimumab treatment.
Figure 3.2.1-1:
Schematic of BMS-986249
Abbreviations: MMP14 = matrix metalloproteinase-14; UPA = urokinase-type plasminogen activator.
3.2.1.1
Generation of an Anti-human CTLA-4 Probody mAb
Lead Antibody Selection
Since ipilimumab has already been approved for the treatment of human tumors, this anti-CTLA- 4 
Ab has been chosen as the basis for a Probody version with reduced target binding capabilities 
outside of the tumor site. The Sponsor has partnered with CytomX to use their Probody mAb
approach, which takes advantage of increased protease activity in tumor tissues to remove a 
masking peptide and reveal the antigen binding site of the Ab.
The Probody Approach: Masking Peptide and Cleavable Linker
In the Probody mAb approach, 2 parameters are critical to determining the efficacy and safety of 
the Probody mAb in comparison to the unaltered parental Ab. The first is the masking peptide that 
binds to the antigen binding site of the Ab and reduces antigen binding. Masking peptides with 
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varying affinities for the Ab can be produced and tested for binding to the target, CTLA-4. ME is 
calculated based on comparing the binding of the masked Ab to the parental Ab to antigen. This 
can be done either by enzyme-linked immunosorbent assay (ELISA) or by staining target 
expressing cells. MEs are then determined as the fold change in the half-maximal effective 
concentration (EC50) of the Probody mAb compared to the parental Ab, with higher MEs 
representing lower affinity for target. Based on CytomX’s experience, probodies with MEs of 
20-50X were initially selected for testing.
Two sets of assays have been used to define the decrease in target binding of the masked 
anti-CTLA–4 Ab compared to the parental Ab. First, ELISA was used to measure the affinity of 
anti- CTLA–4 probodies for protein (Figure 3.2.1.1-1). Binding to CTLA-4 expressed on cells was 
also tested and showed significantly reduced binding. Cells used for these assays include 58α–β–
/CD3ζ cells, which overexpress CTLA-4 as well as endogenous CTLA-4 expressed by activated 
cluster of differentiation 4 (CD4) cells (Figure 3.2.1.1-2). Although the absolute value of the shift 
in EC50 may vary depending on assay, the ranking of probodies is broadly conserved.
Figure 3.2.1.1-1:
Binding of Ipilimumab Probodies to CTLA-4 by ELISA
Abbreviations: Ab = antibody; CTLA-4 = cytotoxic T lymphocyte-associated protein 4; ELISA = enzyme-linked 
immunoassay; Pb = Probody mAb.
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Figure 3.2.1.1-2:
Binding of Ipilimumab Probody mAbs to Overexpressed and 
Endogenous CTLA-4 by FACS
Abbreviations: Ab = antibody; CD4 = cluster of differentiation 4; CTLA-4 = cytotoxic T lymphocyte-associated 
protein 4; FACS = fluorescence-activated cell sorting; GMFI = geometric mean fluorescence intensity; mAb = 
monoclonal antibody; ME = masking efficiency ; Pb = Probody.
The linker containing specific protease sites is also an important determinant of efficacy and safety. 
Linkers that are more easily cleaved by specific proteases or cleaved by a broader range of 
proteases are expected to have higher efficacy, but may also result in higher cleavage systemically, 
which would result in a lower safety margin. Three linkers were considered for the CTLA-4 
Probody mAb, one with specificity for MMPs (885), one with specificity for serine proteases 
(2787), and a hybrid linker that incorporates specificity for both MMPs and serine proteases 
(1490). Due to unexpected stability issues with the 1490 sequence, this was later mutated to 1490 
DNP, which has very similar protease cleavage activity (Table 3.2.1.1-1).
Table 3.2.1.1-1:
KCAT/KM Values for Protease Linker Sequence
Matriptase
UPA
MMP14
MMP9
MMP7
MMP2
2787
1.0E+05
5.4E+03
885
1.6E+04
3.2E+04
1.2E+03
5.8E+04
1490
2.5E+03
7.0E+02
1.2E+04
1490DNP
1.9E+03
8.4E+01
7.6E+03
9.0E+02
Abbreviations: MMPx = matrix metalloproteinase-[number]; UPA = urokinase-type plasminogen activator.
Blank cells signify not tested.
Cleavage was measured by capillary electrophoresis Units on the numbers are Moles-1Sec-1.
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To confirm that reduction of antigen binding was sufficient to reduce functional activity of the 
Probody mAb, BMS-986249 was tested in the in vitro staphylococcal enterotoxin B (SEB) assay. 
In this assay, the superantigen SEB is added to human peripheral blood mononuclear cell (PBMC)
and induces T cell activation and cytokine release. Ipilimumab has been shown to increase 
interleukin 2 (IL-2) secretion in this assay in a dose-dependent manner. In comparison to parental 
ipilimumab, BMS-986249 treatment significantly reduced secretion of IL-2 in response to SEB. 
Depending on the donor, BMS-986249 either showed reduced or complete loss of IL-2 secretion 
compared to ipilimumab.3 This reduction was expected since the tumor proteases required for 
cleavage were not active in the assay.
3.2.1.2
BMS-986249 Nonclinical Pharmacology
BMS-986249 binds CTLA-4 with a 41-fold higher (ie, less potent) EC50 than ipilimumab when 
the masking peptide is intact. This reduction in binding affinity also translates to a reduction in 
functional activity. In a human T cell functional assay using SEB to stimulate IL-2 production, 
ipilimumab induced higher levels of IL-2 compared to the prodrug version. Antibody-dependent 
cell-mediated cytotoxicity (ADCC) induced by BMS-986249 in a reporter assay was decreased 
compared to ipilimumab.
The in vivo activity of BMS-986249 has also been studied using CTLA-4 knock-in (KI) mice that 
express the extracellular domain of human CTLA-4 in the place of mouse CTLA-4.4 Human 
CTLA-4 binds to mouse CD80 and CD86 similarly to mouse CTLA-4, and these mice have been 
shown to behave similar to wild-type mice with no signs of autoimmunity. In the MC38 mouse 
syngeneic tumor model, dose titrations of both ipilimumab and BMS-986249 inhibited tumor 
growth to a similar extent, 97% and 95% at the highest dose level, respectively, and resulted in 
similar numbers of complete tumor regressions, 10/16 for ipilimumab and 13/16 for BMS-986249. 
Immune monitoring of T cell populations indicated that BMS-986249 reduced Tregs similarly to 
ipilimumab, with a 67% and 61% reduction, respectively. Systemic pharmacodynamic markers of 
ipilimumab activity, such as increased Ki-67 and inducible T cell costimulator (ICOS) levels on T
cell subsets in the spleen were significantly reduced in BMS-986249–treated animals compared to 
ipilimumab. Therefore, BMS-986249 has been shown to maintain anti-tumor activity and tumoral 
pharmacodynamic effects while reducing systemic pharmacodynamic effects.
In vitro and in vivo data indicate that BMS-986249 should have reduced activity outside of the 
tumor site compared to ipilimumab while preserving its anti-tumor efficacy, supporting the 
development of this Ab for the treatment of cancer.
3.2.1.3
BMS-986249 Nonclinical Pharmacokinetics
The PK of BMS-986249, a Probody mAb of ipilimumab (Yervoy™), was evaluated in mice and 
cynomolgus monkeys. After an intravenous (IV) dose of BMS-986249 in mice (5-mg/kg single 
dose) or monkeys (5-mg/kg single dose and 10- and 50-mg/kg weekly doses for 4-weeks), BMS-
986249-related exposure was measured as intact BMS-986249, its mono- and dual-cleavage 
products, and total Ab. BMS-986249 exhibited typical Ab PK characteristics: low total body 
plasma clearance of 25 and 9.7 to 10 mL/d/kg, limited volume of distribution at steady state (Vss) 
of 147 and 80 to 95 mL/kg, and long apparent elimination half-lives (T-HALF) of 4.2 and 6.7 to 
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7.6 days in mice and monkeys, respectively. In both species, the T-HALF of the intact Probody
mAb was shorter than the T-HALF of the total Ab (21 and 17 to 18 days, respectively), consistent 
with the intact Probody mAb being slowly converted to mono- and dual-cleaved products. In 
monkeys, BMS-986249 and its mono- and dual-cleavage products and total Ab exhibited a dose-
proportional increase in exposure between 10- and 50-mg/kg doses. The intact Probody mAb was 
53% converted to the fully active Ab in mice and 30% to 34% in monkeys. BMS-986249 was 
immunogenic in monkeys; anti-drug Ab (ADA) formation was observed in some of the monkeys 
in both dose groups. The ADA response returned to baseline after Day 29 in all monkeys except 
for 1 monkey in the 10-mg/kg dose group and 2 monkeys in the 50-mg/kg dose group. In addition, 
the ADA did not appear to impact the exposures of BMS-986249, except for 1 monkey in the 
10-mg/kg dose group.
The human efficacious dose of BMS-986249 is projected to be 240 mg, based on the comparable 
exposure-efficacy relationship observed for BMS-986249 and ipilimumab in human CTLA-4 KI 
mice bearing the MC38 tumor, combined with the projected human PK parameters. Assuming the 
Probody mAb cleavage in the MC38 tumor is the same as the cleavage in human tumors, the 
efficacious dose of BMS-986249 in order to achieve the same clinical efficacy as ipilimumab will 
be the same as the clinical approved ipilimumab monotherapy dose of 3 mg/kg, which is also being 
tested in various combination therapies with nivolumab. The optimal dosing regimen of 
BMS-986249 will be determined in the clinic.
3.2.1.4
BMS-986249 Nonclinical Toxicology
In a 1-month toxicity study in monkeys (n = 5/sex/group) at weekly IV doses of 10 or 50 mg/kg 
BMS-986249 or 10 or 50 mg/kg ipilimumab,5 BMS-986249 T cell activation/pharmacodynamic 
responses were reduced relative to the corresponding dose-matched ipilimumab group in both a 
dose and time-dependent manner correlating with a delayed conversion of BMS-986249 to active 
dual-clipped ipilimumab. BMS-986249 was clinically well tolerated at doses up to 50 mg/kg and, 
in general, resulted in reduced toxicity compared to ipilimumab at corresponding doses. At 
50 mg/kg ipilimumab, 1 monkey was euthanized early within 4 weeks of the recovery period 
(Day 55) due to a progressively deteriorating clinical condition, and skeletal muscle degeneration 
and necrosis secondary to inflammation. The predominant BMS-986249- and ipilimumab-related 
microscopic finding was generally dose-related lymphohistiocytic inflammation within a variety 
of tissues at both doses, but with higher incidence and wider tissue distribution of inflammatory 
changes in the ipilimumab groups compared to BMS-986249. 
Based on the lack of clinical signs, and minimal to moderate histopathological changes in target 
organs, the highest non-severely toxic dose (HNSTD) for BMS-986249 was considered to be 
50 mg/kg (mean total area under the concentration-time curve from time zero to 168 hours 
[AUC(0-168h)] =
(μg•h/mL). In contrast, based on mortality, and pathologic effects at 
50 mg/kg (mean total area under the curve [AUC][AUC(0-168h)=
 (μg•h/mL)], and 
minimal effects at 10 mg/kg, the HNSTD for ipilimumab was considered to be 10 mg/kg (mean 
total AUC[0-168h] = 44,600 (μg•h/mL).
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The BMS-986249 HNSTD corresponds to exposure (area under the concentration-time curve 
[AUC]) multiples of approximately 51-fold and 5.1× the projected exposures at the proposed 
starting first in human (FIH) dose (3 mg/kg IV, AUC[4-week] 
 (μg•h/mL) and highest 
projected dose for the FIH study (30 mg/kg IV, AUC[4-week] 
 (μg•h/mL), respectively. 
Because BMS-986249 has an identical binding region sequence to ipilimumab, the cytokine 
release studies performed with ipilimumab were utilized to support BMS-986249.6,7,8,9
Ipilimumab induced minimal proliferation (ie, mean peak stimulation index [SI] of 12) and 
minimal selective cytokine release (ie, IL-2, tumor necrosis factor alpha [TNF-α], IL-6, IL-8; mean 
peak SI ranging from 2 to 6) in PBMC from individual donors using an immobilized assay format. 
By comparison, the positive control anti-CD28 Ab induced profound proliferation (ie, mean peak 
SI of 139) and elicited a release of several cytokines (ie, interferon [IFN, IFN-δ], TNF-α, IL-2, IL-
4, IL-5, IL-6, and IL-8) in all donors at a relatively high magnitude (mean peak SI ranging from 4 
to 137). No substantial cytokine release from human PBMC was observed with ipilimumab using 
a soluble assay format.8 These findings are in agreement with clinical data indicating that 
ipilimumab generally does not elicit adverse cytokine release in humans.9
Overall, BMS-986249 has demonstrated acceptable pharmacologic, nonclinical PK, 
pharmacodynamic, and risk profiles to support initiation of a FIH clinical study in participants 
with cancer.
3.2.1.5
BMS-986249 Clinical Pharmacokinetics
Preliminary PK analysis from the Part 1A monotherapy cohorts suggest lower systemic plasma 
exposure of the active dual-cleaved Probody species (ipilimumab equivalent) compared to 
preclinical simulations and historical ipilimumab data. Overall, the systemic dual-cleaved Probody 
species represented approximately 3.7% to 5.9% of total circulating antibody following the first 
dose of BMS-986249.
Preliminary analysis of the first dosing interval of 240 mg BMS-986249 monotherapy 
demonstrated the plasma peak concentration (Cmax1 ≈ μg/mL) was 5-fold lower as compared 
to preclinical simulations (Cmax1 ≈ μg/mL), with an exposure of 1.7% as compared to historical 
3 mg/kg ipilimumab data (Cmax1 ≈
 μg/mL). Similarly, preliminary analysis of the first dosing 
interval of 800 mg BMS-986249 monotherapy indicated peak plasma exposure was 2.5% 
(Cmax1 ≈ μg/mL) compared to historical 
 mg/kg ipilimumab data (Cmax1 ≈
 μg/mL). 
Preliminary PK analysis suggests that following the first dose across the doses investigated in Part 
1A, the majority of the systemic circulating antibody species are the intact Probody, with the 
mono-cleaved Probody species representing approximately 
 to 
 of total antibody. 
Consistent with the in vivo protease-mediated cleavage process, both mono- and dual-cleaved 
Probody species appeared to be formed gradually with time, supporting the investigation of longer 
dosing intervals (eg, every 8 week [Q8W] regimens). With limited data, initial assessment of Part 
1B suggests co-administration of nivolumab did not significantly impact the BMS-986249 PK
profile. Preliminary assessment of tumoral BMS-986249 exposures based on a single on-treatment 
biopsy across the different doses in Part 1 suggests a more efficient cleavage process with mono-
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and dual-cleaved BMS-986249 species representing an average of approximately 45% and 10% 
of total Ab, respectively. Additional information on the preliminary PK results of BMS-986249 
can be found in the IB.10
3.2.1.6
Clinical Safety Summary
As of the date of this protocol, the overall safety experience with BMS-986249 as either a 
monotherapy or in combination with nivolumab is under active investigation and currently 
emerging. BMS-986249 monotherapy in Part 1A has been administered every 4 weeks (Q4W) at 
doses of 240 mg, 800 mg, 1,600 mg, and 2,400 mg. In addition, 1,600 mg BMS-986249 has also 
been administered Q8W. Doses of 240 mg BMS-986249 in combination with 480 mg nivolumab,
800 mg BMS-986249 in combination with 480 mg nivolumab, and 1,200 mg BMS-986249 in 
combination with 480 mg nivolumab have been administered Q4W in Part 1B. In addition, 800 
mg BMS-986249, 1,200 mg BMS-986249, and 1,600 mg BMS-986249 have also been 
administered Q8W in combination with 480 mg nivolumab administered Q4W. The maximum 
tolerated dose (MTD) of BMS-986249 as a monotherapy or in combination with nivolumab has 
not been reached. Overall, the safety profile of BMS-986249 as a single agent and in combination 
with nivolumab is clinically manageable and consistent with the established safety profile of the 
active form, ipilimumab. Of note, there may be a possibility of an increased risk of encephalitis 
associated with BMS-986249 (refer to Section 7.5.2 and Appendix 9). 
Upon preliminary evaluation of the available safety profile in Part 1, an increased number of 
TRAEs was observed with increasing dose of BMS-986249 administered Q4W alone and in 
combination with nivolumab. When BMS-986249 was administered at the alternative dosing 
schedule of Q8W a lower number of TRAEs were reported.
Additional details on the safety of BMS-986249 are summarized in the BMS-986249 IB.10
3.2.2
Nivolumab
Nivolumab is a fully human, immunoglobulin (Ig) G4 (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 PD-1 to its ligands, programmed death ligand-1 (PD-L1) and 
programmed death ligand-2 (PD-L2). 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 and cytomegalovirus 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 125527.11 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 IB.12
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-986249 and nivolumab have not been 
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conducted and are not required by the International Council for Harmonisation S9 Note for 
Guidance on Nonclinical Evaluation for Anticancer Pharmaceuticals.13 The safety of the 
combination will be carefully monitored in the planned 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.12 Nivolumab has been 
approved by the United States (US) Food and Drug Administration (FDA) for the treatment of 
unresectable or metastatic melanoma (as a single agent and in combination with ipilimumab), 
melanoma with lymph node involvement or metastatic disease after complete resection in the 
adjuvant setting, metastatic NSCLC after progression on or after platinum-based chemotherapy, 
metastatic or recurrent NSCLC with no epidermal growth factor receptor (EGFR) or anaplastic 
lymphoma kinase (ALK) genomic tumor aberrations as first-line treatment (in combination with 
ipilimumab and 2 cycles of platinum-doublet chemotherapy), metastatic NSCLC expressing 
PD-L1 ≥1%, metastatic SCLC with progression after platinum-based chemotherapy and at least 1
other line of therapy, advanced RCC previously treated with anti-angiogenic therapy, previously
untreated advanced RCC with intermediate or poor risk (in combination with ipilimumab), 
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease 
progression on or after a platinum-based therapy, classical Hodgkin’s lymphoma that has relapsed 
or progressed, locally advanced or metastatic urothelial carcinoma, MSI-H or mismatch repair 
deficient (dMMR) metastatic CRC (as a single agent and in combination with ipilimumab), 
sorafenib-treated hepatocellular carcinoma (HCC) (as a single agent and in combination with 
ipilimumab), unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma
after fluoropyrimidine- and platinum-based chemotherapy, and previously untreated unresectable 
malignant pleural mesothelioma.12
For nivolumab monotherapy, the safety profile is similar across tumor types. The only exception 
is pulmonary inflammation AEs, which may be numerically greater in participants with NSCLC. 
In NSCLC participants, 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.12
3.2.2.1
Clinical Pharmacokinetics of Nivolumab
Single-dose PK of nivolumab was evaluated in 39 participants with multiple tumor types in 
CA209001 in the dose range of 0.3 to 10 mg/kg. The median time of maximum observed 
concentration (Tmax) across dose levels ranged from 1.6 to 3.1 hours with individual values 
ranging from 0.9 to 7 hours. The PK of nivolumab was linear in the range of 0.3 to 10 mg/kg with 
dose-proportional increase in maximum observed concentration (Cmax) and AUC(INF). 
Geometric mean clearance after a single IV dose ranged from 0.13 to 0.19 mL/h/kg, while mean 
volume of distribution of terminal phase (Vz) varied between 83 to 113 mL/kg across doses. The 
mean terminal T-HALF of nivolumab was 17 to 25 days, consistent with half-life of endogenous 
IgG4, indicating that the elimination mechanism of nivolumab may be similar to IgG4. Both 
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elimination and distribution of nivolumab appeared to be independent of dose within the dose 
range studied.
The multiple dose PK of nivolumab given every 2 weeks (Q2W) in participants with multiple 
tumor types was determined from the CA209003 study as well as population PK (PPK) analyses 
using data from 909 participants across nivolumab studies. Multiple-dose PK of nivolumab 
following Q2W dosing was linear with dose proportional increase in Cmax and AUC(TAU) in the 
studied range of 0.1 to 10 mg/kg. The geometric mean of terminal T-HALF was 26.7 days and the 
typical clearance was 8.7 mL/h, which are consistent with those of full human immunoglobulin 
antibodies.
A dose of 480 mg nivolumab Q4W is currently under active clinical evaluation across multiple 
tumor types. Using a PPK model, 480 mg nivolumab Q4W is predicted to provide average 
steady-state concentrations similar to 3 mg/kg nivolumab Q2W. A dose of 480 mg nivolumab 
Q4W is predicted to provide a greater (approximately 40%) peak steady state concentration
(Cmaxss) and lower (approximately 20%) trough steady state concentrations (Cminss). Nivolumab 
has been shown to be safe and well tolerated up to doses of 10 mg/kg Q2W and has not 
demonstrated a clear dose response or exposure-response safety relationship. Based on these safety 
findings, the predicted Cmaxss at 480 mg Q4W is not considered to put participants at increased 
risk for AEs. The approved doses of 3 mg/kg Q2W and 240 mg Q2W have shown survival benefit 
across multiple tumor types compared to respective standards of care. Nivolumab exposure was 
not a predictor of survival in exposure response efficacy analyses conducted for multiple tumor 
types. The Cminss values following 480 mg nivolumab Q4W are predicted to be in the range of 
those on the flat part of the exposure-response efficacy curves and are not expected to impact 
efficacy. 
As of Jun-2017, approximately 310 participants in the nivolumab clinical development programs 
have received at least 1 dose of 480 mg nivolumab Q4W, either as the starting therapy or as 
maintenance treatment following 240 mg nivolumab Q2W. The Sponsor has a clinical safety 
program that monitors symptoms potentially related to infusion-related reactions reported on the 
day of infusion and the following day. For the approximately 310 participants treated with 
30-minute infusions of 480 mg nivolumab, there have been no reports of any symptoms that may 
potentially be linked to infusion reactions on the day of infusion or the following day. There have 
been no new safety signals identified during routine clinical and pharmacovigilance monitoring of 
these studies. Clinical evaluation of this dose regimen is ongoing; as such, summaries of safety 
information, PK, and immunogenicity are not currently available. A dose of 480 mg nivolumab 
Q4W infused over 30 minutes was FDA-approved in Mar 2018 for the majority of the approved 
indications. The European Medicines Agency’s Committee for Medicinal Products for Human Use 
(CHMP) has also recommended adding the option of a 4-week dosing schedule to the label for 
nivolumab for the treatment of patients with advanced melanoma and previously treated RCC.
Additional details are provided in the current version of the nivolumab IB.12
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3.2.3
Ipilimumab
Ipilimumab (BMS-734016, MDX010, and MDX-CTLA-4) is a fully human monoclonal IgG1κ 
specific for human CTLA-4, CD152. CTLA-4 is expressed on a subset of activated T cells on 
which it acts as a negative regulator of T cell activity. Ipilimumab is a mAb that binds to CTLA-4 
and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has 
been shown to augment T cell activation and proliferation, including the activation and 
proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce 
Treg function, which may contribute to a general increase in T cell responsiveness, including the 
anti-tumor response. Ipilimumab has been administered to more than 28,686 participants (total 
number of participants enrolled in ipilimumab studies) in several cancer types in completed and 
ongoing studies, as well as a compassionate use program. Ipilimumab has been approved for use 
in over 47 countries including the US (Mar-2011), the European Union (Jul-2011), and Australia 
(Jul-2011).
The focus of the monotherapy clinical program has been in melanoma, with advanced melanoma 
and adjuvant melanoma being the most comprehensively studied indications. Ipilimumab is being 
investigated in combination with other modalities such as chemotherapy, radiation therapy, and 
other immunotherapies in multiple tumor types. 
In melanoma, 2 completed Phase 3 studies (MDX010-20 and CA184024) demonstrated a 
clinically meaningful and statistically significant survival benefit in pretreated advanced 
melanoma and previously untreated advanced melanoma, respectively.
The safety profile of ipilimumab is generally consistent across studies, with a) the majority of AEs 
being inflammatory in nature, which is consistent with the proposed mechanism of action of 
ipilimumab; b) the same types of such immune-mediated AEs in the gastrointestinal (GI) tract, 
skin, liver, and endocrine system being reported; and c) most of these events being manageable 
with immune suppressive therapies.
In participants with advanced melanoma who received 3 mg/kg ipilimumab monotherapy in a 
Phase 3 study (MDX010-20), the most frequently reported adverse reactions (≥10% of 
participants) were diarrhea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, and 
abdominal pain. The majority of AEs were mild to moderate (Grade 1-2), and treatment was 
discontinued for adverse reactions in 10% of participants.
Long-term survival benefit of treatment with 3 mg/kg ipilimumab was demonstrated through a 
pooled analysis of overall survival (OS) data from clinical trials in participants with previously 
treated and treatment naive advanced melanoma (N = 965). The Kaplan-Meier OS curve revealed 
a plateau beginning around year 3 (OS rate = 21% [95% confidence interval (CI): 17 to 24]) that 
extended up to 10 years in some participants.
Dose-dependent toxicity as well as relative efficacy of ipilimumab 3 mg/kg versus 10 mg/kg were 
established in a Phase 3 study in advanced melanoma (CA184169). Ipilimumab resulted in a 
median OS of 15.70 months in participants treated with 10 mg/kg and 11.53 months in participants 
treated with 3 mg/kg. Ipilimumab 10 mg/kg demonstrated statistically significant improvement in 
OS (primary efficacy endpoint) compared with 3 mg/kg ipilimumab (hazard ratio [HR] = 0.84, 
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95% CI: 0.70, 0.99; P-value = 0.0400). Best objective response rate (ORR) was 15.3% 
(95% CI: 11.8, 19.5) for 10 mg/kg and 12.2% (95% CI: 9.0, 16.0) for 3 mg/kg.14
Ipilimumab monotherapy prolongs survival in patients with pretreated and previously untreated 
advanced melanoma and has demonstrated anti-tumor activity in other malignancies, including 
lung cancer, prostate cancer, and RCC.15
Additional details on the safety profile and clinical benefit of ipilimumab alone and in combination 
with nivolumab, including results from clinical studies in melanoma, prostate, lung, kidney, 
bladder, or breast tumors are summarized in the ipilimumab and nivolumab IBs.12, 15
3.2.4
Nivolumab Combined with Ipilimumab
Multiple clinical studies have evaluated nivolumab combined with ipilimumab at different doses 
and schedules. The following information describes the results of initial early phase clinical studies 
that were the basis for the nivolumab and ipilimumab combination regimens that have been 
explored in late phase clinical development.
In the Phase 1 study CA209004, ascending doses of nivolumab have been studied concomitantly 
with ascending doses of ipilimumab in participants with unresectable or metastatic melanoma. In 
each arm in this multi-arm study, ipilimumab was administered once every 3 weeks (Q3W) for 
4 doses with nivolumab administered once Q3W for 8 doses. Starting at Week 24, ipilimumab and 
nivolumab were administered once every 12 weeks (Q12W) for 8 doses. The 3 initial dose-
escalation cohorts consisted of Cohort 1 (0.3 mg/kg nivolumab in combination with 3 mg/kg 
ipilimumab; n=14), Cohort 2 (1.0 g/kg nivolumab in combination with 3 mg/kg ipilimumab; n=17) 
and Cohort 3 (3.0 mg/kg nivolumab in combination with 3 mg/kg ipilimumab; n=6). Later, the 
study was amended to include Cohort 2a which evaluated 3 mg/kg nivolumab in combination with
1 mg/kg ipilimumab (n=16). The primary objective was to assess safety/tolerability; the secondary 
objective was to assess preliminary efficacy.
Of the 52 participants evaluable for response as of the 15-Feb-2013 clinical cut-off in CA209004, 
21 participants (40%) had an objective response by modified World Health Organization (mWHO) 
criteria. In an additional 2 participants (4%) there was an unconfirmed objective response. In 
Cohort 1 (0.1 mg/kg nivolumab in combination with 3 mg/kg ipilimumab), 3 out of 14 evaluable 
participants had an objective response by mWHO (21%), including 1 complete response (CR) and 
2 partial responses (PRs).16 In Cohort 2 (1 mg/kg nivolumab in combination with 3 mg/kg 
ipilimumab), 9 out of 17 (53%) evaluable participants had an objective response by mWHO, 
including 3 CRs (18%) and 6 PRs (35%). In Cohort 2a (3 mg/kg nivolumab in combination with
1 mg/kg ipilimumab), 6 out of 15 (40%) response evaluable participants had an objective response 
by mWHO, including 1 CR (7%) and 5 PRs (33%). In Cohort 3 (3 mg/kg nivolumab in 
combination with 3 mg/kg ipilimumab), 3 out of 6 (50%) evaluable participants had an objective 
response by mWHO, all 3 of which were PRs (50%).
Preliminary analysis revealed 16 of the 52 evaluable participants (31%) had > 80% reduction in 
the size of target tumor lesions by the Week 12 evaluation. This is compared to < 2% for 3 mg/kg 
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ipilimumab monotherapy based on CA184020 (N=540) and < 3% for nivolumab monotherapy 
based on CA209003 (N=94, 0.1-10 mg/kg).
The following dose limiting toxicities (DLTs) were observed: in Cohort 1, Grade 3 elevated 
aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (1 participant); in Cohort 2, 
Grade 3 uveitis (1 participant) and Grade 3 elevated AST/ALT (1 participant) and in Cohort 3, 
Grade 4 elevated lipase (2 participants) and Grade 3 elevated lipase (1 participant). Based on these 
data, Cohort 2 was identified as the MTD and Cohort 3 exceeded the MTD.
A total of 53 melanoma participants were treated with nivolumab combined with ipilimumab in 
CA209004 across Cohorts 1, 2, 2a, and 3. At least 1 AE regardless of causality has been reported 
in 98% of participants treated. The most common (reported at > 10% incidence) TRAEs (any 
Grade 93%; Grade 3-4 53%:) are rash (55%; 4%), pruritus (47%; 0%), vitiligo (11%; 0%), fatigue 
(38%; 0%), pyrexia (21%, 0%), diarrhea (34%; 6%), nausea (21%, 0%), vomiting (11%, 2%), ALT 
increased (21%; 11%), AST increased (21%; 13%), lipase increased (19%; 13%), amylase 
increased (15%, 6%), headache (11%, 0%), and cough (13%, 0%).
The majority of AEs leading to discontinuation (regardless of causality) were Grade 3-4 (reported 
in 11 of 53 participants, 21%). Grade 3 events included lipase increased, ALT increased, AST 
increased, troponin I increased, colitis, diverticular perforation, pancreatitis, tachycardia, renal 
failure acute, choroiditis, autoimmune disorder, and pneumonitis. One participant each 
discontinued due to Grade 4 events of blood creatinine increased and AST increased. No drug-
related deaths were reported.16
The combination of nivolumab with ipilimumab is being studied in the Phase 1 study CA209016. 
Participants with metastatic RCC (mRCC) (Karnofsky performance status ≥ 80%; untreated or any 
number of prior therapies) were randomized to receive 3 mg/kg nivolumab in combination with
1 mg/kg ipilimumab (arm N3 + I1) or 1 mg/kg nivolumab in combination with 3 mg/kg ipilimumab 
(arm N1 + I3) IV Q3W for 4 doses followed by 3 mg/kg nivolumab IV Q2W until 
progression/toxicity. The primary objective was to assess safety/tolerability; secondary objective 
was to assess anti-tumor activity. 
Participants were randomized to N3 + I1 (n = 47) and N1 + I3 (n = 47). Approximately half (n = 46; 
51%) had prior systemic therapy (N3 + I1: 22; N1 + I3: 26). 
After a median follow-up of 22.3 months, the confirmed ORR per Response Evaluation Criteria 
in Solid Tumors version 1.1 (RECIST 1.1) was 40.4% (n = 47) in both Arms N3 + I1 and N1 + I3; 
42.1% (n = 8) and 36.8% (n = 7) had an ongoing response, with a median duration of response 
(DOR) of 88.7 weeks (95% CI: 37.14, NA) and 85.9 weeks (95% CI: 35.14, not available), 
respectively. Median PFS was 7.7 months (95% CI: 3.71, 14.29) and 9.4 months (95% CI: 
5.62, 18.63) in Arms N3 + I1 and N1 + I3, respectively. OS at 12 months was 80.9% and 85.0% 
in Arms N3 + I1 and N1 + I3, respectively, and at 24 months was 67.3% and 69.6%, respectively.
The safety of nivolumab combined with ipilimumab was assessed in study CA209016. TRAEs 
were seen in 88/94 pts (94%), including 43/47 (92%) in N3 + I1 and 45/47 (96%) in N1 + I3. The 
most frequently reported drug-related AEs in N3 + I1 included fatigue (66%), cough (53.2%), and 
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arthralgia (51.1%); the majority were Grade 1-2. The most frequently reported drug-related AEs 
in N1 + I3 included fatigue (74.5%), nausea (55.3%), and diarrhea (53.2%). The majority were 
Grade 1-2. 
TRAEs leading to discontinuation (31.9% versus 10.6%), and treatment-related serious adverse 
events (SAEs) (34% versus 23.4%) occurred more commonly in participants in the N1 + I3 arm 
than in the N3 + I1 arm, respectively.17
CA209012 was a multi-arm Phase 1b trial evaluating the safety and tolerability of nivolumab in 
participants with chemotherapy-naïve advanced NSCLC, as either a monotherapy or in 
combination with other agents including ipilimumab, at different doses and schedules. The primary 
endpoint of the study was safety with secondary endpoints of ORR per RECIST v1.1 and 24-week 
PFS. Participants were assigned to receive 3 mg/kg nivolumab Q2W in combination with 1 mg/kg 
ipilimumab Q12W (n=38), 3 mg/kg nivolumab Q2W in combination with 1 mg/kg ipilimumab
every 6 weeks (Q6W) (n=39) and 3 mg/kg nivolumab Q2W (n=52). The confirmed ORR was 47% 
(N3 Q2W + I1 Q12W), 39% (N3 Q2W + I1 Q6W) and 23% (N3 Q2W). The median DOR was 
not reached in any of these groups. 
The rate of TRAEs in the Q12W (82%) and Q6W (72%) arms were comparable to monotherapy 
(72%). In the study, Grade 3-4 AEs were 37%, 33%, and 19% for the Q12W, Q6W, and nivolumab 
monotherapy arms, respectively. Grade 3-4 TRAEs led to discontinuation in 5% and 8% of 
participants in the Q12W and Q6W cohorts, respectively, and were similar to nivolumab 
monotherapy. There were no treatment-related deaths. The treatment-related select AEs in 
participants administered the optimized dosing schedule (3 mg/kg of nivolumab Q2W in 
combination with 1 mg/kg of ipilimumab Q6W) were skin-related (36%), GI (23%), endocrine 
(20%), and pulmonary (5%) and there were ≤ 5% Grade 3-4 TRAEs per category.18
3.3
Benefit/Risk Assessment
Patients who have advanced solid tumors have a poor prognosis and few curative options.
Immunotherapy with ipilimumab or nivolumab has demonstrated clinical activity in patients with 
melanoma or advanced NSCLC, RCC, SCCHN, HCC, and other tumors. TRAEs include those 
associated with autoimmune activation, such as colitis, pneumonitis, thyroiditis, hepatitis, and 
adrenal insufficiency.
There is no prior human experience with BMS-986249; therefore, clinical benefit has not been 
established in patients with advanced cancer. However, nonclinical models are suggestive of at 
least similar anti-tumor activity that has been observed with ipilimumab.
In the absence of previous clinical studies with BMS-986249, the initial evaluation of risk is based 
primarily on the potential effects based on the proposed mechanism of action as well as on 
information from nonclinical studies with BMS-986249 in monkeys (Section 3.2.1) and clinical 
evidence from ipilimumab therapy.
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The nonclinical Good Laboratory Practice (GLP) toxicology assessment of BMS-986249 has 
demonstrated a dose-related toxicity profile of irAEs and cytokine release potential compatible 
with the expected mechanism of action (see Section 3.2.1). 
For the combination of BMS-986249 and nivolumab, as observed with ipilimumab and nivolumab
combination therapy, it is possible that a higher incidence of irAEs may occur. The safety profile 
of nivolumab monotherapy and the combination of ipilimumab and nivolumab are characterized
based on experience with more than 23,507 participants as either monotherapy or in combination 
therapy. The frequency and types of immune-mediated adverse reactions are similar across 
multiple types of tumors and are described in the Reference Safety Information in the current 
nivolumab and ipilimumab IBs.12,15 Unanticipated side effect events may also occur.
The proposed clinical studies of BMS-986249 have been designed to minimize the overall risk to 
participants; measures will include the following:
•
Continuous safety assessments will be utilized by the investigators and Sponsor to determine 
whether additional safety measures, or termination of the study is required at any time. In 
addition, AEs and SAEs will be reviewed on an ongoing basis by the Medical Monitor (or 
designee) and Global Pharmacovigilance and Epidemiology (GPVE) representatives to 
monitor for any safety signals or trends. As BMS-986249 is an experimental agent, it is 
possible that unforeseen, unknown, or unanticipated reactions may occur. However, based on 
the nonclinical safety profile of BMS-986249 built into the planned starting dose of 240 mg
(equivalent to approximately 3 mg/kg), the potential safety risks are expected to be minimized. 
•
Doses above 800 mg (equivalent to approximately 10 mg/kg) will only be evaluated if lower 
doses are deemed tolerable and if the PK profile of BMS-986249 appears consistent with the 
expected effects of a Probody mAb, specifically, if the systemic exposure to the cleaved 
prodrug (ie, ipilimumab) and peripheral pharmacodynamic effects are reduced.
•
The administration will occur at infusion centers with medical monitoring and the capability 
to manage infusion reactions or anaphylaxis. The protocol provides a treatment algorithm for 
infusion reactions (see Section 7.5.5). In addition to conventional safety measures for infusion 
of biologic agents, all participants will undergo observation and assessment for signs of 
infusion reaction for a 60-minute period after the completion of the infusion for the first 3 doses 
for each participant.
•
Furthermore, to assess for potential effects of lymphocyte activation, a sentinel participant will 
be monitored for 5 days at each dose level. The sentinel participant approach is used to closely 
monitor early-onset safety events in the monotherapy and combination therapy arms because 
the doses are escalated in a staggered manner.
•
Management algorithms for ipilimumab/nivolumab-induced AEs involving GI, renal, 
pulmonary, hepatic, endocrinopathy, skin, cardiac, and neurologic systems are included in the 
protocol (see Appendix 9).
•
Participants
who develop irAEs may require prolonged treatment with high-dose 
corticosteroids and other immunosuppressive agents. This could increase the risk of 
opportunistic infections. The irAE management algorithms in the protocol recommend 
antibiotic prophylaxis against opportunistic infections in such situations.
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•
Complete blood counts and chemistry (including liver enzyme) tests will be carried out prior 
to administration of study therapy and on a weekly basis during the first 8 weeks of treatment 
in monotherapy and the first 8 weeks of the combination between BMS-986249 and 
nivolumab. In addition, complete physical examinations (PEs) will be conducted on Day 1 of 
each new cycle, along with weekly symptom-directed targeted PEs during the first 8 weeks of 
treatment. Due to the potential risk of exaggerated inflammatory response, participants with 
autoimmune disorders, chronic viral infections, or who are at risk for flare of autoimmunity 
will be excluded.
•
The mandated biopsies pose limited risk to the participant and include discomfort, pain, and 
bleeding. Section 9.8.2 gives guidance on lesions that are appropriate for a research biopsy, 
and participants who are not able to undergo a biopsy with an acceptable risk can participate 
in some situations and upon agreement with the study director/Medical Monitor. Because of 
the need for development of predictive biomarkers for participants treated with BMS-986249 
in future studies or the clinical setting, the limited risk of a research biopsy in selected (low 
risk) participants is considered appropriate in an early-phase research setting.
•
The amount of blood sampling poses limited risk to the participant and includes discomfort, 
pain, and bleeding. The amount of total blood is reduced to the minimal quantity required to 
address the need of safety monitoring, standard of care, PK/ADA, and biomarker needs and is 
below the recommended daily limits for each treatment day.
In conclusion, the potential direct benefit to participants who participate in this study is that both 
single-agent and combined therapies with these investigational agents may result in a greater 
proportion of participants with stabilization of disease, ORR, PFS, OS, or increased DOR than 
those observed with standard therapy or other investigational immunotherapy.
The potential for direct benefit described above warrants evaluating BMS-986249 both as a single 
agent and in combination with nivolumab in this Phase 1/2 clinical study with risk mitigation 
described above. 
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of BMS-986249 may be found in the IB.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints: The Dose Escalation Phase (Part 1)
Objectives
Endpoints
Primary
•
To characterize the safety, tolerability, and DLTs and 
to determine the MTD/RP2D of BMS-986249 
administered as monotherapy and in combination with 
nivolumab in participants with advanced solid tumors
(Parts 1A and 1B)
•
Incidence of AEs, SAEs, AEs meeting 
protocol-defined DLT criteria, AEs leading to 
discontinuation, death, and laboratory 
abnormalities
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Table 4-1:
Objectives and Endpoints: The Dose Escalation Phase (Part 1)
Objectives
Endpoints
Secondary
•
To characterize the PK of BMS-986249 when 
administered alone and in combination with 
nivolumab 
•
To assess the preliminary anti-tumor activity of 
BMS-986249 alone and in combination with 
nivolumab in advanced solid tumors (Parts 1A and 
1B) using RECIST v1.1 or PCWG3 (for prostate 
cancer)
•
Summary measures of PK parameters of 
BMS-986249
•
ORR, DOR, PFS, and TTR per RECIST v1.1 
or PCWG3 (for prostate cancer)
Exploratory
•
To explore the associations between PK of 
BMS-986249 and nivolumab, safety, efficacy, and 
clinical biomarkers such as, but not limited to
T cell-specific genes
•
Association measures between BMS-986249
PK levels, select outcomes, and biomarkers of 
interest
•
To characterize the immunogenicity of BMS-986249 
and nivolumab
•
Incidence of ADA to nivolumab and 
BMS-986249
•
To assess the potential effect of BMS-986249 when 
administered as monotherapy on the QTc interval
•
Summary measures of ECG parameters and 
changes in QTcF (ΔQTcF) from baseline
Abbreviations: ADA = anti-drug antibody; AE = adverse event; DLT = dose-limiting toxicity; DOR = duration of 
response; ECG = electrocardiogram; MTD = maximum tolerated dose; ORR = Objective Response Rate; PCWG3 = 
Prostate Cancer Working Group 3; PFS = progression-free survival; PK = pharmacokinetics; QTc = QT interval 
corrected; QTcF = QT interval corrected for heart rate using Fridericia’s formula; RECIST = Response Evaluation 
Criteria in Solid Tumors; RP2D = recommended Phase 2 dose of BMS-986249; SAE = serious adverse events; 
TTR = time to response.
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Table 4-2:
Objectives and Endpoints: The Dose Expansion Phase in Melanoma
(Part 2A)
Objectives
Endpoints
Primary
•
To evaluate the preliminary safety and tolerability 
of BMS-986249 in combination with nivolumab 
(Arm C and Arm F) relative to ipilimumab in 
combination with nivolumab (Arm D) in 
participants with previously untreated, 
unresectable or metastatic melanoma
•
Incidence of treatment-related Grade 3-5 AEs 
within 24 weeks
•
To evaluate the preliminary efficacy of BMS-
986249 in combination with nivolumab (Arm C
and Arm F) relative to historic nivolumab 
monotherapy data in participants with previously 
untreated, unresectable or metastatic melanoma
•
ORR as assessed by investigator using RECIST 
v1.1
Secondary
•
To assess the anti-tumor activity of BMS-986249 
in combination with nivolumab (Arm C and Arm 
F) and ipilimumab in combination with nivolumab 
(Arm D) in participants with previously untreated, 
unresectable or metastatic melanoma
•
ORR, DOR, PFS, and TTR as assessed by 
investigator using RECIST v1.1
•
To assess the safety and tolerability of BMS-
986249 in combination with nivolumab (Arm C
and Arm F), and ipilimumab in combination with 
nivolumab (Arm D) in participants with previously 
untreated, unresectable or metastatic melanoma
•
Incidence of AEs, SAEs, AEs leading to 
discontinuation, death, and laboratory 
abnormalities
•
To characterize the PK of BMS-986249 when 
administered in combination with nivolumab
•
Summary measures of PK parameters of 
BMS-986249 in combination with nivolumab
•
To evaluate time to deterioration (TTD) in Quality 
of Life (QoL) and physical functioning
•
TTD as defined by a minimally important decrease 
from baseline ≥10 points on the EORTC QLQ-C30 
global health status/quality of life subscale (items 
29 & 30) and Physical Functioning Scale (items 1 
to 5)
Exploratory
•
To explore the associations between PK of 
BMS-986249, ipilimumab and nivolumab, safety, 
efficacy, and clinical biomarkers such as, but not 
limited to T cell-specific genes 
•
Association measures between BMS986249, 
ipilimumab, and nivolumab PK levels, select 
outcomes, and biomarkers of interest
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Table 4-2:
Objectives and Endpoints: The Dose Expansion Phase in Melanoma
(Part 2A)
Objectives
Endpoints
•
To characterize the immunogenicity of 
BMS-986249, ipilimumab and nivolumab
•
Incidence of ADA to ipilimumab, nivolumab, and 
BMS-986249
•
To explore OS of BMS-986249 in combination 
with nivolumab (Arm C and Arm F), and
ipilimumab in combination with nivolumab 
(Arm D)
•
OS rate at 1 and 2 years
•
To evaluate changes in QoL, health status, and 
patient reported tolerability
•
Mean scores and post-baseline score changes for 
all EORTC QLQ-C30 subscales, EQ-5D-3L utility 
index and VAS, and n (%) of endorsing 
participants by arm and time point for FACIT GP5 
item and PRO-CTCAE items
Abbreviations: ADA = anti-drug antibody; AE = adverse event; DOR = duration of response; EORTC QLQ-C30 = 
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30; EQ-5D-3L = 
European Quality of Life – 5 Dimension – 3 Level Questionnaire; FACIT GP5 = Functional Assessment of Chronic 
Illness Therapy General Physical item 5; ORR = Objective Response Rate; OS = overall survival; PFS = progression-
free survival; PK = pharmacokinetics; PRO-CTCAE = Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event;; TTD = time to deterioration; TTR = time to response; VAS = visual analogue 
scale.
Table 4-3:
Objectives and Endpoints: The Dose Expansion Phase in Additional 
Tumors (Part 2B)
Objectives
Endpoints
Primary
•
To evaluate the preliminary safety and tolerability of 
BMS-986249 in combination with nivolumab in 
participants with previously treated HCC, CRPC, and 
TNBC
•
Incidence of treatment-related Grade 3-5 AEs 
within 24 weeks
Secondary
•
To assess the preliminary anti-tumor activity of 
BMS-986249 in combination with nivolumab in 
participants with previously treated HCC, CRPC, and
TNBC
•
To characterize the safety and tolerability of BMS-
986249 in combination with nivolumab in participants 
with previously treated HCC, CRPC, and TNBC
•
To characterize the PK of BMS-986249 when 
administered in combination with nivolumab in 
participants with previously treated HCC, CRPC, and 
TNBC
•
ORR, DOR, PFS, and TTR as assessed by 
investigator per RECIST v1.1 or PCWG3 (for 
prostate cancer). PSA response rate for prostate 
cancer
•
Incidence of AEs, SAEs, AEs leading to 
discontinuation, death, and laboratory 
abnormalities
•
Summary measures of PK parameters of 
BMS-986249 in combination with nivolumab
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Table 4-3:
Objectives and Endpoints: The Dose Expansion Phase in Additional 
Tumors (Part 2B)
Objectives
Endpoints
Exploratory
•
To explore the associations between PK of 
BMS-986249 and nivolumab, safety, efficacy, and 
clinical biomarkers such as, but not limited to
T cell-specific genes
•
Association measures between BMS-986249
and nivolumab PK levels, select outcomes, and 
biomarkers of interest
•
To characterize the immunogenicity of BMS-986249 
and nivolumab
•
Incidence of ADA to nivolumab and 
BMS-986249
•
To explore OS
•
To evaluate changes in QoL, health status, and patient 
reported tolerability
•
OS rate at 1 and 2 years
•
Mean scores and post-baseline score changes 
for all EORTC QLQ-C30 subscales, EQ-5D-3L 
utility index and VAS, and n (%) of endorsing 
participants by arm and time point for FACIT 
GP5 item and PRO-CTCAE items
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CRPC = castration-resistant prostate cancer; DOR = 
duration of response; EQ-5D-3L = European Quality of Life – 5 Dimension – 3 Level Questionnaire; EORTC QLQ-
C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30; FACIT 
GP5 = functional assessment of chronic illness therapy general physical item 5; HCC = hepatocellular carcinoma;
ORR = objective response rate; OS = overall survival; PCWG3 = Prostate Cancer Working Group 3; PFS = 
progression-free survival; PK = pharmacokinetics; PRO-CTCAE = patient reported outcomes version for Common 
Terminology Criteria for Adverse Events; PSA = prostate-specific antigen; QoL = quality of life; RECIST = Response 
Evaluation Criteria in Solid Tumors; SAE = serious adverse events; TNBC = triple-negative breast cancer; TTR = time 
to response; VAS = visual analogue scale.
Table 4-4:
Primary Estimands Part 2A
Objectives
Endpoints
Primary
Primary
To evaluate the preliminary safety and tolerability of 
BMS-986249 in combination with nivolumab (Arm C 
and Arm F) relative to ipilimumab in combination with 
nivolumab (Arm D) in participants with previously 
untreated, unresectable or metastatic melanoma
Incidence of treatment-related Grade 3-5 AEs within 
24 weeks
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Table 4-4:
Primary Estimands Part 2A
Objectives
Endpoints
Main Estimand for the Primary Objective
Treatment: 1200 mg BMS-986249 IV Q8W + 480 mg nivolumab IV Q4W (Arm C); 3 mg/kg ipilimumab Q3W + 
1 mg/kg nivolumab IV Q3W for 4 doses followed three weeks later by 480 mg nivolumab IV Q4W(Arm D); 600 mg 
BMS-986249 IV Q4W +480 mg nivolumab IV Q4W (Arm F)
Population: All treated participants 
Variable: Treatment Related AE with CTCAE Grade 3 or higher that occurred within 24 weeks from first dose
Intercurrent events: early discontinuation of study
Treatment Policy: Patients that discontinue treatment early will have a 100 days post last dose safety follow-up. 
AEs occurring after this safety follow-up window will not be included in the analysis, even if they occurred 
within the 24 weeks from first dose.
Intercurrent event: initiation of subsequent anti-cancer therapy
While on treatment: Patients that initiate an anti-cancer subsequent therapy will be discontinued from study but 
will be followed up for safety events 100 days from last dose. Safety events regardless of whether they occur 
before or after subsequent therapy will be include in the analysis. AEs occurring past 100 days safety follow-up
will not be included in the analysis, even if they occurred within the 24 weeks from first dose.
Intercurrent event: death and  withdrew 
While on treatment: Patients who die or withdraw consent before reaching the 24 weeks landmark will be 
included in the analysis and their Grade 3 to 5 treatment related AEs will be include in the summary.
Population level summary: Grade 3 to 5 treatment related adverse event incidence rate, comparison of Arm C vs 
Arm D and Arm F vs Arm D with estimated difference and odd ratio and 80% confidence interval using Cochran 
Mantel Haenszel methodology adjusting for stratification factors will be computed. Adjusted and unadjusted chi 
square test will be performed and p-values will be provided.
Objective
Endpoint
Primary
Primary
To evaluate the preliminary efficacy of BMS-986249 
in combination with nivolumab (Arm C and Arm F) 
relative to historic nivolumab monotherapy data in 
participants with previously untreated, unresectable or 
metastatic melanoma
ORR as assessed by investigator using RECIST v1.1
Main Estimand for the Primary Objective
Treatment: 1200 mg BMS-986249 IV Q8W + 480 mg nivolumab IV Q4W (Arm C); 3 mg/kg ipilimumab Q3W + 
1 mg/kg nivolumab IV Q3W for 4 doses followed three weeks later by 480 mg nivolumab IV Q4W(Arm D); 600 mg 
BMS-986249 IV Q4W + 480 mg nivolumab IV Q4W (Arm F)
Population: All treated participants with evaluable baseline tumor assessment per RECIST v1.1
Variable: BOR, defined as the best response, as determined by investigator, per RECIST 1.1
Intercurrent events: early discontinuation of study
Treatment policy (all post-baseline tumor assessment regardless of on-treatment status will contribute to BOR 
determination)
Intercurrent event: initiation of subsequent anti-cancer therapy
While on treatment (all post-baseline tumor assessment up to initiation of subsequent anticancer therapy will 
contribute to BOR determination)
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Table 4-4:
Primary Estimands Part 2A
Objectives
Endpoints
Population level summary: ORR, defined as the number of randomized participants who achieve a BOR of 
confirmed CR or confirmed PR based on investigator assessments (using RECIST 1.1) divided by the number of 
all response-evaluable participants in each treatment group, with two sided 60% confidence interval
Estimated odd ratio and 60% confidence interval using Cochran Mantel Haenszel methodology adjusting for 
stratification factors will be computed. Adjusted and unadjusted chi square test will be performed and p-value will 
be provided. The difference in ORR (adjusted and unadjusted) will also be provided.
Abbreviations: AE = adverse event; BOR = best overall response; CR = complete response; CTCAE = Common 
Terminology Criteria for Adverse Events; IV = intravenous; ORR = objective response rate; PR = partial response;
Q3W = every 3 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; RECIST= Response Evaluation Criteria in 
Solid Tumors.
Table 4-5:
Primary Estimands Part 2B
Objective
Endpoint
Primary
Primary
To evaluate the preliminary safety and tolerability of 
BMS 986249 in combination with nivolumab in 
participants with previously treated HCC, CRPC, and 
TNBC
Incidence of treatment-related Grade 3-5 AEs within 
24 weeks
Main Estimand for the Primary Objective
Treatment: 1200 mg BMS-986249 IV Q8W +480 mg nivolumab IV Q4W
Population: All treated participants in Part 2B
Variable: Treatment Related AE with CTCAE Grade 3 or higher that occurred within 24 weeks from first dose
Intercurrent events: early discontinuation of study
Treatment Policy: Patients that discontinue treatment early will have a 100 days post last dose safety follow-up. 
AEs occurring after this safety follow-up window will not be included in the analysis, even if they occurred 
within the 24 weeks from first dose.
Intercurrent event: initiation of subsequent anti-cancer therapy
While on treatment: Patients that initiate an anti-cancer subsequent therapy will be discontinued from study but 
will be followed-up for safety events 100 days from last dose. Safety events regardless of whether they occur 
before or after subsequent therapy will be include in the analysis. AEs occurring past 100 days safety follow-up 
will not be included in the analysis, even if they occurred within the 24 weeks from first dose.
Intercurrent event: death and lost of consent
While on treatment: Patients who die or withdrew consent before reaching the 24 weeks landmark will be 
included  in the analysis and their Grade 3 to 5 treatment related AEs will be included in the summary.
Population level summary: Grade 3 to 5 treatment related adverse event incidence rate
Abbreviations: AE = adverse event; CRPC = castration-resistant prostate cancer; CTCAE = Common Terminology 
Criteria for Adverse Events; HCC = hepatocellular carcinoma; IV = intravenous; Q4W = every 4 weeks; Q8W = every 
8 weeks; TNBC = triple-negative breast cancer.
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5
STUDY DESIGN
5.1
Overall Design
This is a Phase 1/2, open-label study of BMS-986249 administered as a single agent and in 
combination with nivolumab in participants with advanced solid tumors. The study is composed 
of 2 parts: dose escalation and dose expansion.
Part 1: The Dose Escalation Phase is where the dose of BMS-986249 will be given alone (Part 1A) 
or in combination with nivolumab (Part 1B). The Part 1A monotherapy dose escalation will 
evaluate different doses of BMS-986249 starting at 240 mg followed by 800, 1,600, and 2,400 mg 
(flat doses, Q4W). If during the monotherapy Dose Escalation Phase (Part 1A) it appears that a
dose is associated with an unacceptable frequency of toxicities, then a conditional dose (eg,
intermediate dose or alternative administration schedule [eg, Q8W, see Appendix 12]) may be 
evaluated in the study after clinical evaluation of the available safety, PK, and 
 
data. Alternative dose schedules will be initiated and documented by a note to file or administrative 
letter following discussions and agreement between the investigators and Medical Monitor (or 
designee).
The BMS-986249 Monotherapy Dose Escalation (Part 1A) will escalate the dose of BMS-986249 
to determine a safe and efficacious dose. The study will first evaluate the safety and tolerability of 
monotherapy BMS-986249 Q4W, based on DLTs using a Bayesian Logistic Regression Model 
(BLRM) employing the escalation with overdose control (EWOC) principle. 
 
The Safety Evaluation of Combination Doses of BMS-986249 with Nivolumab (Part 1B) will 
evaluate the safety and tolerability of doses of BMS-986249 in combination with nivolumab. 
Part 1B will begin only when data (safety and PK) on BMS-986429 at 240 mg (equivalent to 
approximately 3 mg/kg) and 800 mg (equivalent to approximately 10 mg/kg) are available from 
the monotherapy dose-escalation cohort (Part 1A). In Part 1B, the dose of BMS-986429 will be 
escalated, whereas the dose of nivolumab will be fixed at 480 mg Q4W. However, if an MTD is 
identified, then additional cohorts with lower doses of nivolumab and then potential higher doses 
of BMS-986249 may be studied as outlined in the study schematic (Figure 5.1-1). Alternative 
administration schedules of BMS-986249 (eg, Q8W, see Appendix 12 and Figure 5.1-1) may also 
be explored after clinical evaluation of available safety, PK, and 
 data.
Alternative dose schedules will be initiated and documented by a note to file or administrative 
letter following discussions and agreement between the investigators and Medical Monitor (or 
designee).
To better estimate the preliminary safety profile and PK of any cohort in Part 1A or 1B, additional 
participants may be enrolled to cohorts deemed tolerable per the BLRM method. 
Part 2: The BMS-986249 Cohort Expansion Combination Therapy Phase will open upon an overall 
assessment of available preliminary safety, PK, and 
data from Part 1A and Part 
1B. The different dose levels selected for Part 2 will not exceed the highest dose level assessed 
and deemed tolerable in Part 1. Part 2 will expand a specific patient population to assess the 
anti-tumor activity, safety, and tolerability of BMS-986249 in combination with nivolumab. PK, 
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, and patient-reported outcome (PRO) information of BMS-986249 in 
combination with nivolumab will also be evaluated.
The BMS-986249 in Combination with Nivolumab Randomized Cohort Expansion in Melanoma 
(Part 2A) will include participants with previously untreated, unresectable or metastatic melanoma. 
Part 2A participants will be stratified by PD-L1 status (≥1% tumor cell surface expression versus 
< 1% tumor cell expression/indeterminate) and American Joint Committee on Cancer Version 7 
(AJCC) M-stage (M0/M1a/M1b versus M1c), and initially randomized 1:1:1:1:1 between 
5 treatment arms:
−
Arm A: 240 mg BMS-986249 in combination with 360 mg nivolumab administered IV
Q3W for 4 doses (Combination Therapy Phase) as a co-administration, followed by 480 
mg nivolumab monotherapy administered IV over approximately 30 minutes Q4W
(Maintenance Phase), which will begin 3 weeks after the last combination dose.
−
Arm B: 800 mg BMS-986249 administered IV Q8W in combination with 480 mg 
nivolumab administered IV Q4W. Co-administration will continue on cycles where both 
study treatments are scheduled, while nivolumab will be administered IV over 
approximately 30 minutes when scheduled as a monotherapy.
−
Arm C: 1,200 mg BMS-986249 administered IV Q8W in combination with 480 mg 
nivolumab administered IV Q4W. Co-administration will continue on cycles where both 
study treatments are scheduled, while nivolumab will be administered IV over 
approximately 30 minutes when scheduled as a monotherapy.
−
Arm D: 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered IV 
Q3W for 4 doses (Combination Therapy Phase), followed by 480 mg nivolumab 
monotherapy administered IV over approximately 30 minutes Q4W (Maintenance Phase),
which will begin 3 weeks after the last combination dose. Nivolumab and ipilimumab will 
be administered sequentially as 2 separate IV infusions. Nivolumab will be given first, over 
approximately 30 minutes, followed by ipilimumab over approximately 30 minutes, 
beginning approximately 30 minutes after completion of the infusion of nivolumab.
−
Arm E: 480 mg nivolumab monotherapy administered IV over approximately 30 minutes 
Q4W.
•
Addendum Per Revised Protocol 07: Part 2A Arm A, Arm B, and Arm E are discontinued for 
further enrollment/randomization. The modification of enrollment/randomization in Part 2A is 
not a consequence of changes in the safety or tolerability profile or benefit/risk assessment of 
BMS-986249 (see Section 5.5.4). Currently active participants in these arms will continue 
treatment as assigned and may remain on treatment until protocol-defined discontinuation 
criteria have been met. In accordance with Revised Protocol 07, participants in Part 2A will be 
randomized across the study approximately 1:1:1 between 3 treatment arms: 
−
Arm C: described above
−
Arm D: described above
−
Arm F: 600 mg BMS-986249 administered IV Q4W in combination with 480 mg 
nivolumab administered IV Q4W as a co-administration.
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The BMS-986249 in Combination with Nivolumab Additional Tumor Cohort Expansion (Part 2B) 
will be comprised of signal seeking expansion cohorts including advanced or intermediate HCC 
participants previously treated with prior anti-PD-(L)1 therapy (Cohort 1), metastatic castration-
resistant prostate cancer
(mCRPC)
participants treated with a prior taxane-containing 
chemotherapy regimen (Cohort 2), and unresectable locally advanced or metastatic TNBC
participants treated with a prior chemotherapy-based treatment (Cohort 3). In each Part 2B single-
arm tumor-specific expansion cohort, participants will receive 1,200 mg BMS-986249 
administered IV Q8W in combination with 480 mg nivolumab administered IV Q4W. Co-
administration will continue on cycles where both study treatments are scheduled, while 
nivolumab will be administered IV over approximately 30 minutes when scheduled as a 
monotherapy. The duration of study participation will be approximately 4 years (treatment of up 
to 2 years and follow-up of up to 2 years).
Addendum per Protocol Amendment 09: The duration of study participation will be approximately
2 years and 3 months (treatment of up to 2 years and Follow-up Period of 100 days post EOT).
At the Sponsor’s discretion, scans will be submitted to an imaging core laboratory and may be 
reviewed by blinded independent central review (BICR) at a later date or at any time during the 
study.
The study design schematic is presented in Figure 5.1-1 (Part 1) and Figure 5.1-2 (Part 2). A 
detailed schematic for study-period and participant flow is presented in Figure 5.1-3.
Figure 5.1-1:
Study Design Schematic - Part 1, the Dose Escalation Phase
Abbreviations: BMS = Bristol Myers Squibb; CRC = colorectal cancer; CRPC = castration-resistant prostate cancer; 
CTLA-4 = cytotoxic T lymphocyte-associated protein 4; DLT = dose-limiting toxicity; NSCLC = non-small cell lung 
cancer; PD-1 = programmed cell death protein 1; PD-L1 = programmed death ligand-1; Q4W = every 4 weeks; Q8W 
= every 8 weeks; RCC = renal cell carcinoma; SCLC = small cell lung cancer.
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a Alternative dosing schedules (eg, Q8W) may occur after evaluation of available safety, PK, and 
 
data, and upon discussion and agreement between the investigators and Medical Monitor (or designee), refer to 
Appendix 12.
b Participants in the monotherapy arm must be anti-CTLA-4-naive. Prior anti-PD-1 or anti-PD-L1 exposure is 
allowed in the monotherapy arm, but at time of enrollment, participants must be at least 5 half-lives (approximately 
100 days) from last dose of PD-1/PD-L1 therapy.
c Intra-participant dose escalation/reduction of BMS-986249 or nivolumab is not permitted.
d Part 1B will not start until demonstration of acceptable safety in at least 2 cohorts from Part 1A has occurred. 
Subsequently, treatment in both parts will occur in parallel.
e Part 1B participants with NSCLC will only be evaluated in a cohort once the DLT evaluation for that cohort has 
been completed.
Figure 5.1-2:
Study Design Schematic - Part 2, the BMS-986249 Cohort Expansion 
Combination Therapy Phase
Abbreviations: AJCC = American Joint Committee on Cancer; CRPC = castration-resistant prostate cancer; HCC = 
hepatocellular carcinoma; IV = intravenous; PD-L1 = programmed death ligand-1; Q3W = every 3 weeks; Q4W = 
every 4 weeks; Q8W = every 8 weeks; TNBC = triple-negative breast cancer.
a Will only open upon evaluation of available data from Parts 1A and 1B.
b Per Revised Protocol 07, Part 2A Arm A, Arm B, and Arm E were closed to enrollment and are not displayed. Part 
2A Arm A, 240 mg BMS-986249 IV Q3W in combination with 360 mg nivolumab IV Q3W for 4 doses followed 
by nivolumab monotherapy Maintenance Phase of 480 mg nivolumab IV Q4W continuous. Part 2A Arm B, 800 
mg BMS-986249 IV Q8W in combination with 480 mg nivolumab IV Q4W continuous. Part 2A Arm E, 480 mg 
nivolumab IV Q4W continuous.
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Figure 5.1-3:
Study Period and Participant Flow
Abbreviations: BMS = Bristol Myers Squibb; EOT = end of treatment, Q4W = every 4 weeks; Q8W =  every 8 
weeks; Q12W = every 12 weeks.
a May be required, refer to Section 2
b With Revised Protocol 07, Part 2A Arm A, Arm B, and Arm E closed to enrollment and are not displayed. Part 2A 
Arm A, 240 mg BMS-986249 IV Q3W in combination with 360 mg nivolumab IV Q3W followed by nivolumab 
monotherapy Maintenance Phase of 480 mg nivolumab IV Q4W continuous. Part 2A Arm B, 800 mg BMS-986249 
IV Q8W in combination with 480 mg nivolumab IV Q4W continuous. Part 2A Arm E, 480 mg nivolumab IV Q4W 
continuous. 
c During follow-up for up to 2 years after EOT, or until death, or initiation of another anti-cancer treatment, whichever 
occurs first. Refer to Section 2 and Section 9.1.1.
5.1.1
Screening Period
The screening period will be up to 30 days and begins by establishing the participant’s initial 
eligibility and signing of the informed consent form (ICF). The screening assessments are shown 
in Table 2-1. If a participant exceeds the 30-day 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 and will require a new participant 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. For Part 2A participants awaiting 
PD-L1 results, the screening window may be extended past the 30-day period upon discussion 
with the Medical Monitor (or designee). However, if screening extends over a prolonged period, 
baseline procedures, such as tumor assessments and labs, may  need to be repeated so that they fall 
within the acceptable protocol-specified window. Within a given disease type, participants meeting 
all eligibility criteria will be enrolled in the study according to the part and treatment arm 
availability.
5.1.2
Treatment Period
The initial dosing regimen of BMS-986249 was selected as Q4W, with an additional dosing 
regimen of Q8W subsequently explored. All participants will be treated for up to 2 years. 
Continuous safety evaluation and tumor assessment occurring in Part 1, Part 2A, and Part 2B will 
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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 2 years).
Weekly study visits will be performed up to the first 12 weeks after the first dose of study treatment 
for the BMS-986249 Monotherapy Escalation (Part 1A), Safety Evaluation of Combination Doses 
of BMS-986249 with Nivolumab (Part 1B), BMS-986249 in Combination with Nivolumab 
Randomized Cohort Expansion in Melanoma (Part 2A), and BMS-986249 in Combination with 
Nivolumab Additional Tumor Cohort Expansion (Part 2B), followed by study visits Q4W 
thereafter. See Section 9.5 for further details. 
For the BMS-986249 Monotherapy Escalation (Part 1A), BMS-986249 will initially be infused 
over approximately 30 minutes for the 240 mg dose. Infusion times for subsequent dose 
concentrations will vary to adjust for the different drug protein concentrations. 
For the Safety Evaluation of Combination Doses of BMS-986249 with Nivolumab (Part 1B), both 
study treatments will be administered as a co-administration through the same IV bag. Initial 
dosing will be 240 mg BMS-986249 in combination with 480 mg nivolumab co-administration 
infused over approximately 120 minutes. Infusion times will vary with subsequent co-
administration doses to adjust for the different drug protein concentrations. If an alternative dosing 
schedule is evaluated, co-administration will continue on cycles where both study treatments are 
scheduled, while nivolumab will be administered IV over approximately 30 minutes when 
scheduled as a monotherapy. 
In the BMS-986249 in Combination with Nivolumab Randomized Cohort Expansion in Melanoma 
(Part 2A) dose administration will vary with treatment arm. See Section 5.1.
In the BMS-986249 in Combination with Nivolumab Additional Tumor Cohort Expansion 
(Part 2B), across all tumor-specific cohorts 1,200 mg BMS-986249 will be administered IV Q8W, 
while 480 mg nivolumab will be administered IV Q4W. Co-administration will continue on cycles 
where both study treatments are scheduled, while nivolumab will be administered IV over 
approximately 30 minutes when scheduled as a monotherapy.
BMS-986249 infusions, as a monotherapy or co-administration, will require a 60-minute 
observation period after the completion of the infusion for the first 3 doses for each participant.
See Table 7.1.1-1 for a complete list of dose selection and timing. Refer to the Pharmacy Manual 
for additional treatment administration, timing, and infusion details for BMS-986249, ipilimumab, 
and nivolumab.
5.1.2.1
BMS-986249 Monotherapy Escalation (Part 1A)
Approximately 45 evaluable participants are expected to be treated during the BMS-986249 
monotherapy dose escalation (Part 1A) of the study guided by BLRM. Each participant will be 
administered IV doses of BMS-986249 in planned flat doses of 240, 800, 1,600, and 2,400 mg. 
Each dose is initially to be administered Q4W for a total of 2 years. 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 additional experience or to investigate dose 
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levels intermediate to those defined in the protocol. Planned dose levels may be modified (eg, 
alternative administration schedule, see Appendix 12), or intermediate dose levels added, based 
upon evaluation of available safety, PK, and 
data.
Sentinel Participant
During the Dose Escalation Phase, a staggered dosing (sentinel participant) approach will be used. 
The first participant to be treated at C1D1 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 5-week DLT period (35 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 7.5.1.
5.1.2.2
Safety Evaluation of Combination Doses of BMS-986249 with 
Nivolumab (Part 1B)
The Safety Evaluation of Combination Doses of BMS-986249 with Nivolumab (Part 1B) will be 
initiated in a staggered manner relative to the BMS-986249 monotherapy cohort once safety and 
preliminary PK data are provided from the first 2 monotherapy cohorts. The safety will be defined 
from BLRM and an overall assessment of available safety, PK, 
 and efficacy 
data of the BMS-986249 Monotherapy Dose Escalation (Part 1A). In each cohort, a flat dose of 
both BMS-986249 and nivolumab will be initially administered Q4W.
Subsequent dose selection of the combination will be based on evaluating the recommendation 
from BLRM and an overall assessment of available safety, PK, and 
 data. The 
dose regimens to be selected are shown in the study design schematic in Figure 5.1-1.
At no time will the dose of BMS-986249 in the Safety Evaluation of Combination Doses of 
BMS-986249 with Nivolumab (Part 1B) exceed the highest tolerated dose in the BMS-986249 
Monotherapy Dose Escalation (Part 1A). Dose escalation in each cohort, within the constraints 
cited above, will be enrolled in parallel (see details in Section 7.2). Additional information on 
DLTs can be found in Section 7.5.1.
Sentinel Participant
During Part 1B, a staggered dosing (sentinel participant) approach will be used. The first 
participant to be treated at C1D1 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 5-week DLT period (35 days) is completed, an extra participant 
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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 7.5.1.
5.1.2.3
Dose Escalation Decisions for the BMS-986249 Monotherapy Escalation 
(Part 1A) and the Safety Evaluation of Combination Doses of BMS-
986249 with Nivolumab (Part 1B)
The Dose Escalation Phase of the study will evaluate the safety and tolerability of BMS-986249, 
given alone or in combination with nivolumab, based on DLTs, using a BLRM (for the 
BMS-986249 Monotherapy Escalation [Part 1A] and for the Safety Evaluation of Combination 
Doses of BMS-986249 with Nivolumab [Part 1B]).
The DLT period will be 5 weeks, based primarily on prior safety knowledge for the active moiety 
(ipilimumab) of the BMS-986249 prodrug, and clinical PK data (Section 3.2.1.5).
The safety profile of ipilimumab as a monotherapy and in combination with nivolumab is generally 
consistent across studies, with a) the majority of AEs being inflammatory in nature, which is 
consistent with the proposed mechanism of action of ipilimumab; b) the same types of such select 
AEs in the GI tract, skin, liver, and endocrine system being reported; and c) most of these events 
being manageable with immune suppressive therapies. Analysis of ipilimumab TRAEs with onset 
in the initial 5 weeks, demonstrated a well-characterized safety profile consistent with the types of 
AEs occurring with longer duration that is generally manageable with established treatment 
algorithms. Treatment risk with BMS-986249 should therefore be recognized and managed with a 
5-week DLT period. Clinical assessment will continue to take into consideration the entirety of 
available data (including AEs that occur outside the 5-week DLT period) from all treated 
participants when assessing the safety of a dose level and determining dosing for the next cohort.
During the Dose Escalation Phase (Part 1), a set of approximately 3 participants will be treated at 
each specified dose level. Cohort tolerability assessment and subsequent dose recommendation 
will occur when at least 2 evaluable participants within a cohort have completed a 5-week DLT 
period. Any toxicities that occur beyond the DLT period will be accounted for in making dose 
level decisions and/or dose level modifications. Additional information on DLTs can be found in 
Section 7.5.1.
If the potential DLT occurring in the third evaluable participant regarding the 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-986249 monotherapy dose escalation (Part 1A) and in 
the Safety Evaluation of Combination Doses of BMS-986249 with Nivolumab (Part 1B), will be 
carried out for each dose level. The dose regimens to be selected are shown in the study design
schematic in Figure 5.1-1.
During the Dose Escalation Phase (Part 1), planned dose levels may be modified (eg, alternative
administration schedule, see Appendix 12 and Figure 5.1-1), or intermediate dose levels added, 
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based upon evaluation of available safety and PK/
 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 
 profiles.
5.1.2.4
The BMS-986249 Cohort Expansion Combination Therapy (Part 2)
The purpose of the cohort expansions is to gather preliminary efficacy information in specific 
populations regarding BMS-986249 in combination with nivolumab. In addition, safety, 
tolerability, PK, and 
 information will be evaluated. Further, patient-reported 
quality of life, symptoms, and treatment tolerability will be assessed using the EORTC QLQ-C30, 
EQ-5D-3L, FACIT GP5, and PRO-CTCAE (see Section 9.9).
The BMS-986249 in Combination with Nivolumab Randomized Cohort Expansion in Melanoma 
(Part 2A) will evaluate the efficacy and safety of BMS-986249 in combination with nivolumab 
relative to ipilimumab combined with nivolumab, and historical nivolumab monotherapy data, in 
a cohort of participants with previously untreated, unresectable or metastatic melanoma. See 
Section 5.1 and Figure 5.1-2.
The BMS-986249 in Combination with Nivolumab Additional Tumor Cohort Expansion (Part 2B) 
will evaluate the safety and tolerability of BMS-986249 in combination with nivolumab through 
single-arm expansion cohorts in previously treated advanced or intermediate HCC, metastatic 
CRPC, and unresectable locally advanced or metastatic TNBC.
Preliminary reviews of the data in Part 1 and Part 2 will occur prior to the final data base lock, in 
order to assess the initial safety, PK, and 
 signal. The earliest assessment of the 
efficacy signal for a Part 2A arm and/or Part 2B tumor cohort may be performed after 
approximately 15 to 20 participants are randomized into the arm/cohort and complete the first 
tumor scan (at about 8 to 12 weeks after start of treatment). The evaluation of this preliminary data 
will assist in further planning for the study, including the option to discontinue treatment arm(s)
or de-escalate individual Part 2 arm/cohort dose levels, if supported by the data. The study is 
expected to continue as planned during this evaluation, until the interpretation of the data is 
complete. Any changes to the design based on such evaluation may be implemented via a protocol 
amendment, unless already anticipated and planned for by the current protocol.
Continuous evaluation of toxicity events in the Part 2 BMS-986249 Cohort Expansions will be 
performed throughout enrollment for all expansion cohorts. Upon clinical evaluation of toxicity 
events, Bayesian posterior probability may be used to trigger decision-making. Specifically, if the 
probability is equal or higher to 95% that the aggregate rate of treatment-related toxicities meeting 
DLT criteria in BMS-986249 is higher than the defined threshold of interest 
, a decision to 
interrupt further enrollment may be discussed with investigators. 
If an arm/cohort is determined to have excess toxicity, the BMS-986249 dose/schedule previously 
evaluated may be replaced with a de-escalated dose/schedule of 800 mg BMS-986249 Q8W in 
combination with 480 mg nivolumab Q4W based on review of the available data and in 
consultation and agreement between Investigators and Sponsor via an administrative letter or note 
to file. If an arm/cohort is determined to have excess toxicity, and an alternative dose/schedule 
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(not defined above) is considered, a revised protocol reflecting the new dose level will be submitted 
prior to enrollment, unless already anticipated and planned for by the current protocol. 
Part 2 participants will be allowed to continue study treatment until the first occurrence of any of 
the following:
•
Completion of the maximum 2 calendar years of study therapy
•
Progressive disease (PD) defined by RECIST v1.1 (Appendix 5) or PCWG3 for prostate cancer 
(Appendix 6) unless participants meet criteria for treatment beyond progression (Section 8.1.1)
•
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
5.1.3
Treatment Beyond Progression
Tumor progression and response endpoints will be assessed using RECIST v1.1 criteria for solid 
tumors (Appendix 5) or PCWG 3 for prostate cancer (Appendix 6). Treatment beyond progression 
may be allowed in selected participants with initial RECIST v1.1 (or PCWG 3 for prostate) defined 
PD after discussion and agreement with the Medical Monitor (or designee), if the benefit-risk 
assessment favors continued administration of study treatment (eg, participants are continuing to 
experience clinical benefit as assessed by the investigator, tolerating treatment, and meeting other 
criteria; see Section 8.1.1).
Participants must be re-consented with an ICF addendum or similar document to continue 
treatment beyond progression. Treatment beyond progression will require continued tumor 
assessments.
5.1.4
Window Visits
A ± 2 day window is permitted to accommodate study participants and schedules during and 
between cycle visit days for all treatment visits, except for Cycle 1 Day 1.
5.1.5
Follow-up
5.1.5.1
Safety Follow-up Period
Upon completion of study therapy (or up to a maximum of 2 years, if applicable) or once the 
decision is made to discontinue the participant from treatment, that is, at end of treatment (EOT), 
all participants will enter a Safety Follow-up Period.
For participants who will 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 will 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.
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After the EOT visit, follow-up study visits should occur at Days 30, 60, and 100 (±7 days) for all 
study participants. Safety reporting of AEs and SAEs should take place from date of informed 
consent through 100 days post EOT. 
All participants should 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.
5.1.5.2
Imaging Follow-up Period
At the time of study treatment discontinuation, participants will continue to have radiologic and 
clinical tumor assessments per Section 2. 
The duration of the Imaging Follow-up Period will be for a total of 2 years following EOT, or until 
death, or initiation of another anti-cancer treatment, whichever occurs first. Radiological 
assessments for participants who have ongoing clinical benefit may continue to be collected after 
participants complete the Survival Follow-up Period of the study. Participants who have disease 
progression after an initial course of study therapy will be evaluated beyond the EOT visit and will 
be allowed to receive other tumor-directed therapy as required.
Addendum per Protocol Amendment 09: The duration of the Imaging Follow-up Period will be 
100 days post EOT or until death, or initiation of another anti-cancer treatment, whichever occurs 
first. Radiological assessments for participants who have ongoing clinical benefit may continue to 
be collected after participants complete the Survival Follow-up Period of the study. Participants 
who have disease progression after an initial course of study therapy will be evaluated beyond the 
EOT visit and will be allowed to receive other tumor-directed therapy as required. The initiation 
of another anti-cancer treatment will indicate the end of the Imaging Follow-up Period.
5.1.5.3
Survival Follow-up Period
In parallel with the Safety Follow-up Period, all participants will start the Survival Follow-up 
Period. 
Participants will be followed by telephone Q12W (from EOT) for 2 years or until death, loss to 
follow-up, withdrawal of consent, or conclusion of the study, whichever comes first. For Part 2 
participants, EQ-5D-3L data will be collected by telephone or email during the Survival Follow-up 
Period. Participants will have both the Imaging Follow-up Period and Survival Follow-up Period 
occur simultaneously. The duration of this follow-up is up to 2 years after EOT, although a longer 
follow-up period could be considered in selected cases if an efficacy signal is apparent. Subsequent 
therapies will also be recorded in this Survival Follow-up Period.
Addendum per Protocol Amendment 09: Since further formal OS analyses will not be conducted, 
the maximum study duration will be through 100 days post EOT. Participants who are in the 
follow-up period past 100 days after EOT should be discontinued from the study. Participants will 
be followed by telephone (from EOT) through 100 days post EOT or until death, loss to follow-up, 
withdrawal of consent, or conclusion of the study, whichever comes first. For Part 2 participants, 
EQ-5D-3L data will be collected by telephone or email during the Survival Follow-up Period. 
Participants will have both the Imaging Follow-up Period and Survival Follow-up Period occur 
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simultaneously. The duration of this follow-up will be through 100 days post EOT. Subsequent 
therapies will also be recorded in this Survival Follow-up Period.
5.1.6
Data Monitoring Committee and Other External Committees
Relative to the exploratory nature of this Phase 1/2 study and the robust experience that already 
exists around use of ipilimumab (which is a surrogate for BMS-986249), a Data Monitoring 
Committee is not needed for this study. In addition to the comprehensive safety monitoring plan 
outlined below, the following key points were considered for this decision:
•
This is an open-label study.
•
The eligibility criteria exclude participants with disease characteristics that could predispose
to higher risk of morbidity (eg, history of interstitial lung disease, recent history of thrombosis).
•
Exclusion of participants with known autoimmunity also applies because they could be at risk 
for exacerbation of their condition by the administration of therapies that relieve immune 
suppression such as BMS-986249 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.
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 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) (or designee), 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 treatments. Furthermore, 
investigators will be kept updated of important safety information, such as DLTs, during 
teleconferences between investigators and the BMS clinical team, which will be held at least Q4W 
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 Medical Monitor and the investigators will have access to all data necessary 
for safety evaluation.
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All participants in this study represent individuals with high unmet medical need because the 
prognosis for advanced/metastatic solid tumors is generally very poor.
5.2
Number of Participants
•
Part 1A Monotherapy Escalation: The total sample size is up to approximately 45 evaluable 
participants.
•
Part 1B Combination Escalation: The total sample size is up to approximately 60 evaluable
participants.
•
Part 2A Expansion in Melanoma: The total sample size is up to approximately 200 evaluable
participants with approximately 60 evaluable participants each treated in Arm C, Arm D, and 
Arm F, respectively. Prior to Revised Protocol 07, up to approximately 20 evaluable 
participants may have been enrolled across Arms A, B, and E, collectively. (See 
Section 10.1.2.)
•
Part 2B Additional Tumor Cohort Expansion: The total sample size is up to approximately 
120 evaluable participants with approximately 40 evaluable participants per tumor type cohort.
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 Section 2 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.
5.4
Scientific Rationale for Study Design
BMS-986249 is being investigated in humans with advanced solid tumors either as monotherapy 
or in combination with nivolumab. 
5.4.1
Rationale for the BMS-986249 Monotherapy Dose Escalation (Part 1A) 
and the Safety Evaluation of Combination Doses of BMS-986249 with 
Nivolumab (Part 1B) Design
The projected human efficacious dose of BMS-986249 is based on the comparable 
exposure-efficacy relationship observed for BMS-986249 and ipilimumab in nonclinical models. 
The human efficacious dose of BMS-986249 is projected to be 3 mg/kg (240 mg flat dose), the 
same as ipilimumab’s approved clinical monotherapy dose. The safety of ipilimumab has been 
extensively characterized in more than 28,686 participants with different cancer types (refer to the 
ipilimumab IB for further details15). In nonclinical experiments, BMS-986249 was well tolerated 
at doses up to 50 mg/kg, with evidence of pharmacodynamic effects at all doses. Thus, this study 
will evaluate dose escalation of BMS-986249 at planned flat doses of 800, 1,600, and 2,400 mg. 
Additional de-escalation doses may be tested.
Furthermore, the study plans to evaluate different dose escalations of BMS-986249 in combination 
with nivolumab. The combination study design and the doses are based on the results of safety 
data from clinical trials evaluating nivolumab and ipilimumab combinations (CheckMate 0671, 
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012,20 and 01619). The study will evaluate BMS-986249 in combination with 480 mg nivolumab 
(flat dose) as outlined in the study design schematic in Figure 5.1-1. 
Modifying the ipilimumab structure with a Probody mAb has the potential to offer decreased 
systemic absorption, which may translate into better tolerability but similar efficacy with 
ipilimumab. Furthermore, the PK data will be evaluated to ensure that there is evidence of 
decreased systemic absorption.
Given that BMS-986249 shares the structure and properties of ipilimumab, the population in this 
study includes participants naive to checkpoint inhibitors in order to minimize bias when 
evaluating safety and efficacy.
5.4.2
Rationale for the Combination of BMS-986249 and Nivolumab
Studies have shown that tumors co-opt some specific immune-checkpoint pathways to engender 
immune resistance, particularly against T cells that are specific for tumor antigens. Co-engagement 
of multiple immune receptors on activated T cells (combination immunotherapy) may result in 
better outcomes as compared with engagement of a single immune receptor. 
This assumption is currently being tested in multiple combination regimens with various agents. 
However, the only combination with proven clinical activity is that of ipilimumab and nivolumab.
CTLA-4 and PD-1 induce tumor evasion from the immune system through complementary but 
distinct mechanisms. Nivolumab interferes with the interaction of PD-1 with its ligands PD-L1 
and PD-L2, allowing for activation and proliferation of exhausted or anergic T-effector cell in the 
tumor. Ipilimumab interferes with the interaction of CTLA-4 with CD80 (B7-1) and CD86 (B7-2) 
molecules expressed on antigen-presenting cells, allowing for T cell activation through 
engagement of the co-stimulatory receptor CD28 that binds to these same B7 ligands.
The combination of ipilimumab and nivolumab is approved in the US for the treatment of advanced 
melanoma. Information regarding safety and efficacy can be found in the nivolumab IB.12 The 
combination of nivolumab and ipilimumab is currently under evaluation in various doses, 
schedules of administration, and other tumor types. Results of the combination studies showed 
promising activity with higher but tolerable toxicity compared with studies on ipilimumab or 
nivolumab alone. Different doses and schedules of administration were evaluated with different 
outcomes in terms of safety, tolerability, and efficacy depending on tumor type. 
Based on the described synergy between ipilimumab and nivolumab, the current study will 
evaluate the safety, tolerability, and efficacy of the combination of BMS-986249 with nivolumab,
with the rationale that BMS-986249 may yield a more tolerable treatment in combination with 
nivolumab. This may provide the opportunity and translate the combination in a more effective 
regimen for a large number of patients in different tumor types.
Furthermore, ipilimumab and nivolumab in combination therapy in participants with NSCLC is 
poorly tolerated, as demonstrated by the results in CheckMate CA209012.20 To minimize the 
introduction of bias, participants with NSCLC will not be included in the cohort during the DLT 
evaluation period. Since there is evidence of efficacy of the combination in NSCLC, once the DLT 
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and the MTD are identified, participants with NSCLC will be evaluated to determine the safety 
and preliminary efficacy of the combination therapy.
5.4.3
Rationale for Tumor Selection for Part 1B
Preliminary tumor types (eg, RCC, NSCLC, melanoma, gastric cancer, and bladder cancer) and 
additional tumor types [eg, SCLC, CRC, CRPC, and esophageal cancer] were selected in Part 1B 
to evaluate the safety and tolerability of BMS-986249 in combination with nivolumab based on 
the following rationale:
•
Previously demonstrated safety profile of ipilimumab in combination with nivolumab in 
patients with melanoma, RCC, NSCLC, urothelial carcinoma, SCLC, gastric cancer, 
gastroesophageal junction cancer, adenocarcinoma of the lower esophagus, and CRC.
•
Previously demonstrated anti-tumor immune responses of ipilimumab alone and in 
combination with nivolumab in patients with melanoma, SCLC, NSCLC, RCC, CRPC, and 
gastric cancer.
Non-clinical data suggests that BMS-986249 maintains activity at the tumor site and reduces 
peripheral systemic exposure to CTLA-4 blockade compared to ipilimumab. Hence, BMS-986249 
may potentially improve the therapeutic index previously seen with ipilimumab treatment in the 
aforementioned tumor types.
5.4.4
Rationale for Treatment Duration
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Evaluation of continuous ipilimumab therapy beyond the recommended regimen of 12 weeks of 
ipilimumab (4 doses Q3W) is currently ongoing, and results are not yet available. Re-induction or 
maintenance therapy Q12W with ipilimumab has been tested in some study participants. Overall, 
the safety profile observed in these participants was consistent with the safety profile observed in 
participants in the induction phase. There were no unexpected toxicities due to re-induction or 
maintenance. The most common TRAEs during re-induction or maintenance affected the GI tract 
and skin and were Grade 1-2 in severity.15 Data from animal models suggest that prolonged 
therapy might be beneficial.
In Study CA209153, participants 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 participants still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
PFS compared to those who were randomized to stop treatment, with median PFS 
(post-randomization) not reached versus 10.3 months, respectively; HR=0.42 (95% CI, 0.25 to 
0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend for 
participants 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.21
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Moreover, accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be 
sufficient for long-term benefit. In Study CA209003, a dose-escalation cohort expansion trial 
evaluating the safety and clinical activity of nivolumab in participants 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.22 These 
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%-18% for squamous and non-squamous NSCLC respectively).23
Taken together, the data suggest shorter duration of nivolumab of only 1 year was associated with 
increased risk of progression in previously treated participants with NSCLC, suggesting that 
treatment beyond 1 year is likely needed. Also, 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.
Collectively, these data suggest that there is minimal, if any, benefit derived from continuing 
immuno-oncology (I-O) treatment beyond 2 years in advanced tumors. However, even though 
immunotherapy is well tolerated, participants will be at risk for additional toxicity with longer 
term treatment. Therefore in Study CA030001, treatment with BMS-986249 and nivolumab will 
be extended for up to 2 years.
5.4.5
Rationale for Treatment Beyond Progression
Immunotherapeutic agents produce atypical clinical response patterns that are not usually observed 
with conventional chemotherapy. Accumulating clinical evidence indicates that some participants 
treated with immune system stimulating agents may develop disease progression by the 
conventional response criteria before demonstrating clinical objective responses and/or stable 
disease (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.
These phenomena were observed in the BMS Phase 2 study (Study CA209003) of nivolumab in 
participants with solid tumors. Two hypotheses potentially explain these phenomena. 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 treatment that might induce a non-conventional response pattern in 
some participants.
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The decision to continue treatment beyond investigator-assessed progression should be discussed 
with the Medical Monitor (or designee) and documented in the study records. The assessment of 
clinical benefit should take into account whether the participant is clinically deteriorating and 
unlikely to receive further benefit from continued treatment.
5.4.6
Rationale for Selecting Melanoma in Part 2A Expansion
Considerable progress in the treatment of metastatic melanoma has been made in the past 10 years 
with the approval of immune checkpoint–blocking antibodies. The safety and efficacy of 
individual checkpoint inhibition was first established with the anti-CTLA-4 ipilimumab, in 
advanced melanoma (See Section 3.2.3). Subsequently, the anti-PD-1 nivolumab, was shown to 
be safe and effective in multiple advanced tumor types including advanced melanoma (See 
Section 3.2.2). A multitude of trials in various advanced cancers have evaluated the combination 
of these 2 agents (See Section 3.2.4). 
The most mature of these trials are in advanced melanoma participants. Studies CA209067 and 
CA209069 demonstrated a greater efficacy with the ipilimumab and nivolumab combination than 
either ipilimumab or nivolumab as a monotherapy. However, 3 mg/kg ipilimumab in combination 
with 1 mg/kg nivolumab, also demonstrated increased toxicity compared to either single agent. 
Given BMS-986249 is a Probody of ipilimumab, combination with nivolumab may be more 
tolerable, and may translate to a more effective treatment regimen for a larger number of metastatic 
melanoma participants than either ipilimumab in combination with nivolumab or nivolumab 
monotherapy.
5.4.7
Rationale for Part 2A Expansion Reference Arms
Evaluating the efficacy of a combination with solely experimental arms can be difficult due to 
many confounding factors, particularly if part of the combination has known anti-tumor activity. 
In addition, given the rapidly changing oncology treatment landscape, historical control data may 
not be fully representative of the current patient population. Hence, Arm D (ipilimumab in 
combination with nivolumab) and Arm E (nivolumab monotherapy) were initially included as 
reference arms to better evaluate the safety, efficacy, 
, and contribution of 
components of BMS-986249 when combined with nivolumab as described further below.
5.4.7.1
Rationale for Ipilimumab and Nivolumab Combination Therapy as a 
Reference
The combination of ipilimumab and nivolumab has been approved in the US, European Union, 
Australia, and additional regions for the treatment of metastatic melanoma. In study CA209067, 
3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab demonstrated a response rate of 58%, 
numerically higher than either single agent. In trial CA209069, the same combination dose
achieved a response rate of 61%, significantly greater than that of ipilimumab alone. While the 
efficacy of the combination was improved, the incidence of serious adverse reactions, adverse 
reactions leading to permanent discontinuation or dosing delays, any grade drug-related select 
AEs, and Grade 3-4 AEs was higher in the combination arm of each study than in the respective 
monotherapy arms (see Table 5.4.7.1-1).24,25
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Table 5.4.7.1-1:
CA209067 Safety Result Summary
Safety Result
Nivolumab (N=313)
Nivolumab in 
Combination with
Ipilimumab Regimen 
(N=313)
Ipilimumab (N=311)
TRAEs - Any grade
257 (82.1%)
299 (95.5%)
268 (86.2%)
TRAEs - Grade 3-4
51 (16.3%)
172 (55.0%)
85 (27.3%)
Drug-related select AEs -
Any grade
25 (8.0%)
150 (47.9%)
69 (22.2%)
Drug-related select AEs -
Grade 3-4
18 (5.8%)
112 (35.8%)
51 (16.4%)
Drug-related AEs leading 
to discontinuation
24 (7.7%)
114 (36.4%)
46 (14.8%)
Abbreviations: AE = adverse event; TRAE = treatment-related adverse event.
The combination of ipilimumab and nivolumab (Arm D) was chosen as a reference arm in Part 2A 
because the combination contains the parental antibody (ipilimumab) of BMS-986249. As an 
anti-CTLA-4 Probody, BMS-986249 is hypothesized to have preferential activity in the tumor 
microenvironment relative to normal tissue. BMS-986249 may then result in a reduction of the 
systemic irAEs seen after treatment with ipilimumab in combination with nivolumab, while 
maintaining anti-tumor activity. Including ipilimumab in combination with nivolumab will 
therefore allow for a more complete assessment of the therapeutic index of BMS-986249 in 
combination with nivolumab.
The dose and schedule of 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab 
administered IV Q3W for 4 doses (Combination Therapy Phase), followed by 480 mg nivolumab 
monotherapy administered IV Q4W (Maintenance Phase), beginning 3 weeks after the last 
combination dose, is based on the approved recommended dose in advanced melanoma.26
5.4.7.2
Rationale for Nivolumab Monotherapy as a Reference
In 2 distinct Phase 3 trials, nivolumab monotherapy demonstrated clinical benefit in participants 
with previously untreated unresectable or metastatic melanoma.12 In the Phase 3 trial, CA209066, 
3 mg/kg nivolumab monotherapy demonstrated an ORR of 40%, significantly greater than that of 
dacarbazine alone (14%).27 In study CA209067, 3 mg/kg nivolumab monotherapy achieved an 
ORR of 45%, this was numerically lower than ipilimumab in combination with nivolumab, but 
significantly greater than that of ipilimumab alone. This pattern of response rate was consistent 
regardless of PD-L1 expression levels (see Table 5.4.7.2-1).12
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Table 5.4.7.2-1:
CA209067 ORR Result Summary by PD-L1 Expression
nivolumab (N=316)
nivolumab in 
combination with
ipilimumab regimen 
(N=314)
ipilimumab (N=315)
Objective Response
141 (45%)
185 (59%)
60 (19%)
ORR by tumour PD-L1 
expression < 1%
35%, n=41/117
55%, n=68/123
19%, n=21/113
ORR by tumour PD-L1 
expression ≥1%
55%, n=94/171
65%, n=101/155
19%, n=31/164
Abbreviations: ORR = objective response rate; PD-L1 = programmed death ligand-1.
In both CA209066 and CA209067, the incidence of AEs was lowest in the nivolumab group, most 
AEs were low-grade (Grade 1-2) with relatively few drug-related high-grade AEs (Grade 3-4, 15% 
in CA209066 and 16% in CA209067, see Table 5.4.7.1-1). In addition, the safety profile was 
consistent with that seen in other tumor types.24,27 These data resulted in nivolumab being 
approved for use by the U.S. FDA in 2014, Marketing Authorization in Europe in 2015, and 
additional regions for the treatment of metastatic melanoma.12
Nivolumab monotherapy was initially chosen as a reference arm in Part 2A because it may have
allowed for a contemporaneous assessment of the contribution of components and therapeutic 
index of BMS-986249 in combination with nivolumab.
The dose and schedule of 480 mg nivolumab administered IV Q4W is based on the approved 
recommended dose in advanced melanoma.26
Nivolumab monotherapy has demonstrated a generally consistent safety profile as a single agent. 
However, the safety profile of nivolumab in combination therapy varies, and both the frequency 
and severity of TRAEs may be greater than that observed with monotherapy. Across melanoma 
studies, nivolumab monotherapy has demonstrated anti-tumor activity; however, outcomes 
analysis of CA209067 with a minimum follow-up of 60 months demonstrated median OS was 
more than 60.0 months (median not reached) in the ipilimumab in combination with nivolumab 
group versus 36.9 months in the nivolumab monotherapy group.28 In addition, the mean 
treatment-free survival for ipilimumab in combination with nivolumab-treated participants was 
19.7 months of the 60-month period versus 9.9 months in the nivolumab group (difference
9.8 months; 95% CI, 6.7–12.8).29
With emergent data, provider and patient treatment preferences are affected by a number of factors 
including efficacy measures, AE profiles, and individual patient characteristics (eg, age, tumor 
burden, brain metastasis).30 Hence, potential participants able to randomize into an ipilimumab in 
combination with nivolumab or nivolumab reference arm may not accurately reflect the broader 
metastatic melanoma patient population. Upon consideration of the evolving melanoma treatment 
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landscape and emergent data from CA209067, no further enrollment/randomization will occur into 
Part 2A Arm E with Revised Protocol 07.
5.4.8
Rationale for Part 2A Stratification by M-Staging and PD-L1 Status
In order to minimize the potential for imbalances across treatment arms, participants will be 
stratified by PD-L1 expression (≥1% tumor cell surface expression versus < 1% tumor cell
expression/indeterminate), and the AJCC M stage (M0/M1a/M1b versus M1c) in Part 2A. 
Prognostic implications of M-Staging are well established.31 Among patients treated with 
nivolumab monotherapy and the combination of ipilimumab and nivolumab, higher response rates 
have been observed in patients with PD-L1 tumor expression ≥1%, thus stratification in this study 
will ensure better balance in baseline characteristics and will minimize bias in terms of response 
across treatment groups.32,33 While both BRAF positive and BRAF wild-type participants are 
eligible, BRAF status is not a stratification factor.
5.4.9
Rationale for Selecting HCC, CRPC, and TNBC in Part 2B Expansion
HCC is a highly lethal cancer, resulting as a third leading cause of cancer-related deaths globally.34
Immunotherapeutic compounds, such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents, either 
as monotherapy or as combination therapy, have shown benefit when used in different lines of 
treatment for unresectable HCC. In CA209040, nivolumab 1 mg/kg and ipilimumab 3 mg/kg Q3W 
combination therapy demonstrated promising efficacy and received accelerated approval by the 
FDA with 33% ORR in the second-line post-sorafenib setting. With this combination, however, 
95% of  participants experienced any-grade TRAEs (53% Grade 3-4 TRAEs) and 29% of the 
participants discontinued treatment due to study treatment toxicity, suggesting a need for a regimen 
with an improved safety and tolerability profile.35 Additionally, the use of anti-PD-(L)1 agents in 
combination with anti-angiogenics (ie, anti-vascular endothelial growth factor [VEGF]) has 
become the standard of care in the unresectable HCC setting not amenable for curative surgery or 
locoregional therapy. However, the inhibition of the VEGF receptor and signaling pathway in HCC 
has shown concerning toxicity, such as hypertension and gastroesophageal variceal bleeding.
Thus, safer alternative regimens that will allow better clinical outcomes are still needed.36,37 Given 
BMS-986249 is a Probody of ipilimumab, participants with HCC may benefit from treatment with 
BMS-98649 in combination with nivolumab.
mCRPC is defined as participants with confirmed castrate levels of testosterone following 
orchiectomy or treatment with androgen deprivation therapy (ADT), and the presence of novel 
distant soft tissue or bony metastases by the National Comprehensive Cancer Network criteria. In 
the initial analysis of the Phase 3 CA184043 trial evaluating mCRPC participants in the post-
docetaxel setting, ipilimumab 10 mg/kg with bone-directed radiotherapy compared with placebo 
with bone-directed radiotherapy demonstrated a significant improvement in PFS (median 4 months
ipilimumab versus 3 months placebo, HR 0.70, 95% CI 0.61-0.82), a high proportion of 
participants with a confirmed > 50% prostate-specific antigen (PSA) decline (13.1% ipilimumab 
versus 5.2% placebo, 95% CI NA), and non-statistically significant benefit in OS (median 
11.2 months ipilimumab versus 9.95 months placebo, p = 0.053). The pre-planned final long-term 
survival analysis (median follow-up of 50 months) showed OS favored the ipilimumab group with 
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survival rates being 2 to 3 times higher than radiotherapy alone at 3 years and beyond.38 Preclinical 
CRPC tumor models indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve anti-tumor activity. Combination therapy of ipilimumab and nivolumab was evaluated in 
CA209650 where durable objective responses in a subset of mCRPC participants was observed
(10% ORR with all responders exhibiting durable responses at time of data cutoff).39 However, 
more than 75% of mCRPC participants in the post-chemotherapy setting were not able to receive
the full 4 planned cycles of the combination dose, 3 mg/kg ipilimumab with 1 mg/kg nivolumab 
Q4W (53% Grade 3-4 TRAEs), suggesting tolerability of the combination regimen may be a 
concern for participants with mCRPC.39 Given BMS-986249 is a Probody of ipilimumab,
participants with CRPC may benefit from treatment with BMS-986249 in combination with 
nivolumab.39
TNBC is defined by the absence of estrogen receptor (ER) and progesterone receptor expression, 
and lack of amplification of the human epidermal growth factor receptor 2 (HER2)/Neu (ErbB2)
gene and/or HER2 protein overexpression. TNBC is considered to be the most immunogenic breast 
cancer (BC) subtype, as reflected by higher rates of tumor-infiltrating lymphocytes, higher rates 
of PD-L1 expression, as well as higher rates of immunogenic gene signatures’ upregulation.40,41,42
To date, PD-L1 inhibition in combination with chemotherapy has demonstrated clinical activity in 
the advanced or metastatic setting with a modestly extended DOR compared to chemotherapy, 
though clinical benefit appears to be limited to participants who are PD-L1 positive.43,44 As 
described in Sections 3.2.3 and 3.2.4, ipilimumab alone and in combination with nivolumab has 
been assessed in a number of tumors and has been shown to generate clinically meaningful and 
durable responses irrespective of PD-L1 status. CTLA-4 is expressed at the cell membrane of a 
subgroup of TNBC tumors and may regulate key signal transducers in tumor cells.45,46 The 
combination of PD-L1 and CTLA-4 inhibition has been assessed in a number of different BC 
preclinical models, which indicate potential synergistic anti-tumor activity.47 In a BC gene 1 
(BRCA1)-deficient TNBC preclinical model, cisplatin treatment combined with dual anti-PD-1 
and anti-CTLA-4 treatment substantially augmented anti-tumor immunity, resulting in an avid 
systemic and intra-tumoral immune response.47 Indeed, in CA209032, combination of nivolumab 
and ipilimumab improved clinical activity (median OS of 10.6 months) but increased toxicity 
events (44% Grade 3-4 TRAEs) in heavily pre-treated participants with metastatic TNBC, as 
compared to nivolumab monotherapy.48 In the neoadjuvant setting, a single dose of ipilimumab 
and cryoablation and/or nivolumab was demonstrated to be safe and tolerable where all 
participants underwent surgery without delay, and all participants in the ipilimumab and 
cryoablation group remaining recurrence free at time of data cutoff with median follow-up of 
66 months. The addition of nivolumab to ipilimumab and cryoablation resulted in a higher 
expression of activation markers on peripheral T cells and downregulation of suppressor cells.49
The Phase 2 DART (SWOG S1609, Cohort 36) study, assessed nivolumab 240 mg combined with 
ipilimumab 1 mg/kg Q6W among 17 participants with pre-treated metastatic metaplastic BC that
were predominantly TNBC with a median of 2 lines prior therapy. ORR of 18% was demonstrated 
with ongoing responses in all 3 participants at time of clinical data cutoff. 24% experienced
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Grade 3-4 TRAEs and 0% discontinuing treatment due to study treatment toxicity.50 Therefore, 
preclinical and clinical evidence suggests the combination of anti-PD-L1 and anti-CTLA-4 may 
provide a new treatment option for patients with TNBC. Given BMS-986249 is a Probody of 
ipilimumab, combination with nivolumab may translate to a clinically meaningful treatment 
regimen for TNBC participants.
5.4.10
Rationale for Quality of Life Evaluation
The evaluation of PROs is an increasingly important aspect of clinical efficacy in oncology trials. 
Such data provide an understanding of the impact of treatment from the participant’s perspective 
and offer insights into patient experience that may not be captured through physician reporting. 
Additionally, generic health-related quality of life measures provide data needed for calculating 
utility values to inform health economic models.
The EORTC QLQ-C30 will be used to assess changes in functioning, symptoms, and QoL over 
time, the EQ-5D-3L will be used to assess general health status, the FACIT GP5 (single item) will 
be used to assess the overall bother of side effects, and the PRO-CTCAE will be used to assess the 
severity, frequency, and interference of side effects. These questionnaires will be used in Part 2A 
and Part 2B.
5.5
Justification for Dose
5.5.1
BMS-986249 Rationale for Starting Dose in Humans
The FIH starting dose of BMS-986249 is selected to be 240 mg (equivalent to approximately 
3 mg/kg) Q4W, assuming a median body weight of 80 kg. This starting dose is the same as the 
approved ipilimumab monotherapy dose in melanoma participants, but with a less frequent 
schedule (Q4W versus the approved Q3W dosing regimen for ipilimumab). The starting dose 
selection is supported by the reduced toxicities and systemic pharmacodynamic responses of 
BMS-986249 compared to ipilimumab in nonclinical pharmacology and toxicology studies. In 
addition, BMS-986249, as a Probody mAb of ipilimumab, is expected to have the same type of
irAEs as those of ipilimumab, which have been well defined in the clinic. The safety risk of 
BMS-986249 at the starting dose, therefore, can be well managed based on the ipilimumab risk 
evaluation and mitigation strategy (REMS) guidelines approved by FDA.
It is expected that BMS-986249 exhibits the same type of irAEs as ipilimumab, irAEs that can be 
clinically monitored and treated. The nonclinical toxicology and pharmacology assessment of 
BMS-986249 demonstrated decreased systemic immune-activating pharmacodynamic responses 
and toxicities in cynomolgus monkeys but similar anti-tumor efficacy in a MC38 mouse tumor 
model in comparison with ipilimumab. Human PK projection suggests that BMS-986249 will 
slowly convert to the fully active species in systemic circulation with a steady-state exposure 
approximately 
 of that of ipilimumab, further indicating less systemic toxicities of 
BMS-986249 than of ipilimumab at the same dose level. Taken together, the approved ipilimumab 
monotherapy dose of 3 mg/kg in melanoma participants is suggested as the starting dose of 
BMS-986249 to offer efficacy benefits and likely reduced toxicity to the FIH trial participants. 
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5.5.1.1
Starting Dose Selection Supported by BMS-986249 Nonclinical 
Pharmacology
In nonclinical pharmacology and toxicology studies, BMS-986249 demonstrated reduced in vitro 
activities, in vivo systemic active drug exposure, and pharmacodynamic responses, yet maintained 
comparable anti-tumor activity in mouse MC38 tumor model. The key differences between 
BMS-986249 and ipilimumab are summarized below.
•
BMS-986249 binds human CTLA-4 expressed on 58 α-β-CTLA-4/CD3 cells with a 41-fold 
higher EC50 than ipilimumab (22 nM versus 0.5 nM). The reduced binding affinity of 
BMS-986249 translates to a 2-fold reduction of activities in SEB human T cell functional assay 
as well as Fcγ receptor-mediated ADCC assay.
•
PK of BMS-986249 in mice and cynomolgus monkeys suggests that the intact Probody mAb
is slowly converted to mono- and dual-cleaved species in vivo. The projected systemic 
exposure of the dual-cleaved Probody mAb, which is equally active as ipilimumab, is 38% of 
ipilimumab exposure when BMS-986249 is administered at the same dose as ipilimumab in 
participants. 
•
In human CTLA-4 knock-in mice bearing MC38 tumors, ipilimumab led to dose-dependent 
immune activation such as increased Ki-67 and ICOS levels on T cell subsets in the spleen; 
whereas BMS-986249 only showed the immune activation pharmacodynamic effects in the 
highest dose group (10 mg/kg), with the activation 2-fold lower than that of ipilimumab at the 
same dose. In contrast to the reduced pharmacodynamic effects in spleen, BMS-986249 
maintained anti-tumor activity comparable to that of ipilimumab. 
•
In a GLP 1-month repeat-dose toxicity study in cynomolgus monkeys, BMS-986249 exhibited 
lower systemic T cell activation/pharmacodynamic responses when compared to ipilimumab 
in a dose- and time-dependent manner, corresponding with a slow conversion of BMS-986249 
to its active forms. The magnitude of pharmacodynamic activity for each dose was 
50 mg/kg/week ipilimumab > 10 mg/kg/week ipilimumab = 50 mg/kg/week BMS-986249 
> 10 mg/kg/week BMS-986249.
Assuming that the reduced in vitro activities, in vivo systemic active drug exposure, and 
pharmacodynamic responses of BMS-986249 relative to ipilimumab in nonclinical studies 
translate to participants with cancer, BMS-986249 at the starting dose of 3 mg/kg may provide 
similar efficacy to ipilimumab at the same dose level but with reduced systemic active drug 
exposure and reduced pharmacodynamic responses that may be responsible for irAEs.
5.5.1.2
Starting Dose Selection Supported by the HNSTD in Monkeys
In the 1-month repeat-dose toxicity study in cynomolgus monkeys, BMS-986249 demonstrated 
overall decreased toxicities when compared to ipilimumab at same doses (10 and 50 mg/kg/week),
and no new toxicities of BMS-986249 were observed compared to ipilimumab. As a result, the 
highest tested dose of 50 mg/kg/week was considered as the HNSTD, 5-fold higher than the 
ipilimumab HNSTD at 10 mg/kg. The FIH starting dose of BMS-986249 from the HNSTD-based 
toxicology approach was 8 mg/kg after applying a safety factor of 6-fold. As a result, the selected 
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BMS-986249 starting dose of 3 mg/kg is nearly 3-fold lower and, thus, is more conservative than 
the starting dose derived from the toxicology approach.
5.5.1.3
Starting Dose Selection Based on Ipilimumab Clinical Safety Data51
The AEs of ipilimumab in cancer patients are mostly irAEs, which have been well defined in terms 
of their incidence, severity, time to onset, and resolution. In participants with advanced melanoma, 
the irAEs of ipilimumab at 3 mg/kg Q3W for 4 cycles occurred in approximately 60% to 65% of 
the participants. These AEs were mostly Grade 1-2 and affected primarily the skin (in 43% to 45% 
of participants) and GI tract (in 29% to 32% of participants), followed by the liver and endocrine 
system (in 6% to 8% of participants). The vast majority of these irAEs occurred within 12 weeks 
of initial dosing, with a median time of Grade 2-4 irAEs occurring at 4.6 weeks.52 In addition, low 
incidence of infusion-related reaction (IRR) of ipilimumab was also reported in 2.2% and 4.3% of
participants treated at 3 and 10 mg/kg infused over 90 minutes and can be treated with 
premedication of diphenhydramine.56 Management of irAEs attributed to ipilimumab treatment 
have been well established in the REMS Guidelines approved by FDA.53
BMS-986249 is expected to have the same type but reduced irAEs compared with ipilimumab 
based on the Probody mAb mechanism, which has been demonstrated in the nonclinical 
pharmacology and GLP toxicology studies. The efficacious dose of BMS-986249 is projected to 
be 3 mg/kg, same as the ipilimumab approved clinical dose. Therefore, an FIH starting dose of 
BMS-986249 at 240 mg (equivalent to approximately 3 mg/kg) may achieve anti-tumor efficacy 
similar to that of ipilimumab and reduced toxicities in participants that can be well managed based 
on ipilimumab REMS guidelines. 
5.5.1.4
Rationale for Flat Dosing
A flat dose (ie, in mg) of BMS-986249 will be used in this study instead of a body size-based (ie, 
body weight or body surface area) dose. Therapeutic mAb doses have been routinely calculated 
on a body size basis. This practice assumes that dosing by body size significantly reduces 
variability in therapeutic mAb exposure.54 However, recent analyses of marketed and experimental 
mAbs have demonstrated that body size-based dosing did not always offer advantages over flat 
dosing in reducing exposure variability. Many mAbs are target-specific with a relatively large 
therapeutic window that increases the tolerability of exposure variability. Additionally, 
patient-specific, disease-specific, and physiologic characteristics often contribute to exposure 
variability, resulting in a generally smaller contribution of body size. Therefore, the dosing 
paradigm for mAbs should be assessed in the context of all of these unique characteristics.
With either dosing strategy, bias with respect to exposure is expected to occur in the extremes of 
the body weight distribution. In general, body size-based dosing could result in higher mAb 
concentrations in the heaviest patients (eg, 90th percentile), whereas flat dosing could lead to 
higher mAb concentrations in the lightest patients (eg, 10th percentile). Body weight distribution 
data from a clinical trial database of over 2,500 adults with solid or hematologic cancers suggest a 
log-normal distribution of body weight with median, 10th, and 90th percentiles of 78, 56, and 
112 kg, respectively.55
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In addition to the above rationale, flat dosing offers practical advantages over body size-based 
dosing, including a convenient approach with respect to pharmacy preparation and clinical 
administration, and is also more likely to reduce the potential for dosing errors related to body 
size-based calculations.54 Because the magnitude of the impact of body size on the human PK of 
BMS-986249 is not yet determined, the PK and safety data from the Phase 1/2a study will be 
evaluated to validate the flat dosing approach. If appropriate, based on the entirety of the 
preliminary data, the Sponsor will consider a revision of the flat dosing strategy.
BMS-986249 will initially be administered Q4W. This dosing frequency is supported by the 
projected human T-HALF for BMS-986249 of 15 days. In addition, it complements the Q4W 
dosing regimen planned in Part 1B, Combination Doses of BMS-986249 with Nivolumab, thereby 
simplifying study logistics for both participants and investigators. An alternative dosing schedule 
may implemented upon evaluation of all available safety, PK, and 
 data. 
Alternative dose schedules in Part 1 that may be explored include Q8W (see Appendix 12 for 
potential alternative schedules of activities and PK/ADA), which will be initiated and documented 
by a note to file or administrative letter following discussions and agreement between the 
Investigators and Medical Monitor (or designee). If a cohort with a more frequent schedule of 
administration is explored, the dose level will be based on the PK data obtained from the Q4W 
dosing schedule, and will not exceed the highest dose level assessed and deemed tolerable.
5.5.2
Rationale for Ipilimumab and Nivolumab 30-minute Infusions
Ipilimumab is currently approved for IV administration over 90 minutes. Recently, Momtaz et al. 
retrospectively reviewed computerized pharmacy records at their institution of all patients with 
metastatic solid tumor malignancies who received at least 1 dose of 3 or 10 mg/kg ipilimumab 
over 90 minutes between 01-Apr-2008 and 30-Jun-2013.56 They found a low incidence of IRRs: 
2.2% and 4.3% for ipilimumab at 3- and 10-mg/kg doses, respectively (P=0.22, Fisher’s exact 
test).56 This finding led the investigators to prospectively evaluate 3 mg/kg ipilimumab 
administered IV over 30 minutes. In the first 120 patients evaluated, the incidence of IRR was 
5.8%, and the few reactions that were observed occurred at the second dose of ipilimumab.56 Two 
out of the 7 IRRs did not occur during the infusion. In addition, 6 out of the 7 IRRs were Grade 2, 
and in no case were the IRRs dose limiting. The investigators concluded that the incidence of IRRs 
in patients receiving 3 mg/kg ipilimumab IV over 30 minutes was acceptably low although slightly 
higher than that of the standard 90-minute infusion.56 The IRRs were managed according to 
institutional guidelines that included premedication with diphenhydramine and/or corticosteroids. 
It was concluded that 3 mg/kg ipilimumab can be safely infused over 30 minutes considering the 
acceptable and manageable low incidence of IRRs.56 In addition, after an IRR, patients can safely 
receive additional doses of ipilimumab with premedication.56
Nivolumab is currently approved for IV administration over 30 minutes for select indications. 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 participants with previously treated 
advanced or metastatic NSCLC.57 In the substudy, 322 participants received 3 mg/kg nivolumab 
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IV Q2W as a 30-minute infusion, and 355 participants received the same nivolumab regimen as a 
60-minute infusion.
Overall, the safety profiles between the 30- and 60-minute infusion groups were similar. TRAEs, 
of any grade were reported in 53% and 51% of participants who were given 30- or 60-minute 
infusions, respectively. Grade 3-4 TRAEs were reported in 12% of participants in each infusion 
group. Among select AEs of any cause, Grade 3-4 events were comparable between infusion 
groups in the pulmonary (3% and 2%), hepatic (2% and 3%), and GI (2% and 2%) categories. 
Hypersensitivity/infusion reactions of any cause were reported in 8 (2%) and 5 (1%) participants 
administered 30-
and 60-minute infusions, respectively. The incidence of Grade 3-4 
hypersensitivity/infusion reactions was < 1% in each infusion group. Hypersensitivity/infusion 
reactions were managed either through dosing interruptions (8 participants given 30-minute 
infusions and 3 participants given 60-minute infusions), discontinuations (1 participant given a 
30-minute infusion and 2 participants given 60-minute infusions), or administration of systemic 
corticosteroids (3 participants given 30-minute infusions and 1 participant given a 60-minute 
infusion). In addition, PPK modelling 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, ipilimumab and nivolumab can be safely administered as 30-minute infusions, with 
a low incidence of irAEs. Given these findings, 30-minute infusions are being implemented across 
the ipilimumab and nivolumab development programs, including the FIH study CA030001.
5.5.3
Rationale for BMS-986249 and Nivolumab Co-administration
Depending on the dosing and schedule, BMS-986249 in combination with nivolumab may be 
co-administered over approximately 60, 120, or 180 minutes through the same IV bag. See Table
7.1.1-1 for a list of dose selection and timing and the pharmacy manual for additional information. 
Co-administration will allow for increased convenience for participants, doctors, nursing staff, 
other health-care staff members, and pharmacists. Key advantages of co-administration of this 
combination are as follows:
•
Participants potentially benefit from less time in the clinic and/or doctor’s office
•
Increased ease of administration
•
Pharmacists require less time in preparation of the IV solution to be administered to the 
participant
Although co-administration may result in overlapping Tmax for BMS-986249 and nivolumab, the 
PK and exposure of BMS-986249 and nivolumab will be the same as when administered 
sequentially. Therefore, sequential versus co-administration is not expected to impact the overall 
safety profile.
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5.5.4
Rationale for Evaluating Different Dose Levels and Schedules of BMS-
986249 in Combination with Nivolumab in Part 2A
Multiple clinical studies have evaluated ipilimumab combined with nivolumab at different doses 
and schedules. Clinical trial experience suggests that the tolerability of the ipilimumab and 
nivolumab combination may be improved by changes in dose and regimen. Indeed the combination 
of ipilimumab and nivolumab has been currently FDA approved at 4 different dosing regimens; 
1) 3 mg/kg ipilimumab and 1 mg/kg nivolumab Q3W for 4 doses in participants with unresectable 
or metastatic melanoma and in patients with HCC who have been previously treated with 
sorafenib, 2) 1 mg/kg ipilimumab and 3 mg/kg nivolumab Q3W for 4 doses in patients with 
intermediate or poor risk, previously untreated advanced RCC and in patients with MSI-H or 
dMMR metastatic CRC that has progressed following treatment with a fluoropyrimidine, 
oxaliplatin, and irinotecan, 3) 1 mg/kg ipilimumab Q6W and 3 mg/kg nivolumab Q2W in adult 
patients with metastatic NSCLC expressing PD-L1 (≥1%) as determined by an FDA-approved 
test, with no EGFR or ALK genomic tumor aberrations, and 4) 1 mg/kg ipilimumab Q6W and 360 
mg nivolumab Q3W in adult patients with unresectable malignant pleural mesothelioma, and in 
combination with 2 cycles of chemotherapy Q3W for adult patients with metastatic or recurrent 
NSCLC with no EGFR or ALK genomic tumor aberrations as first-line treatment.11 Furthermore, 
as described in Section 3.2.4, a number of early clinical studies demonstrated the rate of Grade 3-4 
TRAEs varied with the dosing schedule of the ipilimumab and nivolumab combination. 
As summarized in Section 3.2.1.6 and consistent with the ipilimumab experience, the tolerability 
of BMS-986249 may also be dose and schedule dependent. Specifically, an increased number of 
TRAEs was observed with higher doses of BMS-986249 administered Q4W alone or in 
combination with nivolumab and a lower number of TRAEs were reported when administered at 
the alternative dosing schedule of Q8W. Hence, based on the preliminary safety, PK, and 
 data available from Part 1 (Dose Escalation Phase), 3 different BMS-986249 
dose/schedule regimens were initially selected for investigation in Part 2A (Section 5.1).
Additional review of the available Part 1 data was recently undertaken. Analyses included 
assessment of cleaved Probody species following various BMS-986249 doses and schedules, 
preliminary quantitative modeling and simulations of exposure and safety (Grade 3+ TRAE) 
relationships, and preliminary evaluation of available target lesion response data. These analyses 
resulted in the decision to close enrollment into Part 2A Arms A and B, and add Part 2A Arm F. 
Specifically for Arm A (BMS-986249 240 mg Q3W in combination with nivolumab 360 mg Q3W 
for 4 doses followed by nivolumab 480 mg Q4W), the induction-only regimen of BMS-986249 
does not fit the desired continuous CTLA-4 inhibition afforded by the greater tolerability with 
Probody technology. Furthermore, limited preliminary analysis suggests clinical activity at all 
Part 1B doses/schedules evaluated; however, preliminary analysis also suggests higher 
administered doses of BMS-986249 may increase the best overall response in the individual tumor
target lesions. Available clinical safety observations from Part 1, as well as preliminary model-
based predictions suggest good tolerability with Arm B (BMS-986249 800 mg Q8W in 
combination with nivolumab 480 mg Q4W) and Arm C (BMS-986249 1,200 mg Q8W in 
combination with nivolumab 480 mg Q4W). Consequently, Arm B may not represent a 
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differentiated regimen from Arm C. Predictions based on the preliminary exposure-safety analysis 
for Arm F (BMS-986249 600 mg Q4W in combination with nivolumab 480 mg Q4W) and Part 1 
Q4W dose escalation data suggest an acceptable safety profile. Furthermore, given the dose and 
administration schedule, Arm F is expected to provide similar average exposures to that of Arm C 
(1,200 mg BMS-986249 Q8W), while maintaining significantly higher trough concentrations, 
which may help maximize the therapeutic potential of BMS-986249. This approach therefore 
provides an opportunity to understand exposure measures underlining pharmacological activities 
and further informs the exposure-response relationship. 
Importantly, none of the doses/schedules selected for Part 2A exceed the highest dose level 
equivalent assessed and deemed tolerable in Part 1B (Safety Evaluation of Combination Doses of 
BMS-986249 with Nivolumab) and modification to Part 2A treatment arms was not based on any 
change in the BMS-986249 safety or tolerability profile, or measures of clinical activity.
5.5.5
Rationale for Q3W dosing of BMS-986249 and Nivolumab in Part 2A 
Arm A
As summarized in Sections 3.2.3 and 3.2.4, different studies of ipilimumab as a monotherapy and 
in combination with nivolumab have demonstrated different outcomes of safety, tolerability, and 
efficacy based on dose and administration schedule. Because BMS-986249 is a Probody of 
ipilimumab, Part 2A Arm A was designed to utilize the ipilimumab in combination with nivolumab 
approved Q3W schedule to minimize the potential confounding impact of administration schedule. 
The Q3W dose of Arm A will be 240 mg and does not exceed the highest dose level equivalent 
assessed and deemed tolerable of BMS-986249 in combination with nivolumab in Part 1B.
PK, safety, and efficacy data indicate that the safety and efficacy profile of 360 mg nivolumab 
Q3W and 480 mg nivolumab Q4W will be similar to that of 3 mg/kg nivolumab Q2W (see 
additional details in Section 3.2.2.1 and the nivolumab IB). Given the above data, 360 mg 
nivolumab Q3W was selected for Part 2A Arm A (BMS-986249 and nivolumab Combination 
Therapy Phase), based on equivalent nivolumab average exposure to the 480 mg Q4W
administration evaluated in Part 1B. As described above, additional review of the available Part 1 
data suggests a longer dosing interval may be more aligned with the BMS-986249 exposure 
profile; in addition, the Probody technology may enable a more tolerable safety profile enabling 
continuous administration, hence as of Revised Protocol 07, no further enrollment/randomization 
will occur into Part 2A Arm A.
5.5.6
Rationale for Dose Selection in Part 2B
BMS-986249 1,200 mg Q8W in combination with nivolumab 480 mg Q4W is selected to be 
further investigated in Part 2B, based on review of the preliminary safety, PK, and clinical activity 
data available from Part 1 (Dose Escalation Phase). Preliminary analysis of target lesion response 
data suggests increased clinical activity with higher administered doses of BMS-986249 alone or 
in combination with nivolumab. Preliminary PPK analysis of BMS-986249 supports the potential 
to deliver increased anti-CTLA-4 in combination with full dose nivolumab (480 mg Q4W or 
3 mg/kg based on average body weight of 80 kg), which may translate into greater therapeutic 
activities beyond that achieved with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg.
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Importantly, available clinical safety observations and preliminary model-based predictions 
suggest a manageable safety profile with good tolerability with the selected dose. Additionally, as 
summarized in Section 3.2.1.6 and consistent with the ipilimumab experience, when a longer 
dosing interval for BMS-986249 was evaluated (Q8W compared to Q4W) a lower incidence of 
TRAEs was observed. The Q8W dosing of BMS-986249 is further supported by the de novo 
gradual formation of the cleaved Probody species over time, which may mitigate the greater 
exposure fluctuations (peak-to-trough ratio) typically associated with prolonged dosing intervals. 
Limited and preliminary data analysis for Part 2A (Dose Expansion Phase in Melanoma) further 
supports the observations seen in Part 1. Additional information on the preliminary clinical results 
of BMS-986249 can be found in the IB.10
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met prior to dosing on Day 1. No 
exceptions will be granted. This study permits the re-enrollment of a participant who has 
discontinued the study as a pretreatment failure. If re-enrolled, the participant must be re-consented 
and meet all inclusion/exclusion criteria.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
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 tumor biopsy samples (see Section 9.8.2 for 
details). 
2) Type of Participants and Target Disease Characteristics
a) Participants must be at least 18 years old and have histologic or cytologic confirmation of 
a solid tumor that is advanced (metastatic, recurrent, and/or unresectable) with measurable 
disease per RECIST v1.1 (Appendix 5) or metastatic disease documented by either bone 
lesions on radionuclide bone scan and/or soft tissue lesions on CT/MRI per PCWG3 criteria 
for prostate cancer (Appendix 6) and have at least 1 soft-tissue tumor lesion accessible for 
biopsy. For Part 2B participants with HCC, intermediate disease is allowed.
b) Eastern Cooperative Oncology Group Performance Status of 0 or 1 (Appendix 7)
c) The BMS-986249 Monotherapy Dose Escalation (Part 1A):
i)
All solid tumor histologies, except for participants with primary central nervous system 
(CNS) tumors or tumors with CNS metastases as the only site of active disease, will be 
permitted during the Dose Escalation Phase.
ii) Participants must have received, and then progressed, relapsed, or been intolerant to, at 
least 1 standard treatment regimen in the advanced or metastatic setting according to 
tumor type, if such a therapy exists.
1) BC participants must have received or been intolerant to, all approved standard 
systemic treatments that have shown a documented benefit in OS per product label.
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iii) Participants in the monotherapy arm must be anti-CTLA-4-naive. Prior anti-PD-1 or 
anti-PD-L1 exposure is allowed in the monotherapy arm, but at time of first study 
treatment, participants must be at least 5 half-lives (approximately 100 days) from last 
dose of PD-1/PD-L1 therapy.
d) The Combination Dose Escalation of BMS-986249 with Nivolumab (Part 1B):
i)
Participants with biopsy-proven SCLC, CRC, CRPC, RCC, bladder cancer, gastric
cancer (including gastro-esophageal junction), esophageal cancer, and melanoma will 
be permitted during dose escalation, except for participants with tumors with CNS 
metastases as the only site of active disease.
Participants with NSCLC will also be permitted in this portion of the study but not as 
part of the initial DLT assessment; instead, NSCLC participants will be evaluated only 
as part of adding additional participants to a previously tested cohort.
ii) Participants with Gastric, Esophageal, or Urothelial cancer:
1) Gastric and esophageal cancer participants must have received, and then 
progressed, relapsed, or been intolerant to, at least 1 standard treatment regimen in 
the advanced or metastatic setting, if such a therapy exists.
2) Urothelial carcinoma participants must have received, and then progressed, 
relapsed, been intolerant to, or ineligible for, at least 1 platinum-containing 
chemotherapy regimen.
iii) Participants with NSCLC:
1) NSCLC participants must have received, and then progressed, relapsed, or been 
intolerant to, at least 1 standard treatment regimen in the advanced or metastatic 
setting, if such a therapy exists.
2) If the tumor is PD-L1 >50% by immunohistochemistry (IHC), they may be 
treatment-naive.
iv) All Part 1B participants must be naive to prior anti-CTLA-4 and anti-PD-1 or 
anti-PD-L1 therapies.
v) Participants with CRC:
1) Participants 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.
2) Participants must have known MSI-H or dMMR status. KRAS, and BRAF status,
if known, should be documented.
3) Participants who have received prior anti-angiogenic therapy (eg, bevacizumab) 
and/or anti epidermal growth factor receptor therapy (eg, cetuximab or 
panitumumab) are eligible.
vi) Participants with SCLC:
1) Histologically or cytologically documented SCLC, limited or extensive stage 
disease.
2) Received at least 1 prior platinum-containing chemotherapy regimen.
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vii)Participants with CRPC:
1) Participants must have at least 1 soft tissue lesion, unrelated to bone, that qualifies 
as measurable disease per RECIST v1.1.
2) Participants must have received and progressed/been intolerant of (or not be a 
candidate for) at least 1 and not more than 3 standard therapies and have been 
considered for all other potentially efficacious therapies.
3) Previous treatment for hormone sensitive prostate cancer does not qualify without 
subsequent treatment for hormone refractory state.
viii)
Participants with RCC:
1) 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-α), vaccine therapy, or treatment with cytotoxics is 
allowed.
2) 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.
e) The BMS-986249 in combination with Nivolumab Randomized Cohort Expansion in 
Melanoma (Part 2A):
i)
Histologically confirmed melanoma (per AJCC staging system) that is unresectable or
metastatic (Refer to Appendix 11).
1) Participants with ocular melanoma are excluded.
ii) No prior systemic anti-cancer therapy for unresectable or metastatic melanoma. 
1) Prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed 
at least 6 weeks prior to randomization, and all related AEs have either returned to 
baseline or stabilized. 
a) Anti-PD-(L)1 therapy with at least 6 months between the last dose and date of 
recurrence is allowed.
2) Participants must be naive to treatment with an anti-PD-L2, anti-CD137, or anti-
CTLA-4 antibody, or any other antibody or drug targeting T cell co-stimulation or 
checkpoint pathways.
iii) In order to be randomized, a participant must have quantifiable PD-L1 expression 
(≥1% or < 1% tumor cell membrane staining) or be classified as PD-L1 indeterminate. 
Tumor PD-L1 expression will be centrally assessed prior to patient randomization. 
(Refer to Table 2-1, Section 9.8.2, and the Laboratory Manual). 
iv) Known BRAF V600 mutation status as determined by local institutional standard or 
participant consent to BRAF V600 mutation testing per local institutional standards 
during the Screening Period, the results of which must be reported within 3 months of 
randomization. All BRAF statuses (BRAF wild-type or BRAF 600 mutation positive) 
are eligible.
v) Prior radiotherapy must have been completed at least 2 weeks prior to study treatment
administration.
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f)
The BMS-986249 in combination with Nivolumab Additional Tumor Cohort Expansion 
(Part 2B):
i)
Cohort 1:Participants with  HCC
1) Participants must have a diagnosis of HCC based on histological confirmation.
a) Participants with only a radiological diagnosis of HCC may be enrolled for 
screening in the study but histological confirmation is mandatory prior to the 
start of study therapy.
b) Known fibrolamellar HCC, sarcomatoid HCC, or combined hepatocellular 
cholangiocarcinoma are excluded.
2) Participants must have advanced or intermediate HCC not eligible for curative 
surgical and/or locoregional therapies.
3) Participants must have received and progressed on or after, or been intolerant to, a 
prior anti-PD-(L)1 therapy when administered as either a monotherapy or as part of 
a combination in the advanced or intermediate setting.
a) No more than 1 intervening therapy is allowed but not required between prior 
anti-PD-(L)1 containing regimen and enrollment.
b) Participants must not have received prior anti-CTLA-4 therapy.
4) Participants with macrovascular invasion are allowed to enroll.
5) Participants with extrahepatic spread are allowed to enroll.
6) Child-Pugh score of 5 or 6 (ie, Child-Pugh A; Appendix 13).
7) Participants are eligible to enroll if they have non-viral HCC, or if they have 
hepatitis B virus (HBV)-HCC, or hepatitis C virus (HCV)-HCC defined as follows:
a) HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface
antibody, detectable HBV core Ab, undetectable HBV deoxyribonucleic acid 
[DNA], and undetectable HBV surface antigen) or chronic HBV infection (as 
evidenced by detectable HBV surface antigen or HBV DNA). Participants with 
chronic HBV infection must have HBV DNA < 500 IU/mL and must be on 
antiviral therapy.
b) HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV 
ribonucleic acid (RNA) or HCV Ab.
c) Participants with active co-infection with both HBV and HCV (as evidenced by 
detectable HBV surface antigen or HBV DNA and HCV RNA) or hepatitis D 
infection in participants with hepatitis B are excluded.
8) Participants with prior hepatic encephalopathy are excluded.
9) Participants with clinically significant ascites as defined by prior ascites that 
required treatment and requires ongoing prophylaxis or current ascites requiring 
treatment are excluded.
10) Participants with presence of portal hypertension with history of bleeding due to 
esophageal or gastric varices within the past 3 months prior to enrollment are 
excluded.
ii) Cohort 2: Participants with CRPC
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1) Participants must have a histologically confirmed adenocarcinoma of the prostate 
without small cell features and with current evidence of metastatic disease 
documented by either bone lesions on radionuclide bone scan and/or soft tissue 
lesions on computed tomography (CT)/magnetic resonance imaging (MRI). 
Metastases may be in regional lymph nodes (N1 per current AJCC staging criteria) 
and/or distant metastases (M1 per current AJCC staging criteria). 
a)
Participants whose disease spread is limited to regional pelvic lymph nodes 
(N1M0) must have a lymph node measuring at least 2 cm in short axis to be 
considered eligible.
2) Participants must have:
a) Documented prostate cancer progression as per PCWG3 criteria within 
6 months prior to screening, with at least 1 of the following:
i) PSA progression* defined by a minimum of 2 rising PSA levels with an 
interval of ≥1 week between each determination. The PSA value should be
≥2 ug/L (2 ng/mL).
*Participants who received an anti-androgen must have PSA progression after 
withdrawal (see below).
ii) Radiographic disease progression in soft tissue disease based on RECIST 
v1.1.
iii) Radiographic disease progression in bone defined as appearance of 2 or 
more new bone lesions on bone scan.
b) Received and progressed on or after, or been intolerant to, a taxane-containing 
regimen and received no more than 2 prior chemotherapy regimens in the metastatic 
setting.
(i) If taxane-based chemotherapy was only given in the metastatic castration-
sensitive setting, participants must also have progressed following prior 
treatment with a second generation hormonal therapy. 
3) Prior second-generation hormonal manipulations (eg, abiraterone acetate, 
enzalutamide, apalutamide), ketoconazole, prostate cancer vaccine therapy,
radiation therapy (including targeted radioligands), radium-223, anti-androgens 
(eg, flutamide), chemotherapy, and diethylstilbestrols or other estrogens are 
allowed up to 28 days prior to study treatment. 
Note: Bicalutamide or nilutamide must be discontinued at least 6 weeks prior to 
treatment.
a) Participants with a history of response to an anti-androgen or adrenal androgen 
production inhibitor and subsequent progression while on that anti-androgen 
should be assessed for anti-androgen withdrawal response for 4 weeks (6 weeks 
for bicalutamide or nilutamide), and must demonstrate progression off anti-
androgen prior to enrollment.
b) For participants that have never responded to anti-androgens, observation for
anti-androgen withdrawal response is not necessary; however, a 2-week 
washout period is required prior to start of study therapy.
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c) Prior radiotherapy must have been completed at least 2 weeks prior to study 
treatment administration.
4) Ongoing ADT with a gonadotropin-releasing hormone (GnRH) analogue or 
bilateral orchiectomy (ie, surgical or medical castration) confirmed by testosterone 
level ≤1.73 nmol/L (50 ng/dL) at the screening visit. Castrate levels of testosterone 
must be maintained by surgical or medical means (luteinizing hormone-releasing 
hormone [LHRH]/GnRH analogues) throughout the conduct of the study.
5) Must be naive to treatment with an anti-PD-(L)1, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T cell co-stimulation or checkpoint
pathways.
6) Not Applicable per Protocol Amendment 08: Participants must not have visceral 
metastases in liver.
7) Participants with superscan on Technecium-99m radionuclide bone scans are not 
eligible for the study. Superscan is defined as a bone scan which demonstrates 
markedly increased skeletal radioisotope uptake relative to soft tissue in association 
with absent or faint renal activity (absent kidney sign).
iii) Cohort 3: Participants with TNBC
1) Males and females with locally recurrent unresectable or metastatic histologically 
confirmed TNBC as defined by the most recent American Society of Clinical 
Oncology/College of American Pathologists guidelines.
2) Participants must have previously received at least 1 standard chemotherapy based 
treatment containing taxane and/or anthracycline for the treatment of TNBC.
a) Participants whose tumors express PD-L1 may have received and progressed 
on or after an anti-PD-(L)1 inhibitor containing chemotherapeutic regimen, if 
available.
b) Participants who were not tested or participants who were tested and are 
negative for PD-L1 must not have received prior anti-PD-(L)1 therapy.
3) Participants are eligible to enroll regardless of PD-L1 status. If PD-L1 status is 
known, PD-L1 status and PD-L1 assay details should be documented.
4) Participants must not have received prior anti-CTLA-4 therapy.
3) Physical and Laboratory Test Findings
a) Adequate hematologic function for participants as defined by the following:
i)
Neutrophils ≥1,500/μL.
ii) Not applicable per Revised Protocol 04: Platelets ≥80 × 103/μL (transfusion to achieve 
this level is not permitted within 2 weeks of first study treatment administration).
iii) Not applicable per Revised Protocol 04: Hemoglobin ≥8 g/dL (transfusion to achieve 
this level is not permitted within 2 weeks of first study treatment administration).
iv) Platelets ≥100 × 103/μL (transfusion to achieve this level is not permitted within 
2 weeks of first study treatment administration).
1) For participants with HCC: Platelets ≥60 × 103/μL
v) Hemoglobin ≥9 g/dL (transfusion to achieve this level is not permitted within 2 weeks 
of first study treatment administration).
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1) For participants with HCC: Hemoglobin ≥8.5 g/dL and white blood cells
≥2000/μL
vi) WBC ≥ 2000/μL
b) Adequate hepatic function (except for HCC)
i)
ALT and 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).
iii) For participants with HCC:
1) Serum albumin ≥2.8 g/dL
2) Total bilirubin ≤3 mg/dL
3) AST and ALT ≤5 x ULN
4) PT/INR ≤2.3 or PT ≤6 seconds above control
c) Normal thyroid function or stable on hormone supplementation 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 
 sample collection, and 
required study follow-up periods.
4) Age and Reproductive Status
a) Males and females, aged at least 18 years old.
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.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception (Appendix 4) for 
the duration of combination therapy treatment with study treatment BMS-986249 plus
5 half-lives of nivolumab plus 30 days (duration of ovulatory cycle), for a total of 155 days 
post treatment completion. WOCBP receiving monotherapy treatment with BMS-986249 
must agree to follow instructions for method(s) of contraception for the duration of 
monotherapy treatment with BMS-986249 plus 5 half-lives of BMS-986249 plus 30 days 
(duration of ovulatory cycle) for total of 105 days post treatment completion. WOCBP 
receiving nivolumab in combination with ipilimumab agree to follow instructions for 
methods of contraception for the duration of combination treatment and 5 months after the 
last dose of study treatment. WOCBP receiving monotherapy nivolumab agree to follow 
instructions for methods of contraception for the duration of monotherapy treatment and 
for 5 months after the last dose of study treatment. Local laws and regulations may require 
use of alternative and/or additional contraception methods. See Appendix 4. All WOCBP 
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must agree not to donate eggs (ova, oocytes) for the purpose of reproduction throughout 
the time period mentioned above.
e) WOCBP who are continuously not heterosexually active are also exempt from 
contraceptive requirements but should still undergo pregnancy testing as described in this 
section.
f)
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception and fetal protection (Appendix 4) during combination treatment 
with study treatment BMS-986249 and nivolumab, plus 5 half-lives of nivolumab 
(approximately 125 days), plus 90 days (duration of sperm turnover), for a total of 215 days 
post treatment completion. Males who are sexually active with WOCBP must agree to 
follow instructions for methods of contraception during monotherapy treatment with BMS-
986249 plus 5 half-lives (approximately 75 days) of BMS-986249 plus 90 days (duration 
of sperm turnover) for a total of 165 days post treatment completion. Males who are 
sexually active with WOCBP while receiving nivolumab in combination with ipilimumab 
must agree to follow instructions for methods of contraception for the duration of 
combination treatment plus 7 months after the last dose of study treatment. Males who are 
sexually active with WOCBP while receiving monotherapy nivolumab must agree to 
follow instructions for methods of contraception for the of monotherapy treatment plus 7 
months after the last dose of study treatment. In addition, male participants must be willing 
to refrain from sperm donation during this time. See Appendix 4.
g) Azoospermic males are exempt from contraceptive requirements unless the potential exists 
for fetal toxicity due to study treatment being present in seminal fluid, even if the 
participant has undergone a successful vasectomy or if the partner is pregnant.
h) Women who are not of childbearing potential are exempt from contraceptive requirements. 
Women participants must have documented proof that they are not of childbearing
potential.
Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy and 
when applicable, the potential of fetal toxicity occurring due to transmission of study treatment, 
present in seminal fluid, to a developing fetus, even if the participant has undergone a successful 
vasectomy or if the partner is pregnant. Investigators shall advise on the use of highly effective 
methods of contraception (Appendix 4), which have a failure rate of < 1% when used consistently 
and correctly. 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.
6.2
Exclusion Criteria
1) Target Disease Exclusions
a) Participants with primary CNS malignancies, tumors with CNS metastases as the only site 
of disease, or active brain metastases will be excluded. Participants with controlled brain 
metastases, however, will be allowed to enroll. 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 
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taking steroids for at least 2 weeks prior to first dose of study treatment and with no new 
or progressive neurological signs and symptoms.
2) Prohibited Treatments
a) Cytotoxic agents, unless at least 4 weeks have elapsed from last dose of prior anti-cancer 
therapy and initiation of study therapy.
b) Noncytotoxic 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. 
If 5 half-lives is shorter than 4 weeks, agreement with the Sponsor/Medical Monitor (or 
designee) is mandatory. See Section 6.1 for additional requirements for prior treatments.
i)
Not applicable per Revised Protocol 04: Continued ADT in men with CRPC after 
progression on an initial ADT regimen is allowed.
ii) Continued LHRH/GnRH agonist therapy in men with CRPC after progression on an 
initial ADT regimen is allowed.
iii) Goserelin (or other applicable GnRH agonist therapy) may be administered per 
institutional guidelines for prevention of premature menopause in premenopausal 
women. 
c) Prior immunotherapy 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.
See Section 6.1 for additional requirements for prior immunotherapy treatments.
d) Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study within 2 weeks prior to treatment. If less than 
2 weeks have elapsed from the last botanical supplement and the initiation of study 
treatment, the participant can be treated at the investigator’s discretion and in agreement
with the Sponsor/Medical Monitor (or designee).
i)
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.
e) Participants currently in other interventional trials, including those for coronavirus disease 
of 2019 (COVID-19), may not participate in BMS clinical trials until the protocol-specific 
washout period is achieved. If a study participant has received an investigational 
COVID-19 vaccine or other investigational product designed to treat or prevent COVID-19 
prior to screening, enrollment must be delayed until the biologic impact of the vaccine or 
investigational product is stabilized, as determined by discussion between the investigator 
and the Medical Monitor (or designee).
3) Medical History and Concurrent Diseases
a) Participants with concomitant second malignancies (except adequately treated 
nonmelanomatous skin cancers or in situ urothelial, 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 Part 2, the BMS-986249 Cohort Expansion Combination Therapy Phase, 
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 
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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 allograft.
d) Toxicity (except for alopecia) related to prior anti-cancer therapy and/or surgery, unless 
the toxicity is 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
(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 
thyroid peroxidase antibodies and thyroid stimulating Ig prior to the first dose 
of study treatment).
(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 or any toxicity that 
resulted in permanent discontinuation from prior immune therapy (eg, anti-CTLA-4 or 
anti-PD-1/PD-L1 treatment or any other Ab 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) Conditions requiring systemic treatment with either corticosteroids > 10 mg daily 
prednisone equivalents or other immunosuppressive medications within 14 days of 
study treatment administration, except for adrenal replacement steroid doses of
> 10 mg daily prednisone equivalent in the absence of active autoimmune disease.
1) Treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating 
study treatment is permitted.
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).
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4) History of other clinically significant heart disease (eg, cardiomyopathy, congestive 
heart failure with New York Heart Association functional classification III to IV 
[Appendix 8], pericarditis, or significant pericardial effusion).
5) History of myocarditis, regardless of etiology.
6) Cardiovascular disease-related requirement for daily supplemental oxygen therapy.
7) QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation 
> 480 msec, except for right bundle branch block.
v) History of chronic hepatitis (except for HCC) as evidenced by the following:
1) Positive test for hepatitis B surface antigen or any positive test result for HBV
indicating presence of the virus.
2) Positive test for qualitative hepatitis C viral load by polymerase chain reaction 
(PCR).
(a) Participants with positive hepatitis C Ab and negative quantitative hepatitis C 
by PCR are eligible. History of resolved hepatitis A virus infection is not an 
exclusion criterion.
(b) Additional testing or substitute testing per institutional guidelines to rule out 
infection is permitted.
vi) Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal 
therapy ≤7 days prior to the first dose of study treatment (except for viral infections 
that are presumed to be associated with the underlying tumor type required for study 
entry).
vii)Not applicable per Revised Protocol 04: Known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
(AIDS).
Note: Testing for HIV must be performed at sites where mandated by local 
requirements.
viii)
Any major surgery within 4 weeks of the first dose of study treatment. Participants 
must have recovered from the effects of major surgery or significant traumatic injury 
at least 14 days before the first dose of study treatment.
ix) Participants who have received live/attenuated vaccine within 30 days of first 
treatment.
1) The use of inactivated seasonal influenza vaccines (eg, Fluzone™) will be 
permitted on study without restriction
x) Receipt of packed red blood cells or platelet transfusion within 2 weeks of the first dose 
of study treatment.
xi) 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 
treatment hazardous to the participants or could adversely affect the ability of the 
participant to comply with or tolerate the study.
xii)Positive test for HIV with an AIDS-defining opportunistic infection within the last year, 
or a current CD4 count < 350 cells/μL. Participants with HIV are eligible if:
1) They have received antiretroviral therapy (ART) for at least 4 weeks prior to study 
treatment as clinically indicated.
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2) They continue on ART as clinically indicated while enrolled on study.
3) CD4 counts and viral load are monitored per standard of care by a local healthcare 
provider while enrolled on study.
Note: Testing for HIV must be performed at sites where mandated by local 
requirements. HIV-positive participants must be excluded where locally mandated (see 
Appendix 14).
xiii) Interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected treatment-related pulmonary toxicity.
xiv) Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 
either suspected or confirmed within 4 weeks prior to screening.
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 investigational treatment.
f)
WOCBP who are pregnant or breastfeeding.
4) Allergies and Adverse Drug Reaction
a) History of allergy to study treatment(s) or any of its 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 person who has been 
imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply, and BMS approval is required).
b) Participants who are compulsorily detained for treatment of either a psychiatric or a 
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.
6.3
Lifestyle Restrictions
There are no lifestyle restrictions applicable for this study given that the participants will receive 
the study investigational products (IPs) IV.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized/entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants and to respond to queries 
from regulatory authorities. Minimal information includes date of consent, demography, screen 
failure details, eligibility criteria, and any serious AEs.
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6.4.1
Retesting During Screening Period
This study permits the re-enrollment of a participant who has discontinued the study as a 
pretreatment failure (ie, participant has not been randomized/has not been treated). If re-enrolled, 
the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments during the extended screening period
will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization 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 Table 2-1, Screening Schedule of 
Activities, may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor (or designee) may be needed to identify whether repeat testing of any 
particular parameter is clinically relevant.
Testing for asymptomatic SARS-CoV-2 infection, (eg, by reverse transcriptase 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, and
•
At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and
•
Acute symptoms (eg, cough, shortness of breath) have resolved, and
•
In the opinion of the investigator, there are no COVID-19-related sequelae that may place the
participant at a higher risk of receiving investigational treatment, and 
•
Negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional, local or 
regional guidelines
7
TREATMENT
7.1
Treatments Administered
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.
An IP, also known as investigational medicinal product in some regions, is defined as a 
pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) differently from the authorized form, or used for an unauthorized 
indication, or when used to gain further information about the authorized form.
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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.
In this protocol, IPs are the following: 
•
BMS-986249
•
Nivolumab
•
Ipilimumab
All 3 drugs used in this open-label study qualify as IPs, per previous text, and their description and 
storage information are described in Table 7.1-1.
Table 7.1-1:
Study Treatments for CA030001
Product 
Description / 
Class and 
Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage 
Conditions
(per Label)
BMS-
986249-01
for injection
160 mg/vial
(40 mg/mL)
IP
Open label
Vial
Store at 2°C to 
8°C. Protect
from light and 
freezing
nivolumab
(BMS-936558) 
solution for 
injection
100 mg/vial
(10 mg/mL)
IP
Open label
Vial
Store at 2°C to 
8°C. Protect 
from light and 
freezing.
ipilimumab
(BMS-734016)
solution for 
injection
200 mg/vial 
(5 mg/mL)
IP
Open label
Vial
Store at 2°C to 
8°C. Protect 
from light and 
freezing.
ipilimumab 
(BMS-734016) 
solution for 
injection
50 mg/vial
(5 mg/mL)
IP
Open label
Vial
Store at 2°C to 
8°C. Protect 
from light and 
freezing.
Abbreviations: IMP = investigational medicinal product, IP = investigational product.
7.1.1
Schedule of Dose for Each Investigational Product
The dosing schedule for each IP is detailed below in Table 7.1.1-1 for all study parts. Planned dose 
levels may be modified (eg, change in administration schedule) or intermediate dose levels may 
be added, based upon evaluation of available safety, PK, and 
 data.
All participants will be monitored continuously for AEs while on study treatment. Treatment 
modifications (eg, dose delay or discontinuation) will be based on specific laboratory and AE 
criteria, as described in Section 7.5.
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Table 7.1.1-1:
Selection and Timing of Dose for All Study Parts
Study Treatmenta
Flat Dose Levels
Frequency of 
Administration
Route of 
Administration
Minimal 
Infusion 
Timeb
(Minutes)
BMS-986249 monotherapy
BMS-986249 monotherapy
BMS-986249 monotherapy
240 - 800 mg
1,600 mg
2,400 mg
Q4W
Q4W or Q8W
Q4W
IV
IV
IV
30
120 
180
BMS-986249 
+ nivolumab
Co-administration
240 mg - 800 mg
+ 480 mg
Q4W or Q8W
IV
120
BMS-986249 
+ nivolumab
Co-administration
1,200 mg
+ 480 mg
Q4W or Q8W
IV
120c
BMS-986249 
+ nivolumab
Co-administration
1,600 mg
+ 480 mg
Q4W or Q8W
IV
180
nivolumab monotherapy
480 mg
Q4W
IV
30
BMS-986249 
+ nivolumab 
Co-administration 
(Combination Therapy 
Phase, Cycles 1-4)
240 mg 
+ 360 mg
Q3W x 4 doses
IV
60
Followed by nivolumab 
monotherapyd
(Maintenance Phase, Cycle 
5 and beyond)
480 mg
Q4W
IV
30
Ipilimumab 
+ nivolumabe
(Combination Therapy 
Phase, Cycles 1-4)
Followed by nivolumab 
monotherapyd
(Maintenance Phase, Cycle 
5 and beyond)
3 mg/kg
+ 1 mg/kg
480 mg
Q3W x 4 doses
Q3W x 4 doses
Q4W
IV
IV
IV
30
30
30
Abbreviations: IV = intravenous; Q3W = every 3 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks.
a Additional dose levels and/or schedules may be explored
b
If needed, flush the IV line with an appropriate amount of diluent (eg, 0.9% sodium chloride or 5% dextrose in 
water) to ensure that the complete dose is administered over the approximate designated infusion time.
c
For participants < 35 kg receiving 1,200 mg BMS-986249 in combination with 480 mg nivolumab, the minimum 
infusion time will be approximately 180 minutes.
d The nivolumab monotherapy Maintenance Phase will begin 3 weeks after the last BMS-986249 or ipilimumab and 
nivolumab Combination Therapy Phase (Cycles 1-4) dose. 
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e Ipilimumab and nivolumab will be administered sequentially as 2 separate IV infusions. Nivolumab will be given 
first, over approximately 30 minutes, followed by ipilimumab over approximately 30 minutes, beginning at least 
approximately 30 minutes after completion of the infusion of nivolumab.
BMS-986249 infusions, as a monotherapy or co-administration, will require a 60-minute 
observation period following the first 3 infusions for each participant.
Additional preparation, administration, storage/handling and infusion details for BMS-986249, 
ipilimumab, and nivolumab are provided in the Pharmacy Manual.
7.2
Method of Treatment Assignment
Participants will be enrolled using an Interactive Response Technology (IRT) system; until this 
system is activated, enrollment will be manually managed by the Sponsor.
During the screening visit, the investigative site will use 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 treated, will be assigned sequential participant
numbers starting with 
 The participant identification 
number (PID) will ultimately be composed of the site number and participant number. 
 
 
. Specific instructions for using the IRT system will be provided to the investigational 
sites in a separate document. 
During dose escalation, all participants will be assigned to Part 1A until the decision is made to 
escalate to the third dose cohort. Subsequently, treatment in Part 1B will be initiated, and dose 
escalation in the 2 parts will occur in parallel. Treatment assignments for participants eligible for 
both Part 1A and Part 1B will prioritize Part 1B through IRT whenever possible. If there are no 
openings in Part 1B, then the participant will be assigned to the next open part/cohort. Prioritization 
of participants eligible for both Part 1A and Part 1B may be modified to ensure the dose of Part 
1B does not exceed the highest tolerated dose in Part 1A. If Part 1 is open upon the decision to 
initiate Part 2, treatment in the 2 parts will occur in parallel. Treatment assignments for participants 
eligible for Part 1A or Part 1B, and Part 2 will prioritize Part 2 through IRT whenever possible. If 
there are no openings in Part 2, then the participant will be assigned to the next open part/cohort.
In the BMS-986249 in Combination with Nivolumab Randomized Cohort Expansion in Melanoma 
(Part 2A) every participant that signs the informed consent form will be assigned a participant 
identification number in IRT. In order to be randomized, pre-treatment tumor tissue obtained in 
the metastatic setting or from an unresectable site of disease must be provided for biomarker 
analyses. A participant must have quantifiable PD-L1 expression (≥1% or < 1% tumor cell 
membrane staining) or be classified as PD-L1 indeterminate. Participants will be stratified by 
PD-L1 expression and M-stage. Participants meeting eligibility criteria were to be randomized in 
a 1:1:1:1:1 ratio to Arms A - E. As of Revised Protocol 07, further enrollment/randomization into
Part 2A Arms A, B, and E is closed, and Arm F is added. Across study randomization for Part 2A 
participants meeting eligibility criteria will randomize in approximately a 1:1:1 ratio to open arms 
(eg, Part 2A Arms C, D, and F). If there is a change to randomization (eg, discontinuation of an 
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Arm or temporarily holding enrollment into an Arm while evaluation is ongoing), the adjusted 
randomization schedule will be documented by a note to file or administrative letter. Within 
7 working days from randomization, the participant must receive the dose of study medication, 
unless otherwise agreed upon with the Medical Monitor (or designee). BMS will create a 
randomization schedule which will be uploaded into the IRT.
In the BMS-986249 in Combination with Nivolumab Additional Tumor Cohort Expansion 
(Part 2B) every participant that signs the informed consent form will be assigned a participant 
identification number in IRT. Participants will be assigned to a tumor-type specific cohort of HCC, 
CRPC, or TNBC, respectively.
For Part 1, 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.
For Part 2, participant replacement will not be allowed for participants who are discontinued after 
dosing.
Study treatment will be dispensed at the study visits as listed in the Schedule of Activities 
(Section 2). 
7.3
Treatment Duration
Participants will be treated for up to 2 years in all study parts (see Section 5.4.4 for rationale).
7.4
Blinding
This is an open-label study and randomized in Part 2A. Designated staff of the Sponsor may 
receive access to treatment codes prior to database lock to facilitate early exploratory data analysis 
and the bioanalytical analysis of PK samples and immunogenicity. A bioanalytical scientist in the 
Sponsor’s Bioanalytical Sciences department (or a designee in the external central bioanalytical 
laboratory) will have access to the randomized treatment assignments in order to minimize 
unnecessary bioanalytical analysis of samples. In addition, the Sponsor’s Research and 
Development team will have access to the treatment codes prior to final data base lock for ongoing 
evaluation of preliminary available data (eg, safety, PK, and 
). 
7.5
Dosage Modification
Intra-participant dose escalation/reduction of BMS-986249, nivolumab, or ipilimumab is not 
permitted in this study in order to allow better evaluation of the safety and efficacy at individual 
dose levels and schedules.
7.5.1
Dose-limiting Toxicities
For the purpose of guiding dose escalation, DLTs will be defined based on the incidence, intensity, 
and duration of AEs that are possibly related to study treatment. The DLT period will be 5 weeks 
(35 days) in both BMS-986249 monotherapy and combination dose escalation (Parts 1A and 1B). 
Any toxicities that occur beyond the DLT period will be accounted for in making final dose level 
decisions. Participants who have received 2 doses of BMS-986249 and have completed or 
discontinued due to a DLT in the 5-week DLT period will be considered as DLT-evaluable 
participants for BMS-986249 monotherapy. Participants receiving either 2 dosing visits of 
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BMS-986249 and nivolumab, or participants who discontinued due to a DLT in the 5-week 
combination treatment DLT period, will be considered as DLT-evaluable participants for 
combination treatment. Participants who withdraw from the study during the DLT evaluation 
period or have received less than 2 dosing visits for reasons other than a DLT in both monotherapy 
and combination therapy will not be considered as DLT-evaluable participants and may be 
replaced with a new participant at the same dose level. Participants who are dose delayed during
the DLT evaluation period for reasons other than a DLT in both monotherapy and combination 
therapy will be considered as DLT-evaluable participants if they received at least 2 doses of 
therapy.
For the purpose of participant management, any drug-related AE that meets DLT criteria, 
regardless of the cycle or cohort (including Part 2) in which it occurs, will lead to discontinuation 
of study treatment. The incidence of DLT(s) during the 5-week DLT evaluation period will be 
used in dose escalation decisions and to define the MTD. AEs occurring after the DLT period will 
be considered for the purposes of defining the recommended Phase 2 dose of BMS-986249 (RP2D)
upon agreement between the Sponsor, Medical Monitor (or designee), and investigators.
AEs will be graded according to the NCI CTCAE v4.03.
Part 1B participants with NSCLC will only be evaluated in a cohort once the initial DLT evaluation 
for that cohort has been completed.
7.5.1.1
Gastrointestinal Dose-limiting Toxicity
The following study treatment-related event will be considered a GI DLT:
•
Grade ≥ 3 diarrhea or colitis, regardless of duration
7.5.1.2
Hepatic Dose-limiting Toxicity
Any of the following study treatment-related events will be considered a hepatic DLT:
•
Grade 4 elevations in serum transaminases (AST and ALT), alkaline phosphatase (ALP), or 
total bilirubin.
•
Grade 3 elevations in serum AST, ALT, or ALP that last longer than 5 days, or is associated 
with clinical symptoms, or bilirubin > 2× ULN in the absence of cholestasis.
•
Grade 2 elevations in AST or ALT with symptomatic liver inflammation (eg, right upper 
quadrant tenderness, jaundice).
•
AST or ALT > 3× ULN and concurrent total bilirubin > 2× ULN without initial findings of 
cholestasis (elevated ALP, eg, findings consistent with Hy’s law or FDA definition of potential 
drug-induced liver injury [p-DILI]). Note that this specific category of DLT uses ULN rather 
than NCI CTCAE grade for definition.
Any of the following study treatment-related events will be considered a hepatic DLT for 
participants with HCC:
•
ALT or AST > 15× ULN, regardless of duration.
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•
ALT or AST > 10× ULN for greater than 2 weeks.
•
Total bilirubin > 8× ULN for participants with elevated bilirubin at study entry or > 5× ULN 
for participants with normal bilirubin at study entry, regardless of duration.
•
ALT > 10× ULN and concurrent total bilirubin > 2× ULN.
7.5.1.3
Hematologic Dose-limiting Toxicity
Any of the following study treatment-related events will be considered a hematologic DLT:
•
Grade 4 neutropenia ≥7 days in duration
•
Grade 4 thrombocytopenia
•
Grade 3 thrombocytopenia with bleeding or any requirement for platelet transfusion
•
Grade 3 hemolysis (ie, requiring transfusion or medical intervention such as steroids)
•
Neutropenic fever of any duration
•
Grade 4 anemia not explained by underlying disease
7.5.1.4
Dermatologic Dose-limiting Toxicity
Any of the following study treatment-related events will be considered a dermatologic DLT: 
•
Grade 4 rash
•
Grade 3 rash if no improvement (ie, resolution to ≤Grade 1) after a 1- to 2-week infusion delay
7.5.1.5
Other Dose-limiting Toxicities
Any of the following events will be considered a DLT:
•
Grade ≥ 4 hypersensitivity reaction or Grade 3 that does not resolve to Grade 1 in < 6 hours
•
Grade 2 pneumonitis that does not respond to dose delay and systemic steroids within 14 days.
•
Any death not clearly due to the underlying disease or extraneous causes 
•
Grade 2 drug-related uveitis, episcleritis, iritis, eye pain, or blurred vision that does not respond
to topical therapy and does not improve to Grade 1 severity within 2 weeks OR requires
systemic treatment.
•
Grade 3 drug-related uveitis, episcleritis, iritis, pneumonitis, bronchospasm, or neurologic 
toxicity
Checkpoint inhibitor molecules, have been uncommonly associated with ocular drug-related AEs. 
Inflammation of components within the eye (eg, episcleritis, uveitis) are uncommon events of 
nivolumab or ipilimumab monotherapy (< 1% of cases). These events are usually of low or 
intermediate grade, reversible, detected early in the course of therapy and manageable with topical 
or systemic steroids. 
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−
Routine eye examinations should be performed in participants receiving immune 
checkpoint inhibitors. Upon clinical suspicion of an ocular event consider 
ophthalmic consult, dose delay, or dose discontinuation
−
Permanently discontinue for clinically significant or severe immune-mediated adverse 
reactions. Initiate systemic corticosteroids for severe immune-mediated adverse 
reactions
−
For Grade 2-4 ophthalmologic reactions that require systemic treatment or that do not 
improve to Grade 1 within 2 weeks while receiving topical therapy, permanently 
discontinue
−
Permanently discontinue for immune-mediated ocular disease that is unresponsive to local 
immunosuppressive therapy
−
Administer corticosteroid eye drops to participants who develop uveitis, iritis, or 
episcleritis
Other ≥Grade 3 study treatment-related toxicity will be considered a DLT. However, the following 
Grade 3-4 events will not be considered DLTs:
−
Grade 3-4 electrolyte abnormalities that are not complicated by associated clinical adverse 
experiences, last less than 72 hours, and either resolve spontaneously or respond to 
conventional medical intervention.
−
Grade 3 nausea or vomiting that lasts less than 48 hours and either resolves spontaneously 
or responds to medical intervention. 
−
Grade 3-4 elevation of amylase or lipase not associated with clinical or radiographic 
evidence of pancreatitis
−
Grade 3 fever not associated with hemodynamic compromise (eg, hypotension, clinical or 
laboratory evidence of impaired end-organ perfusion)
−
Grade 3 endocrinopathy that is well controlled by hormone replacement
−
Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or 
suspected tumor)
−
Grade 3 fatigue lasting < 1 week
−
Grade 3 infusion reaction that returns to Grade 1 in < 6 hours
7.5.2
Management Algorithms for Immuno-oncology Agents
I-O agents are associated with irAEs that can differ in severity and duration from AEs caused by 
other therapeutic classes. BMS-986249, ipilimumab, and nivolumab are considered I-O agents 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 
ipilimumab and nivolumab to assist investigators in assessing and managing the following groups 
of irAEs:
•
GI
•
Renal
•
Pulmonary
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•
Hepatic
•
Endocrinopathies
•
Skin
•
Neurological (including encephalitis)
•
Myocarditis 
The clinical nature of AEs noted with BMS-986249 will determine the role of the algorithms for 
use in toxicities related to its use in this study. The standard algorithms recommended for the 
management of irAEs in this protocol are in Appendix 9. 
GI AE management for BMS-986249 Grade 2 diarrhea/colitis irAEs may require earlier initiation 
of steroids.
7.5.3
Dose Delays Due To Toxicity
If an event is attributed to BMS-986249, ipilimumab, or nivolumab, alone or in combination, then 
all study treatments must be delayed until treatment can resume (See Section 7.5.3.1). Tumor 
assessments for all participants should continue per protocol even if dosing is delayed. Participants 
who experience the following must have all study treatment(s) withheld:
•
SARS-CoV-2 infection either confirmed or suspected
•
Potential DLTs, until DLT relatedness is defined
•
Drug-related select AEs and laboratory abnormalities as follows:
−
Any Grade ≥2 non-skin AE, with the following exceptions:
o
Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay
−
Dose delay for AST, ALT, or total bilirubin abnormalities in HCC participants should be 
managed as follows:
o
If baseline AST, ALT, or bilirubin is within normal limits, delay dosing for Grade ≥ 2 
toxicity
o
If baseline AST, ALT, or bilirubin is within the Grade 1 toxicity range, delay dosing 
for Grade  ≥ 3 toxicity
o
If baseline AST, ALT, or bilirubin is within the Grade 2 toxicity range, delay dosing 
for a 2-fold drug-related increase in AST, ALT, or bilirubin, or for AST, ALT, or 
bilirubin values 8× ULN (whichever is lower).
−
Grade 3 skin AE
−
Grade 3 laboratory abnormality, with the following exceptions:
o
Grade 3 lymphopenia does not require a dose delay
o
≥ Grade 3 amylase or lipase abnormality that is not associated with clinical 
manifestations or radiographic evidence of pancreatitis does not require dose delay
−
All troponin elevations require a dose delay
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−
AE, laboratory abnormality, or concurrent illness that, in the judgment of the investigator, 
warrants delaying study treatment administration
Participants who require a delay of study treatment should be re-evaluated weekly or more 
frequently if clinically indicated. For participants receiving a combination (eg, Part 1B and Part 
2), if dosing is delayed, then both study treatments must be delayed together. If dosing with both 
study treatments is to be resumed after a delay, then both must be resumed on the same day. Criteria 
for participants who are required to permanently discontinue study treatments are listed in Section 
8.2. In addition, all Grade 2 GI, renal, pulmonary, hepatic, and neurological AEs should be 
evaluated and managed per the toxicity management algorithms in Appendix 9. Participants not 
meeting guidelines for permanent discontinuation will be permitted to resume therapy based on 
the criteria specified below in Section 7.5.3.1. Participants eligible to resume study therapy will 
resume study therapy at the nominal treatment visit after their last received study medication dose.
7.5.3.1
Criteria to Resume Treatment
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 treatment 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 8.1) must resolve to baseline prior to resuming study therapy.
•
Participants who require dose delays for drug-related elevations in AST, ALT, or total bilirubin
may resume treatment when laboratory values return to baseline CTCAE Grade or normal and 
management with corticosteroids (if needed) is complete, provided the criteria for permanent 
discontinuation are not met (Section 8.1).
−
For HCC participants with baseline Grade 1 AST, ALT, or total bilirubin who require dose 
delays for reasons other than a drug-related hepatic event may resume treatment in the 
presence of Grade 2 AST, ALT, or total bilirubin.
•
Participants with combined Grade 2 AST/ALT and total bilirubin values meeting DLT criteria 
(Section 7.5.1) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.
•
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. Adrenal insufficiency requires discussion with 
and approval from the Medical Monitor (or designee).
•
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume 
treatment after all of the following:
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at least 10 days (20 days for severe/critical illness) have passed since symptoms first 
appeared or positive test result (eg, RT-PCR or viral antigen), and
−
resolution of acute symptoms (including at least 24 hours has passed since last fever 
without fever reducing medications), and
−
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
−
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.
7.5.4
Exceptions to Permanent Discontinuation Criteria
Any drug-related AE occurring at any time that meets DLT criteria as outlined in Section 7.5.1
will require permanent discontinuation, with the exception of the following:
•
Grade 3 nausea, vomiting, or abdominal pain that returns to Grade 1 or baseline within 48 hours 
either spontaneously or with medical intervention.
•
Grade 3 pruritus or rash that returns to Grade 1 or baseline within 7 days with medical 
intervention.
•
Isolated Grade 3-4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 3 days of 
their onset.
•
Grade 4 neutropenia < 7 days in duration.
•
Grade 4 lymphopenia or leukopenia.
•
Grade 3-4 increase in amylase or lipase that is not associated with clinical or radiographic 
evidence of pancreatitis.
•
Grade 3 infusion reactions that return to Grade 1 in < 6 hours.
•
Grade 3 fever not associated with hemodynamic compromise (eg, hypotension, clinical, or 
laboratory evidence of impaired end-organ perfusion).
•
Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or 
suspected tumor).
•
Grade 3 fatigue lasting < 1 week
•
Grade 3-4 drug-related endocrinopathy AEs, such as adrenal insufficiency, adrenocorticotropic 
hormone, hyper- or hypothyroidism, or glucose intolerance, which resolve or adequately 
controlled with physiologic hormone replacement (corticosteroids, thyroid hormones) or 
glucose-controlling agents, respectively, may not require discontinuation after discussion with 
and approval from the Medical Monitor (or designee).
•
Any event that leads to delay in dosing, lasting > 8 weeks from the previous dose, requires 
discontinuation, with the exception of the following:
−
Dosing delays 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 
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previous dose, the Medical Monitor (or designee) 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 Q4W, 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 Medical Monitor (or designee). 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks, the 
Medical Monitor (or designee) must be consulted.
•
Any AE, laboratory abnormality, or concurrent illness, which, in the judgment of the 
investigator, presents a substantial clinical risk to the participant with continued dosing.
Even if the criteria to resume treatment are met, the consideration to re-initiate study therapy under 
the following exception will be made on a case-by-case basis after considering the overall benefit-
risk profile and in consultation between the investigator and the Sponsor. Any AE with clinical 
risk will be assessed on a case-by-case basis with the investigator and the Medical Monitor (or 
designee) to determine the risks and benefits of continuing on therapy following resolution versus 
discontinuing therapy permanently.
All participants who discontinue IP should comply with protocol-specified follow-up procedures 
as outlined in Sections 2 and 8.2. 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 case report form (CRF) page.
7.5.5
Management of Drug-related Infusion Reactions
Because BMS-986249, ipilimumab, and nivolumab contain only human Ig protein sequences, they 
are unlikely to induce hypersensitivity reactions. However, based on the nonclinical toxicology 
evaluation of BMS-986249, infusion reactions due to T cell activation and cytokine release may 
occur in both monotherapy and combination with nivolumab. If such a reaction were to occur, it 
might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, 
hypertension, bronchospasm, or other allergic-like reactions. All Grade 3-4 infusion reactions 
should be reported within 24 hours to the Medical Monitor (or designee) and reported as an SAE. 
Infusion reactions should be graded according to NCI CTCAE v4.03 guidelines.
Treatment recommendations for infusion reactions are provided below and may be modified based 
on local treatment standards and guidelines, as appropriate.
For Grade 1 symptoms (mild reaction, infusion interruption not indicated, intervention not 
indicated), recommendations are as follows:
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•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1,000 mg at least 30 minutes before 
study treatment administrations.
For Grade 2 symptoms (moderate reaction requiring therapy or infusion interruption but 
responding promptly to symptomatic treatment such as antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids, or prophylactic 
medications indicated for ≤24 hours), recommendations are as follows:
•
Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the 
participant 
with 
diphenhydramine 
50 mg 
IV 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1,000 mg; remain at bedside and monitor participant until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, then the rate may be increased to 100% of the original infusion rate. Monitor 
participant closely. If symptoms recur, then no further BMS-986249, ipilimumab, or 
nivolumab will be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1,000 mg 
should be administered at least 30 minutes before study treatment infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3-4 symptoms (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms after initial 
improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]; Grade 4: life-threatening; pressor or ventilatory support indicated), 
recommendations are as follows:
•
Immediately discontinue infusion of study treatment. Begin an IV infusion of normal saline 
and treat the participant as follows: recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Study treatment will be 
permanently discontinued except for a Grade 3 infusion reaction that returns to Grade 1 in less 
than 6 hours. Investigators should 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).
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7.6
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator or designee where permitted, to ensure that IP 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 contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
IP 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 treatments not provided by BMS and obtained commercially by the site, storage should
in accordance with the product label.
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride solution) will not be 
supplied by the Sponsor and should be purchased locally if permitted by local regulations.
Please refer to the current version of the IB and/or Pharmacy Manual/reference sheets for complete 
storage, handling, dispensing, and infusion information for BMS-986249, ipilimumab, and 
nivolumab.
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 and the Pharmacy Manual.
7.6.1
Retained Samples for Bioavailability/Bioequivalence
Not applicable.
7.7
Treatment Compliance
Not applicable.
7.8
Concomitant Therapy
7.8.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.2)
•
Loco-regional therapies for HCC
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•
Any concurrent approved or investigational anti-neoplastic therapy (ie, chemotherapy, 
hormonal therapy, immunotherapy). For participants with CRPC, castrate status should be 
maintained, therefore, participants who have not had an orchiectomy can continue on 
LHRH/GnRH agonist therapy. For TNBC participants, Goserelin (or other applicable GnRH 
agonist therapy) may be administered per institutional guidelines for prevention of premature 
menopause in premenopausal women.
•
Any non-palliative radiation therapy. Radiation therapy administered with palliative intent (ie,
for pain, bleeding, spinal cord compression, brain metastasis, new or impending pathologic 
fracture, superior vena-cava syndrome, or obstruction) is permitted. See Section 7.8.2.
•
Any complementary medications (eg herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such medications are permitted if they are used as 
supportive care.
•
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, measles, 
mumps, and rubella) during treatment and until 100 days post last dose.
7.8.2
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 in the absence of active 
autoimmune disease
•
A brief (less than 3 weeks) 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)
•
Participants may continue to receive hormonal replacement therapy if initiated prior to 
enrollment. 
•
Participants already receiving agents for the management of skeletal-related events are allowed 
to continue with anti-bone resorptive therapy (including, but not limited to, bisphosponate or 
receptor activator of nuclear factor kappa ligand inhibitor), as per institutional standard-of-care
guidelines, if on stable dose for more than 28 days prior to start of study treatment.
•
HCC participants on antiviral therapy for HBV or HCV should continue the treatment during 
the study. Changing of dosage and regimens of antiviral therapy will be at the discretion of the 
Investigator.
−
If a participant has a > 1 log IU/mL increase in HBV DNA, then virologic breakthrough 
should be considered and HBV DNA confirmed. Adherence to current antiviral therapy 
should be assessed, and resistance testing performed according to local practices. If a 
participant has documented virologic breakthrough due to antiviral resistance, then this 
should be managed based on standardized regional guidelines and study treatment should 
be temporarily held. The participant may resume study treatment once virologic control is 
re-established (HBV DNA < 500 IU/mL).
−
For HCC participants who continue to be HCV RNA positive after receiving BMS-986249
in combination with nivolumab, current guidelines for management of chronic HCV 
infection, including those from American Association for the Study of Liver Disease, 
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European Association for the Study of the Liver, or Asian Pacific Association for the Study 
of the Liver may be consulted. Initiation of direct-acting antivirals for HCV is allowed at 
the discretion of the Investigator after discussion with the Medical Monitor (or designee).
•
COVID-19 vaccines that are NOT live are allowed and should be handled in the same manner 
as other vaccines. Administration may occur during the study, including during the 
administration of the BMS study treatment and after the last administration of the BMS study 
treatment.
−
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-986249 is unknown.
7.8.3
Palliative Local Therapy
Palliative and supportive care for disease-related symptoms may be offered to all participants on 
the study. Limited radiation treatment or surgery to control isolated lesions may be permitted for 
participants following consultation with the Medical Monitor (or designee). 
Participants should not receive study treatment during radiation because the potential for 
overlapping toxicities with radiotherapy and study treatment is not known. If palliative 
radiotherapy in short courses and for isolated fields is required to control symptoms not clearly 
related to disease progression, then study treatment 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 treatment, radiotherapy-related AEs should resolve to 
Grade ≤1 or baseline, and participants must meet relevant eligibility criteria as determined by the 
Medical Monitor (or designee) in discussion with the investigator. The Medical Monitor (or 
designee) must be consulted prior to re-initiating study treatment in a participant with a dosing 
delay lasting > 8 weeks from the previous dose.
Details of palliative radiotherapy should be documented in the source records and CRF. Details in 
the source records should include dates of treatment, anatomic site, dose administered and 
fractionation schedule, and AEs.
Symptoms requiring palliative radiotherapy must be evaluated for objective evidence of disease 
progression (ie, imaging). If a participant is considered to have progressed at the time of palliative 
therapy, then they must meet the treatment beyond progression criteria (Section 8.1.1) prior to re-
initiating study treatment. Participants receiving palliative radiation of target lesions will have the 
evaluation of ORR just prior to radiotherapy, but these participants will no longer be evaluable for 
the determination of response subsequent to the date palliative radiation occurs.
For participants who need to undergo surgery during the study, it is recommended to hold study 
treatment(s) for at least 2 weeks before (if elective) and 2 weeks after surgery, or until the 
participant recovers from the procedure, whichever is longer. Prior to resuming study treatment, 
surgery-related AEs should resolve to Grade 1 or baseline, and participants must meet relevant 
eligibility criteria as determined by the Medical Monitor (or designee) in discussion with the 
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investigator. The Medical Monitor (or designee) must be consulted prior to re-initiating study 
treatment in a participant with a dosing delay lasting > 8 weeks from the previous dose.
7.8.3.1
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 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 tattoos, 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.
7.9
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 a maximum [if applicable] treatment 
duration 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-986249 is 
terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
study objectives; or c) the participant can obtain medication from a government-sponsored or 
private health program. In all cases BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue IP for any of the following reasons:
•
Documented disease progression as defined by RECIST v1.1 (Appendix 5) or PCWG3 
(Appendix 6) unless participants meet criteria for treatment beyond progression (Section 
8.1.1).
•
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 7.5.1
will require permanent discontinuation. Exceptions to permanent discontinuation are listed in 
Section 7.5.4.
•
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 
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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.
•
Termination of the study by the Sponsor.
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required).
•
Inability to comply with protocol.
•
Discretion of the investigator.
•
Pregnancy.
•
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 
Medical Monitor (or designee) 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 Medical Monitor (or designee). 
•
For Part 2A Arms A and D during the Combination Therapy Phase, decisions to discontinue 
study treatment therapy must include both nivolumab as well as BMS-986249 or ipilimumab. 
It is not permitted to continue nivolumab without BMS-986249 or ipilimumab. Part 2A Arm 
A and D participants who do not complete all scheduled cycles of BMS-986249 or ipilimumab 
and nivolumab combination therapy will not be eligible for the nivolumab monotherapy 
Maintenance Phase.
•
For Part 1B, Part 2A Arms B, C, and F, and Part 2B, the assessment for discontinuation of 
nivolumab should be made separately from the assessment made for discontinuation of 
BMS-986249, if possible. Although there is overlap among the discontinuation criteria, if 
discontinuation criteria are met only for BMS-986249 but not for nivolumab, treatment with 
nivolumab may continue after discussion and approval by the Medical Monitor (or designee). 
Treatment with BMS-986249 may continue if nivolumab is discontinued only if the 
investigator is able to clearly determine the discontinuation event is only related to nivolumab
treatment and the decision is discussed with and approved by the Medical Monitor (or 
designee).
BMS-986249, as a Probody of ipilimumab, is predicted to have a similar but attenuated irAE 
profile compared to ipilimumab. The activation of a pre-existing but attenuated immune response 
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to cancer by checkpoint blockade is associated with an AE profile that is inherent to immune 
activation. Hence, distinguishing between an ipilimumab and nivolumab AE can be difficult. 
Clinical trial experience and labeled indications have characterized the AE profiles of ipilimumab
and nivolumab and suggest that some events are more frequently associated with a specific agent 
(eg, pneumonitis is more common with nivolumab than ipilimumab). Listed below are the most 
common irAE and AEs of ipilimumab and nivolumab. Refer to section 7.5.1 for information on 
DLTs.
The irAEs associated with ipilimumab include; colitis, hepatitis, nephritis, endocrinopathy, 
neurologic, eye, myocarditis, myositis, and skin AEs. The most common adverse reactions (≥5%) 
are fatigue, diarrhea, pruritus, rash, and colitis. Additional common adverse reactions at the 10 
mg/kg dose (≥5%) include nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, 
and insomnia. 
The overall safety experience with nivolumab is based on experience with approximately 
23,507 participants as either monotherapy or in combination with other therapeutics and include: 
pneumonitis, colitis, hepatitis, nephritis, endocrinopathy, neurologic, eye, myocarditis, myositis 
and skin. Most common adverse reactions (≥20%) in participants were: fatigue, rash, 
musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased 
appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.
Further safety information will be provided once available from Part 1A BMS-986249 
monotherapy escalation that may to help distinguish AEs due to BMS-986249 from those due to 
nivolumab in Part 1B.
•
If a participant in any of the BMS-986249 in combination with nivolumab arms meets criteria 
for discontinuation and the investigator is unable to determine whether the event is related to 
both or one study treatment, the participant should discontinue both nivolumab and 
BMS-986249 and be taken off the treatment phase of the study.
In the case of pregnancy, the investigator must immediately notify the Medical Monitor/designee 
of this event. In the event a normal healthy female participant becomes pregnant during a clinical 
trial, the study treatment must be discontinued immediately. In most cases, the study treatment will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
participant safety). Please call the Medical Monitor/designee 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 Medical 
Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. 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 (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
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If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records per local regulatory 
requirements in each region/country and entered on the appropriate CRF page.
8.1.1
Treatment Beyond Progression
As described in Section 5.4.5, accumulating evidence indicates that a minority of participants with 
tumors treated with immunotherapy may derive clinical benefit despite initial evidence of PD.58
Participants will be permitted to continue treatment beyond initial PD defined by RECIST v1.1 
(see Appendix 5) or PCWG3 for prostate cancer (see Appendix 6), assessed by the investigator, as 
long as they meet the following criteria:
•
Investigator-assessed clinical benefit and no rapid disease progression.
•
Continue to meet all other study protocol eligibility criteria. 
•
Tolerance of study treatment.
•
Stable performance status.
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases).
•
Participant provides written informed consent, using an ICF describing any reasonably 
foreseeable risks or discomforts, or other alternative treatment options prior to receiving any 
additional nivolumab, ipilimumab, or BMS-986249 treatment.
•
Radiographic assessment/scan(s) should continue in accordance with Section 2 for the duration 
of the treatment beyond progression and should be submitted to the central imaging vendor.
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 in the study and continue to be monitored according
to the Schedule of Activities (see Section 2). All decisions to continue treatment beyond initial 
progression must be discussed with the Medical Monitor (or designee), and an assessment of the 
benefit/risk of continuing with study therapy must be documented in the study records (see 
Appendix 2).
8.1.1.1
Discontinuation Due to Further Progression (Confirmed Progression)
Participants will continue to be monitored according to the on-treatment assessments in Section 2. 
Radiographic assessment, by CT (preferred) or MRI described in Section 9.1.1, is required when 
participants continue post-progression treatment and should be performed. A follow-up scan 
should be performed within 6 weeks (± 5 days) of original investigator-assessed PD to determine 
whether there has been a decrease in the tumor size, or continued progression of disease. 
Subsequent scans should be performed as outlined in Table 2-2, Table 2-3, Table 2-4 and detailed 
in Section 9.1.1. Participants should discontinue study therapy upon evidence of further 
progression, defined as an additional 10% or greater increase in tumor burden volume with a 
minimum 5 mm absolute increase from the time of initial progression (including all target lesions 
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and new measurable lesions). In situations where the 10% relative increase in total tumor burden
is solely due to inclusion of new lesions which become measurable, these new lesions must 
demonstrate an absolute increase of at least 5 mm.
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 according to the 
following:
•
For solid tumors: 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 or PCWG3-defined 
progression will be considered to have investigator-assessed PD at the time of the initial 
progression event.
8.1.2
Post-treatment Study 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 should 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 5.1.5 until death or the conclusion of the study.
Participants who discontinue study treatment may continue to be followed.
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 the 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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8.2.1
Individual Discontinuation Criteria
•
A participant may withdraw completely from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. The participant will be permanently discontinued both 
from the study intervention and from the study at that time. This is expected to be uncommon.
Stopping study intervention is not considered withdrawal from the study.
•
At the time of discontinuing from the study, if possible, an early termination visit should be 
conducted, as shown in the Schedule of Activities. See the Schedule of Activities for data to 
be collected at the time of study discontinuation and follow-up and for any further evaluations 
that need to be completed.
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 3
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 (see Section 2). 
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 
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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 the ICF 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 in compliance with local regulations. Laboratory toxicities (eg, suspected 
drug-induced liver enzyme evaluations) will be monitored during the follow-up phase via on-
site/local laboratories until all study treatment-related toxicities resolve, return to baseline, or are 
deemed irreversible.
If a participant shows pulmonary-related signs (eg, hypoxia, fever, or cough) or symptoms 
(eg, dyspnea) 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 9.
Some of the assessments referred to in this section may not be captured as data in the CRF. They 
are intended to be used for 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
Efficacy assessments for the anti-tumor activity of BMS-986249, alone and in combination with
nivolumab, ipilimumab in combination with nivolumab, and nivolumab monotherapy will be 
based on tumor measurements, using RECIST v1.1 (all indications except prostate) or PCWG3 
criteria (for prostate cancer). 
Only data for the procedures and assessments specified in this protocol should be submitted to the 
Sponsor or Designee on a CRF. Additional procedures and assessments may be performed as part 
of standard of care. However, data for these assessments should remain in the participant’s medical 
record and should not be provided to the Sponsor or Designee, unless specifically requested from 
BMS or Designee.
9.1.1
Imaging Assessment for the Study
Images will be submitted to an imaging core laboratory and, at the Sponsor’s discretion, may be 
reviewed by BICR at a later date or at any time during the study. Sites should be trained prior to 
scanning the first study participant. Image acquisition guidelines and the submission process will 
be outlined in the CA030001 Imaging Manual to be provided by the core laboratory.
Screening, on-treatment, and follow-up images should be acquired as outlined in Section 2.
Tumor assessments at other time points may be performed if clinically indicated and should be 
submitted to the central imaging vendor.
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known/suspected sites of 
disease should be performed for tumor assessments.
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For participants with HCC, a triphasic CT/MRI of the liver is required.
For participants with TNBC without measurable lesions outside of the breast, contrast-enhanced 
MRI of the breasts should be performed along with body imaging.
Participants with prostate cancer should have bone lesions assessed using technetium-99m 
radionuclide bone scans at each imaging assessment. Anterior and posterior whole body planar 
images should be acquired. Additional (including spot views and single-photon emission 
computerized tomography) images should also be submitted if acquired. Participants with other 
malignancies may have bone scans as clinically indicated.
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.
Should a participant have contraindication for a CT IV contrast, a non-contrast CT of the chest and 
a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of disease 
should be obtained. If the primary tumor is not of lung origin, a contrast-enhanced MRI of the 
chest may be obtained instead of a non-contrast CT of the chest. 
Should a participant have contraindication for both MRI and CT IV contrasts, a non-contrast CT 
of the chest and a non-contrast MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained. If the primary tumor is not of lung origin, a non-contrast MRI of the
chest, abdomen, pelvis, and other known/suspected sites of disease is also acceptable.
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT IV contrast, a non-contrast CT of the chest, abdomen, pelvis, and other 
known/suspected sites of disease is acceptable.
Use of CT component of a positron emission tomography (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; therefore, it is 
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 that 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.
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Brain and/or bone scans may be collected per local standards, as clinically indicated.
Tumor assessments for all participants should continue per protocol even if dosing is delayed or 
discontinued. Changes in tumor measurements and tumor responses will be assessed by the 
investigator per study design using RECIST v1.1 or PCWG3 (for prostate cancer) criteria.
Assessments of PR and CR must be confirmed at least 4 weeks after initial response. A Best 
Response of SD can only be made after the participant is on-study for a minimum of 49 days from 
the date of treatment initiation (ie, first dose). Investigators will also report the number and size of 
new lesions that appear while on study. Investigators will also report the number and size of new 
lesions that appear while on study treatment. The time point of tumor assessments will be reported 
on the CRF based on the investigator’s assessment.
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
For all study participants, safety reporting of all AEs (non SAEs and SAEs) should take place from 
date of informed consent through 100 days post EOT. All SAEs, and all AEs (SAEs and 
non-serious AEs) associated with confirmed or suspected SARS-CoV-2 infection, must be 
collected from the date of the participant’s written consent through 100 days following EOT.
The IB describes the Reference Safety Information to determine expectedness of SAEs for 
expedited reporting. Following the participant’s written consent to participate in the study, all 
SAEs, whether related or not related to study treatment, must be collected, including those thought 
to be associated with protocol-specified procedures.
•
All AEs and SAEs must be collected that occur during the screening period and through 
100 days post EOT, 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 should be reported as an SAE.
•
The investigator must report any SAE that occurs after these time periods and that is believed 
to be related to study treatment or protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the CRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated
in Appendix 3.
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•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
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
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. In order to prevent reporting bias, participants should not be questioned
regarding the specific occurrence of 1or more AEs.
Every AE must be assessed by the investigator with regard to whether it is considered immune-
mediated. For events which are potentially immune-mediated, additional information will be 
collected on the participant’s CRF.
9.2.3
Follow-up of AEs and SAEs
•
Non-serious AEs should be followed to resolution or stabilization or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
All identified non-serious AEs must be recorded and described on the non-serious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and non-serious AEs of special interest (as defined in 
Section 9.2), including those associated with confirmed or suspected SARS-CoV-2 infection, will 
be followed until resolution, until the condition stabilizes, until the event is otherwise explained, 
until the event is deemed irreversible, until 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 
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the IB and will notify the Institutional Review Board/Independent Ethics Committee, 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 
5 half-lives after product administration, the investigator must immediately notify the Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please call the Medical Monitor (or 
designee) within 24 hours of awareness of the pregnancy.
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.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Sponsor or designee. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
In cases where a study treatment can be present in seminal fluid, at exposures sufficient to 
potentially cause fetal toxicity, and if any sexual activity (eg, vaginal, anal, oral) has occurred 
between a male participant and a pregnant WOCBP partner(s), the information should be reported 
to the Sponsor or designee, even if the male participant has undergone a successful vasectomy. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner(s) must sign an informed consent form for disclosure of this 
information. Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious 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.
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•
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
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 that were exacerbated by the induction of autoimmunity. Information supporting the 
assessment will be collected on the participant’s CRF.
9.2.8
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a p-DILI event. All occurrences of p-DILIs, meeting the defined 
criteria must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting details).
A p-DILI is defined as follows: 
1) Aminotransaminases (ATs; ALT or AST) elevation > 3× ULN
AND
2) Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum ALP),
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.
For HCC participants, a p-DILI is defined as follows and takes into account anticipated baseline 
compromise of liver function: 
1) Concurrent ALT  ≥ 10× ULN
AND
2) Total bilirubin ≥2× ULN or baseline value (if elevated bilirubin at study entry)
AND
3) No other immediately apparent possible causes of ALT elevation and hyperbilirubinemia, 
including, but not limited to, tumor progression, acute viral hepatitis, cholestatis, pre-
existing hepatic disease, or the administration of other drug(s), herbal medications, and 
substances known to be hepatotoxic.
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The key responsibilities for investigators 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 p-DILI cases via SAE forms. Following 
the gathering and assessment of relevant clinical information, BMS is responsible for (1) timely 
evaluation and triaging of p-DILI cases, (2) expedited reporting of p-DILI cases, and (3) expanded 
review of p-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 p-DILI criteria. They are expected to promptly 
notify BMS of all p-DILI cases. p-DILI 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 p-DILI criteria is a candidate for study treatment 
discontinuation. Any confirmed p-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.
9.2.9
Other Safety Considerations
Any significant worsening noted during interim or final PE, electrocardiogram (ECG), and x-ray 
filming, and any other potential safety assessment required or not required by protocol, should also 
be recorded as a non-serious or serious AE, as appropriate, and reported accordingly.
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.
For this study, any dose of BMS-986249, ipilimumab, or nivolumab greater than the assigned dose 
and considered excessive and medically important by the investigator will be considered an 
overdose.
All occurrences of overdose must be reported as SAEs (see Section 9.2).
In the event of an overdose the investigator should:
1) Contact the Medical Monitor (or designee) immediately.
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2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
BMS-986249, ipilimumab, or nivolumab can no longer be detected systemically (at least 
125 days).
3) Obtain a blood sample for PK analysis after the last dose of study treatment if requested 
by the Medical Monitor (or designee) (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 (or designee) 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 (Section 2).
Safety assessments will be based on reported AE and the measurement results of vital signs, ECGs, 
PEs, and clinical laboratory tests. AEs will be coded using the most current version of Medical 
Dictionary for Regulatory Activities and the incidence of observed AEs will be tabulated and 
reviewed for potential significance and clinical importance. For all study participants, safety 
reporting of all AEs (non SAEs and SAEs) should take place from date of informed consent 
through 100 days post EOT. Local laboratory will perform the clinical laboratory tests and will 
provide reference ranges for these tests. Both AEs and laboratory tests will be graded using the 
NCI CTCAE v4.03. Testing for COVID-19 to inform decisions about clinical care during the study 
should follow local standard practice.
9.4.1
Physical Examinations
Refer to the Schedule of Activities for timing of assessments in Table 2-1, Table 2-2, Table 2-3, 
Table 2-4, and Table 2-5.
9.4.2
Vital Signs
Refer to the Schedule of Activities for timing of assessments in Table 2-1, Table 2-2, Table 2-3, 
Table 2-4, and Table 2-5.
9.4.3
Electrocardiograms
Refer to the Schedule of Activities for timing of assessments in Table 2-1, Table 2-2, Table 2-3,
and Table 2-4.
The effect of BMS-986249 on the corrected QT interval will be evaluated by a central reader using 
all of the ECG data collected. For BMS-986249 Monotherapy Dose Escalation (Part 1A) ECGs 
will be taken in triplicate at select time points (see Table 2-2) along with time-matched PK
(eg, 1 ECG test equals 3 consecutive individual 12-lead ECGs performed 5 minutes apart). All 
other ECGs completed in screening, on-treatment in Parts 1B, 2A, and 2B, and in follow-up will 
be a single 12-lead ECG at select time points (see Section 2).
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Anti-CTLA-4 Probody mAb
For the purposes of monitoring participant safety, outside the central reader time points the 
investigators will review the 12-lead ECGs using their site’s standard ECG machines throughout 
the study. 
The QTcF will be applied to each ECG reading.
9.4.4
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
•
A local laboratory, unless otherwise specified, 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 9.4.4-1.
•
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 9.4.4-1:
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)a
Serum Chemistry
Aspartate aminotransferase 
Alanine aminotransferase 
Total bilirubin
Direct bilirubin (reflex)b
Alkaline phosphatase
Lactate dehydrogenase 
Creatinine
Creatine kinase/ Creatine phosphokinase
C-reactive protein
Blood urea nitrogen 
Uric acid 
Glucose
Lipase
Amylase
Total protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatinine clearance (Cockcroft-Gault method, at 
screening only)
Troponin
Serum Alpha-fetoproteine
Prostate-specific antigen (PSA)f
Testosteronef
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Anti-CTLA-4 Probody mAb
Table 9.4.4-1:
Clinical Laboratory Assessments
Gamma glutamyl transferase (reflex only)c
Thyroid stimulating hormone
Free T3 and T4 (screening and reflex only)d
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)
Additional testing for viral hepatitis required and must be completed at the central laboratory for HCC 
participants only: Epstein-Barr virus Ab, hepatitis B surface Ab, hepatitis B core Ab, hepatitis B DNA viral load 
(PCR), HCV RNA viral load (PCR), hepatitis D Ab (if chronic HBV infection). See Section 2.
Other Analyses
Pregnancy test (WOCBP only: screening, predose, and discharge).
Follicle stimulating hormone (screening only and women only)
Abbreviations: Ab = antibody; aPTT = activated partial thromboplastin time; CRPC = castration-resistant prostate 
cancer; DNA =  deoxyribonucleic acid; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis 
C virus; HIV = human immunodeficiency virus; INR = international normalized ratio; PCR = polymerase chain 
reaction; PSA = prostate-specific antigen; PT = prothrombin time; RNA = ribonucleic acid; T3 = triiodothyronine; T4 
= thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
a PT, aPTT, and INR required for participants with HCC and CRPC as outlined in Section 2.
b Reflex testing to be performed only if total bilirubin is abnormal.
c Reflex testing to be performed only if liver function test is abnormal.
d Reflex testing to be performed only if TSH is abnormal.
e Required for participants with HCC only.
f Required for participants with CRPC only.
9.4.5
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 per standard 
medical/clinical judgment.
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9.5
Pharmacokinetics and Immunogenicity Assessments
The PK of BMS-986249 will be derived from plasma concentration-time data. The PK parameters 
that will be assessed following serial PK collection are shown in Table 9.5-1. Sparse ipilimumab 
and nivolumab serum samples will be collected and may be used in an integrated PPK or exposure 
response analysis along with data from other ipilimumab and nivolumab studies, which would be 
the subject of a separate report. Separate PK and ADA samples will be collected for BMS-986249, 
ipilimumab, and nivolumab at the end of a sequential dosing or co-administration. Separate 
samples will be collected for PK and ADA assessments using validated methods.
ADA samples for BMS-986249 and serum samples for ipilimumab and nivolumab ADA will be 
collected from all participants at specified time points (see Table 9.5-2 through Table 9.5-9). Blood 
samples may be analyzed by an exploratory method that measures different forms of the Probody
mAb for technology exploration purposes; exploratory results may be reported. Blood samples 
designated for PK or biomarker assessments may also be used for immunogenicity analysis if 
required (eg, insufficient volume for complete immunogenicity assessment or to follow up on 
suspected immunogenicity-related AEs), and vice versa.
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Table 9.5-1:
BMS-986249 Pharmacokinetic Parameters
Parameters
Definition
Cmax
Maximum observed concentration
Tmax
Time of maximum observed concentration
AUC(0-T)
Area under the concentration-time curve from time zero to time of last quantifiable 
concentration; may be calculated if concentrations are not quantifiable up to TAU across a 
treatment group
AUC(TAU)
Area under the concentration-time curve in 1 dosing interval
Ctau
Observed concentration at the end of a dosing interval
Ctrough
Trough observed concentrations (this includes predose concentrations [C0] and Ctau)
Parameters That May be Assessed Following the Dose Administration in Cycle 4
CLT
Total body clearance
Css-avg
Average concentration over a dosing interval (AUC[TAU]/tau) at steady state
AI
Ratio of an exposure measure at steady state to that after the first dose (exposure measure 
includes AUC[TAU] and Cmax)
T-HALF
Terminal half-life
Individual participant PK parameter values will be derived by noncompartmental methods using a 
validated PK analysis program. Actual times will be used for all formal analyses.
Table 9.5-2 through Table 9.5-9 list the sampling schedule to be followed for the assessment of 
PK in Parts 1A, 1B, 2A, and 2B. Further details of blood collection and processing will be provided 
to the site in the Laboratory Manual.
All predose samples should be taken within approximately 30 minutes prior to the start of the
infusion. Since the end of infusion-PK (EOI-PK) sample is drawn with the intent of accurately 
estimating the Cmax of the study treatment, draw the EOI-PK when all the study treatment has 
been infused. If the site infuses study treatment without a flush, then collect the EOI-PK sample 
within approximately 5 minutes after EOI. If a flush is administered to clear the IV lines of the
study treatment and to ensure delivery of the entire study treatment dose, then draw the EOI-PK 
sample within approximately 5 minutes after end of the flush. Do not draw EOI samples from the 
same IV access that the study treatment was administered. Refer to Table 7.1.1-1 for infusion 
duration. 
On-treatment PK samples are intended to be drawn relative to actual dosing days. If a dose occurs 
on a different day within the cycle due to delays or minor schedule adjustments, PK samples should 
be adjusted accordingly. If it is known that a dose is going to be delayed, then the predose sample 
should be collected just prior to the delayed dose. A PK and ADA sample may be taken in the 
event of a Grade 3+ infusion reaction or hypersensitivity reaction. Further details of sample 
collection, processing, and shipment will be provided in the Laboratory Manual.
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Anti-CTLA-4 Probody mAb
Addendum per Protocol Amendment 09: Removed all PK and ADA samples after Cycle 3 Day 1 
(C3D1), with the exception of occurrence of Grade 3+ infusion reactions to decrease participant 
and site burden as available sample collections are sufficient for proposed analysis of the secondary 
objective of PK characterization and the exploratory objective of ADA analysis.
Table 9.5-2:
PK and ADA Sampling Schedule for BMS-986249 Q4W 
Monotherapy in Dose Escalation (Part 1A)
Study Day of 
Sample Collection
(1 cycle = 4 weeks)
Event
Time
(Relative To Start of 
BMS-986249 Infusion)
Hour: Min
BMS-986249 PK
Plasma Sample
BMS-986249 ADA 
Serum Samples
C1D1
Predosea
00:00
X
X
EOI
See noteb
X
04:00
X
C1D2
24:00
X
C1D4 ( ± 1 days)
72:00
X
C1D8 ( ± 2 days)
168:00
X
C1D15 ( ± 2 days)
336:00
X
C1D22 ( ± 2 days)
504:00
X
C2D1
Predosea
00:00
X
X
EOI
See noteb
X
C2D8 ( ± 3 days)
168:00
X
C3D1
Predosea
00:00
X
X
EOI
See noteb
X
Grade 3+ Infusion 
Reaction
X
X
Abbreviations: ADA = anti-drug antibody; C = cycle; D = day; EOI = end of infusion; PK = pharmacokinetics; 
Q4W = every 4 weeks.
a Predose: All predose samples should be taken within approximately 30 minutes prior to the start of the infusion,
unless previously discussed with Medical Monitor (or designee).
b Refer to Section 9.5 and Table 7.1.1-1 for additional information and infusion duration. If the EOI is delayed to 
beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly.
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Anti-CTLA-4 Probody mAb
Table 9.5-3:
PK and ADA Sampling Schedule for BMS-986249 Q4W in 
Combination with Nivolumab Q4W in Dose Escalation (Part 1B)
Study Day of 
Sample 
Collection
(1 cycle = 4 
weeks)
Event
Time (Relative To 
Start of 
BMS-986249 in 
Combination with
nivolumab 
Co-administration 
Infusion)
Hour: Min
BMS-
986249 PK
Plasma 
Sample
nivolumab 
PK Serum 
Sample
BMS-
986249 
ADA Serum 
Samples
nivolumab 
ADA 
Serum 
Samples
C1D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
04:00
X
C1D2
24:00
X
C1D8 ( ± 2 days)
168:00
X
C1D15 ( ± 2 days)
336:00
X
C1D22 ( ± 2 days)
504:00
X
C2D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
C2D8 ( ± 3 days)
168:00
X
C3D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
Grade 3+ Infusion 
Reaction
X
X
X
X
Abbreviations: ADA = anti-drug antibody; C = cycle; D = day; EOI = end of infusion; PK = pharmacokinetics; 
Q4W = every 4 weeks.
a Predose: All predose samples should be taken within approximately 30 minutes prior to the start of the infusion,
unless previously discussed with Medical Monitor (or designee).
b Refer to Section 9.5 and Table 7.1.1-1 for additional information and infusion duration. Separate EOI samples 
(1 each for BMS-986249 and nivolumab) should be collected following co-administration of BMS-986249 and 
nivolumab and recorded as having the same collection time. If the EOI is delayed to beyond the nominal infusion 
duration, the collection of this sample should also be delayed accordingly.
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BMS-986249
Anti-CTLA-4 Probody mAb
Table 9.5-4:
PK and ADA Sampling Schedule for Part 2A Arm A
Study Day of 
Sample Collection 
(1 cycle = 3 weeks 
for Cycles 1-4 
Combination 
Therapy Phase, 
then 
1 cycle = 4 weeks 
starting Cycle 5 
nivolumab 
monotherapy 
Maintenance 
Phase)
Event
Time 
(Relative 
To Start of 
nivolumab
Infusion) 
Hour:Min
BMS-986249 
PK Plasma 
Sample
nivolumab 
PK Serum 
Sample
BMS-986249 
ADA Plasma
Samples
nivolumab 
ADA Serum 
Samples
C1D1
Predosea
0:00
X
X
X
X
EOI
See noteb
X
X
4:00
X
C1D2
24:00
X
C1D5c
(± 3 days)
See note
96:00
X
C1D8
( ± 2 days)
168:00
X
C1D15 ( ± 2 days)c
336:00
X
C2D1
Predosea
0:00
X
X
X
X
EOI
See noteb
X
X
C2D8 ( ± 3 days)c
168:00
X
C3D1
Predosea
0:00
X
X
X
X
EOI
See noteb
X
X
Grade 3+ Infusion 
Reaction
X
X
X
X
Abbreviations: ADA = anti-drug antibody; C = cycle; D = day; EOI = end of infusion; PK = pharmacokinetics.
a Predose: All predose samples should be taken within approximately 30 minutes prior to the start of the infusion, 
unless previously discussed with Medical Monitor (or designee).
b Refer to Section 9.5 and Table 7.1.1-1 for additional information and infusion duration. Separate EOI samples 
(1 each for BMS-986249 and nivolumab) should be collected following co-administration of BMS‑986249 and 
nivolumab and recorded as having the same collection time. If the EOI is delayed to beyond the nominal infusion 
duration, the collection of this sample should also be delayed accordingly.
c To align with the scheduled 
, the time window can be the same as 
 (± 3 days). 
C1D5 and C2D8 PK samples should only be collected if participant is scheduled for a corresponding 
.
If 
 is assigned, C1D5 and C2D8 PK samples should not be collected. C1D15 PK sample should be 
collected at the time of 
. If 
 is assigned at C1D15, PK sample should still be collected. See Table 
2-3.
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Anti-CTLA-4 Probody mAb
Table 9.5-5:
PK and ADA Sampling Schedule for Part 2A Arm B and Arm C
Study Day of 
Sample 
Collection 
(1 cycle = 
4 weeks)
Event
Time 
(Relative To 
Start of 
nivolumab 
Infusion) 
Hour:Min
BMS-986249 
PK Plasma 
Sample
nivolumab 
PK Serum 
Sample
BMS-986249 
ADA Plasma 
Samples
nivolumab 
ADA Serum 
Samples
C1D1
Predosea
0:00
X
X
X
X
EOIb
See note
X
X
C1D2
24:00
X
C1D5c
(± 3 days)
See note
96:00
X
C1D8
( ± 2 days)
168:00
X
C1D15 
( ± 2 days)c
336:00
X
C1D22
( ± 2 days)
504:00
X
C2D1
Predosea
0:00
X
X
X
EOIb
See note
X
C2D8c
( ± 3 days)
See note
168:00
X
C3D1
Predosea
0:00
X
X
X
X
EOIb
See note
X
X
Grade 3+ 
Infusion 
Reaction
X
X
X
X
Abbreviations: ADA = anti-drug antibody; C = cycle; D = day; EOI = end of infusion; PK = pharmacokinetics.
a Predose: All predose samples should be taken within approximately 30 minutes prior to the start of the infusion, 
unless previously discussed with Medical Monitor (or designee).
b Refer to Section 9.5 and Table 7.1.1-1 for additional information and infusion duration. For co-administration visits, 
separate EOI samples (1 each for BMS-986249 and nivolumab) should be collected following co-administration of 
BMS-986249 and nivolumab and recorded as having the same collection time. If the EOI is delayed to beyond the 
nominal infusion duration, the collection of this sample should also be delayed accordingly.
c To align with the scheduled 
, the time window can be the same as 
 (± 3 days). 
C1D5 and C2D8 PK samples should only be collected if participant is scheduled for a corresponding 
. 
If 
 is assigned, C1D5 and C2D8 PK samples should not be collected. C1D15 PK samples should be 
collected at the 
. If 
 is assigned at C1D15, PK sample should still be collected. See Table 
2-4.
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BMS-986249
Anti-CTLA-4 Probody mAb
Table 9.5-6:
PK and ADA Sampling Schedule for Part 2A Arm D
Study Day of Sample 
Collection
(1 cycle = 3 weeks for 
Cycles 1-4 
Combination Therapy 
Phase; then 1 cycle = 4 
weeks starting Cycle 5 
nivolumab 
monotherapy 
Maintenance Phase)
Event
Time 
(Relative To 
Start of 
nivolumab 
Infusion) 
Hour:Min
nivolumab 
PK Serum 
Sample
ipilimumab 
PK Serum 
Sample
nivolumab 
ADA 
Serum 
Sample
ipilimumab 
ADA Serum 
Sample
C1D1
Predosea
0:00
X
X
X
X
EOIb
See note
X
X
C1D5c
See note
96:00
X
C1D15c
See note
336:00
X
C2D1
Predosea
0:00
X
X
X
X
EOIb
See note
X
X
C2D8c
See note
168:00
X
C3D1
Predosea
0:00
X
X
X
X
EOIb
See note
X
X
Grade 3+ Infusion 
Reaction 
X
X
X
X
Abbreviations: ADA = anti-drug antibody; C = cycle; D = day; EOI = end of infusion; PK = pharmacokinetics.
a Predose: All predose samples should be taken within approximately 30 minutes prior to the start of the infusion, 
unless previously discussed with Medical Monitor (or designee).
b Refer to Section 9.5 and Table 7.1.1-1 for additional information and infusion duration. Separate EOI samples 
(1 each for ipilimumab and nivolumab) should be collected immediately after stopping the infusion of ipilimumab 
(preferably within 2 minutes) and recorded as having same collection time. If the EOI is delayed to beyond the 
nominal infusion duration, the collection of this sample should also be delayed accordingly.
c To align with the scheduled 
, the time window can be the same as 
 (± 3 days). 
C1D5, C1D15, and C2D8 PK samples should only be collected if participant is scheduled for corresponding 
 
. See Table 2-3.
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 9.5-7:
PK and ADA Sampling Schedule for Part 2A Arm E
Study Day of Sample 
Collection
(1 cycle = 4 weeks)
Event
Time 
(Relative To Start of 
nivolumab Infusion) 
Hour:Min
nivolumab PK 
Serum Sample
nivolumab ADA 
Serum Sample
C1D1
Predosea
0:00
X
X
EOI
See noteb
X
C2D1
Predosea
0:00
X
X
EOI
See noteb
X
C3D1
Predosea
0:00
X
X
EOI
See noteb
X
Grade 3+ Infusion 
Reaction
X
X
Abbreviations: ADA = anti-drug antibody; C = cycle; D = day; EOI = end of infusion; PK = pharmacokinetics.
a Predose: All predose samples should be taken within approximately 30 minutes prior to the start of the infusion, 
unless previously discussed with Medical Monitor (or designee).
b Refer to Section 9.5 and Table 7.1.1-1 for additional information and infusion duration. If the EOI is delayed to 
beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly.
Table 9.5-8:
PK and ADA Sampling Schedule for Part 2A Arm F
Study Day of 
Sample 
Collection 
(1 cycle = 4 
weeks)
Event
Time (Relative to 
Start of 
BMS-986249 in 
Combination with
Nivolumab 
Co-administration 
Infusion)
Hour: Min
BMS-
986249 PK
Plasma 
Sample
Nivolumab 
PK Serum 
Sample
BMS-
986249 
ADA 
Plasma
Samples
Nivolumab 
ADA 
Serum 
Samples
C1D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
C1D2
24:00
X
C1D5c
( ± 3 days)
See note
96:00
X
C1D8 ( ± 2 days)
168:00
X
C1D15c
( ± 2 days)
336:00
X
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 9.5-8:
PK and ADA Sampling Schedule for Part 2A Arm F
Study Day of 
Sample 
Collection 
(1 cycle = 4 
weeks)
Event
Time (Relative to 
Start of 
BMS-986249 in 
Combination with
Nivolumab 
Co-administration 
Infusion)
Hour: Min
BMS-
986249 PK
Plasma 
Sample
Nivolumab 
PK Serum 
Sample
BMS-
986249 
ADA 
Plasma
Samples
Nivolumab 
ADA 
Serum 
Samples
C1D22 ( ± 2 days)
504:00
X
C2D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
C2D8 c
( ± 3 days)
See note
168:00
X
C3D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
Grade 3+ Infusion 
Reaction
X
X
X
X
Abbreviations: ADA = anti-drug antibody; C = cycle; D = day; EOI = end of infusion; Min = minutes; 
PK = pharmacokinetics.
a Predose: All predose samples should be taken within approximately 30 minutes prior to the start of the infusion, 
unless previously discussed with Medical Monitor (or designee).
b Refer to Section 9.5 and Table 7.1.1-1 for additional information and infusion duration. Separate EOI samples 
(1 each for BMS-986249 and nivolumab) should be collected following co-administration of BMS-986249 and 
nivolumab and recorded as having the same collection time. If the EOI is delayed to beyond the nominal infusion 
duration, the collection of this sample should also be delayed accordingly.
c To align with the scheduled 
, the time window can be the same as 
 (± 3 days). 
C1D5 and C2D8 PK samples should only be collected if participant is scheduled for corresponding 
; 
if 
 is assigned, C1D5 and C2D8 PK samples should not be collected. C1D15 PK samples should be 
collected at the 
. If 
 is assigned at C1D15, PK sample should still be collected. See Section 2.
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Table 9.5-9:
PK and ADA Sampling Schedule for Part 2B
Study Day of Sample 
Collection 
(1 cycle = 4 weeks)
Event
Time (Relative to 
Start of 
Nivolumab Infusion)
Hour:Min
BMS-986249 PK 
Plasma Sample
Nivolumab PK 
Serum Sample
BMS-986249 ADA 
Plasma Samples
Nivolumab ADA 
Serum Samples
C1D1 
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
C1D2
24:00
X
C1D8 
(± 2 Day)
168:00
X
C1D15
(± 3 Day)
See notec
336:00
X
C1D22
(± 2 Day)
504:00
X
C2D1
Predosea
00:00
X
X
X
EOI
See noteb
X
C2D8
(± 2 Day) 
168:00
X
C3D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
Grade 3+ Infusion Reaction
X
X
X
X
Abbreviations: ADA = anti-drug antibody; C = cycle; D = day; EOI = end of infusion; Min = minutes; PK = pharmacokinetic.
a Predose: All predose samples should be taken within approximately 30 minutes prior to the start of the infusion, unless previously discussed with Medical 
Monitor (or designee).
b Refer to Section 9.5 and Table 7.1.1-1 for additional information and infusion duration. For co-administration visits, separate EOI samples (1 each for 
BMS-986249 and nivolumab) should be collected following co-administration of BMS-986249 and nivolumab and recorded as having the same collection time. 
If the EOI is delayed to beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly.
c C1D15 PK sample should be collected at the 
. See Table 2-4.
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9.7
Pharmacogenomics
Not applicable.
9.7.1
ADME Sampling
Not applicable.
9.8
Biomarkers
 
. Additional biomarkers related to mechanism of action, such as, but not 
limited to safety biomarkers, and associations with response to BMS-986249 alone and in 
combination with nivolumab, ipilimumab in combination with nivolumab, and nivolumab 
monotherapy will be explored.
 
 If biomarker samples are drawn but study treatment(s) is not administered, samples 
will be retained. A detailed description of each biomarker sample analysis and assessment is 
described below, and a schedule of biomarker sample collections is provided in Table 9.8.3-1. 
Further details of blood, serum, and tumor tissue collection and processing will be provided to the 
site in the Laboratory Manual.
Addendum per Protocol Amendment 09: Biomarker sample collection after 
 has been
reduced to decrease participant and site burden as available sample collections are sufficient for 
proposed analysis of the exploratory endpoint.
9.8.1
Peripheral Blood Biomarkers
A variety of factors that may impact the immunomodulatory properties and efficacy of 
BMS-986249, ipilimumab, and nivolumab will be investigated in peripheral blood specimens 
taken from all participants prior to or during treatment at the time points indicated in Table 9.8.3-
1. Results from these investigations will be evaluated for associations with dose, response, 
survival, and/or safety (AE) data. Several analyses will be completed and are described briefly 
below.
9.8.1.1
Soluble Biomarkers
Serum samples as well as blood samples used for PK analysis may also be used to evaluate 
circulating levels of immune factors, such as 
, over the course of the treatment. 
 
 
 
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9.8.1.2
Immunophenotyping
The proportion of specific lymphocyte subsets and expression levels of T cell co-stimulatory 
markers in PBMC preparations will be quantified by flow cytometry. 
 
 
 
9.8.1.3
T cell Repertoire Analysis
The diversity of the peripheral T cell compartment and changes over the course of treatment with 
immunotherapeutic agents may be related to the mechanism of action of BMS-986249. 
 
 
 
 
9.8.1.4
Germline DNA Variants
Whole blood will be collected from all participants prior to treatment to generate genomic DNA 
for single nucleotide polymorphism (SNP) analyses and to serve as a reference for tumor genomic 
testing, including tumor mutational load assessment. 
 
 
 
9.8.2
Tumor Samples
Tumor biopsy specimens will be obtained from all participants to characterize immune cell 
populations and expression of selected tumor markers including, dMMR and MSI-H. See Section 2
and Table 9.8.3-1 for the tumor collection schedule time points. Pre-treatment biopsy tissue 
required for all participants. Refer to Table 2-1 and Laboratory Manual for details.
•
For Part 1: The on-treatment biopsy will be collected on 
, and tumor specimens may be 
collected within 3 days of the specified time point and must be obtained prior to administration 
of study treatments. Bone lesion biopsies are unacceptable for submission.
•
For Part 2A: Pre-treatment tumor tissue specimens will be submitted for central PD-L1 IHC
assessment prior to randomization (refer to Laboratory Manual for details). These biopsy 
samples should be excisional, incisional, punch or core needle. Fine needle aspirates or other 
cytology specimens are insufficient for downstream biomarker analyses. PD-L1 stained tissue 
sections will be assessed by a pathologist and scored as PD-L1 positive if membrane staining 
is observed in ≥1% tumor cells among a minimum of a hundred (100) evaluable tumor cells. 
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Samples with < 1% tumor cell membrane staining in a minimum of a hundred (100) evaluable 
tumor cells will be scored as PD-L1 negative and samples where membrane staining is 
obscured by high cytoplasmic staining or melanin content, but contain the minimum number 
of evaluable tumor cells will be deemed PD-L1 indeterminate.
•
For Part 2A: The on-treatment biopsy will be first collected on 
 for approximately the 
first 75 participants treated (about 25 participants per active Arm), and then collected per 
Investigator preference on 
 or 
for approximately the next 105 participants treated 
(about 35 participants per active Arm). On-treatment tumor specimens may be collected within 
3 days of the specified time point and must be obtained prior to administration of study 
treatment. Bone lesion biopsies are unacceptable for submission.
•
For Part 2A: 
 
 
. The varying number of participants for 
each of the different timed on-treatment tumor biopsy collections is to enable a sufficient 
number of samples for analysis while accounting for on-treatment attrition and factors related 
to biopsy heterogeneity.
•
For Part 2B, the on-treatment biopsy will be collected on
. Tumor specimens may be 
collected within 3 days of the specified time point and must be obtained prior to administration 
of study treatment. Bone lesion biopsies are unacceptable for submission.
•
A tumor biopsy is mandatory upon confirmation of PD (within 7 days) except for:
−
Participants who have an on-treatment biopsy and progress within 4 cycles.
−
Participants who will be imminently (within 4 weeks) enrolling in a subsequent clinical 
research study that requires a screening biopsy, then the new trial enrollment criteria 
supersede the required post-progression tumor biopsy.
−
Participants who consent to be treated beyond progression will only require the PD biopsy 
at the subsequent confirmation of progression.
•
Both the screening and on-treatment tumor biopsies should be preferentially collected from the 
same site, if feasible. At the time of progression, the biopsy should be performed using a 
progressive lesion or a new lesion, if feasible.
•
Tumor biopsy samples should be excisional, incisional, or core needle as fine needle aspirates 
and other cytology specimens are insufficient for downstream biomarker analyses. Bone lesion 
biopsies are unacceptable for submission.
•
On-treatment and PD biopsies are mandated at acceptable clinical risk (as determined by the 
investigator). Notify the Medical Monitor (or designee) if on-treatment biopsy may pose 
unacceptable clinical risk or if tumor at the time of on-treatment biopsy is not accessible for 
sampling. Institutional guidelines for the safe performance of biopsies should be followed.
•
All tumor tissue collection (fresh biopsy or archival) will follow the same guidance 
methodology for sample collections provided in the Laboratory Manual.
 
 In addition, tissue biopsies will assist 
in characterizing the PK of ipilimumab and the various Probody species. 
 
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If available, 
 and IHC expression between fresh 
formalin-fixed, paraffin-embedded and archival tumor specimens may also be made.
9.8.2.1
Characterization of Tumor Immune Microenvironment
IHC will be used to assess the number and composition of immune infiltrates in order to define 
the immune cell subsets present within tumor tissue before and after exposure to therapy. 
 
 
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9.8.3
Biomarker Sampling Schedule
Table 9.8.3-1:
Biomarker Sampling Schedule for All Study Parts
Study Day of Sample 
Collection
Time
Tumor 
Biopsya
Serum
Whole Blood
(Germline and 
TCR)
Whole Blood 
(PAXgene) 
Blood (Immuno-
phenotyping)
Plasma
Anti-
SARS-
CoV-2 
Serology
(Relative to
infusion time)
Hour:Min
Abbreviations: 
; PD = progressive disease; SARS-CoV-2 = severe acute 
respiratory syndrome coronavirus 2; TCR = T cell receptor.
a For additional information regarding tumor sample collection, refer to Section 2, Section 9.8.2, and Laboratory Manual for details.
 
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9.8.4
Additional Research Collection
This protocol will include both sample collection and residual sample storage for additional 
research (AR).
For All Sites:
Additional research is required for all study participants, except where prohibited by IRBs/ethics 
committees, prohibited by local laws or regulations, or academic/institutional requirements.
•
If the IRB/ethics committees and site agree to the mandatory additional research retention 
and/or collection, then the study participant must agree to the mandatory additional research 
as a requirement for inclusion in the study.
•
If optional participation is permitted and approved, then the study participants may opt out of 
the additional research retention and/or collection.
Additional research is intended to expand the R&D capability at Bristol-Myers Squibb, and will 
support as yet undefined research aims that will advance our understanding of disease and options 
for treatment. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression, and response to treatment.
Sample Collection and Storage
All requests for access to samples or data for AR will be vetted through a committee of the study 
Sponsor’s senior leaders in Research and Development to ensure the research supports appropriate 
and well-defined scientific research activities.
Samples kept for future research will be securely stored at the 
 
, or a BMS-approved third-party storage management facility.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than 15 years after 
the end of the study or the maximum allowed by applicable law.
Transfers of samples by research Sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no BMS researcher will have access to the key. The 
key is securely held by the investigator at the clinical site, so there is no direct ability for a BMS
researcher to connect a sample to a specific individual.
Further details of sample retention and processing will be provided to the site in the Laboratory 
Manual. See Table 9.8.4-1 for time points for retention of each sample type.
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Table 9.8.4-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Time points for which residual samples will be retained
PK/ADA
All
Tumor Biopsy
All
Blood biomarker 
samples
All
Abbreviations: ADA = anti-drug antibody; PK = pharmacokinetic.
9.9
Patient-reported Outcomes
Quality of life (QoL) in oncology clinical studies is becoming increasingly important to understand 
the impact of benefit/risk from the patient perspective. Participants enrolled in the BMS-986249 
in Combination with Nivolumab Randomized Cohort Expansion in Melanoma (Part 2A) and 
Participants enrolled in BMS-986249 in Combination with Nivolumab Additional Tumor Cohort 
Expansion (Part 2B) will be asked to complete the EORTC QLQ-C30, EQ-5D-3L, FACIT GP5 
item, and a selection of items from the PRO-CTCAE prior to first dose, at designated on-treatment 
clinic visits, and at safety follow-up visits 1, 2 and 3. Only the EQ-5D-3L will be completed, via 
telephone, during Survival Follow-up Period. 
The questionnaires will be provided in the participant’s preferred language if available. The 
EQ-5D-3L may be administered by telephone during survival follow-up. There exists a 
standardized guide that can be used to facilitate telephone administration of the EQ-5D-3L. 
Section 2 provides information regarding the timing of PRO assessments. The questionnaires 
should be administered at the start of any visit before the participant sees the physician and before 
any study-related procedures are performed. If exceptional circumstances preclude the continued 
administration of measures using planned modalities, then alternate administration methods may 
be required.
9.9.1
EORTC QLQ-C30
Health-related QoL will be assessed using the EORTC QLQ-C3059. The EORTC QLQ-C30 is a 
30-item instrument that has gained wide acceptance in oncology clinical studies and is composed 
of multi-item and single-item scales. The global health status/QoL scale is composed of 2 items. 
In addition to the global health status/QoL scale, the EORTC QLQ-C30 includes 5 functional 
scales (physical, role, emotional, social, and cognitive), 3 symptom scales (fatigue, nausea and 
vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, 
and financial difficulties). The overall health status/QoL responses are 7-point Likert scales 
ranging from 1 (Very Poor) to 7 (Excellent), while the responses for all functional and symptom 
items are 4-point categorical scales ranging from 1 (Not at all) to 4 (Very much). Scale items are 
scored using recommended EORTC procedures.60 Raw scores are transformed to a linear scale 
ranging from 0 to 100, with a higher score representing a higher global health status/QoL. A score 
difference of 10 is used as an estimate of the minimal important difference (MID) for the subscales 
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of the EORTC QLQ-C30.61 The reliability and validity of the questionnaire is highly consistent 
across different language-cultural groups.
9.9.2
EQ-5D-3L
General health status will be measured using the EQ-5D-3L.62 The EQ-5D-3L is a standardized 
instrument used to measure self-reports of health status and functioning. The instruments 
descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression. Each dimension has 3 levels, reflecting “no health problems”, “moderate 
health problems” and “extreme health problems”. A dimension for which there are no problems is 
said to be at level 1, while a dimension for which there are extreme problems is said to be at level 
3. Thus the vectors 11111 and 33333 represent the best health state and the worst health state, 
respectively. Altogether, the EQ-5D-3L describes 243 different health states. Empirically derived 
weights can be applied to an individual’s response to the EQ-5D-3L descriptive system to generate 
an index measuring the value to society for that specific health state. Such preference weighting 
systems have been developed for many geographical areas. In addition, the EQ-5D-3L includes a 
visual analogue scale (VAS) that allows respondents to rate their own current health on a 100-point 
scale, ranging from “best imaginable” to “worst imaginable” health. The utility data generated 
from the EQ-5D-3L is recommended for, and commonly used in, cost effectiveness analyses. A 
score difference of 0.08 for the EQ-5D utility score and of 7 for the EQ VAS will be used as MID 
estimates for the EQ-5D-3L.63
9.9.3
FACIT GP5
A single item drawn from the FACIT measurement system, item GP5, will be administered to 
assess the overall extent of perceived bother due to symptomatic adverse events (symAEs). 
Evidence exists for the validity of this item and its usefulness as an overall summary measure of 
burden due to symptomatic treatment toxicities.64
9.9.4
PRO-CTCAE
Given evidence that clinicians underreport symptomatic AEs, selected items from the 
PRO-CTCAE will be used to enhance the assessment of symAEs in the study. Items will be chosen 
based on the known clinical profile of ipilimumab in combination with nivolumab, clinical 
judgement, experience of the study team members, and what is known for Part 2A and Part 2B 
treatments. 
9.10
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.
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10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
10.1.1
Dose Escalation
Dose escalation in Part 1A (BMS-986249 monotherapy) and Part 1B (BMS-986249 combination 
therapy with nivolumab) will be guided by BLRM employing the EWOC principle
 
. The BLRM 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. Furthermore, the BLRM uses the 
knowledge gained from participants treated with ipilimumab (for Part 1A) or ipilimumab in 
combination with nivolumab (for Part 1B). 
 
 
 
 The use of the EWOC principle limits the risk of exposing 
participants in the next cohort to an intolerable dose by ensuring that the posterior probability of 
the DLT rate exceeding 
 at any dose is capped at 
.
Approximately 4 participants (3 + 1) will be treated at the starting dose levels of BMS-986249 
alone or BMS-986249 in combination with nivolumab. While the BLRM will use DLT 
information from the DLT period only, clinical assessment will take into consideration the entirety 
of available preliminary data, including PK/
 from all treated participants in 
assigning a dose level for the next cohort of 3 participants. AEs meeting DLT criteria outside of 
the 5-week DLT period may also be incorporated into the BLRM and dose de-escalation may be 
considered as appropriate based on the BLRM recommendation. At least 6 DLT-evaluable 
participants will be treated at the BLRM-recommended MTD (BLRM-MTD). A maximum of 
12 DLT-evaluable participants will be treated at each dose level. Once the BLRM-MTD is 
identified, then additional participants may be treated at the BLRM-MTD or any dose level below 
the BLRM-MTD for further evaluation of safety, PK, or
 parameters as required. 
The maximum number of participants to be treated will be up to 45 for Part 1A (BMS-986249 
monotherapy) and up to 60 for Part 1B (BMS-986249 combination therapy with nivolumab).
The BLRM-MTD is the dose that satisfies the following 3 conditions:
•
The empirical posterior probability that the “DLT rate of 16% to 
” is greater than a 
pre-specified value (ie, 50%).
•
This probability needs to be the largest among the dose levels that satisfy the EWOC condition 
 
•
A minimum number of participants (ie, 6) was treated at this dose level.
The final MTD/RP2D will be based on the recommendations from the BLRM and overall clinical 
assessment of all available safety, PK, 
, and efficacy data. Lower doses may be 
tested if none of the planned doses are found to be tolerable. Such decisions will be made after 
discussion and agreement between the investigators and the Medical Monitor (or designee).
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10.1.2
Part 2A Cohort Expansion
10.1.2.1
Original Sample Size Calculation
The BMS-986249 in Combination with Nivolumab Randomized Cohort Expansion in Melanoma 
(Part 2A) sample size determination is based on primary efficacy and primary safety objectives. 
The sample size estimation takes into consideration:
The potential for detecting a higher ORR in BMS-986249 in combination with nivolumab (Arms 
A, B, and C) relative to nivolumab monotherapy (Arm E).
The potential for detecting improved tolerability based on incidence of Grade 3-5 TRAEs within 
24 weeks in BMS-986249 in combination with nivolumab (Arms A, B, and C) relative to 
ipilimumab in combination with nivolumab (Arm D). 
Approximately 270 evaluable participants will be randomized in a 1:1:1:1:1 ratio to Arms A - E
respectively, with at least 54 evaluable participants in each arm. Randomization will be stratified 
by PD-L1 status and AJCC M-staging. Assuming a 
 ORR in nivolumab monotherapy (Arm 
E), the two-sided 60% CIs for the difference in ORR comparing each BMS-986249 in combination 
with nivolumab arm (Arms A, B, and C) versus nivolumab monotherapy for a range of ORRs in 
BMS-986249 in combination with nivolumab arm (Arms A, B, and C) close to the ORR observed 
in ipilimumab in combination with nivolumab based on Study CA209067 are presented in
 
. At 60% confidence level, the lower bound of the two-sided CI will exceed a minimum 
 difference in ORR if an ORR of 
 or higher is observed in BMS-986249 in combination 
with nivolumab arm (Arm A, B, and C).
In addition, assuming a 
 incidence rate of drug-related Grade 3-5 AEs within 24 weeks in 
ipilimumab in combination with nivolumab (Arm D), with 54 evaluable participants in each of 
BMS-986249 in combination with nivolumab arms (Arm A, B, and C) and ipilimumab in 
combination with nivolumab arm (Arm D), 60% two-sided CI of treatment difference in incidence 
rate for each BMS-986249 in combination with nivolumab arm (Arm A, B, and C) versus
ipilimumab in combination with nivolumab arm (Arm D) is 
 for a 
 drop in 
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incidence rate of drug-related Grade 3-5 AEs within 24 weeks in BMS-986249 in combination 
with nivolumab arms (Arm A, B, and C). Besides the primary safety endpoint of drug-related 
Grade 3-5 AEs by within weeks, the safety profile will also be evaluated based on the entirety of 
available clinical safety data. 
The final analysis will take place when all randomized participants have completed at least 
36 weeks follow-up or discontinue earlier. Due to exploratory nature of the proof of concept (PoC) 
design, no multiplicity adjustment will be made for testing multiple endpoints or multiple 
treatment arms. 
10.1.2.2
Changes to Sample Size Assumptions for Revised Protocol 07
The original sample size calculation was based on a 60% two-sided CI of ORR for the difference 
between treatments and required 54 participants per arm. As participants in Arm E will not be 
randomized as originally planned, the efficacy evaluation and the statistical comparison will use a 
reference value of 
 based on nivolumab monotherapy historical data in melanoma (see 
Section 5.4.7.2).
One of the main objectives of this study is to evaluate the preliminary safety and tolerability of 
BMS-986249 in combination with nivolumab (Part 2A Arm C and Arm F). 
Based on final analysis of CA209511, the ipilimimab 3 mg/kg in combination with nivolumab 
1 mg/kg, the incidence rate of drug-related Grade 3-5 AEs within 24 weeks is estimated to be 
. 
A 
 relative improvement in the incidence of Grade 3-5 TRAEs is considered to be clinically
relevant. 
Using a two group χ2 test with a 0.10 one-sided significance alpha level, assuming a 1:1 
randomization ratio of experimental BMS-986249 in combination with nivolumab containing 
regimen to control ipilimumab in combination with nivolumab, a sample size of 60 participants 
per arm will have approximately 70% power to detect a ratio in favor of the alternative hypothesis 
of 
 compared to the null hypothesis proportion of 
.
The null hypothesis is the ratio of proportions above or equal to 1, the alternative hypothesis is the 
ratio of  proportion is below to 1.
H0: P1 / P2 ≥ 1. H1: P1 / P2 = R1 < 1
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The final analysis will take place when all randomized participants have completed at least 
36 weeks follow-up or discontinue earlier. Due to exploratory nature of the PoC design, no 
multiplicity adjustment will be made for testing multiple endpoints or multiple treatment arms. 
10.1.3
Part 2B Cohort Expansion
In Part 2B, approximately 40 participants will be treated in tumor-specific cohorts of HCC, CRPC,
and TNBC, respectively. 
This sample size will allow for a meaningful safety analyses assuming the incidence rate of drug-
related Grade 3-5 AEs within 24 weeks for historical ipilimumab 3 mg/kg in combination with 
nivolumab 1 mg/kg
 and is similar across the tumor types (see Section 5.5.6). A target 
of 
 Grade 3-4 TRAE is considered to be clinically relevant in these patient populations.
Using a one group χ2 test with a 0.10 one-sided significance alpha level, a sample size of 
40 participants per arm will have approximately 95% power to detect the difference between the 
Null hypothesis proportion of 
 and the alternative proportion of 
.
This sample size will provide reasonable power across the range of safety benchmark assuming an 
alpha level of 10% one sided 
.
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This sample size will also provide reasonable power across the range of efficacy benchmarks cited 
in the Part 2B tumor types assuming an alpha level of 20% one-sided 
.
For the HCC protocol-defined population, the lowest ORR response value is predicted to be 
 
and the target ORR response is assumed to be 
.
For the CRPC and TNBC protocol-defined populations, the lowest ORR response value is 
predicted to be 
 and the target ORR response is assumed to be 
.
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10.2
Populations for Analyses
For purposes of analysis, the populations are defined in Table 10.2-1.
Table 10.2-1:
Populations for Analyses
Population
Description
Enrolled 
All participants who sign informed consent
Randomized
All participants who are randomized to treatment arm (Part 2A)
Treated
All participants who take at least 1 dose of study treatment
Pharmacokinetic
All treated participants who have evaluable concentration-time data
Immunogenicity
All treated participants who have baseline and at least 1 post-baseline 
pre-infusion immunogenicity assessment for the analyte evaluated 
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Table 10.2-1:
Populations for Analyses
Population
Description
Biomarker
All treated participants with available biomarker data.
Patient-reported outcome
All treated participants with patient-reported outcome data at baseline and at 
least 1 post-baseline assessment.
10.3
Statistical Analyses
The Statistical Analysis Plan will be developed, finalized, and signed before database lock. Below 
is a summary of planned statistical analyses of the primary and secondary endpoints. The final 
analysis is planned when all participants have successfully completed at least two post-baseline 
scans or discontinued early. Based on the post baseline scan assessment this is due approximately 
6 months after the last participant first visit.
10.3.1
Analyses
The Part 2A efficacy analyses will be performed on the randomized population, with supplemental 
analyses on the treated population, while the efficacy analysis of Part 2B will be performed on the 
treated population (Table 10.3.1-1). The efficacy and safety analysis for Part 2B will be evaluated 
by tumor-specific cohort. Analysis of the treated participants from Part 1 will be presented 
separately. The following censoring rules will be applied for the definition of PFS and DoR:
•
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment.
•
Subjects who did not have any evaluable on study tumor assessments and did not die will be 
censored on their date of randomization (for Part 2A) or first dosing (Part 1 and Part 2B).
•
Subjects who receive subsequent anti-cancer therapy prior to documented progression or death
will be censored at the date of the last evaluable tumor assessment conducted on or prior to the 
date of initiation of the subsequent anti-cancer therapy.
Additional details of the calculation of time-to-event endpoints such as DOR and PFS will be 
described in the Statistical Analysis Plan.
The efficacy and safety data from participants randomized in Part 2A Arms A, B, and E before 
Revised Protocol 07 will be analyzed using descriptive measures only.
Table 10.3.1-1:
Efficacy - Statistical Analysesa
Endpoint
Statistical Analysis Methods
Best observed response (BOR)
BOR for a participant will be assessed per 
RECIST v1.1 or PCWG3 by investigator, unless 
otherwise specified
Summary and listing of BOR
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Table 10.3.1-1:
Efficacy - Statistical Analysesa
Endpoint
Statistical Analysis Methods
ORR
ORR is defined as the proportion of participants whose 
BOR is either CR or PR per RECIST v1.1 in the 
population of interest or PCWG3 for participants with 
prostate cancer.
Point estimate and CI by arm/cohort in Parts 2A and 
2B
Part 2A: Chi square test and sensitivity analysis using 
Cochran-Mantel-Haenszel test with the stratification 
factors as strata
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 PCWG3 or death, 
whichever occurs first.
Median and CI by K-M method for participants who
responded, by arm/cohort
PFS
PFS for a participant is defined as the time from the 
first dosing date (Part 1, Part 2B) or randomization date 
(Part 2A) to the date of first objectively documented 
disease progression per RECIST v1.1 or PCWG3 or 
death due to any cause, whichever occurs first. 
Median and CI by K-M method and PFS rates
PSA Response Rate (For Part 2B CRPC Participants 
Only)
Decrease in the level of PSA of at least 50% from 
baseline maintained for at least 3 weeks
Point estimate and CI
TTR
TTR is defined as the time from the first dosing date 
(Part 1, Part 2B) or randomization date (Part 2A) to the 
date of the first confirmed response (CR or PR) per 
RECIST v1.1 or PCWG3.
Summary statistics for TTR
OS
OS is defined as the time from enrollment (Part1, Part 
2B) or randomization (Part 2A) to the date of death from 
any cause
Median and CI by K-M method (including OS rates, 
for example at 1 year and 2 years)
Abbreviations: BOR = best overall response; CI = confidence interval; CR = complete response; DOR = duration of 
response; K-M = Kaplan Meier ; ORR = Objective Response Rate; OS = overall survival; PCWG3 = Prostate Cancer 
Working Group 3; PFS = progression-free survival; PR = partial response; PSA = prostate-specific antigen; 
RECIST = Response Evaluation Criteria in Solid Tumors; TTR = time to response.
a Efficacy analyses will be executed with a 60% two-sided CI.
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10.3.2
Safety Analyses
All safety analyses will be performed on the treated population. See Table 10.3.2-1 for a 
description of the safety analyses.
Table 10.3.2-1:
Safety - Statistical Analyses
Endpoint
Statistical Analysis Methods
Incidence of DLTs (Part 1 only), AEs, SAEs, AEs 
leading to discontinuation, and death
AEs will be graded according to CTCAE v4.03
DLT rate by dose level, frequency distribution of treated 
participants with AE using the worst CTC grade. Participants 
will be counted only (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.
Incidence of treatment-related Grade 3-5 AEs 
within 24 weeks
Incidence rate (Part 2A, Part 2B) along with the ratio and 
difference in incidence rates (Part 2A) will be presented by 
point estimates and CIsa (Parts 2A and 2B)
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; DLT = dose-limiting toxicity; PT = preferred term; SAE = serious adverse event.
a Safety analyses will be executed with an 80% two-sided CI for primary endpoint of related Grade 3-4 AE rates.
10.3.3
Pharmacokinetic Analysis for BMS-986249
PK analyses are described in Table 10.3.3-1.
Table 10.3.3-1:
Pharmacokinetic ̻ Statistical Analyses
Endpoint
Statistical Analysis Methods
Cmax, AUC(0-T), AUC(TAU), Ctau, CLT, 
Css-avg, AI_Cmax, AI_AUC, and T-HALF
Summary statistics: geometric means and coefficients of 
variation
Cmax, AUC(0-T), and AUC(TAU)
Scatter plots versus dose for each cycle measured; dose 
proportionality based on a power model and a CI around the 
power coefficient
Tmax
Summary statistics: medians and ranges
Ctrough 
Summary statistics to assess attainment of steady state: 
geometric means and coefficients of variation, by treatment and 
by day; plots versus time by dose
Abbreviations: AI_AUC = ratio of an exposure measure at steady state to that after the first dose (exposure measure 
includes AUC[TAU]); AI_Cmax = ratio of an exposure measure at steady state to that after the first dose (exposure 
measure includes Cmax); AUC(0-T) = area under the blood concentration-time curve from time zero to time of last 
quantifiable concentration (may be calculated if concentrations are not quantifiable up to TAU across a treatment 
group); AUC(TAU) = area under the concentration-time curve in 1 dosing interval; CLT = total body clearance; Cmax 
= maximum observed concentration; Css-avg = average blood concentration over a dosing interval (AUC[TAU]/tau) 
at steady state; Ctau = observed blood concentration at the end of a dosing interval; Ctrough = trough observed blood 
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concentrations (this includes predose concentrations [C0] and Ctau); T-HALF = terminal blood half-life; Tmax =
median time of maximum observed concentration.
PK concentration-time data for ipilimumab and/or nivolumab may be pooled with data from other 
studies for integrated PPK and exposure analyses, which will be presented in a separate report.
10.3.4
Immunogenicity
Immunogenicity analyses are described in Table 10.3.4-1.
Table 10.3.4-1:
Immunogenicity - Statistical Analyses
Endpoint
Statistical Analysis Methods
Incidence of ADA
Baseline ADA-positive participant is defined as a participant 
who has an ADA-detected sample at baselinea,b
ADA-positive participant is a participant with at least 1 ADA-
positive sample relative to baseline after initiation of the 
treatment
Frequency distribution of baseline 
ADA-positive participants and ADA-positive 
participants after initiation of the treatment for 
each analyte
Abbreviation: ADA = anti-drug antibody.
a Baseline sample is the last sample before initiation of the treatment.
b Details of the immunogenicity data analysis, including ADA titers, will be provided in the Statistical Analysis Plan.
10.3.5
Biomarker Analyses
Biomarker statistical analyses are described in Table 10.3.5-1.
Table 10.3.5-1:
Biomarker - Statistical Analyses
Endpoint
Statistical Analysis Methods
10.3.6
ECG Analyses
All ECG data analyses, including summaries of each ECG parameter, frequency distribution of 
participants’ maximum values/changes, and scatter plots, will be performed following the current 
practice of ECG data analysis. Concentration-response analysis may be performed using mixed 
effect model, if appropriate, for participants with time matched ECG and PK data collection
(Part 1A). The details of ECG data analysis will be provided in the Statistical Analysis Plan.
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10.3.7
Patient-Reported Outcome Analyses
PRO analyses are described in Table 10.3.7-1.
Table 10.3.7-1:
PRO - Statistical Analyses
Secondary Endpoint
Statistical Analysis Methods
To evaluate TTD in Global Health Status/QoL of the 
EORTC QLQ-C30 (Part 2A only)
TTD in Global Health Status/QoL and Physical 
Functioning will be defined as the time from 
randomization until a clinically meaningful decline (ie,
reduction ≥10 points) from baseline in EORTC QLQ-
C30 global health/quality of life subscale score and 
Physical Functioning Scale score. Estimates for both 
Global Health Status/QoL and Physical Functioning 
will be provided with associated 95% CIs.
To evaluate TTD in Physical Functioning Scale of the 
EORTC QLQ-C30 (Part 2A only)
The analysis will use all available data from 
randomized participants, including data collected 
during post-treatment follow up. Median deterioration 
times, hazard ratios, and 95% CIs will be calculated
Abbreviations: CI = confidence interval; EORTC = European Organisation for Research and Treatment of Cancer; 
PRO = patient-reported outcome; QLQ-C30 = Quality of Life Questionnaire – Core 30; QoL = quality of life; TTD = 
time to deterioration.
Analyses of PRO will be performed on participants who have an assessment at baseline and at 
least 1 post-baseline assessment.
Further exploratory analyses for Part 2A and Part 2B not specified here will be described in the 
Statistical Analysis Plan, which will be finalized before database lock and may be presented 
separately from the main clinical study report.
10.3.8
Interim Analyses
Interim analyses may be performed for administrative purposes or publication. Preliminary 
reviews of the data in Part 1 and Part 2 will occur prior to the final data base lock in order to assess 
the initial safety, PK, and 
 signal. The earliest exploratory analysis may also be 
performed for a Part 2A arm and/or Part 2B tumor cohort after approximately 15 to 20 participants 
are randomized based upon the available preliminary information including safety, PK, 
, and tumor response data after the first tumor scan. No formal inferences 
requiring any adjustment to statistical significance level will be performed.
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11
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
Ab
antibody
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
ADT
androgen deprivation therapy
AE
adverse event
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AIDS
acquired immune deficiency syndrome
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AR
additional research
ART
antiretroviral therapy
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
BC
breast cancer
BICR
blinded independent central review
BLRM
Bayesian Logistic Regression Model
BMS
Bristol Myers Squibb
BOR
best overall response
BRAF
B-Raf proto-oncogene
C
cycle
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Term
Definition
CD4
cluster of differentiation 4
CFR
Code of Federal Regulations
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CLT
total body clearance
Cmax
maximum observed concentration
Cmaxss
maximum observed steady state concentration
Cminss
trough steady state concentrations
CNS
central nervous system
COVID-19
coronavirus disease of 2019
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CRC
colorectal cancer
CRF
Case Report Form
CRPC
castration resistant prostate cancer
Css-avg
average concentration over a dosing interval at steady state
CT
computed tomography
CTA
clinical trial agreement
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
CTLA-4
cytotoxic T lymphocyte-associated protein 4
Ctrough
trough observed concentration
CXDY
cycle X day Y
D
day
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
dMMR
mismatch repair deficient
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Term
Definition
DNA
deoxyribonucleic acid
DOR
duration of response
EC50
half-maximal effective concentration
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EFGR
epidermal growth factor receptor
EHR
electronic health record
ELISA
enzyme-linked immunosorbent assay
EMR
electronic medical record
EOI
end of infusion
EOI-PK
end-of-infusion pharmacokinetic sample
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire – Core 30
EOT
end of treatment
EQ-5D-3L
European Quality of Life – 5 Dimension – 3 Level Questionnaire
ER
estrogen receptor
EWOC
escalation with overdose control
FACIT GP5
Functional Assessment of Chronic Illness Therapy General Physical item 
5
FACS
fluorescence-activated cell sorting
FDA
Food and Drug Administration
FIH
first in human
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GLP
Good Laboratory Practices
GnRH
gonadotropin-releasing hormone
GPVE
Global Pharmacovigilance and Epidemiology
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
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Term
Definition
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICOS
inducible T cell costimulator
IFN
interferon
Ig
immunoglobulin
IHC
immunohistochemistry
IL
interleukin
IMP
investigational medicinal products
INR
international normalized ratio
I-O
immuno-oncology
IP
investigational product
irAE
immune-related adverse event
IRB
Institutional Review Board
iRECIST
modified RECIST v 1.1 for immune-based therapeutics
IRR
infusion-related reactions
IRT
Interactive Response Technology
IU
international unit
IV
intravenous
KI
knock-in
K-M
Kaplan Meier
KRAS
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
LHRH
luteinizing hormone-releasing hormone
mAb
monoclonal antibody
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Term
Definition
mCRPC
metastatic castration-resistant prostate cancer
ME
masking efficiency
MID
minimal important difference
MMP
matrix metalloproteinase
mRCC
metastatic renal cell carcinoma
MRI
magnetic resonance imaging
MSI-H
microsatellite instability-high
MST
Medical Surveillance Team
MTD
maximum tolerated dose
mWHO
modified World Health Organization
N
number of subjects or observations
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
p-DILI
potential drug-induced liver injury
Pb
Probody
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PCWG3
Prostate Cancer Working Group 3
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed death ligand-1
PD-L2
programmed death ligand-2
PE
physical examination
PET
positron emission tomography
PFS
progression-free survival
PID
participant identification number
PoC
proof of concept
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Term
Definition
PK
pharmacokinetics
PPK
population pharmacokinetic
PR
partial response
PRO
Patient-Reported Outcomes
PRO-CTCAE
Patient-Reported Outcomes version of the Common Terminology 
Criteria for Adverse Events
PSA
prostate-specific antigen
PT
prothrombin time
Q12W
every 12 weeks
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q6W
every 6 weeks
Q8W 
every 8 weeks
QoL
quality of life
QTc
QT interval corrected
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
REMS
risk evaluation and mitigation strategy 
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose of BMS-986249
RT-PCR
reverse transcriptase polymerase chain reaction
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCCHN
squamous cell carcinoma of the head and neck
SCLC
small cell lung cancer
SD
stable disease
SEB
staphylococcal enterotoxin B
SI
stimulation index
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Term
Definition
SNP
single nucleotide polymorphism
SUSAR
suspected, unexpected serious adverse reaction
symAEs
symptomatic adverse events 
T3
triiodothyronine
T4
thyroxine
TCR
T-cell receptor
T-HALF
terminal half-life
Tmax
time of maximum observed concentration
TNBC
triple-negative breast cancer
TNF-α
tumor necrosis factor alpha
TRAE
treatment-related adverse event
Tregs
regulatory T cells
TSH
thyroid stimulating hormone
TTD
time to deterioration
TTR
time to response
ULN
upper limit of normal
uPA/UPA
urokinase-type plasminogen activator
US
United States
VAS
visual analogue scale
VEGF
vascular endothelial growth factor
Vss
volume of distribution at steady state
Vz
volume of distribution of terminal phase
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The terms “participant” and “subject” refer to a person who has consented to participate in the 
clinical research study. Typically, the term “participant” is used in the protocol and the term 
“subject” is used in the Case Report Form (CRF).
REGULATORY AND ETHICAL CONSIDERATIONS
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines
•
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines
•
Applicable laws, regulations, and requirements.
The study will be conducted in compliance with the protocol. The protocol,
any 
revisions/amendments,
and the participant
informed consent form (ICF) will receive 
approval/favorable opinion by Institutional Review Board/Independent Ethics Committee 
(IRB/IEC), and regulatory authorities according to applicable regulations prior to initiation of the 
study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation) that is likely to affect,
to a significant degree, one or more of the following: (1) the rights, physical safety or mental 
integrity of one or more participants; (2) the scientific value of the clinical trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP regulation(s) or 
trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, Investigator’s Brochure, product labeling information, ICF,
participant recruitment materials (eg, advertisements), and any other written information to be 
provided to participants.
The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, administrative letters) annually, or more 
frequently, in accordance with regulatory requirements or institution procedures.
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The investigator is responsible for providing oversight of the conduct of the study at the site and 
adherence to requirements of the following where applicable:
•
ICH guidelines,
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
European Union Directive 2001/20/EC; or
•
European Regulation 536/2014 for clinical studies (if applicable),
•
European Medical Device Regulation 2017/745 for clinical device research (if applicable),
•
the IRB/IEC
•
and all other applicable local regulations.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to:
•
IRB/IEC
•
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/participants currently enrolled in the study if they are affected by the amendment; and (3) 
the new form must be used to obtain consent from new subjects/participants 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.
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INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants 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/participants, 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. 
•
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/participants, 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/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects'/participants’ signed ICF, and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
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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/participants are the most important 
considerations and should prevail over interests of science and society.
BMS COMMITMENT TO DIVERSITY IN CLINICAL TRIALS
The mission of BMS is to transform patients’ lives through science by discovering, developing, 
and delivering innovative medicines that help them prevail over serious diseases. 
BMS is committed to doing its part to ensure that patients have a fair and just opportunity to 
achieve optimal health outcomes.
BMS is working to improve the recruitment of a diverse participant population with the goal that 
the clinical trial becomes more reflective of the real-world population and the people impacted by 
the diseases studied.
DATA PROTECTION, DATA PRIVACY, AND DATA SECURITY
BMS collects and processes personal data of study participants, patients, health care providers, 
and researchers for biopharmaceutical research and development to advance innovative, high-
quality medicines that address the medical needs of patients. BMS ensures the privacy, protection, 
and confidentiality of such personal data to comply with applicable laws. To achieve these goals, 
BMS has internal policies that indicate measures and controls for processing personal data. BMS 
adheres to these standards to ensure that collection and processing of personal data are limited and 
proportionate to the purpose for which BMS collects such personal data. This purpose is clearly 
and unambiguously notified to the individual at the time of collection of personal data. In the true 
spirit of science, BMS is dedicated to sharing clinical trial information and data with participants, 
medical/research communities, the media, policy makers, and the general public. This is done in a 
manner that safeguards participant privacy and informed consent while respecting the integrity of 
national regulatory systems. Clinical trial data, health-related research, and pharmacovigilance 
activities on key-coded health data transferred by BMS across national borders is done in 
compliance with the relevant data protection laws in the country and GCP requirements.
BMS protects Personal Information with adequate and appropriate security controls as indicated 
under the data protection laws. To align with the recommended security standards, BMS has 
adopted internal security standards and policies to protect personal data at every stage of 
its processing.
To supplement these standards, BMS enters into Clinical Trial Agreements (CTAgs) with 
confidentiality obligations to ensure proper handling and protection of personal data by third 
parties accessing and handling personal data.
BMS takes unauthorized access and disclosure of Personal Information very seriously. BMS has 
adopted the security standards that include National Institute of Standards and Technology 
Cybersecurity Framework for studies in the US. BMS aligns with these standards to continuously 
assess and improve its ability to protect, detect, and respond to cyber attacks and other 
unauthorized attempts to access personal data. These standards also aid in mitigating possible 
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adverse effects. Furthermore, BMS Information Technology has defined 6 principles to protect our 
digital resources and information: 
1) Responsibilities of IT Personnel
2) Securing the BMS Digital Infrastructure
3) Identity and Access Management
4) External Partner Connections
5) Cyber Threat Detection and Response
6) Internal Cyber Incident Investigation
SOURCE DOCUMENTS
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be explained.
•
The Investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available.
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.
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.
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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
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for
bioavailability/bioequivalence/biocomparability, 
if applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form.
Sourced by site, and not supplied by 
BMS or its vendors (examples include IP 
sourced from the site’s 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.
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 
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be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If an 
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/participants must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a sub-investigator and who is delegated this task on the 
Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF approval 
task. For 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.
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 
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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).
Partially used study interventions and/or 
empty containers may be destroyed after 
proper reconciliation and documentation. But 
unused IMP must be reconciled by site 
monitor/Clinical Research Associate prior to 
destruction.
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 site’s stock 
or commercial supply or a specialty pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, 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:
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•
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.
STUDY AND SITE START AND CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to:
•
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
•
Inadequate recruitment of participants by the Investigator
•
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
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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
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the following criteria will be used to select the signatory investigator:
•
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)
SCIENTIFIC PUBLICATIONS
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 
forth in the clinical trial agreement (CTAg) governing 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 CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors.  No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
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4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
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).
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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.
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
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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 9.2.8 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).
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.
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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.
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: worldwide.safety@BMS.com
SAE Facsimile Number: Will be provided by local site monitor.
SAE Telephone Contact (required for SAE and pregnancy reporting): Will be provided by local 
site monitor.
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
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CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure. For combination therapy with BMS-986249 plus 
nivolumab, relevant systemic exposure is defined as 125 days after the end of study treatment, plus 
30 days, for a total of 155 days post treatment completion. For monotherapy with BMS-986249, 
relevant systemic exposure is defined as 75 days after the end of study treatment, plus 30 days, for 
a total of 105 days post treatment completion. For ipilimumab in combination with nivolumab 
therapy, the end of relevant systemic exposure is defined as 5 months after the end of study 
treatment. For monotherapy with nivolumab, the end of relevant systemic exposure is defined as 
5 months after the end of study treatment.
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (These methods of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited)b 
−
Oral (birth control pills)
−
Intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
Transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
Oral 
−
Injectable 
Highly Effective Methods That Are User Independent 
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)b
•
Intrauterine device (IUD)c
•
Intrauterine hormone-releasing system (IUS) (This method of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited)b c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
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•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants choose to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the investigational medicinal product (IMP) and other study medications will not alter hormonal 
exposures such that contraception would be ineffective or result in increased exposures that could be potentially 
hazardous. In this case, alternative methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.
•
Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
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CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until the end of relevant 
systemic exposure, defined as 165 days after the end of BMS-986249 monotherapy treatment,  
215 days after the end of BMS-986249 + nivolumab combination therapy treatment, 7 months 
after the end of ipilimumab + nivolumab combination therapy treatment, and 7 months after 
the end of nivolumab monotherapy treatment in the male participant.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as during the study treatment 
and until 165 days after the end of BMS-986249 monotherapy treatment, 215 days after the 
end of BMS-986249 + nivolumab combination therapy treatment , 7 months after the end of 
ipilimumab + nivolumab combination therapy treatment, and 7 months after the end of 
nivolumab monotherapy treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 165 days after the end of BMS-986249 monotherapy treatment,
215 days after the end of BMS-986249 + nivolumab combination therapy treatment, 7 months 
after the end of ipilimumab + nivolumab combination therapy treatment, and 7 months after 
the end of nivolumab monotherapy treatment. 
•
Refrain from donating sperm for the duration of the study treatment and for 165 days after the 
end of BMS-986249 monotherapy treatment, 215 days after the end of BMS-986249 + 
nivolumab combination therapy treatment, 7 months after the end of ipilimumab + nivolumab 
combination therapy treatment, and 7 months after the end of nivolumab monotherapy 
treatment.
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
RECIST 1.1 CRITERIA
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Measurable disease 
is defined by the presence of at least 1 measurable tumor lesion. When computed tomographic 
(CT) scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable.
1.1
Measurable Lesions
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:
•
10 mm by computed tomography (CT)/magnetic resonance imaging (MRI) scan (CT/MRI 
scan slice thickness no greater than 5 mm)
•
10 mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as nonmeasurable)
•
20 mm by chest X-ray
•
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
is recommended to be no greater than 5 mm). At baseline and in follow-up, only the short
axis will be measured and followed.
1.2
Non-measurable Lesions
•
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥10 to < 15 mm short axis), as well as truly non-measurable lesions
•
Lesions considered truly nonmeasurable include the following: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of the skin or lung, and abdominal masses/abdominal organomegaly identified 
by physical examination that are not measurable by reproducible imaging techniques
1.3
Special Considerations Regarding Lesion Measurability
1.3.1
Bone Lesions
•
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions. 
•
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 
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considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
•
Blastic bone lesions are nonmeasurable.
1.3.2
Cystic Lesions
•
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts.
•
‘Cystic lesions’ thought to represent cystic metastases can be considered measurable lesions 
if they meet the definition of measurability described above in Section 1.1. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions.
1.3.3
Lesions with Prior Local Treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion.
1.4
Specifications by Methods of Measurements
1.4.1
Measurement of Lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 30 days before the 
beginning of the treatment.
1.4.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Unless the lesions being followed 
cannot be imaged, and are assessable only by clinical examination, imaging-based evaluation 
should always be done.
1.4.2.1
CT/MRI Scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
1.4.2.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated 
lung.
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1.4.2.3
Clinical Examination
Lesions identified by clinical examination will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers. For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
suggested. As previously noted, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study.
1.4.2.4
Ultrasound
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
2.1
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) that are representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
should be representative of all involved organs, and should lend themselves to reproducible
repeated measurements.
A sum of the diameters for all target lesions will be calculated and reported as the baseline sum
diameters. For non-nodal lesions, the longest axis should be included in the baseline sum 
diameters. If lymph nodes are to be included in the sum, then as noted below, only the short axis 
is added into the baseline sum diameters. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease.
2.1.1
Lymph Nodes
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. Pathological nodes that are defined as 
measurable, and may be identified as target lesions, must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum
diameters. Nodes that have a short axis < 10 mm are considered nonpathological and should not 
be recorded or followed.
2.2
Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
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these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION
3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must also have reduction in the short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions,
taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the 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 1 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.
3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
Lymph Nodes
Lymph nodes merit special mention since they are normal anatomical structures that may be visible 
by imaging even if not involved by tumor. Pathological nodes that are defined as measurable and 
may be identified as target lesions must meet the criterion of a short axis of ≥15 mm by CT scan. 
Only the short axis of these nodes will contribute to the baseline sum. Nodes that have a short axis 
< 10 mm are considered non-pathological and should not be recorded or followed.
3.1.1.2
Target Lesions That Become ‘Too Small to Measure’
All lesions (nodal and nonnodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation. If the radiologist is able to provide an actual measurement,
even if it is below 5 mm it should be recorded.
However, when such a lesion becomes difficult to assign an exact measurement to then:
•
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.
•
If the lesion or lymph node is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned =. This default value is derived from 
the 5-mm CT-slice thickness (but should not be changed with varying CT-slice thickness).
3.1.1.3
Target Lesions That Split or Coalesce on Treatment
•
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should 
be added together to calculate the target lesion sum.
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•
As lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the ‘coalesced lesion’.
3.2
Evaluation of Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the timepoints specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must also be 
nonpathological in size (< 10 mm short axis).
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) above the normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: The 
appearance of 1 or more new lesions is also considered progression.)
3.2.1
Special Notes on Assessment of Non-Target Lesions
The concept of progression of non-target disease requires additional explanation.
3.2.1.1
When the Subject Also Has Measurable Disease
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease such that, even in the 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 1 or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. 
3.2.1.2
When the Subject Has Only Non-Measurable Disease
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be 
an overall level of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. 
•
A modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. 
•
Because worsening in non-target disease cannot be easily quantified as the lesions are 
nonmeasurable, a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required 
to declare PD for target disease: that is, an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase in diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’
or an increase in lymphangitic disease from localized to widespread or may be described in 
protocols as ‘sufficient to require a change in therapy’. 
•
If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD 
at that point.
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3.2.1.3
Tumor Markers
Tumor markers alone cannot be used to assess objective tumor responses. If markers are initially 
above the upper normal limit, however, they must normalize in order for a subject to be considered 
as having attained a CR.
3.3
New Lesions
The appearance of new malignant lesions denotes PD. The finding of a new lesion should be 
unequivocal: that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (eg, some ‘new’ bone 
lesions may be simply healing or a flare of pre-existing lesions). This distinction is particularly 
important when the subject’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate PD. An example of this is the subject who has visceral 
disease at baseline and while on study has a CT or MRI brain scan that reveals metastases. The 
subject’s brain metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then PD should be declared using the date of the initial scan.
3.3.1
FDG-PET Evaluation
While [18F] fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of the qualitative assessment of FDG-PET scanning 
to complement CT scanning in assessment of PD (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: 
•
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD based 
on a new lesion. 
•
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 by CT, 
additional follow-up CT scans are needed to determine if there is truly PD occurring at that 
site (if so, the date of PD will be the date of the initial positive 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.
4
RESPONSE CRITERIA
4.1
Timepoint Response
A response assessment should occur at each timepoint specified in the protocol. 
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For subjects who have measurable disease at baseline Table 4.1-1 provides a summary of the 
overall response status calculation at each timepoint.
Table 4.1-1:
Timepoint Response: Subjects with Target (+/– Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
NonCR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
NonPD or not all evaluated
No
PR
SD
NonPD or not all evaluated
No
SD
Not all evaluated
NonPD
No
NE
PD
Any
Yes or No
PD
Any 
PD
Yes or No
PD
Any
Any 
Yes
PD
Abbreviation: NE =not evaluable
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the subject is not evaluable 
at that timepoint. If only a subset of lesion measurements are made at an assessment, the subject
is also considered NE at that timepoint, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned timepoint 
response.
4.1.1
Confirmation Scans
•
Verification of Response: Confirmation of PR and CR is required at least 4 weeks following 
initial assessment to ensure responses identified are not the result of measurement error.
4.2
Best Overall Response: All Timepoints
The best overall response is determined once all the data for the subject are known. It is the best 
response recorded from the start of the study treatment until the date of objectively documented 
PD based on RECIST v1.1, taking into account any requirement for confirmation or the date of 
subsequent anti-cancer therapy, whichever occurs first in the study. The subject’s best overall 
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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. 
The best overall response is defined as the best response across all timepoints with subsequent 
confirmation. CR or PR may be claimed only if the criteria for each are met at a subsequent 
timepoint as specified in the protocol (generally 4 weeks later).
In this circumstance, the best overall response can be interpreted as specified in Table 4.2-1. When 
SD is believed to be best response, it must meet the protocol specified minimum time from 
baseline. Measurements must have met the SD criteria at least once after study entry at a minimum 
interval (in general, not less than 6 to 8 weeks) that is defined in the study protocol.
Table 4.2-1:
Best Overall Response When Confirmation of CR and PR Is 
Required
Overall Response
Overall Response
Best Overall Response
First Timepoint
Subsequent Timepoint
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
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
.
a If a CR is truly met at the first timepoint, then any disease seen at a subsequent timepoint, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since the disease must have reappeared after CR). 
The best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may 
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be claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not 
CR at the first timepoint. Under these circumstances, the original CR should be changed to PR and the best response 
is PR.
4.3
Duration of Response
4.3.1
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
4.3.2
Duration of Stable Disease
SD is measured from the start of the treatment (in randomized trials, from date of randomization) 
until the criteria for progression are met, taking as reference the smallest sum on study (if the 
baseline sum is the smallest, this is the reference for calculation of PD).
CR (Complete Remission)
The designation of CR requires all of the following:
1. Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms, if present before therapy.
a) Typically FDG-avid lymphoma: in patients without a pre-treatment PET scan or if the 
pre-treatment PET scan was positive, a post-treatment residual mass of any size is 
permitted as long as it is PET negative.
b) Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pre-treatment 
PET scan, or if a pre-treatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed on CT scan to normal size (≤1.5 cm in their greatest transverse 
diameter for nodes > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 
1.5 cm in their long axis and > 1.0 cm in their short axis before treatment must have 
decreased to ≤1.0 cm in their short axis after treatment.
2. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should disappear. 
However, determination of splenic involvement is not always reliable because a spleen 
considered normal in size may still contain lymphoma, whereas an enlarged spleen may reflect 
variations in anatomy, blood volume, the use of hematopoietic growth factors, or causes other 
than lymphoma.
3. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is made 
must be adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample that is negative by 
immunohistochemistry, but demonstrates a small population of clonal lymphocytes by flow 
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cytometry, will be considered a CR until data become available demonstrating a clear 
difference in patient outcome.
PR (Partial Remission)
The designation of PR requires all of the following:
1. At least a 50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the 
largest dominant nodes or nodal masses. These nodes or nodal masses should be selected 
according to all of the following: they should be clearly measurable in at least 2 perpendicular 
dimensions; if possible, they should be from disparate regions of the body; and they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
2. No increase should be observed in the size of other nodes, liver, or spleen.
3. Splenic and hepatic nodules must regress by ≥50% in their SPD or, for single nodules, in the 
greatest transverse diameter.
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable, and no measurable disease should be present.
5. Bone marrow assessment is irrelevant for determination of a PR, if the sample was positive 
before treatment. However, if positive, the cell type should be specified (eg, large-cell 
lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria but 
have persistent morphologic bone marrow involvement will be considered partial responders. 
When the bone marrow was involved before therapy and a clinical CR was achieved but with 
no bone marrow assessment after treatment, patients should be considered partial responders.
6. No new sites of disease should be observed.
7. FDG:
a) Typically FDG-avid lymphoma: for patients without a pre-treatment PET scan or if the 
pre-treatment PET scan was positive, the post-treatment PET scan should be positive in at 
least 1 previously involved site.
b) Variably FDG-avid lymphomas/FDG
avidity unknown: for patients without a 
pre-treatment PET scan, or if a pre-treatment PET scan was negative, CT criteria should 
be used. In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only 
indicated with 1 or at most 2 residual masses that have regressed by > 50% on CT; those 
with more than 2 residual lesions are unlikely to be PET negative and should be considered 
partial responders.
SD (Stable Disease)
1. The designation of SD requires all of the following: A patient is considered to have SD when 
he or she fails to attain the criteria needed for a CR or PR but does not fulfill those for PD (see 
Relapsed Disease [after CR]/PD [after PR, SD]).
2. Typically FDG-avid lymphomas: the PET should be positive at prior sites of disease with no 
new areas of involvement on the post-treatment CT or PET scan.
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3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pre-treatment 
PET scan or if the pre-treatment PET was negative, there must be no change in the size of the 
previous lesions on the post-treatment CT scan.
PD: Relapsed Disease (after CR)/PD (after PR, SD)
Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of the short 
axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if its 
short axis is > 1.0. Lymph nodes ≤1.0 × ≤1.0 cm will not be considered abnormal for relapse or 
progressive disease.
1. Appearance of any new lesion > 1.5 cm in any axis during or at the end of therapy, even if 
other lesions are decreasing in size. Increased FDG uptake in a previously unaffected site 
should only be considered relapsed or PD after confirmation with other modalities. In patients 
with no prior history of pulmonary lymphoma, new lung nodules identified by CT are mostly 
benign. Thus, a therapeutic decision should not be made solely on the basis of the PET scan 
without histologic confirmation.
2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single 
involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be considered 
PD, a lymph node with a diameter of the short axis of < 1.0 cm must increase by ≥50% and to 
a size of 1.5 × 1.5 cm or > 1.5 cm in the long axis.
3. At least a 50% increase in the longest diameter of any single previously identified node > 1 cm 
in its short axis.
4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was 
PET positive before therapy, unless the lesion is too small to be detected with current PET 
systems (< 1.5 cm in its long axis by CT).
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these assessments, the spleen is considered nodal disease. Disease that is only assessable by 
physical examination (eg, pleural effusions, bone lesions) will be recorded as present or absent 
only, unless, while an abnormality is still noted by imaging studies or physical examination, it is 
found to be histologically negative.
In clinical trials where PET is unavailable to the vast majority of participants, or where PET is not 
deemed necessary or appropriate for use (eg, a trial in patients with mucosa-associated lymphoid 
tissue lymphoma), response should be assessed as above, but only using CT scans. However, 
residual masses should not be assigned CRu status but should be considered a PR.
Reference: Cheson BD, Pfisner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 
2007;25:579-86.
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APPENDIX 6
PCWG3 GUIDELINES (WITH MODIFIED RECIST CRITERIA FOR 
SOFT TISSUE LESION ASSESSMENT)
1
EVALUATION OF LESIONS
Bone lesions should be evaluated with Technecium-99m based radionuclide bone scan as per 
PCWG3.
At baseline, soft tissue 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 soft tissue 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 bone lesions
Bone lesions will be assessed with Technecium-99m based radionuclide bone scans as per 
PCWG3.
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 20 
lesions total (and a maximum of 5 lesions per organ system) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.
Note: A maximum of 5 lesions can be selected per organ system. For example, a maximum of 5 
lung lesions can be selected. A maximum of 5 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. Pelvic lymph nodes and extrapelvic 
lymph nodes (retroperitoneal, mediastinal, thoracic and other) may be reported separately, per 
PCWG3. 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 (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
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).
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•
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 (e.g., 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 
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 
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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 (see below) 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 (see examples in Appendix 2 and further details below). 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 
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: i.e., an increase in tumor burden representing an additional 
73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in 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 
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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
New bone lesions
New bone lesions should be evaluated as per PCWG3 criteria. Bone lesions will be assessed by 
radionuclide bone scan only. Radiographic progression on bone scan is defined by the following 
criteria:
•
At least 2 new lesions on the first posttreatment bone scan, on the next scan (performed at least 
6 weeks later) AND with at least two additional lesions as compared to the first post-treatment
bone scan. Date of progression is then the date of first post-treatment scan.
•
For scans after the first post-treatment scan, at least 2 new lesions relative to the first post-
treatment scan AND confirmed on a subsequent scan (performed at least 6 weeks later). Date 
of progression is the date of the scan that first documents at least 2 new lesions relative to the 
first post-treatment scan.
New soft tissue lesions
The appearance of new malignant soft tissue 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. 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.
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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 per PCWG3 criteria, 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: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
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Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
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&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&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 (e.g., 
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 (e.g., 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.
Reference: 
Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations 
From the Prostate Cancer Clinical Trials Working Group 3. Scher et al. J Clin Oncol 2016, 
34(12):1402-1418
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APPENDIX 7
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS
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APPENDIX 8
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 9
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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HEPATIC ADVERSE EVENT MANAGEMENT ALGORITHM (Modified for Part 2B Cohort 1: HCC Participants)
BMS has developed a standardized approach for the management of hepatic events based on cumulative data across the CTLA-4 and 
PD-1 programs in participants with normal hepatic function. Across most studies and CA030001 patient populations, the eligibility 
criteria for inclusion are based on a maximum AST or ALT < 3× ULN; therefore, only participants with normal to grade 1 LFTs have 
been enrolled.
Participants with HCC generally have underlying cirrhosis with decreased hepatic function. They may also have a concomitant 
chronic viral infection. For CA030001 Part 2B Cohort 1: HCC Participants, the upper limits for inclusion were adjusted to account for 
baseline liver dysfunction. Participants with AST or ALT elevations within the CTCAE Grade 2 range are eligible for inclusion. 
Criteria for dose delay, resumption, & discontinuation are in Section 7.4.3, Section 7.4.3.1, and Section 8.1, respectively. 
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APPENDIX 11
AJCC MELANOMA STAGING
Table 1:
TNM Staging Categories for Cutaneous Melanoma
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Table 2:
Anatomic Stage Groupings for Cutaneous Melanoma
Source: Balch CM, Gershenwald JE, Soong SJ, et al. Final Version of 2009 AJCC Melanoma Staging and 
Classification.  J Clin Oncol 2009;27:6199-6206.
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APPENDIX 12
SCHEDULE OF ACTIVITIES AND PHARMACOKINETICS 
SAMPLING SCHEDULE FOR POTENTIAL ALTERNATIVE DOSE 
SCHEDULE IN FOR PART 1 CA030001
Detailed in the tables below are the on-treatment schedule of activities and pharmacokinetic (PK) 
sampling schedule for potential alternative every-8-weeks (Q8W) BMS-986249 dosing 
administration that may be explored in The Dose Escalation Phase (Part 1) of CA030001 following 
evaluation of preliminary available safety, PK, and 
 data and upon discussion 
and agreement between the Investigators and Medical Monitor (or designee) (Section 5 main 
protocol). The alternative dosing schedule in Part 1 was initially initiated via administrative letter 
03 to evaluate 1600 mg BMS-986249 Q8W monotherapy in Part 1A, and via administrative letter 
04 to evaluate 800 mg BMS-986249 Q8W + 480 mg nivolumab Q4W combination therapy in Part 
1B.
•
Table 1: On-Treatment Schedule of Activities for BMS-986249 Q8W Dosing Schedule in the 
Dose Escalation Phase (Part 1) in CA030001
•
Table 2: PK and ADA Sampling Schedule for Part 1A BMS-986249 Q8W Monotherapy in 
Dose Escalation in CA030001
•
Table 3: PK and ADA Sampling Schedule for Part 1B BMS-986249 Q8W Combination in 
Dose Escalation in CA030001
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Table 1:
On-Treatment Schedule of Activities for BMS-986249 Q8W Dosing Schedule in 
the Dose Escalation Phase (Part 1) in CA030001
Procedure
Cycle 1
(28 days in length)
Cycle 2
(28 days in length)
Cycles 3 and 
Beyond
EOTa,b
Notes
(each cycle 28 days 
in length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Safety Assessments
ECOG Performance 
Status
X
X
X
X
PE
X
X
X
X
Symptom-directed 
PE
X
X
X
X
X
X
Weight
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
Oxygen Saturationc
X
X
X
ECGd
X
X
X
X
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Table 1:
On-Treatment Schedule of Activities for BMS-986249 Q8W Dosing Schedule in 
the Dose Escalation Phase (Part 1) in CA030001
Procedure
Cycle 1
(28 days in length)
Cycle 2
(28 days in length)
Cycles 3 and 
Beyond
EOTa,b
Notes
(each cycle 28 days 
in length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Laboratory Tests
X
X
X
X
X
X
X
X
X
X
There will be a 72-
hour window for 
collection of 
laboratory tests on D1. 
If screening laboratory 
tests are within 72 
hours of C1D1, 
laboratory tests 
performed at screening 
can be used for C1D1. 
Coagulation 
assessment at 
screening only. 
See Section 9.4.4 and
Table 9.4.4-1.
Urinalysis
X
X
As clinically 
indicated; 
microscopic urine 
reflex only for 
urinalysis positive 
for blood/protein/ 
leukocyte esterase.
Pregnancy Test
X
X
X 
X
(WOCBP only)e
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 1:
On-Treatment Schedule of Activities for BMS-986249 Q8W Dosing Schedule in 
the Dose Escalation Phase (Part 1) in CA030001
Procedure
Cycle 1
(28 days in length)
Cycle 2
(28 days in length)
Cycles 3 and 
Beyond
EOTa,b
Notes
(each cycle 28 days 
in length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Adverse Event Reporting and Concomitant Medication Assessments
Monitor for Non-
SAEs
Non-SAEs will be collected starting with the first dose of study medication and through 100 days 
following discontinuation of study treatment.
See Appendix 3 and 
Section 9.2 in the main 
protocol.
Monitor for SAEs
All SAEs must be collected from the date of the participant’s written consent until 100 days 
following discontinuation of study treatment.
See Appendix 3 and 
Section 9.2 in the main 
protocol.
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
PK Assessments
Serial Blood 
Sampling
See Table 2 for the PK and immunogenicity sampling schedule and Section 9.5 in the main protocol.
Immunogenicity 
(ADA)
See Table 2 for the PK and immunogenicity sampling schedule and Section 9.5 in the main protocol.
Assessments
Imaging Assessments
Body Imagingf
See Section 9.1.1 in the main protocol. Tumor imaging assessments should occur every 8 weeks (± 7 days) 
starting from the first dose up until Week 48, and then continue every 12 weeks (± 7 days).
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 1:
On-Treatment Schedule of Activities for BMS-986249 Q8W Dosing Schedule in 
the Dose Escalation Phase (Part 1) in CA030001
Procedure
Cycle 1
(28 days in length)
Cycle 2
(28 days in length)
Cycles 3 and 
Beyond
EOTa,b
Notes
(each cycle 28 days 
in length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Brain Imaging
See Section 9.1.1 in the main protocol. Participants with history of brain metastasis should have surveillance 
MRI performed approximately every 12 weeks or sooner if clinically indicated. CT of the brain without and 
with contrast can be performed if MRI is contraindicated.
Bone Scan
See Section 9.1.1 in the main protocol. Required for participants with prostate cancer only (PCWG3 
Assessment). For participants with prostate cancer, bone scans should occur every 8 weeks starting from the 
first dose (± 7 days).up until Week 48, and then continue every 12 weeks (± 7 days). Others only as 
clinically indicated per local standards.
Biomarker Assessments
See Section 9.5 and 
Section 9.8 in the main 
protocol and Table 2 
in Appendix 12
On-treatment Tumor 
Biopsyg
X
Mandatory tumor 
biopsies must be 
performed at 
; 
specimens may be 
collected within 3 days 
of the time point.
Required Post-
progression Tumor 
Biopsy
A tumor biopsy is required upon confirmation of PD (within 7 days) except for: 1) participants who have an 
on-treatment biopsy and progress within 4 cycles; 2) participants who will be imminently (within 4 weeks) 
enrolling in a subsequent clinical research study that requires a screening biopsy; and 3) participants who 
consent to be treated beyond progression will require the biopsy only at the subsequent confirmation of 
progression.
See Section 9.8.2 in 
the main protocol.
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 1:
On-Treatment Schedule of Activities for BMS-986249 Q8W Dosing Schedule in 
the Dose Escalation Phase (Part 1) in CA030001
Procedure
Cycle 1
(28 days in length)
Cycle 2
(28 days in length)
Cycles 3 and 
Beyond
EOTa,b
Notes
(each cycle 28 days 
in length)
D1
D8
D15
D22
D1
D8
D15
D22
D1
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 
days)
(± 2 days)
Exploratory Biomarker Assessments
See Section 9.5 and 
Section 9.8 in the main 
protocol and Table 3
Clinical Treatment Supplies
BMS-986249 
Administration Q8W 
(Part 1A and Part 1B)
X
X
BMS-986288 to be 
supplied by BMS.
(Every other cycle 
starting at Cycle 3 
[eg, C3, C5, C7, 
etc])
Nivolumab 
Administration Q4W 
(Part 1B)
X
X
X
Nivolumab to be 
supplied by BMS.
Abbreviations: ADA = anti-drug antibody; BMS = Bristol-Myers Squibb; C = cycle; CT = computed tomography; CXDY = Cycle X Day Y, as an example; 
D = day; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; EOT = end of treatment; 
hCG = human chorionic gonadotropin; MRI = magnetic resonance imaging; NSCLC = non-small cell lung cancer; PD = progressive disease; PE = physical 
examination; PK = pharmacokinetic; Q8W = every 8 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; 
WOCBP = women of childbearing potential.
a
EOT is defined as the visit where the decision is made to discontinue the participant from treatment. Evaluations will be performed prior to study discharge, or 
for participants who are prematurely discontinued.
b
For participants who complete all scheduled cycles of therapy, the EOT visit will be the same as the last scheduled and completed on-treatment visit (eg, 
C26D1) and 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); it does not need to be repeated and will be considered as the start of the safety follow-up period.
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Anti-CTLA-4 Probody mAb
c
Vital signs will be obtained before the infusion BMS-986249 and then every 15 minutes (± 5 minutes) until 60 minutes after completion of the infusion; oxygen 
saturation to also be performed in conjunction with vital signs monitoring on these days. For all cycles after C5 and for nivolumab infusion, vital signs and 
oxygen saturation are to be taken before the infusion and at the end of infusion. If any vital sign is abnormal (based upon clinician assessment) at the final 
check, the participant must be observed further for a period of time, as clinically indicated.
d
ECGs should be recorded after the participant has been supine for at least 5 minutes and prior to blood draws. For Part 1A, triplicate ECGs are performed at 
predose and EOI on C1D1 and C5D1. Single predose safety ECGs to be performed for all other time points. For Part 1B, single predose ECGs are performed 
for all time points and also at EOI for C1D1 & C5D1. See Section 9.4.3 of the main protocol). 
e
Serum/urine to be collected within 24 hours prior to BMS-986249 or nivolumab dosing. For Part 1A this would be collected prior to D1 of odd cycles (e.g. C1, 
C3, C5, etc), for Part 1B this would be collected prior to D1 of all cycles Pregnancy test may be completed on the first day of treatment, provided the results 
are available before the start of study therapy. Serum or urine pregnancy test must be performed within 24 hours prior to administration of study treatment 
(urine pregnancy test: minimum sensitivity 25 IU/L or equivalent units of hCG).
f
The same imaging modality is to be used for all assessments, per RECIST v1.1 (Appendix 5). Tumor assessment to be performed prior to initiating next cycle 
of treatment.
g
Pre-treatment (screening) biopsy can be performed optionally on C1D1. Mandatory tumor biopsies must be performed at 
; specimens may be collected 
within 3 days of the time point and must be obtained prior to administration of study treatments. Bone lesion biopsies are unacceptable for submission. See 
Section 9.8.2 of the main protocol.
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BMS-986249
Anti-CTLA-4 Probody mAb
Table 2:
PK and ADA Sampling Schedule for Part 1A BMS-986249 Q8W Monotherapy in Dose Escalation in 
CA030001
Study Day of Sample Collection 
(1 cycle = 4 weeks)
Event
Time (Relative To Start 
of BMS-986249 Infusion) 
Hour: Min
BMS-986249 PK Plasma 
Sample
BMS-986249 ADA Serum 
Samples
C1D1
Predosea
0:00
X
X
EOI
See noteb
X
4:00
X
C1D2
24:00
X
C1D4
( ± 1 days)
72:00
X
C1D8
( ± 2 days)
168:00
X
C1D15
( ± 2 days)
336:00
X
C1D22
( ± 2 days)
504:00
X
C2D1
672:00
X
C2D8c
(± 3 days)
840:00
X
C3D1
Predosea
0:00
X
X
EOI
See noteb
X
C4D1
672:00
X
C4D2
696:00
X
C4D4
( ± 1 days)
744:00
X
C4D8
( ± 2 days)
840:00
X
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BMS-986249
Anti-CTLA-4 Probody mAb
Table 2:
PK and ADA Sampling Schedule for Part 1A BMS-986249 Q8W Monotherapy in Dose Escalation in 
CA030001
Study Day of Sample Collection 
(1 cycle = 4 weeks)
Event
Time (Relative To Start 
of BMS-986249 Infusion) 
Hour: Min
BMS-986249 PK Plasma 
Sample
BMS-986249 ADA Serum 
Samples
C4D15
( ± 2 days)
1008:00
X
C4D22
( ± 2 days)
1176:00
X
C5D1
( ± 2 days)
Predosea
0:00
X
X
EOI
See noteb
X
C7D1
( ± 2 days)
Predosea
0:00
X
X
Every fourth cycle after C7 until 
EOT (C11D1, C15D1, C19D1, etc 
until EOT)
Predosea
0:00
X
X
EOT
X
X
30-day follow-up
X
X
60-day follow-up
X
X
100-day follow-up
X
X
Grade 3+ Infusion Reaction
X
X
Abbreviations: C = cycle; D = day.
a
Predose: All predose samples should be taken within 30 minutes prior to the start of the infusion.
b
EOI samples should be collected immediately after stopping the infusion (preferably within 2 minutes). Refer to Table 7.1.1-1 for infusion duration. If the EOI 
is delayed to beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly.
c
To align with the scheduled tumor biopsy, the time window can be the same as tumor biopsy collection (± 3 days)
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 3:
PK and ADA Sampling Schedule for Part 1B BMS-986249 Q8W Combination in Dose Escalation in 
CA030001
Study Day of Sample 
Collection 
(1 cycle = 4 weeks)
Event
Time (Relative 
To Start of 
nivolumab 
Infusion) 
Hour:Min
BMS-986249 PK 
Plasma Sample
nivolumab PK 
Serum Sample
BMS-986249 ADA 
Serum Samples
nivolumab ADA 
Serum Samples
C1D1
Predosea
0:00
X
X
X
X
EOI
See noteb
X
X
4:00
X
C1D2
24:00
X
C1D4 (± 1 day)
72:00
X
C1D8 (± 2 days)
168:00
X
C1D15 (± 2 days)
336:00
X
C1D22 (± 2 days)
504:00
X
C2D1
Predosea
0:00
X
X
X
X
C2D8c (± 3 days)
168:00
X
C3D1
Predosea
0:00
X
X
X
X
EOI
See noteb
X
X
C4D1
Predosea
0:00
X
X
X
X
C4D2
24:00
X
C4D4 (± 1 days)
72:00
X
C4D8 (± 2 days)
168:00
X
C4D15 (± 2 days)
336:00
X
C4D22 (± 2 days)
504:00
X
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Table 3:
PK and ADA Sampling Schedule for Part 1B BMS-986249 Q8W Combination in Dose Escalation in 
CA030001
Study Day of Sample 
Collection 
(1 cycle = 4 weeks)
Event
Time (Relative 
To Start of 
nivolumab 
Infusion) 
Hour:Min
BMS-986249 PK 
Plasma Sample
nivolumab PK 
Serum Sample
BMS-986249 ADA 
Serum Samples
nivolumab ADA 
Serum Samples
C5D1 (± 2 days)
Predosea
0:00
X
X
X
X
EOI
See noteb
X
X
C7D1 (± 2 days)
Predosea
0:00
X
X
X
X
Every fourth cycle after 
C7 until EOT (C11D1, 
C15D1, C19D1, etc 
until EOT)
Predosea
0:00
X
X
X
X
EOT
X
X
X
X
30-day follow-up
X
X
X
X
60-day follow-up
X
X
X
X
100-day follow-up
X
X
X
X
Grade 3+ Infusion 
Reaction
X
X
X
X
Abbreviations: C = cycle; D = day
a
Predose: All predose samples should be taken within 30 minutes prior to the start of the infusion.
b
EOI samples should be collected immediately after stopping the infusion (preferably within 2 minutes). Refer to Table 7.1.1-1 for infusion duration. For co-
administration visits, separate EOI samples (1 each for BMS-986249 and nivolumab) should be collected following co-administration of BMS-986249 and 
nivolumab and recorded as having the same collection time, if applicable. If the EOI is delayed to beyond the nominal infusion duration, the collection of this 
sample should also be delayed accordingly.
c
To align with the scheduled tumor biopsy, the time window can be the same as tumor biopsy collection (± 3 days)
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
APPENDIX 13
CHILD-PUGH SCORE
Score
Points
Child-Pugh A
5 - 6
Child-Pugh B
7 - 9
Child-Pugh C
> 9
Scoring
Score
Measure
1 Point
2 Points
3 Points
Ascites
Absent
Slight
Moderate
Serum bilirubin (mg/dL)
< 2.0
2.0 - 3.0
> 3.0
Serum albumin (g/dL)
> 3.5
2.8 - 3.5
< 2.8
PT prolongation
or INR
< 4 sec
< 1.7
4 - 6 sec
1.7 - 2.3
> 6 sec
> 2.3
Encephalopathy grade
None
1 - 2
3 - 4
Encephalopathy Grading
Encephalopathy
Grade
Clinical Definition
Grade 0
Normal consciousness, personality, and neurological examination
Grade 1
Restless, sleep disturbed, irritable/agitated, tremor, and impaired 
handwriting
Grade 2
Lethargic, time-disoriented, inappropriate, asterixis, and ataxia
Grade 3
Somnolent, stuporous, place-disoriented, hyperactive reflexes, and 
rigidity
Grade 4
Unrousable coma, no personality/behavior, decerebrate
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
APPENDIX 14
COUNTRY SPECIFIC REQUIREMENTS/DIFFERENCES
Country/Location 
Requirement
Original 
Language/Section 
Number
Country-specific Language or Differences
Argentina, Germany,
Romania
Section 6.2 : 
Exclusion Criteria 
Exclusion criterion 
3)e)xii) 
“Known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS)” to be replaced 
with “Positive test for HIV” 
OR
Standard language in exclusion criterion add “Countries 
where exclusion of HIV positive participants is locally 
mandated.”
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
APPENDIX 15
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 08, 22-Feb-2022
The primary reasons for Protocol Amendment 08 are to update and/or clarify the inclusion criteria 
to align with the current disease state and treatment landscape based on investigator feedback for 
Part 2.
Additional revisions, including in sections of the Protocol Synopsis, have been made to align the 
protocol with respect to these changes. This amendment incorporates the changes from approved 
Administrative Letters 05 and 06, which are indicated in the Document History but not listed in 
the Summary of Key Changes below.
Summary of key changes for Protocol Amendment 08
Section Number & Title
Description of Change
Brief Rationale
Figure 5.1-2: Study Design 
Schematic - Part 2, the BMS-
986249 Cohort Expansion 
Combination Therapy Phase
Section 5.4.9: Rationale for 
Selecting HCC, CRPC, and 
TNBC in Part 2B Expansion
Updated the study design figure to include 
participants with intermediate hepatocellular 
carcinoma (HCC) in Part 2B Cohort 1 and 
updated the section on rationale for 
expanding participant population to 
intermediate HCC in Part 2B Expansion.
To align with current disease 
state and treatment landscape.
Section 6.1: Inclusion Criteria
•
Clarified Inclusion Criterion 2)a).
•
Clarified Inclusion Criterion 2)e)ii)1) 
and 2).
•
Modified Inclusion Criterion 2)f)i)2) and 
3). 
•
Updated Inclusion Criterion 2)f)i)10). 
•
Modified Inclusion Criterion 2)f)ii)3).
•
Added new Inclusion Criterion
2)f)ii)3)c.
•
Inclusion Criterion 2)f)ii)6) was marked 
“Not Applicable per Protocol 
Amendment 08.”
•
To clarify measurability for 
Response Evaluation 
Criteria in Solid Tumors 
(RECIST) v1.1 vs Prostate 
Cancer Working Group 3 
(PCWG3) criteria.
•
To support melanoma 
participants given recent 
changes in adjuvant 
standard of care.
•
To support HCC 
participants given recent 
changes in first-line 
treatment landscape.
•
To create consistency across 
Bristol Myers Squibb 
(BMS)-sponsored protocols.
•
To allow for radiotherapy in 
alignment with recent 
treatment landscape.
•
To increase clarity.
•
To allow for inclusion of 
Part 2B castration-resistant 
prostate cancer (CRPC) 
participants with liver 
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BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Protocol Amendment 08
Section Number & Title
Description of Change
Brief Rationale
metastasis based on 
investigator feedback.
Section 7.4.1: Dose-limiting 
Toxicities 
Modified text in this section. 
For increased clarity.
Section 7.7.2: Permitted 
Therapy
•
Addition of text indicating that non-live 
COVID-19 vaccines are allowed.
•
Addition of a COVID-19 vaccine 
benefit/risk statement.
To clarify COVID-19 
vaccination language.
Section 8.2.1: Individual 
Discontinuation Criteria
Section 9.8.4: Additional 
Research Collection
Added new section and revised text.
To increase clarity.
Appendix 2: Study Governance 
Considerations
Appendix 3: Adverse Events 
and Serious Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow 
up and Reporting
•
Updated text in Monitoring and Source 
Documents sections.
•
Added new sections “Study and Site 
Start and Closure” and “Dissemination 
of Clinical Study Data.”
•
Updated contact information for 
reporting of SAEs.
To increase clarity.
Appendix 9: Management 
Algorithms
Updated formatting of HCC-specific 
management algorithm.
To align with other BMS-
sponsored HCC studies.
All
Minor formatting, clarification, and 
typographical corrections; additional 
amendments to align the protocol with 
respect to the key changes outlined above.
Corrections for clarity and 
consistency within the document 
were minor, and therefore have 
not been summarized.
Overall Rationale for the Revised Protocol 07, 15-Nov-2020
This is a revised protocol to modify the treatment arms in the Part 2A Expansion Phase and define 
the Part 2B Expansion Phase. The Part 2A Expansion Phase will now include concurrent 
evaluation of 3 treatment arms in a randomized setting in melanoma (2 different dose regimens of 
BMS-986249 in combination with nivolumab and 1 standard-of-care reference arm) rather than 
the previously defined 5 treatment arms. The Part 2B Expansion Phase will evaluate a single-dose 
regimen of BMS-986249 in combination with nivolumab in 3 tumor tumor-specific cohorts. This 
protocol revision also includes global changes to reduce redundancies and increase readability; 
incorporates updated learnings for BMS-986249, nivolumab, and ipilimumab; and adds language 
around COVID-19.
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Date: 14-Mar-2023
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CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Title page
Updated names, titles, and contact 
information.
To comply with new protocol model 
document.
Section 2, Schedule of Activities, 
Tables 2-1 through 2-5
Relocated instructions for when 
multiple procedures are required at 
a single time point. Updated 
activities related to Part 2A and Part 
2B. Removed stool sample 
collection from required activities. 
Added EORTC-QLQ-C30, EQ-5D-
3L, FACIT GP5, and PRO-CTCAE 
requirements to EOT visit. Added 
requirement for assessment of 
participant survival status to 
Follow-up 1, 2, and 3.Restructured 
and condensed table headings and 
rows.
To increase readability. To include 
and support the modified Part 2A 
design and introduction of Part 2B. 
To align with current nivolumab 
essential protocol elements (EPE). 
Section 2.1, Schedule of 
Activities, Tables 2-1 through 2-5, 
Table 4-2, Table 4-3, Section 6.2, 
Exclusion Criteria, Section 6.4.1, 
Retesting During Screening
Section 7.4.3, Dose Delays due to 
Toxicity, Section 7.4.3.1, Criteria 
to Resume Treatment, Section 
9.2.1, Time Period and Frequency 
for Collecting AE and SAE 
Information and Section 9.2.3, 
Follow-up of AEs and SAEs 
Criteria to Resume Treatment, 
Section 9.8.1.6, Other Assessment, 
Table 9.8.3-1, Biomarker 
Sampling Schedule for All Study 
Parts
Added language around SARS-
CoV-2 and COVD-19.
To align with proposed COVID-19 
language for oncology protocols.
Section 3.2.1.5, BMS-986249 
Clinical Pharmacokinetics
Updated systemic exposure data for 
BMS-986249
To update with most recent analysis 
to support Part 2A and Part 2B.
Table 4-2, Objectives and 
Endpoints for Part 2A
Removed Arm A and Arm B from 
the objectives and added Arm F.
To support Part 2A modified design.
Table 4-3, Objectives and 
Endpoints for Part 2B
Added primary, secondary, and 
exploratory objectives for Part 2B.
To support incorporation of Part 2B.
Section 5.1, Overall Design
Added addendum per Revised 
Protocol 07. Added treatment 
dosing and schedule for Part 2B
participants. Updated Figure 5.1-2 
and 5.1-3.
To support Part 2A modified design. 
To support incorporation of Part 2B.
Section 5.1.1, Screening Period
Added instructions for if a 
participant exceeds the 30-day 
screening period due to a study-
related procedure.
To increase participant/site 
convenience.
Protocol Amendment No.: 09
Date: 14-Mar-2023
278
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Section 5.1.2.4, The BMS-986249 
Cohort Expansion Combination 
Therapy (Part 2)
Clarified instructions for clinical 
evaluation of toxicity events.
To support Part 2A modified design. 
To support incorporation of Part 2B.
Section 5.1.5.2, Imaging Follow-
up Period
Removed tumor assessment 
schedule and added a reference to 
Section 2.
To increase readability.
Section 5.2, Number of 
Participants
Adjusted sample sizes for Part 2A 
and added information on the 
number of participants for Part 2B.
To support modification of Part 2A 
design and introduction of Part 2B.
Old Section 5.4.7, Rationale for 
Evaluating Different Dose Levels 
and Schedules of BMS-986249 in 
Combination with Nivolumab in 
Part 2A
Relocated to Section 5.5.4.
To increase readability.
Section 5.4.7.2, Rationale for 
Nivolumab Monotherapy as a 
Reference
Updated language around stopping 
enrollment/randomization into Part 
2A Arm E as of Revised Protocol 
07.
To provide rationale for modified 
Part 2A design.
Section 5.4.9, Rationale for 
Selecting HCC, CRPC, and TNBC 
in Part 2B Expansion
Added rationale for selecting HCC, 
CRPC, and TNBC in Part 2B.
To provide rationale to support Part 
2B design.
Section 5.5.4, Rationale for 
Evaluating Different Dose Levels 
and Schedules of BMS-986249 in 
Combination with Nivolumab in 
Part 2A
Relocated from Section 5.4.7. 
Added language around recent 
analysis resulting in decision to 
modify enrollment/randomization 
into Part 2A.
To increase readability. To provide 
rationale for modified Part 2A 
design.
Section 5.5.5, Rationale for Q3W 
Dosing of BMS-986249 and 
Nivolumab in Part 2A Arm A
Added statement that as of Revised 
Protocol 07, no further 
enrollment/randomization will 
occur for Part 2A Arm A.
To provide rationale for modified 
Part 2A design.
Section 5.5.6, Rationale for Dose 
Selection in Part 2B
Added rationale for dose selection 
in Part 2B.
To provide rationale to support Part 
2B design.
Section 6.1, Inclusion Criteria and 
Section 6.2, Exclusion Criteria
Added inclusion/exclusion criteria 
specific for participants with HCC, 
CRPC, and TNBC in Part 2B. 
Added that WOCBP must agree not 
to donate eggs for reproduction. 
Removed leptomeningeal 
metastasis as an exclusion criterion. 
Changed window for botanical 
preparations from within 4 weeks to 
prior to treatment to within 2 weeks 
prior to treatment. Clarified 
exclusion criterion regarding a 
positive test for hepatitis B virus. 
Updated exclusion criterion 
regarding a positive test for HIV.
To support introduction of Part 2B.
To align with current nivolumab 
EPE.
Protocol Amendment No.: 09
Date: 14-Mar-2023
279
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Table 7.1.1-1, Selection and 
Timing of Dose for All Study 
Parts
Added footnote b, clarifying 
infusion time for participants < 35 
kg receiving 1,200 mg BMS-
986249 + 480 mg nivolumab. 
Added footnote e regarding 
flushing of the IV line.
To increase participant convenience 
while maintaining safe infusion 
limits for those with low weight. To 
align with current nivolumab EPE.
Section 7.2, Method of Treatment 
Assignment
Added that as of Revised Protocol 
07, enrollment/randomization into 
Part 2A Arms A, B, and E is closed 
and method of IRT assignment for 
Part 2B.
To support modification of Part 2A 
design and introduction of Part 2B.
Section 7.4.1.2, Hepatic Dose-
limiting Toxicity
Added hepatic DLT criteria for 
participants with HCC.
To support HCC population in Part 
2B.
Section 7.7.1, Prohibited and/or 
Restricted Treatments and Section 
7.7.2, Permitted Therapy
Added prohibited and permitted 
therapies for HCC, TNBC, and 
CRPC participants. Added non-
palliative radiation therapy as a 
prohibited treatment. 
To support introduction of Part 2B 
patient populations. To align with 
current nivolumab EPE.
Section 9.1.1, Imaging Assessment 
for the Study
Removed imaging assessment 
schedule and added reference to 
Section 2. Added and moved 
language to support HCC, TNBC, 
and CRPC.
To increase readability. To support 
introduction of Part 2B patient 
populations.
Section 9.2.8, Potential Drug-
induced Liver Injury
Added potential DILI criteria for 
HCC participants.
To support Part 2B HCC patient 
population.
Table 9.4.4-1, Clinical Laboratory 
Assessments
Added assessments to align with 
Section 2 Schedule of Activities.
To support introduction of Part 2B.
Section 9.5, Pharmacokinetics and 
Immunogenicity Assessments 
Table 9.5-5, PK and ADA 
Sampling Schedule for Part 2A 
Arm B and Arm C
Modified Tables 9.5-4, 9.5.-5 and 
9.5-6 and footnotes (as applicable) 
to align with biomarker sample 
collection. Added Tables 9.5-8 and 
9.5-9 and corresponding footnotes.
To support modification of Part 2A 
design and introduction of Part 2B.
Section 9.8.2, Tumor Samples
Updated tumor specimen language 
for Part 2A and added for Part 2B.
To support modification of Part 2A 
design and introduction of Part 2B.
Section 9.8.3, Gut Microbiome 
Analysis
Removed entire section and 
requirement for stool collection.
To increase participant convenience.
Table 9.8.3-1, Biomarker 
Sampling Schedule for All Study 
Parts
Removed stool collection, modified 
Part 2A biopsy timing, and added 
Part 2B biopsy collection.
To support modification of Part 2A 
design, introduction of Part 2B, and 
increased participant convenience.
Section 9.9, Patient-reported 
Outcomes
Added that PROs will be collected 
for Part 2B participants.
To support introduction of Part 2B.
Section 10.1.2.2, Changes to 
Sample Size Assumptions for 
Revised Protocol 07
Added changes to sample size 
assumptions for Part 2A in Revised 
Protocol 07.
To support modification of Part 2A 
design.
Protocol Amendment No.: 09
Date: 14-Mar-2023
280
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Section 10.1.3, Additional Tumor 
Cohort Expansion (Part 2B)
Added sample size assumptions for 
Part 2B. Added Figures 10.1.3-1 
and 10.1.3-2.
To support introduction of Part 2B.
Section 10.3, Statistical Analyses
Modified analysis details for Part 
2A and added details for Part 2B.
To support modification of Part 2A 
design and introduction of Part 2B.
Appendix 9, Management 
Algorithms
Modified Appendix 9.
To support HCC participants in Part 
2B.
Appendix 13, Child-Pugh Score
Added Appendix 13.
To support HCC participants in Part 
2B.
Appendix 14, Country-specific 
Requirements/Differences
Added Appendix 14.
To support local and country-
specific requirements.
Overall Rationale for the Revised Protocol 06, 05-Aug-2019
This is a revised protocol that defines the selected BMS-986249 + nivolumab doses and schedules 
for Part 2A Arms A - C, updates modified intermediate dose levels in Part 1B, and incorporates 
other minor clarifying edits. 
Summary of key changes for Revised Protocol 06
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Text in synopsis updated
Synopsis was updated to reflect the 
changes made in the protocol
Section 2 Schedule of Activities
Arm B reference removed from 
Table 2-2 and Table 2-3 and added 
to Table 2-4.
Updated to align and support the 
selected BMS-986249 + nivolumab 
doses and schedules for Part 2A 
Arms A - C. 
Section 3.2.1.5 BMS-986249 
Clinical Pharmacokinetics; 
Section 3.2.1.6 Clinical Safety 
Summary
Section 5.4.7 Rationale for 
Evaluating Different Dose Levels 
and Schedules of BMS-986249 in 
Combination with Nivolumab in 
Part 2A
Section 5.5.1.7 Rationale for Q3W 
dosing of BMS-986249 and 
Nivolumab in Part 2A Arm A
Sections updated
Section 5.1 Overall Design;
Section 5.1.2 Treatment Period; 
Section 5.1.2.4 The BMS-986249 
Cohort Expansion Combination 
Therapy (Part 2)
•
Updated Figure 5.1-3
•
Doses and schedules for Part 
2A Arms A - C defined
Protocol Amendment No.: 09
Date: 14-Mar-2023
281
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 06
Section Number & Title
Description of Change
Brief Rationale
Section 7.1.1 Schedule of Dose for 
Each Investigational Product
Table 7.1.1-1 updated
Section 7.2 Method of Treatment 
Assignment
Clarification added to prioritize 
participants in Part 2.
Section 9.5: Pharmacokinetics and 
Immunogenicity Assessments
Arm B reference removed from 
Table 9.5-4 and added to 9.5-5
Section 5.1 Overall Design
Updated Figure 5.1-2
Study design updated to include 
modified intermediate dosing cohorts 
in Part 1B
All
Minor formatting, typographical 
changes, and edits were made for 
consistency and clarity
Minor, therefore have not been 
summarized
Overall Rationale for the Revised Protocol 05, 01-May-2019
This is a revised protocol to explicitly mention encephalitis as an example of a possible 
neurological adverse event, updates management algorithms for immuno-oncology agents, 
updates PD-L1 stratification criteria for Part 2A, clarifies screening biopsy criteria for Part 2A, 
and incorporates other clarifying modifications.
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
Schedule of Activities 
Table 2-2 
For Part 2A, fresh screening biopsy is 
optional as long as archival tissue is 
available and fulfills specific criteria
Align with clinical practice
Section 3.2.1.6: Clinical Safety 
Summary
Section added
Provide summary of Part 1 
BMS-986249 doses explored 
and clinical safety
Section 7.4.1.5 Other Dose-
limiting Toxicities
DLT criteria updated
Address protocol inconsistency 
and align with BMS standard 
language
Section 7.4.2 and Appendix 9: 
Management Algorithms for 
Immuno-oncology Agents
Added encephalitis as an example of a 
neurological irAE and cardiac management 
algorithms
Provide clarity and align with 
BMS standard language for 
increased patient safety
Schedule of Activities Table 2-
2, Sections 5.1.2.4, 5.4.8.2, 
5.4.8.3, 6.1, 7.2, and 9.8.2
Changed PD-L1 stratification for Part 2A 
from 5% to 1%
1% may be closer to medium 
cutoff based on prevalence
Appendix 2
Updated Serious Breach Definition
Clarity and alignment with 
updated SOP
Protocol Amendment No.: 09
Date: 14-Mar-2023
282
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
Updated Clinical Study Report and 
Scientific Publication
Updated BMS Publication 
Policy
All
Minor typographical errors were corrected 
and edits were made for consistency and 
clarity
Minor, therefore have not been 
summarized
Overall Rationale for the Revised Protocol 04, 01-Mar-2019
This is a revised protocol to define the Part 2A Expansion Phase, which includes concurrent 
evaluation of three different dose regimens of BMS-986249 in combination with nivolumab in 
relation to two standard of care reference arms in a randomized setting in melanoma. The 
expansion design allows for a more comprehensive understanding of the safety, efficacy, and 
profile of the BMS-986249 + nivolumab combination. This may also allow for 
the identification of an optimized combination regimen with 1) a high exposure of BMS-986249 
with nivolumab that has an acceptable safety profile and potentially increased efficacy, and 2) a 
lower BMS-986249 exposure in combination with nivolumab that has a potentially optimal safety 
and tolerability profile without a change in efficacy. This protocol revision also updates DLT 
criteria, updates inclusion/exclusion criteria, changes the on-treatment biopsy timing, and provides
clarifications around planned dose level modifications/intermediate dose levels, and incorporates 
other clarifying modifications.
Summary of key changes for Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 2: Schedule of Activities: 
All tables
Updated Section 2 Schedule of 
Activities to incorporate activities for 
Part 2A 
Updated to include and support 
the BMS-986249 Cohort 
Expansion Combination 
Therapy Phase (Part 2) study 
design, especially in relation to 
defining the BMS-986249 in 
Combination with Nivolumab 
Randomized Cohort Expansion 
in Melanoma (Part 2A)
Section 3.2: Background
Added Section 3.2.2.1: Clinical 
Pharmacokinetics of Nivolumab and 
Section 3.2.4: Nivolumab Combined 
with Ipilimumab
Table 4-2: Objectives and 
Endpoints: The Dose Expansion 
Phase in Melanoma (Part 2A)
Added Objectives and Endpoints for Part 
2A
Protocol Amendment No.: 09
Date: 14-Mar-2023
283
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 5.1: Overall Design
Added figures supporting Part 2A. 
Updated details in the treatment period, 
overall design, Imaging, and added 
description of activities in Part 2A. 
Study design also updated to represent 
intermediate dose levels evaluated in 
Part 1 escalation.
Section 5.2: Number of 
Participants
The number of participants was 
increased in Part 1, added information 
on the number of participants for Part 2.
Section 5.4: Scientific Rationale 
for Study Design
Added individual Sections to include:
•
Rationale for Selecting Melanoma in 
Part 2A Expansion
•
Rationale for Testing Three Different 
Dose Exposures of BMS-986249 in 
Combination with Nivolumab in Part 
2A
•
Rationale for Part 2A Expansion 
Reference Arms
•
Rationale for Ipilimumab and 
Nivolumab Combination Therapy as 
a Reference
•
Rationale for Nivolumab 
Monotherapy as a Reference
•
Rationale for Part 2A Stratification 
by M-Staging and PD-L1 Status
•
Rationale for Quality of Life 
Evaluation
Section 5.5: Justification for 
Planned Dose Selection
Added Section 5.5.1.7: Rationale for 
Q3W dosing of BMS-986249 and 
Nivolumab in Part 2A Arm A and Arm 
B
Table 7.1-1: Study Treatments for 
CA030001
Ipilimumab included
Table 7.1.1-1: Selection and 
Timing of Dose for All Study Parts
Updated table numbering and added 
Timing of Dose for Part 2A
Section 7.2: Method of Treatment 
Assignment
Added method of treatment assignment 
and randomization for Part 2A
Section 8.1: Discontinuation from 
Study Treatment
Added discontinuation criteria for Part 
2A
Protocol Amendment No.: 09
Date: 14-Mar-2023
284
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 9.1.1: Imaging Assessment 
for the Study
Added imaging details for Part 2A
9.3: Overdose
Ipilimumab and nivolumab added
Section 9.5: Pharmacokinetics and 
Immunogenicity Assessments
Tables: 9.5-4, 9.5-5, 9.5-6 and 9.5-7 
added 
Section 9.8: Biomarkers
Added details of tumor collection for 
Part 2A, gut microbiome analysis, and 
updated Table 9.8.4-1. 
Section 9.9: Health Economics
Added individual Sections to include:
•
Patient Reported Outcomes
•
EORTC QLQ-C30
•
EQ-5D-3L
•
FACIT GP5
•
PRO-CTCAE
Section 10.1: Sample Size 
Determination
Added Section 10.1.2: Cohort Expansion 
and Table 10.1.2-1 for Part 2A 
Table 10.2-1: Populations of 
Analyses
Added randomization for Part 2A and 
details about patient-reported outcome.
Section 10.3: Statistical Analyses
Added analyses details for the 
randomized population for Part 2A, and 
updated analysis details for Part 1
Section 10.3.8: Interim Analyses
Section updated 
Section 6.1: Inclusion Criteria
Added criteria for participants with RCC 
and for Part 2A. . Laboratory test 
findings updated.
Updated to provide clarity in 
enrollment criteria.
Updated to support the Part 2 
study design.
Section 6.2: Exclusion Criteria
Criteria regarding interstitial lung 
disease added. Section updated to 
include Part 2
Section 7.4.1: Dose-limiting 
Toxicities 
DLT criteria updated in Sections 7.4.1.1, 
7.4.1.3, and 7.4.1.5
Modified to align with BMS 
standard language for increased 
patient safety. 
Section 7.7.3: Palliative Local 
Therapy
Section added 
Provide clarity around allowed 
palliative local therapy.
Section 7.7.1: Prohibited and/or 
Restricted Treatments
Details regarding botanical preparations 
added
Align with BMS standard 
language.
Details regarding live/attenuated vaccine 
was added
Section 9.2: Adverse Events
Updated Section 9.2.2 and Section 9.2.5
Protocol Amendment No.: 09
Date: 14-Mar-2023
285
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Table 9.5-3: Pharmacokinetics and 
Immunogenicity Assessments
Updated to include event of a Grade 3+ 
infusion reaction or hypersensitivity 
reaction
Appendix 03: AE and SAE 
(Definitions and procedures for 
Recording, Evaluating, Follow-up, 
and Reporting)
Appendix was updated
Appendix was updated as part 
of an update to BMS protocol 
standards
Appendix 4: Women of 
Childbearing Potential Definitions 
and Methods of Contraception
Updated contraception guidance for 
female and male participants 
Updated to align with revisions 
to the Part 2 study design and 
align with BMS standard 
language 
Appendix 12: Schedule of 
Activities and pharmacokinetics 
sampling schedule for potential 
alternative dose schedule in 
CA030001
Appendix 12 was added 
Dose modification language 
clarified throughout protocol 
and Appendix 12 added for 
increased completeness
All
Minor typographical errors were 
corrected and edits were made for 
consistency and clarity.
Minor, therefore have not been 
summarized.
Protocol Amendment No.: 09
Date: 14-Mar-2023
286
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Overall Rationale for the Revised Protocol 03, 25-May-2018
This is a revised protocol to reduce the DLT period from 8 to 5 weeks, incorporate clinic visit 
windows, revise participant cohort assignment, and provide clarifying modifications.
Summary of key changes for Revised Protocol 03
Section Number & Title
Description of 
Change
Brief Rationale
Title Page
Title page was updated.
EUDRACT 
number was added.
Section 2: Schedule of Activities, 
Table 2-2: On Treatment - Schedule of Activities for the 
BMS-986249 Monotherapy Escalation (Part 1A), the Safety 
Evaluation of Combination Doses of BMS-986249 with 
Nivolumab (Part 1B), 
Section 5.1.2.6: Window Visits, 
Table 9.5-2: Pharmacokinetic and ADA Sampling Schedule 
for BMS-986249 Q4W Monotherapy in Dose Escalation (Part 
1A), 
Table 9.5-3: Pharmacokinetic and ADA Sampling Schedule 
for BMS-986249 Q4W in Combination with Nivolumab Q4W 
in Dose Escalation (Part 1B), 
Table 9.8.3-1: Biomarker Sampling Schedule for All Study 
Parts
Window visits were
added to permit a 2-day 
window for clinic visits.
Accommodate 
participant 
schedules and 
emerging data.
Section 3.2.1.5: BMS-986249 Clinical Pharmacokinetics,
Section 5.1.2.1: The BMS-986249 Monotherapy Escalation 
(Part 1A),
Section 5.1.2.2: The Safety Evaluation of Combination Doses 
of BMS-986249 with Nivolumab (Part 1B),
Section 5.1.2.3: Dose Escalation Decisions for the BMS-
986249 Monotherapy Escalation (Part 1A) and the Safety 
Evaluation of Combination Doses of BMS-986249 with 
Nivolumab (Part 1B),
Section 7.5.1: Dose-limiting Toxicities,
Section 10.1.1: Dose Escalation,
Sections were updated to 
reduce DLT period from 8 
to 5 weeks.
Supported by the 
known ipilimumab 
safety profile and 
new clinical BMS-
986249 safety and 
pharmacokinetic 
data.
Section 7.3: Method of Treatment Assignment
Section was updated to 
change treatment 
assignments to prioritize 
Part 1B in participants 
eligible for both Part 1A 
and Part 1B.
Enable enrollment 
to Part 1B.
Protocol Amendment No.: 09
Date: 14-Mar-2023
287
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes for Revised Protocol 03
Section Number & Title
Description of 
Change
Brief Rationale
Appendix 06: PCWG3 Guidelines (with Modified RECIST 
Criteria for Soft Tissue Lesion Assessment)
Appendix was updated.
Appendix was 
updated as part of 
an update to BMS 
protocol standards.
All
Minor typographical 
errors were corrected and 
edits were made for 
consistency and clarity.
Minor, therefore 
have not been 
summarized.
Protocol Amendment No.: 09
Date: 14-Mar-2023
288
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Overall Rationale for the Revised Protocol 02, 24-Jan-2018
This is a revised protocol to enable co-administration of BMS-986249 and nivolumab in Part 1B,
expand Part 1B eligible tumor types, adjust imaging assessments, adjust biomarker requirements, 
and provide clarifying modifications.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Synopsis was updated.
Synopsis was updated to reflect the 
changes made to the protocol.
Table 2-1: Screening Schedule 
of Activities for All Study Parts
Bone scan and consent for post-
progression tumor biopsy were 
updated.
Bone scan was updated to clarify 
the requirement for prostate cancer 
only. Consent for post-progression 
tumor biopsy was updated as 
mandatory.
Table 2-2: On Treatment -
Schedule of Activities for the 
BMS-986249 Monotherapy 
Escalation (Part 1A), the Safety 
Evaluation of Combination 
Doses of BMS-986249 with 
Nivolumab
Body imaging, bone scan, and post-
progression tumor biopsy were 
updated.
Body imaging was updated to 
clarify the change in frequency of 
scans up to Week 48 versus 
thereafter. Bone scan was updated 
to clarify the requirement for 
prostate cancer only. Post-
progression tumor biopsy was 
updated as mandatory.
Table 2-3: Follow-up Procedural 
Outline for All Study Parts
Response Follow-up was changed to 
Imaging Follow-up. Tumor/response 
assessments was updated.
Response Follow-up was changed to 
Imaging Follow-up to clarify the 
follow-up period. Tumor/response 
assessments was updated to clarify 
the change in frequency of scans.
Table 4-1: Objectives and 
Endpoints
Objectives and endpoints were 
updated.
Secondary objective was updated to 
clarify use of RECIST v1.1 and 
PCWG3 and exploratory objective 
was updated to clarify use of 
iRECIST and PCWG3.
Figure 5.1-1: Study Design 
Schematic
Study design schematic was updated.
Study design schematic was updated 
to include Part 1B expansion tumor 
types.
Figure 5.1-2: Study Period and 
Participant Flow
Study period and participant flow 
schematic was updated.
Study period and participant flow 
schematic was changed from 
response follow-up to imaging 
follow-up to clarify the follow-up 
period.
Section 5.1.2: Treatment Period
Treatment period was updated.
Treatment period was updated to 
correct the cycle during the 
treatment period and for Part 1B to 
utilize co-administration of BMS-
986249 + nivolumab and clarify the 
frequency of tumor assessments.
Protocol Amendment No.: 09
Date: 14-Mar-2023
289
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Section 5.1.2.1: The BMS-
986249 Monotherapy Escalation 
(Part 1A)
Number of participants was updated.
Number of participants was updated 
to align with the protocol.
Section 5.1.2.2: The Safety 
Evaluation of Combination 
Doses of BMS-986249 with 
Nivolumab (Part 1B)
Imaging assessments were updated.
Imaging was updated to clarify the 
change in frequency of scans up to 
Week 48 versus thereafter.
Section 5.1.2.5: Treatment 
Beyond Progression
Tumor progression and response 
endpoints were updated.
Tumor progression and response 
endpoints were updated to add 
PCWG3 for prostate cancer.
Section 5.1.3.2: ImagingFollow-
up Period
Imaging follow-up period was 
updated.
Imaging follow-up period was 
updated to clarify the follow-up 
period and the change in frequency 
of scans up to Week 48 versus 
thereafter.
Section 5.4.3: Rationale for 
Tumor Selection for Part 1B
Rationale for tumor selection for Part 
1B was added.
Rationale for tumor selection for 
Part 1B was added for tumor 
expansion.
Section 5.4.4: Rationale for 
Treatment Duration
Rationale for treatment duration was 
updated.
Rationale for treatment duration was 
updated to address 2 year treatment 
duration.
Section 5.5.1.5: Rationale for 
BMS-986249 and Nivolumab 
30-minute Infusion
Rationale for 30-minute infusion was 
updated.
Rationale for 30-minute infusion 
was updated ton indicate that 
nivolumab is currently approved for 
IV administration over 30 minutes 
for select indications.
Section 5.5.1.6: Rationale for 
BMS-986249 and Nivolumab 
Co-administration
Rationale for BMS-986249 and 
nivolumab co-administration was 
added.
Rationale for BMS-986249 and 
nivolumab co-administration was 
added to address the advantages and 
overall safety profile.
Section 6.1: Inclusion Criteria
Inclusion criterion 1)b), 2)a), and 4)g) 
were updated and criterion 2)d)i), 
2)d)ii), 2)d)ii)1), 2)d)iii)1-2), 2)d)v)1-
3), 2)d)vi)1-2), and 2)d)vii)1-2 were 
added.
Inclusion criteria 1)b) was updated 
to make progression tumor biopsy 
samples mandatory, 2)a) was 
updated to add PCWG3 for prostate 
cancer, and 4)g) was updated to 
remove WOCBP exemption. 
Criterion 2)d)i), 2)d)ii), 2)d)ii)1), 
2)d)iii)1-2), 2)d)v)1-3), 2)d)vi)1-2), 
and 2)d)vii)1-2 were added or 
updated for Part 1B tumor 
expansion.
Section 6.2: Exclusion Criteria
Exclusion criteria 2)b)i) was added.
Exclusion criteria 2)b)i) was added 
for Part 1B tumor expansion.
Table 7.2-1: Selection and 
Timing of Dose for All Study 
Parts
Selection and timing of dose for all 
study parts was updated.
Selection and timing of dose for all 
study parts was updated to add co-
Protocol Amendment No.: 09
Date: 14-Mar-2023
290
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
administration of BMS-986249 + 
nivolumab.
Section 7.5.3: Dose Delays Due 
to Toxicity
Imaging assessments were updated.
Imaging was updated to clarify the 
change in frequency of scans up to 
Week 48 versus thereafter.
Section 7.6: Preparation/ 
Handling/Storage/Accountability
Section was updated to remove 
ipilimumab.
Section was updated to remove 
ipilimumab to reflect the protocol.
Section 7.8.1: Prohibited and/or 
Restricted Treatments
Concurrent anti-neoplastic therapy 
was updated.
Concurrent anti-neoplastic therapy 
was updated to address Part 1B 
tumor expansion in CRPC.
Section 8.1: Discontinuation 
from Study Treatment
Documented disease progression was 
updated.
Documented disease progression 
was updated to add PCWG3 for 
prostate cancer.
Section 8.1.1: Treatment Beyond 
Progression
Documented disease progression was 
updated.
Documented disease progression 
was updated to add PCWG3 for 
prostate cancer.
Section 8.1.1.1: Discontinuation 
Due to Further Progression 
(Confirmed Progression)
Follow-up scan and subsequent scans 
were updated and addressing new 
lesions was added.
Follow-up scan and subsequent 
scans were updated to clarify that 
the scans should be performed until 
further progression is determined 
and address new lesions and 
PCWG3 was added for prostate 
cancer.
Section 9.1: Efficacy 
Assessments
Efficacy assessments were updated.
Efficacy assessments were updated 
to add PCWG3 for prostate cancer 
and use of iRECIST using BICR as 
an exploratory objective.
Section 9.1.1: Imaging 
Assessment for the Study
Imaging assessments were updated.
Imaging was updated to clarify the 
change in frequency of scans up to 
Week 48 versus thereafter and 
prostate cancer requirements.
Section 9.2.1: Time Period and 
Frequency for Collecting AE 
and SAE Information
SAEs occurring after the start of a 
new anti-neoplastic therapy was 
updated.
SAEs occurring after the start of a 
new anti-neoplastic therapy was 
updated from ‘will’ to ‘should.’
Section 9.5: Pharmacokinetic 
and Immunogenicity 
Assessments
PK and ADA samples for co-
administration of BMS-986249 + 
nivolumab were added.
PK and ADA samples for co-
administration of BMS-986249 + 
nivolumab were added.
Table 9.5-2: Pharmacokinetic 
and ADA Sampling Schedule for 
BMS-986249 Q4W 
Monotherapy in Dose Escalation 
(Part 1A)
Table was updated.
Table was updated to clarify the 
time was relative to the start of 
infusion.
Table 9.5-3: Pharmacokinetic 
and ADA Sampling Schedule for 
BMS-986249 Q4W in 
Table was updated.
Table was updated to clarify the 
time was relative to the start of 
Protocol Amendment No.: 09
Date: 14-Mar-2023
291
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Combination with Nivolumab 
Q4W in Dose Escalation (Part 
1B)
infusion and sample schedule was 
updated.
Section 9.8: Biomarkers
Biomarker measures were updated.
Biomarker measures were updated 
to add upon disease progression.
Section 9.8.2: Tumor Samples
Tumor samples were updated.
Tumor samples were updated to add 
screening and upon disease 
progression fresh biopsy specimens 
and add tumor biopsy requirements.
Table 9.8.3-1: Biomarker 
Sampling Schedule for All Study 
Parts
Table was updated.
Sample schedule was updated and 
plasma sample analysis was 
clarified.
Table 10.3.1-1: Efficacy -
Statistical Analyses
Table was updated.
Table was updated to add PCWG3 
for prostate cancer.
Section 10.3.3: Pharmacokinetic 
Analysis for BMS-986249
Section was updated to remove 
ipilimumab.
Section was updated to remove 
ipilimumab to reflect the protocol.
Appendix 1: Abbreviations
Abbreviations were updated.
New abbreviations were added.
Appendix 6: PCWG3 Guidelines 
(with Modified RECIST Criteria 
for Soft Tissue Lesion 
Assessment)
Appendix was added.
Appendix was added for Part 1B 
tumor expansion into prostate 
cancer.
All
Minor typographical use of the words 
participants, patients, and subjects 
were made for consistency and clarity.
Minor, therefore have not been 
summarized
Protocol Amendment No.: 09
Date: 14-Mar-2023
292
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Overall Rationale for the Revised Protocol 01, 20-Nov-2017
The revised protocol addresses questions provided by the US FDA and fixes some typographical 
errors present in the original protocol. These apply to all participants.
Summary of key changes of Revised Protocol 01
Section 
Number & 
Title
Description of Change
Brief Rationale
6.1: Inclusion 
Criteria, 2), d), 
iii)
Inclusion criteria updated: urothelial carcinoma 
patients must have received, and then progressed, 
relapsed, been intolerant to, or ineligible for, at least 1 
platinum-containing chemotherapy regimen.
Inclusion criteria was updated to 
ensure that patients received 
appropriate prior therapy.
6.1: Inclusion 
Criteria, 2), c), ii)
Inclusion criteria updated: breast cancer patients must 
have received or been intolerant to, all approved 
standard systemic treatments that have shown a 
documented benefit in overall survival per product 
label.
Inclusion criteria was updated to 
ensure that patients received 
appropriate prior therapy.
Synopsis, 5.1.2: 
Treatment 
Period, Table 
7.2-1
Added specific infusion times for specific doses of 
BMS-986249
Infusion times for escalating doses 
need to be increased because of 
endotoxin limitations
7.5.1.1: 
Gastrointestin-al 
Dose Limiting 
Toxicity
Added Grade 4 diarrhea or colitis, regardless of 
duration 
Added for participant safety
7.5.1.3: 
Hematologic 
Dose Limiting 
Toxicity
Changed to neutropenic fever of any duration 
Added for participant safety
7.5.1.5: Other 
Dose Limiting 
Toxicities
Added any death not clearly due to the underlying 
disease or extraneous causes 
Added for participant safety
7.5.1.5: Other 
Dose Limiting 
Toxicities
The following Grade 3 or 4 events will not be 
considered DLTs: grade 3 fatigue lasting < 1 week
Added for participant safety
7.5.1.5: Other 
Dose Limiting 
Toxicities
Section has been revised and text has been added to 
provide general guidance for management of potential 
ocular adverse events
Added for participant safety
7.5.4:
Exceptions to 
Permanent 
Discontinua-tion 
Criteria
The following event will not lead to permanent 
discontinuation: Grade 3 fatigue < 1 week
To be consistent with comment 
above for Section 7.5.1.5
8.1: Discontinua-
tion from Study 
Treatment
Provide guidance for investigators to help distinguish 
adverse events due to BMS-986249 from those due to 
nivolumab.
General guidance and specific 
imAE and AE profiles were added 
Protocol Amendment No.: 09
Date: 14-Mar-2023
293
10.0
Approved
930119402
10.0
v
Approved
1.0
v

Clinical Protocol
CA030001
BMS-986249
Anti-CTLA-4 Probody mAb
Summary of key changes of Revised Protocol 01
Section 
Number & 
Title
Description of Change
Brief Rationale
9.8.2: Tumor 
Samples
Added fresh tumor biopsy specimens will be obtained 
prior to treatment to characterize immune cell 
populations and expression of selected tumor markers 
including dMMR and MSI-H.
Further clarify which tumor 
markers will be investigated 
Tables 2-2 and 2-
3 and Section 
9.1.1 Imaging 
Assessment for 
the Study
Corrected imaging assessment timing to Q8W and 
inserted: and at the Sponsor’s discretion, may be 
reviewed by blinded independent central review at a 
later date or at any time during the study, for image 
review
Corrected typographical errors and 
added clarifying language
Tables 2-2, 9.8.3-
1, and 9.8.4-1
Corrected on-treatment biopsy timing 
Corrected typographical errors
All
Minor formatting and typographical corrections
Minor, therefore have not been 
summarized
Protocol Amendment No.: 09
Date: 14-Mar-2023
294
10.0
Approved
930119402
10.0
v
Approved
1.0
v