A Phase 1/2 Dose Escalation and Combination Cohort Study to Evaluate the Safety and Tolerability, Pharmacokinetics, and Efficacy of BMS-986226 Alone or in Combination With Nivolumab or Ipilimumab in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Cancer, Tumors, Neoplasm, Malignancy
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 1/2 Dose Escalation and Combination Cohort Study to Evaluate the Safety and 
Tolerability, Pharmacokinetics, and Efficacy of BMS-986226 (anti-ICOS mAb) Alone or in 
Combination with Nivolumab or Ipilimumab in Patients with Advanced Solid Tumors 
 
NCT Number: NCT03251924 
Document Date (Date in which document was last revised): May 31, 2019 

Page:
1
Protocol Number:
CA021002
IND Number:
133,788
EUDRACT Number:
2017-000238-73
Date:
26-May-2017
Revised Date:
31-May-2019
CLINICAL PROTOCOL CA021002
A Phase 1/2 Dose Escalation and Combination Cohort Study to Evaluate the Safety and 
Tolerability, Pharmacokinetics, and Efficacy of BMS-986226 (anti-ICOS mAb) Alone or in 
Combination with Nivolumab or Ipilimumab in Patients with Advanced Solid Tumors
Revised Protocol 04
Study Director/Medical Monitor
Telephone (office): 
Fax: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
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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).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
04
31-May-2019
•
Fasting glucose testing was limited to the Screening Period; on-
treatment glucose testing can be non-fasting.
•
Guidance for premedication was added.
Revised Protocol 
03
02-Dec-2018
•
The eligibility criteria was modified to include additional tumor types, 
including but not limited to Cervical Cancer (CC), Melanoma (MEL), 
Renal Cell Carcinoma (RCC) and Triple Negative Breast Cancer 
(TNBC).
•
The eligibility criteria was modified to allow for up to three prior 
lines of systemic therapy.
•
The requirement for ICOS expression confirmation by IHC in pre-
treatment biopsies prior to start of treatment was removed.
•
The protocol was modified to require tetanus booster administration 
3-7 days prior to first treatment.
•
The protocol was modified to optimize sample collection for 
pharmacokinetic, pharmacodynamic 
 analysis. 
•
The option for retreatment was removed from the protocol.
Revised Protocol 
02
03-Apr-2018
•
This protocol has been revised to modify the combination escalation 
of BMS-986226 with either nivolumab (Part B) or ipilimumab (Part 
C) to include and prioritize a Q12W dosing schedule.
•
On-treatment biopsy collections were changed to Q2W and Q12W. 
•
A tetanus booster will be administered to capture pharmacodynamic 
activity in an antigen-specific context.
•
Treatment duration of BMS-986226 in combination with nivolumab 
or ipilimumab will be 2 years.
Revised Protocol 
01
20-Jul-2017
Preliminary safety cohort added
Original Protocol
26-May-2017
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OVERALL RATIONALE FOR REVISED PROTOCOL 04:
This protocol has been revised to include recommended premedication for all participants 
receiving BMS-986226 treatment. In addition, fasting glucose assessment was limited to 
Screening, while on-treatment glucose testing may be non-fasting.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Table 2-1 Screening Procedural Outline 
(CA021002); 
Table 2-2 On-treatment Procedural 
Outline (CA021002);
Table 9.4.4-1 Clinical Laboratory Tests
Fasting glucose testing 
was limited to Screening. 
On-treatment glucose 
testing may be non-fasting
To clarify that fasting 
glucose assessment is 
not required for 
subjects while on
treatment.
Synopsis; 
Table 2-2 On-treatment Procedural 
Outline (CA021002);
Section 3.3 Benefit/Risk Assessment;
Section 5.1.2.1 Monotherapy Dose 
Escalation (Preliminary Safety Cohorts 
and Part A);
Section 5.1.2.2 BMS-986226 and 
Nivolumab Combination Therapy Cohort 
(Parts B1 and B2);
Section 5.1.2.3 BMS-986226 and 
Ipilimumab Combination Therapy 
Cohort (Parts C1 and C2); 
Section 5.1.2.4 Combination Expansion 
Arms (Parts D and E);
Section 7.1 Treatments Administered
Participants are 
recommended to receive 
premedication with 
diphenhydramine and 
acetaminophen to reduce 
risk of infusion-related 
reactions.
Premedication 
recommendation was 
instituted in order to 
reduce the risk of 
infusion-related 
reactions associated 
with BMS-986226 
treatment.
Section 3.2.2.4 Clinical Pharmacology 
and Safety
Updated safety data.
Updated to provide 
most recent data.
Section 7.3.6 Management of Drug-
related Infusion Reactions
Updated data on 
drug-related infusion 
reactions. 
Updated to provide 
most recent 
data/information on 
drug-related infusion 
reactions.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Appendix 02 Study Governance 
Considerations
Updated potential serious 
breach language and 
included additional 
language updates per 
BMS protocol standards.
Updated per BMS 
protocol standards.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 04: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04 ......................... 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Research Hypothesis ................................................................................ 
3.2 Background ....................................................................................................... 
3.2.1 Indication Background ............................................................................. 
3.2.2 BMS-986226 ............................................................................................ 
3.2.2.1 Pharmacology of BMS-986226 ....................................................... 
3.2.2.2 Toxicity of BMS-986226 ................................................................. 
3.2.2.3 Nonclinical Metabolism and Pharmacokinetics of BMS-986226 ... 
3.2.2.4 Clinical Pharmacology and Safety ................................................. 
3.2.2.5 Pharmacokinetics of BMS-986226 ................................................. 
3.2.3 Nivolumab ................................................................................................ 
3.2.3.1 Pharmacology and Mechanism of Action of Nivolumab ................ 
3.2.3.2 Clinical Pharmacology and Safety of Nivolumab ........................... 
3.2.4 Ipilimumab ............................................................................................... 
3.2.4.1 Pharmacology and Mechanism of Action of Ipilimumab ............... 
3.2.4.2 Clinical Pharmacology and Safety ................................................. 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Screening.................................................................................................. 
5.1.2 Treatment Phase ...................................................................................... 
5.1.2.1 Monotherapy Dose Escalation (Preliminary Safety Cohorts and 
Part A) ................................................................................................... 
5.1.2.2 BMS-986226 and Nivolumab Combination Therapy Cohort (Parts 
B1 and B2) ............................................................................................ 
5.1.2.3 BMS-986226 and Ipilimumab Combination Therapy Cohort (Parts 
C1 and C2) ............................................................................................ 
5.1.2.4 Combination Expansion Arms (Parts D and E) .............................. 
5.1.3 Follow-up ................................................................................................. 
5.1.3.1 Safety Follow-up ............................................................................. 
5.1.3.2 Survival Follow-up.......................................................................... 
5.1.3.3 Response Follow-up ........................................................................ 
5.1.4 Treatment with Additional Cycles ............................................................ 
5.1.5 Treatment Beyond Progression ................................................................ 
5.1.6 Data Monitoring Committee and Other External Committees ................ 
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5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.4.1 Rationale for BMS-986226 First-in-Human Dose (Preliminary Safety 
Cohorts and Part A Monotherapy) ............................................................. 
5.4.2 Rationale For Treatment Duration .......................................................... 
5.4.2.1 Rationale for 24-week Duration of BMS-986226 Monotherapy ..... 
5.4.2.2 Rationale for 2-year Duration of BMS-986226 in Combination with 
Nivolumab or Ipilimumab ..................................................................... 
5.4.3 Rationale for Treatment Beyond Progression ......................................... 
5.5 Justification for Dose and Schedules for BMS-986226, Nivolumab, and 
Ipilimumab ........................................................................................................ 
5.5.1 Rationale for BMS-986226 Flat Dosing and Schedule ............................ 
5.5.2 Rationale for Nivolumab Dose Selection ................................................. 
5.5.3 Rationale for Ipilimumab Dose Schedule ................................................ 
5.5.4 Rationale for Dose-escalation Phase Design .......................................... 
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 ..................................................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.1.1 Method of Treatment Assignment ............................................................ 
7.2 Blinding............................................................................................................. 
7.3 Dosage Modification ......................................................................................... 
7.3.1 Treatment Delay ....................................................................................... 
7.3.2 BMS-986226 Dose-limiting Toxicities ..................................................... 
7.3.3 Management Algorithms for Immuno-oncology Agents .......................... 
7.3.4 Dose Delays Due To Toxicity .................................................................. 
7.3.5 Exceptions to Permanent Discontinuation Criteria ................................. 
7.3.6 Management of Drug-related Infusion Reactions.................................... 
7.4 Preparation/Handling/Storage/Accountability .................................................. 
7.4.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.5 Treatment Compliance ...................................................................................... 
7.6 Concomitant Therapy........................................................................................ 
7.6.1 Prohibited and/or Restricted Treatments................................................. 
7.6.1.1 Imaging Restriction and Precautions ............................................. 
7.6.2 Permitted Therapy ................................................................................... 
7.6.3 Palliative Local Therapy .......................................................................... 
7.7 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
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8.1.1 Criteria to Resume Treatment .................................................................. 
8.1.2 Treatment Beyond Disease Progression .................................................. 
8.1.3 Discontinuation Due to Further Progression (Confirmed Progression) . 
8.1.4 Post-study Treatment Study Follow-up .................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-up .............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Methods of Assessment ............................................................................ 
9.1.2 Primary Efficacy Assessments ................................................................. 
9.1.3 Secondary Efficacy Assessments .............................................................. 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug-induced Liver Injury ....................................................... 
9.2.8 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 .................................................. 
9.4.5 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetic and Immunogenicity Assessments ........................................ 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
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9.9 Health Economics or Medical Resource Utilization and Health Economics ... 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.1.1 Preliminary Safety Cohorts and Dose Escalation (Part A) ................... 
10.1.2 BMS-986226 and Nivolumab or Ipilimumab Combination Therapy 
Cohorts (Parts B and C) ............................................................................. 
10.1.3 Combination Expansion Arms (Parts D and E) ..................................... 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Pharmacokinetic Analyses ..................................................................... 
10.3.4 Immunogenicity Analyses ....................................................................... 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 RECIST 1.1 CRITERIA........................................................................ 
APPENDIX 6 MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS ................................................................................................................. 
APPENDIX 7 EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ................................................................................... 
APPENDIX 8 CONSORT PUBLISHING REQUIREMENTS ................................... 
APPENDIX 9 NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION ................................................................................................ 
APPENDIX 10 STATISTICAL METHODOLOGY ................................................... 
APPENDIX 11 PROSTATE CANCER WORKING GROUP 3 (PCWG3) 
GUIDELINES (WITH MODIFIED RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (RECIST) CRITERIA FOR SOFT TISSUE LESION 
ASSESSMENT) ...................................................................................................... 
APPENDIX 12 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
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SYNOPSIS
Protocol Title: A Phase 1/2 Dose Escalation and Combination Cohort Study to Evaluate the 
Safety and Tolerability, Pharmacokinetics, and Efficacy of BMS-986226 (anti-ICOS mAb) 
Alone or in Combination with Nivolumab or Ipilimumab in Patients with Advanced Solid 
Tumors
Study Phase: 1/2
Rationale:
Subsequent to the approval of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and 
programmed death-1 (PD-1) pathway-blocking agents as anti-tumor therapies, the field of tumor 
immunotherapy is expanding rapidly. In addition to blocking co-inhibitory pathways, activating 
co-stimulatory pathways with the goal of potentiating anti-tumor immune responses are now
considered a promising additional approach. With recent emerging clinical evidence that supports 
the significant anti-tumor activity of single-agent immunotherapies, combination therapies are 
now explored in an attempt to increase overall patient survival as exemplified by the combination 
therapy of anti-PD-1 and anti-CTLA-4 antibodies in patients with advanced melanoma. These 
findings raise the possibility that combining checkpoint blocking antibodies with agonistic 
antibodies that target T-cell co-stimulatory molecules could also be beneficial. 
In this study, participants with advanced tumors will be treated with BMS-986226 (an agonistic 
antibody targeting inducible T-cell co-stimulator [ICOS]) in monotherapy or in combination with
nivolumab (BMS-936558, PD-1 receptor blocking monoclonal antibody [mAb]) or ipilimumab 
(BMS-734016/MDX010; a checkpoint blocking antibody that recognizes CTLA-4).
Research hypothesis: 
It is anticipated that BMS-986226, anti-ICOS mAb, administered as single agent or in combination 
with nivolumab (BMS-936558/MDX, anti-PD-1 antibody) or ipilimumab (BMS-734016/MDX, 
anti-CTLA-4 antibody), will demonstrate acceptable safety and tolerability and a favorable 
risk/benefit profile that will support further clinical testing. No prospective hypotheses are being 
formally evaluated in this study.
Study Population:
Eligible participants will have advanced solid tumors, including, but not limited to cervical cancer 
(CC), colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), melanoma 
(MEL), non-small cell lung cancer (NSCLC), prostate cancer (PRC), renal cell carcinoma (RCC), 
triple negative breast cancer (TNBC) and urothelial carcinoma (UCC). There must be histological 
or cytological confirmation of a malignancy that is advanced (metastatic and/or unresectable) with 
measureable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1
or Prostate Cancer Working Group 3 (PCWG 3) (prostate only), including at least 1 lesion 
accessible for biopsy in addition to the target lesion.
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Objectives and Endpoints:
Objective
Endpoint
Primary
To characterize the safety and tolerability of 
BMS-986226 administered alone and in 
combination with nivolumab or ipilimumab 
in participants with advanced solid tumors
Incidence of AEs, SAEs, AEs meeting protocol 
defined DLT criteria, AEs leading to 
discontinuation, and AEs resulting in death.
Incidence of clinical laboratory test 
abnormalities
Secondary
To explore the preliminary efficacy of 
BMS-986226 administered alone and in 
combination with either nivolumab or 
ipilimumab in participants with advanced 
solid tumors
ORR, median DOR, and PFS rate at 24 weeksa
To characterize the PK of BMS-986226 
when administered alone and in 
combination with either nivolumab or 
ipilimumab in participants with advanced 
solid tumors
PK parameter estimates of BMS-986226
To characterize the immunogenicity of 
BMS-986226 when administered alone and
in combination with either nivolumab or 
ipilimumab in participants with advanced 
solid tumors
Incidence of anti-drug antibodies (ADA) 
specific for BMS-986226
To monitor target engagement of BMS-
986226 administered alone and in 
combination with either nivolumab or 
ipilimumab in participants with advanced 
solid tumors
Summary measures of changes from baseline 
(% or absolute change) in cell surface ICOS 
expression on T cells and ICOS-ligand + B cells
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a These endpoints will be assessed based on RECIST v1.1 or PCWG3 (prostate only) criteria and will be determined 
based on tumor measurements occurring every 8 weeks (± 1 week) during the treatment period and at least every 
12 weeks (± 2 week) in the response and survival follow-up periods. For Part A, scans will be collected centrally 
and may be reviewed by BICR at a later date, or at any time during the study. For Parts B, C, D and E scans will 
be collected centrally to be reviewed in real time by BICR.
Abbreviations: BICR = blinded independent central review; DLT = dose-limiting toxicity; DOR = duration of 
response; 
 ICOS-L = Inducible T-cell COStimulator ligand; ORR = objective response rate; 
 PFS = progression-free survival; PK = pharmacokinetics; 
 
TIL = tumor-infiltrating lymphocytes.
Overall Design:
•
This is a Phase 1/2, open-label study of BMS-986226 administered as a monotherapy or in 
combination with either nivolumab or ipilimumab in participants with advanced solid tumors. 
The study will be conducted in 3 parts: 1) dose-escalation monotherapy (Preliminary Safety 
Cohorts and Part A); 2) dose-escalation combination therapy with either nivolumab (Part B) 
or ipilimumab (Part C); 3) a dose expansion phase with either nivolumab (Part D) or 
ipilimumab (Part E). 
•
All participants receiving treatment with BMS-986226 in all study parts are recommended to 
receive premedication as described in Section 7.1 of the protocol. 
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•
Monotherapy consists of 2 different cohorts as follows:
−
Preliminary Safety Cohorts with BMS-986226 administered as monotherapy at 2 mg and 
8 mg once every 4 weeks (Q4W) for 24 weeks
−
Part A, with BMS-986226 administered at 25 mg, 80 mg, 200 mg, 400 mg, and 800 mg 
Q4W for 24 weeks
•
The study will first evaluate the safety and tolerability of BMS-986226 administered Q4W, 
given alone, based on dose-limiting toxicities (DLTs), guided by a Bayesian Logistic 
Regression Model (BLRM) employing the escalation with overdose control principle.
•
Parts B and C consist of different combination cohorts comprising: 
−
B1: BMS-986226 administered every 12 weeks (Q12W) + nivolumab 480 mg Q4W at 
three dose levels of BMS-986226.
−
B2: BMS-986226 Q4W + nivolumab 480 mg Q4W at up to three dose levels of BMS-
986226 evaluated in part B1.
−
C1: BMS-986226 Q12W + ipilimumab 3 mg/kg Q4W at three dose levels of BMS-986226.
−
C2: BMS-986226 Q4W + ipilimumab 3 mg/kg Q4W at up to three dose levels of BMS-
986226 evaluated in part C1.
•
Parts B1 and C1 will enroll concurrently. Parts B2 and C2 will enroll if additional safety, PK, 
or PD data is required to optimize dose and/or schedule selection, and can enroll concurrently 
with B1 and C1.
•
BMS-986226 will be administered as a single agent (Preliminary Safety Cohorts and Part A),
in combination with either nivolumab (Part B or Part D) or ipilimumab (Part C or Part E) in
disease-restricted populations as follows: 
−
Preliminary Safety Cohorts and Part A: CC, CRC, HNSCC, MEL, NSCLC, RCC, PRC, 
TNBC and UCC
−
Parts B and C: CC, CRC, HNSCC, MEL, NSCLC, RCC, PRC, TNBC and UCC
−
Parts D and E: To be determined based on safety, tolerability, PK, and PD data from Parts 
A, B, and C
Starting dose selection of BMS-986226 for the combination therapy cohorts will be one dose level 
lower than the highest monotherapy dose (Part A) that has cleared the DLT period. Subsequent 
doses of BMS-986226 will be determined based on all available safety (clinical and laboratory) 
and PK data, as well as changes in peripheral target engagement markers (eg, ICOS 
downregulation on T cells and ICOS + B cells) previous and completed portions of current cohorts, 
and BLRM-Copula model.
•
The Preliminary Safety Cohorts consists of a single participant per dose level with 
BMS-986226 administered as monotherapy at 2 mg or 8 mg Q4W for up to 24 weeks of study 
treatment. Additional participants may be enrolled in the Preliminary Safety Cohorts per dose 
level as early as 5 days after the first participant is treated at each dose level to gather additional 
information on the safety, PK, and pharmacodynamic (PD) profile. The DLT period will be 28 
days (4 weeks) in the Preliminary Safety Cohorts. Once the safety (during the 4 weeks DLT 
period) of 2 mg and 8 mg of BMS-986226 has been established in a single, independent 
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participant per dose, Part A will start. Intra-participant dose escalation is only allowed in the 
Preliminary Safety Cohorts as follows:
−
Once the observation period of 4 weeks for 8 mg is completed, participant(s) treated at 
2 mg may be offered the possibility to dose escalate at 8 mg.
−
Once the DLT period of 5 weeks for 25 mg is completed, participant(s) treated at 2 mg that 
escalated to 8 mg or participant(s) treated with 8 mg may be offered the possibility to dose 
escalate at 25 mg.
•
Part A consists of a multiple ascending dose schema that will evaluate the following dose
levels of BMS-986226: 25 mg, 80 mg, 200 mg, 400 mg, and 800 mg. Enrollment in the next 
dose level can begin after at least 2 evaluable participants have completed 5 weeks of therapy 
(during the DLT evaluation) at the preceding dose level and the available safety data has been 
reviewed. Up to approximately 34 participants with the tumor types listed above may be treated
during this part of the study (Preliminary Safety Cohorts and Part A).
•
Part B1 and Part B2 are dose escalation combination cohorts that consists of BMS-986226 
administered in combination with nivolumab for duration of 2 years in the disease-restricted 
populations listed above. Part B1 is a combination cohort that consist of BMS-986226 
administered every 12 weeks (Q12W) + nivolumab 480 mg Q4W. Part B2 is a combination 
cohort that consists of BMS-986226 Q4W + nivolumab 480 mg Q4W at a dose level of 
BMS-986226 tested in Part B1. Up to 3 different dose levels of BMS-986226 will be tested in 
Part B1, as determined by safety, PK and PD data. The starting dose level used in combination 
with nivolumab (Part B) will be one dose level lower than a monotherapy (Part A) dose that 
has cleared the DLT period. At each dose level, approximately 6 evaluable participants will be 
treated, where a sentinel participant will be enrolled in Part B1 (BMS-986226 Q12W + 
nivolumab 480 mg Q4W) and observed for 5 days before additional participants in Part B1 at 
the same dose level receive study treatment. Part B2 (BMS-986226 Q4W + nivolumab 480 mg 
Q4W) will be opened at dose levels evaluated in Part B1. Approximately 6-12 evaluable 
participants will be treated per cohort, to better characterize safety, PK, and PD of the 
combination. Part B2 will be utilized to provide a more granular assessment of safety and PD
of BMS-986226. More than 1 dose level (no more than 3 different dose levels) may be enrolled, 
should additional safety, PK, and PD data be needed. Once the safety (during the DLT 
evaluation) of a combination of BMS-986226 and nivolumab has been established and a 
recommended BMS-986226 dose regimen has been selected for Part D, additional participants 
(up to 6 additional evaluable participants) may be treated at the recommended dose to better 
characterize the safety, PK, and PD profile.
•
Part C1 and Part C2 are dose escalation combination cohorts that consist of BMS-986226 
administered in combination with ipilimumab for duration of 2 years in the disease-restricted 
populations listed above. Part C1 is a combination cohort that consists of BMS-986226 
administered every 12 weeks (Q12W) + ipilimumab 3 mg/kg Q4W. Part C2 is a combination 
cohort that consists of BMS-986226 Q4W + ipilimumab 3 mg/kg Q4W at a dose level of BMS-
986226 tested in Part C1. Part C1 aims to determine the kinetics of ICOS receptor 
downregulation and re-expression (and/or change in selected target engagement/
) following administration of BMS-986226 Q12W in combination with ipilimumab 
administered Q4W for a duration of 2 years. Continuous evaluation of toxicity events in the 
combination cohort will be performed throughout the enrollment. Up to 3 different dose levels 
of BMS-986226 will be tested in Part C1, as determined by safety, PK and PD data. At each 
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dose level, approximately 6 evaluable participants will be treated, where a sentinel participant
will be enrolled in Part C1 (BMS-986226 Q12W + ipilimumab 3mg/kg Q4W) and observed 
for 5 days before additional participants in Part C1 at the same dose level receive study 
treatment. Part C2 (BMS-986226 Q4W + ipilimumab 3 mg/kg Q4W) will be opened at dose 
levels evaluated in Part C1. Approximately 6-12 evaluable participants will be treated per dose 
cohort, to better characterize safety, PK, and PD of the combination. Part C2 will be utilized 
to provide a more granular assessment of safety and PD of BMS-986226. More than 1 dose 
level (no more than 3 different dose levels) may be enrolled, should additional safety, PK, and 
PD data be needed. Once the safety (during the DLT evaluation) of a combination of BMS-
986226 and ipilimumab has been established and a recommended BMS-986226 dose regimen 
has been selected for Part E, additional participants (up to 6 additional evaluable participants)
may be treated at the recommended dose to better characterize the safety, PK, and PD profile. 
•
Part D and Part E are cohort expansion that consist of BMS-986226 in combination with 
either nivolumab (Part D) or ipilimumab (Part E). Continuous evaluation of toxicity events in 
the cohort expansions will be performed throughout enrollment in the expansion cohorts. If, at 
any time, the aggregate rate of treatment-related toxicities meeting DLT criteria exceeds 33% 
across all participants treated, the findings will be discussed and further enrollment will be 
interrupted. Depending on the nature and the grade of the toxicity, and after assessing the 
risk/benefit ratio, a new dose for all cohorts may be initiated at a lower dose level. The dose 
and schedule of BMS-986226 in Parts D and E will be determined based on all available safety, 
tolerability, efficacy, PK, and PD data from Parts A, B, and C. Parts D and E will enroll 
approximately 40 participants in each cohort. Safety, efficacy, PK, and PD data will be used 
to determine the precise patient population that will be enrolled in the expansion arms.
•
Participants will be enrolled using the Interactive Response Technology (IRT) during the 
screening phase.
•
For Parts A, scans will be collected centrally and may be reviewed by BICR at a later date or 
at any time during the study. For Parts B, C, D and E scans will be collected centrally to be 
reviewed in real time by BICR.
Number of Participants: 
The number of participants for this study will be approximately 234. Up to approximately 34 of 
these participants may be treated with monotherapy (Preliminary Safety Cohorts and Part A); 
approximately 6 evaluable participants may be treated at each dose level for Parts B1 and C1; 
approximately 6-12 evaluable participants may be treated at each dose level for Parts B2 and C2;
up to 6 additional evaluable participants may be treated in Parts B and/or C at a recommended 
BMS-986226 dose regimen for Parts D and/or E to better characterize the safety, PK, and PD
profile; approximately 80 participants will be treated in combination expansion arms, Parts D and 
E.
Study Phases and Duration:
Screening: The screening phase will last for up to 28 days and take place prior to the first 
administration of study treatment for all parts. During the screening phase, the participant’s initial 
eligibility will be established and written informed consent will be obtained. Tumor biopsies 
collected for all participants will be centrally evaluated for
ICOS expression by 
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immunohistochemistry (IHC). Stool samples will be collected for baseline microbiota composition 
analysis. All participants will receive the tetanus booster vaccine 3-7 days prior to Cycle 1 Day 1 
of first administration of study treatment. Participants will be allocated to treatment groups using 
the Interactive Response Technology (IRT). 
Treatment Phase: 
•
Preliminary Safety Cohorts: The planned dose levels of BMS-986226 in the Preliminary Safety 
Cohorts will be 2 mg and 8 mg Q4W for 24 weeks. Following each treatment cycle, the 
decision to treat a participant with additional cycles of study treatment (up to a maximum of 
24 weeks), will be based on safety and tolerability and tumor assessments performed every 
8 weeks (±1 week).
•
Part A: The initial dose level of BMS-986226 in Part A will be 25 mg Q4W for 24 weeks. 
Planned dose levels for dose escalation are 80, 200, 400, and 800 mg. Participants may be 
treated for up to 24 weeks. Following each treatment cycle, the decision to treat a participant 
with additional cycles of study treatment (up to a maximum of 24 weeks), will be based on 
safety and tolerability and tumor assessments performed every 8 weeks (± 1 week).
•
Part B1: Combination therapy will consist of BMS-986226 administered every 12 weeks 
(Q12W) + nivolumab 480 mg administered in 4-week cycles for up to 2 years of treatment.
Following each treatment cycle, the decision to treat a participant with additional cycles of 
study treatment, will be based on safety and tolerability and tumor assessments performed 
every 8 weeks (± 1 week).
•
Part B2: Combination therapy will consist of BMS-986226 administered every 4 weeks (Q4W) 
+ nivolumab 480 mg administered in 4-week cycles for up to 2 years of treatment. Following 
each treatment cycle, the decision to treat a participant with additional cycles of study 
treatment, will be based on safety, tolerability, and tumor assessments performed every 
8 weeks (± 1 week).
•
Part C1: Combination therapy will consist of BMS-986226 administered every 12 weeks 
(Q12W) + ipilimumab 3 mg/kg Q4W for up to 2 years of treatment. Following each treatment 
cycle, the decision to treat a participant with additional cycles of study treatment, will be based 
on safety, tolerability, and tumor assessments performed every 8 weeks (± 1 week).
•
Part C2: Combination therapy will consist of BMS-986226 administered every 4 weeks (Q4W) 
+ ipilimumab 3 mg/kg Q4W for up to 2 years of treatment. Following each treatment cycle, 
the decision to treat a participant with additional cycles of study treatment, will be based on 
safety, tolerability, and tumor assessments performed every 8 weeks (± 1 week).
The treatment phase in the Preliminary Safety Cohort and Part A consists of up to six 4-week 
treatment cycles (1 cycle = 28 days). In the Preliminary Safety Cohort and Part A, each treatment 
cycle will consist of BMS-986226 monotherapy for a total of 24 weeks.
In Parts B1 and C1, 4 week cycles will be used, such that BMS-986226 + nivolumab or ipilimumab 
will be administered starting on Cycle 1 Day 1. Nivolumab and ipilimumab will be administered 
on Day 1 of each cycle. BMS-986226 will be administered Q12W, or on Day 1 of every third cycle 
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(Cycle 1 Day1, Cycle 4, Day1, Cycle 7 Day1, etc.). Participants on Parts B1 and C1 may continue 
treatment for up to a total of 2 years.
The treatment phase in Parts B2 and C2 will consist of BMS-986226 + nivolumab or ipilimumab 
administered on Day 1 of each cycle for up to a total of 2 years. Participants in Parts B2 and C2 
will be enrolled if additional safety, PK, or PD data is required to optimize dose and/or schedule 
selection.
Follow-up: Safety follow-up will occur 30, 60, and 100 days (± 7 days) after either the last dose 
or the date of discontinuation. All participants treated with monotherapy or combination therapy 
will enter the survival follow-up period after the last safety visit. All participants treated with 
monotherapy or combination therapy with ongoing stable disease (SD), partial response (PR), or 
complete response (CR) will enter the response follow-up period after the last safety visit. If the 
participant discontinues treatment for any reason other than PD, radiological follow-up will 
continue until the participant receives additional treatment.
The duration of this phase is up to 2 years from the last dose of study treatment, although a longer 
follow-up period could be considered in selected cases if an efficacy signal is apparent. Survival
follow-up will continue approximately every 3 months (12 weeks) until death, loss to follow-up
or subsequent treatment, withdrawal of consent, or conclusion of the study, whichever comes first. 
Participants who have disease progression following the initial course of study treatment will not 
be evaluated for response beyond the end of treatment visit and will be allowed to receive other 
tumor-directed therapy as required. 
A study design schematic is provided in Figure 1-1.
Figure 1-1:
Study Design Schematic
* Note: Arms B2 and C2 will enroll only if additional safety, PK, and PD data are required to inform dose expansion 
decisions. The dose levels assessed in B2 and C2 will not exceed those evaluated in Part A, B1, or C1.
Abbreviations: CC = cervical cancer; CRC = colorectal carcinoma; HNSCC = head and neck squamous cell 
carcinoma; 
MEL = melanoma; 
NSCLC = non-small-cell 
lung 
cancer;
RCC = renal 
cell 
carcinoma;
PRC = adenocarcinoma of the prostate; RD = receptor downregulated; TNBC = triple negative breast cancer;
UCC = urothelial carcinoma.
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Study treatment: 
Study Treatment for CA021002
Medication 
Potency 
IP/Non-IP 
BMS-986226-01
10 mg/mL
IP
Nivolumab
10 mg/mL
IP
Ipilimumab
5 mg/mL
IP
Tetanus vaccine
Per locala
IP
a Tetanus vaccine (Tdap preferred, Td or equivalent after discussion with the Study Director/Medical Monitor (or 
designee)) will be obtained as local commercial product in countries if allowed by local regulations or through 
investigating sites standard prescribing procedures.
IP = investigational product.
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA021002)
Procedure
Screening Visit
(Day -28
to -1)
Day -7 to 
-3 Visit
Day -3 to 
-1 Visit
Notes
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol specific informed 
consent is signed.
IRT Participant 
Assignment/Treatment 
Assignment
X
After the participant consents, the site will use the IRT to have the participant 
number assigned. After the participant has completed all screening procedures, 
IRT will be used for treatment assignment or discontinuing the participant. 
Subsequent visits will need to be registered into the IRT system for drug supply. 
Inclusion/Exclusion Criteria
X
Medical History
X
Includes history of any toxicities or allergy related to previous treatments, 
irAEs, cardiac signs/symptoms/disease, and immunization (eg, influenza 
vaccine).
Prior Systemic Therapies
X
Tobacco History/Status
X
Document participant’s history and current status of tobacco use.
Archived Tumor Tissue 
Sample
X
Additional archival tumor tissue samples, if available, may be provided for 
participants in all parts as 1 paraffin block or 15-20 FFPE unstained slides. 
Samples must be shipped to central laboratory.
Fresh Pretreatment Tumor 
Biopsy
X
All participants require a mandatory pretreatment biopsya during 
screening.
Archival specimens may not be substituted for this baseline specimen (See
Section 6.1 for exceptions) but can be submitted to help understand the 
evolution of the tumor (ie, ICOS expression changes over time).
Tumor tissue to be sent for assessment of tumor content and ICOS expression.
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Table 2-1:
Screening Procedural Outline (CA021002)
Procedure
Screening Visit
(Day -28
to -1)
Day -7 to 
-3 Visit
Day -3 to 
-1 Visit
Notes
and C4D1-pre-dose. The biopsy after dose escalation will be optional in 
participants in the Preliminary Safety Cohorts who intra-dose escalate up to 
8 and/or 25 mg
Safety Assessments
Full Physical Exam (PE)
X
If the screening physical examination is performed within 24 hours prior to 
dosing on Cycle 1 Day 1, then a single examination may count as both the 
screening and pre-dose evaluation.
Physical Measurements
X
Includes height and weight.
ECOG Performance Status
X
See Appendix 7.
Vital Signs
X
Includes body temperature, respiratory rate, as well as seated blood pressure and 
heart rate. Blood pressure, respiratory rate, and heart rate should be measured 
after the participant has been seated for at least 5 minutes. 
12-lead ECG
X
12-lead electrocardiograms should be recorded after the participant has been 
supine for at least 5 minutes. 
All screening ECG tests should be performed as a single ECG.
Laboratory Tests
Laboratory tests listed below must be completed within 2 weeks of 
Cycle 1Day 1 unless otherwise noted. 
Chemistry
X
See Section 9.4.4, Table 9.4.4-1. Includes assessments for sodium, potassium, 
chloride, total serum calcium, magnesium, carbon dioxide, phosphorus, BUN, 
creatinine, creatinine kinase, CrCl (screening only), fasting glucose (screening 
only; on-treatment assessments do not require fasting), total protein, albumin, 
amylase, lipase, CRP, LDH, AST, ALT, total bilirubin, direct bilirubin (reflex 
only), ALP, GGT (reflex only), and Testosterone (PRC only).
CBC with Differential and 
Platelets
X
Urinalysis
X
Urine to be checked for protein, glucose, blood, leukocyte esterase, specific 
gravity, and pH. Microscopic examination of sediment if positive for blood, 
protein, or leukocyte esterase on dipstick.
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Table 2-1:
Screening Procedural Outline (CA021002)
Procedure
Screening Visit
(Day -28
to -1)
Day -7 to 
-3 Visit
Day -3 to 
-1 Visit
Notes
Thyroid Function Tests
X
TSH with reflex to free T3 and T4.
Serum Tumor Markers 
X
Should be performed for tumor types, included in this study, with known 
serologic markers (eg, CEA, CA19-9, and PSA)
Viral Status
X
HNSCC and CC only: Sites should submit and document prior human 
papillomavirus (HPV) status within 28 days of dosing.
Serology Tests
X
Within 28 days of dosing: hepatitis B surface antigen and hepatitis C antibody 
(if positive reflex to hepatitis C RNA) or hepatitis C RNA.
Note: Testing for HIV-1 and HIV-2 must be performed at sites, only where 
mandated by local requirements.
Pregnancy Test
X
For WOCBP only; serum/urine pregnancy test must be performed (urine 
pregnancy test: minimum sensitivity 25 IU/L or equivalent units of hCG) at 
screening and within 24 hours prior to dosing. The serum pregnancy test may be 
completed on the first day of treatment provided that the results are available 
before the start of study treatment. If performed within 24 hours of dosing on 
Cycle 1 Day 1, then Cycle 1 Day 1 pregnancy test is not required.
Follicle-stimulating 
Hormone
X
Women only, if needed to document postmenopausal status (refer to 
Appendix 4).
Tetanus booster
X
To be performed on all participants in preliminary safety cohort, Parts A, B1, 
B2, C1, C2, D and E, using an approved tetanus vaccine. 
The tetanus booster must be administered between Day -7 and Day -3, prior to 
dosing. A tetanus booster does not have to be administered if the participant 
received a tetanus booster within 6 weeks of starting study drug.
AE Reporting and Concomitant Medication Assessments
Clinical Complaints
X
Complaints related to the disease under study collected during
the 2 weeks prior to dosing.
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Table 2-1:
Screening Procedural Outline (CA021002)
Procedure
Screening Visit
(Day -28
to -1)
Day -7 to 
-3 Visit
Day -3 to 
-1 Visit
Notes
Concomitant Medications
X
All concomitant medications taken within 4 weeks prior to study treatment 
administration must be recorded on the CRF.
Monitor for SAEs
X
All SAEs must be collected from the date of participant’s written consent until 
100 days after last dose of study drug. eSAEs should be approved in the 
electronic capture system within 5 business days of entry.
Efficacy Assessments
Body Imaging
X
See Section 9.1.
Brain Imaging
X
See Section 9.1. As clinically indicated (eg, participants with history or 
symptoms of brain metastasis).
Bone Scan
X
See Section 9.1. As clinically indicated (eg, participants with history or 
symptoms of bone metastases). Bone scans will not be considered a modality 
for assessment for measurable disease.
a Samples collected after the last cancer treatment (either systemic or local) will be considered as fresh biopsies.
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
C1 = Cycle 1; CA19-9 = cancer antigen 19-9; CBC = complete blood count; CEA = cancer embryonic antigen; CrCl = creatinine clearance; CRF = Case Report 
Form; CRP = C-reactive protein; D1 = Day 1; 
 ECOG = Eastern Cooperative Oncology Group; eSAE = electronic serious adverse 
event; FFPE = formalin-fixed paraffin-embedded; GGT = gamma-glutamyl transferase; HIV = human immunodeficiency virus; ICOS = Inducible T-cell 
COStimulator; IRT = Interactive Response Technology; LDH = lactate dehydrogenase; NSCLC = non-small-cell lung cancer; PD-L1 = programmed death 
ligand 
1; 
PSA = prostate-specific 
antigen; 
RNA = ribonucleic 
acid; 
SAE = serious 
adverse 
event; 
T3 = triiodothyronine; 
T4 = thyroxine; 
TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
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Table 2-2:
On-treatment Procedural Outline (CA021002)
Procedures for Safety 
Cohort, and Parts A, B, 
C, D and Ea,b
C1
C2 to 
beyond
C2 
Only
C2 
Only
Notes
Procedure
D1
D2
D8
± 1
days
D15
± 1
days
D22
± 1
days
D1
D2
D8
± 1
days
EOT
c,d,e
Safety Assessments
Full PE
X
X
Pre-dose (Cycle 1 Only)
Symptom-directed PE
X
X
X
X
X
To include signs and symptoms
Physical measurements
X
X
Includes weight only. Should be collected on 
Day 1 of every cycle, prior to start of 
treatment. 
ECOG Performance 
Status
X
X
X
ECOG score (Appendix 7).
Vital Signs
X
X
X
See note in Table 2-1.
For BMS-986226, vital signs will be obtained 
before the infusion and then every 15 minutes 
(± 5 minutes) until 4 hours after completion of 
the infusion on Cycle 1 Day 1. For cycle 2
Day 1 and every infusion thereafter, vital 
signs will be obtained before the infusion and 
then every 15 minutes (± 5 minutes) for 60 
minutes after the completion of the infusion, 
For nivolumab or ipilimumab, vital signs will 
be obtained before the infusion and then every 
30 minutes (± 10 minutes) until the start of 
BMS-986226 infusion or per institution 
guidelines for administration of nivolumab or 
ipilimumab. The 30-minute post nivolumab or 
ipilimumab infusion vital signs may 
correspond to the pre-infusion BMS-986226 
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Table 2-2:
On-treatment Procedural Outline (CA021002)
Procedures for Safety 
Cohort, and Parts A, B, 
C, D and Ea,b
C1
C2 to 
beyond
C2 
Only
C2 
Only
Notes
Procedure
D1
D2
D8
± 1
days
D15
± 1
days
D22
± 1
days
D1
D2
D8
± 1
days
EOT
c,d,e
vital signs. In the event BMS-986226 
administration is delayed, nivolumab or 
ipilimumab vital signs will be obtained until 
60 minutes after completion of the infusion.
If any vital sign is abnormal (based on 
clinician assessment) at the final check, the 
participant must be observed further for a 
period of time, as clinically indicated.
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Table 2-2:
On-treatment Procedural Outline (CA021002)
Procedures for Safety 
Cohort, and Parts A, B, 
C, D and Ea,b
C1
C2 to 
beyond
C2 
Only
C2 
Only
Notes
Procedure
D1
D2
D8
± 1
days
D15
± 1
days
D22
± 1
days
D1
D2
D8
± 1
days
EOT
c,d,e
Laboratory Tests
See Section 9.4.4.
On-study laboratory tests (including 
pregnancy testing) to be done on site/local 
within 72 hours prior to dosing on Day 1 of 
each cycle.
Chemistry
X
X
X
X
X
X
X
X
X
See note in Table 2-1. On-treatment Glucose 
is not required to be fasting.
Every cycle on Day 1.
For parts B1 and C1, Cycle 2 Day 2 only and 
Cycle 2 Day 8 only, assessments should take 
place on Cycle 4 Day 2 and Cycle 4 Day 8. 
CBC with Differential 
and Platelets
X
X
X
X
X
X
X
X
X
Should also be collected at each time point 
where samples 
 are 
collected
 
 For parts B1 and 
C1, Cycle 2 Day 2 only and Cycle 2 Day 8 
only assessments should take place on Cycle 4 
Day 2 and Cycle 4 Day 8.
Thyroid Function Tests
X
X
(see 
notes)
To include TSH with reflex testing (free T3 
and free T4), if applicable. Results should be 
examined by the investigator or appropriate 
designee within 48 hours of dose 
administration. To be performed during odd 
cycles (eg, Cycles 1, 3, and 5) only.
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Table 2-2:
On-treatment Procedural Outline (CA021002)
Procedures for Safety 
Cohort, and Parts A, B, 
C, D and Ea,b
C1
C2 to 
beyond
C2 
Only
C2 
Only
Notes
Procedure
D1
D2
D8
± 1
days
D15
± 1
days
D22
± 1
days
D1
D2
D8
± 1
days
EOT
c,d,e
Urinalysis
As clinically indicated.
See note in Table 2-1. 
See Section 9.4.4.
Pregnancy Test 
(WOCBP)
X
X
X
Serum/urine pregnancy test must be 
performed (urine pregnancy test: minimum 
sensitivity 25 IU/L or equivalent units of 
hCG) within 24 hours prior to administration 
of study treatment.
If the pregnancy test result is positive, hold all 
study treatments and perform confirmatory 
testing. If pregnancy is confirmed, 
permanently discontinue all study treatment 
and immediately notify BMS Medical 
Monitor/Study Director or designee
(see Section 9.2.5).
AE Reporting and Concomitant Medication Assessments
Concomitant Medication 
Assessments
X
Review prior to dosing.
Monitor for Non-serious 
AEs
X
Non-serious AEs will be collected starting 
with the first dose of study treatment and 
through 100 days after last dose of study drug, 
or until new anti-cancer treatment is initiated, 
whichever comes first.
Monitor for SAEs
X
See note in Table 2-1.
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Table 2-2:
On-treatment Procedural Outline (CA021002)
Procedures for Safety 
Cohort, and Parts A, B, 
C, D and Ea,b
C1
C2 to 
beyond
C2 
Only
C2 
Only
Notes
Procedure
D1
D2
D8
± 1
days
D15
± 1
days
D22
± 1
days
D1
D2
D8
± 1
days
EOT
c,d,e
Sample Collection
PK Assessments
See Table 9.5-1, Table 9.5-2, Table 9.5-3, and Table 9.5-4
See Section 9.5. To be performed in all 
participants.
Immunogenicity 
Assessments
See Table 9.5-1, Table 9.5-2, Table 9.5-3, and Table 9.5-4.
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Table 2-2:
On-treatment Procedural Outline (CA021002)
Procedures for Safety 
Cohort, and Parts A, B, 
C, D and Ea,b
C1
C2 to 
beyond
C2 
Only
C2 
Only
Notes
Procedure
D1
D2
D8
± 1
days
D15
± 1
days
D22
± 1
days
D1
D2
D8
± 1
days
EOT
c,d,e
Efficacy Assessments
Body Imaging
Every 8 
weeks 
(± 1
week) 
prior to 
dosing 
at C3 
and C5
X
See Section 9.1.
Brain Imaging
For participants with history of brain metastases, surveillance 
scans to be done per standard of care frequency, or sooner if 
clinically indicated.
See Section 9.1.
Bone Scan
As clinically indicated.
See Table 2-1.
See Section 9.1.
Study Treatment Administration
Details regarding preparation and 
administration are provided in site training 
materials.
In all study parts, participants will be 
observed for at least 60 minutes following the 
completion of BMS-986226 infusion due to 
the potential risk of, and to monitor for, 
infusion reactions.
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Table 2-2:
On-treatment Procedural Outline (CA021002)
Procedures for Safety 
Cohort, and Parts A, B, 
C, D and Ea,b
C1
C2 to 
beyond
C2 
Only
C2 
Only
Notes
Procedure
D1
D2
D8
± 1
days
D15
± 1
days
D22
± 1
days
D1
D2
D8
± 1
days
EOT
c,d,e
All Parts:
Premedication
X
X
In all study parts, participants are 
recommended to receive premedication
30 minutes prior to infusion of any study 
drug, to reduce the risk of infusion-related 
reactions, as described in Section 7.1 and 
Section 7.3.6. Any modification to the 
recommended regimen must be discussed and 
agreed upon with BMS Medical 
Monitor/Study Director.
All Parts:
BMS-986226 
Administration
X
X
Use vials assigned per IRT.
Safety Cohort and Part A
BMS-986226 will be administered every 4 
weeks on the first day of each cycle
Parts B1 and C1:
BMS-986226 will be administered on Day 1 
every 12 weeks (Cycle 1 Day1, Cycle 4 Day1, 
Cycle 7 Day 1, etc)
Parts B2 and C2:
BMS-986226 will be administered every 4 
weeks on the first day of each cycle 
Parts D and E: 
The dose and schedule of BMS-986226 will 
be determined based on available data from 
Parts A, B1, B2, C1 and C2.
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Table 2-2:
On-treatment Procedural Outline (CA021002)
Procedures for Safety 
Cohort, and Parts A, B, 
C, D and Ea,b
C1
C2 to 
beyond
C2 
Only
C2 
Only
Notes
Procedure
D1
D2
D8
± 1
days
D15
± 1
days
D22
± 1
days
D1
D2
D8
± 1
days
EOT
c,d,e
Parts B1, B2, and D 
ONLY:
Nivolumab 
Administration
X
X
Use vials assigned per IRT. Nivolumab is 
administered ONLY for those participants 
enrolled in Parts B1, B2, and D.
Parts C1, C2, and E 
ONLY:
Ipilimumab 
Administration
X
X
Use vials assigned per IRT. Ipilimumab is 
administered ONLY for those participants 
enrolled in Parts C1, C2 and E.
a The procedural outline for participants who receive additional cycles are outlined in Table 2-4.
b Participants taking 2 or 8 mg of BMS-986226 in the Preliminary Safety Cohorts will follow the same procedure schedule as in Part A. In the event that participants 
taking 2 or 8 mg of BMS-986226 should be permitted to intra-dose escalate up to 8 and/or 25 mg, the sampling schedule should be restarted at Cycle 1 Day 1 at 
each dose escalation, and an additional tumor biopsy may be optionally re-collected at C1D15.
c EOT is defined as the visit where a decision is made to discontinue the participant from treatment.
d 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, Cycle 6 
Day 175) and the start of the Week 1 safety follow-up visit.
e 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 does not need to be repeated, and it will be considered the start of the Week 1 safety follow-up visit.
Abbreviations: AE = adverse event; C1 = Cycle 1; C2 = Cycle 2; C3 = Cycle 3; C5 = Cycle 5; C6 = Cycle 6; CBC = complete blood count; 
; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; D1 = Day 1; D2 = Day 2; D4 = Day 4; D8 = Day 8; 
D15 = Day 15; 
D21 = Day 21; 
hCG = human 
chorionic 
gonadotropin; 
IRT = Interactive 
Response 
Technology; 
PE = physical
examination; 
PK = pharmacokinetic; PD = pharmacodynamic; Q12W = every 12 weeks; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; 
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
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Table 2-3:
Follow-up Procedural Outline (CA021002)
Procedure
Safety Follow-upa
Survival/Response Long-term Follow-up
Notes
FU 1
30 days
(± 7 days) 
FU 2
60 days
(± 7 days)
FU 3
100 days
(± 7 days)
Begins After Completion of Safety 
Follow-up Q12W (Q12W ± 2 weeks) 
Until 2 Years After Last Dose of Study 
Treatment
Safety Assessments
Symptom-directed PE
X
X
X
Symptom-directed only.
ECOG Performance Status
X
X
X
ECOG score (Appendix 7)
Vital Signs
X
X
X
See note in Table 2-1.
Laboratory Tests
See note in Table 2-1.
Chemistry
X
X
X
See note in Table 2-1.
CBC with Differential and 
Platelets
X
X
X
See note in Table 2-2.
Thyroid Function Tests
X
X
X
See note in Table 2-2.
Urinalysis
As clinically indicated.
See Section 9.4.4.
See note in Table 2-1.
Pregnancy Test
X
X
X
See note in Table 2-2.
AE Reporting
Concomitant Medication 
Assessments
X
X
X
Monitor for Non-serious 
AEs
X
X
X
See note in Table 2-2.
Monitor for SAEs
X
X
X
See note in Table 2-1.
Sample Collection
PK Assessments
See Table 9.5-1, Table 9.5-2, Table 9.5-
3, and Table 9.5-4
See Section 9.5.
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Table 2-3:
Follow-up Procedural Outline (CA021002)
Procedure
Safety Follow-upa
Survival/Response Long-term Follow-up
Notes
FU 1
30 days
(± 7 days) 
FU 2
60 days
(± 7 days)
FU 3
100 days
(± 7 days)
Begins After Completion of Safety 
Follow-up Q12W (Q12W ± 2 weeks) 
Until 2 Years After Last Dose of Study 
Treatment
Immunogenicity (eg, ADA) 
Assessments
Efficacy Assessments 
Body Imaging
X
Xb
See Section 9.1. Participants should 
undergo tumor assessment via 
CT/MRI scans at least Q12W during 
the survival follow-up period until 
beginning a new anti-cancer therapy.
Brain Imaging
For participants with history of brain metastases, surveillance scans to be done per 
standard of care frequency, or sooner if clinically indicated.
See Section 9.1.
Bone Scan
As clinically indicated.
See Section 9.1.
Assessment of Participant
Survival Status
X
Participant status will be assessed by 
either a clinic visit or a telephone 
contact.
New Anti-cancer Therapies
X
X
X
X
Any new anti-cancer therapies 
(including surgery and radiotherapy) 
will be recorded.
a Follow-up visits at Days 30, 60, and 100 (± 7 days each) should occur after the last dose or on the date of discontinuation (± 7 days).
b Only participants with SD, PR, or CR at the EOT visit.
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CBC = complete blood count; CR = complete response; CT = computed tomography; 
ECOG = Eastern Cooperative Oncology Group; FU = follow-up; MRI = magnetic resonance imaging; PE = physical examination; PK = pharmacokinetic;
PD = pharmacodynamic; PR = partial response; Q12W = every 12 weeks; SAE = serious adverse event; SD = stable disease.
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Table 2-4:
Additional Treatment Procedural Outline (CA021002)
Procedure
Additional Cycles
EOTa,b,c
Notes
D1
Safety Assessments
Full PE
X
Cycle 1 only.
Symptom-directed PE
X
X
Cycles 2 and beyond. To include signs and symptoms.
Physical Measurements
X
Includes weight.
ECOG Performance Status
X
X
ECOG score (See Appendix 7).
Vital Signs
X
X
For BMS-986226, vital signs will be obtained before the infusion and then 
every 15 minutes (± 5 minutes) until 60 minutes after completion of the 
infusion.
Laboratory Test
See Section 9.4.4.
On-study laboratory tests (including pregnancy testing) to be done on 
site/local within 72 hours prior to dosing.
Chemistry
X
X
See Section 9.4.4, Table 9.4.4-1. Includes assessments for sodium, 
potassium, chloride, total serum calcium, magnesium, carbon dioxide, 
phosphorus, BUN, creatinine, creatinine kinase, CrCl, fasting glucose, 
total protein, albumin, amylase, lipase, CRP, LDH, AST, ALT, total 
bilirubin, direct bilirubin (reflex only), ALP, and GGT (reflex only).
CBC with Differential and 
Platelets
X
X
Thyroid Function Tests
X
X
To include TSH with reflex testing (free T3 and free T4), if applicable. 
Results should be examined by the investigator or appropriate designee 
within 48 hours of dose administration.
Urinalysis
X
X
See Section 9.4.4.
Pregnancy Test (WOCBP)
X
X
Serum/urine pregnancy test must be performed (urine pregnancy test: 
minimum sensitivity 25 IU/L or equivalent units of hCG) within 24 hours 
prior to administration of study treatment.
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anti-ICOS
Table 2-4:
Additional Treatment Procedural Outline (CA021002)
Procedure
Additional Cycles
EOTa,b,c
Notes
D1
If the pregnancy test is positive, hold all study treatments and perform 
confirmatory testing. If pregnancy is confirmed, permanently discontinue 
all study treatment and immediately notify BMS Medical Monitor/Study 
Director or designee (see Section 9.2.5).
AE Reporting and Concomitant Medication Assessments
Clinical Complaints
X
To be completed within 2 weeks of Day 0 only if participant entered 
survival follow up.
Concomitant Medication 
Assessments
X
Review prior to dosing.
Monitor for Non-serious 
AEs
X
Non-serious AEs will be collected starting with the first dose of study 
medication and through 100 days after last dose of study drug.
Monitor for SAEs
X
See note in Table 2-1.
Efficacy Assessments
Body Imaging
Every 8 weeks (± 1 week)
prior to dosing at C3 and C5
X
See Section 9.1.
Brain Imaging
For participants with history of brain metastases, 
surveillance scans to be done per standard of care 
frequency, or sooner if clinically indicated.
See Section 9.1.
Bone Scan
As clinically indicated.
See Section 9.1.
Study Treatment Administration
Details regarding preparation and administration are provided in site 
training materials.
All Parts:
BMS-986226 
Administration
X
Use vials assigned per IRT.
Safety Cohort and Part A
BMS-986226 will be administered every 4 weeks on the first day of each 
cycle
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a EOT is defined as the visit where a decision is made to discontinue the participant from treatment.
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, Cycle 6 Day 175) and the start of the Week 1 safety follow-up visit.
c 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 does not need to be repeated, and it will be considered the start of the Week 1 safety follow-up visit.
Abbreviations: AE = adverse event; D1 = Day 1; C = Cycle; CBC = complete blood count; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; 
hCG = human chorionic gonadotropin; IRT = Interactive Response Technology; min = minutes; PE = physical examination; PK = pharmacokinetic; 
Q12W = every 12 weeks; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
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Table 2-5:
Additional Treatment Follow-up Procedural Outline (CA021002)
Procedure
Safety Follow-upa
Survival/Response Long-term Follow-up
FU 1
30 days
(± 7 days) 
FU 2
60 days
(± 7 days)
FU 3
100 days
(± 7 days)
Begins After Completion of Safety 
Follow-up Q12W (± 2 weeks) Until 2 years 
After Last Dose of Study Treatment
Notes
Safety Assessments
PE
X
X
X
Symptom-directed only.
ECOG Performance 
Status
X
X
X
ECOG score (Appendix 7)
Vital Signs
X
X
X
See note in Table 2-1.
Laboratory Tests
See note in Table 2-1.
Chemistry
X
X
X
See note in Table 2-1.
CBC with Differential 
and Platelets
X
X
X
See note in Table 2-2.
Thyroid Function Tests
X
X
X
See note in Table 2-2.
Urinalysis
X
X
X
See note in Table 2-1.
Pregnancy Test
X
X
X
See note in Table 2-2.
AE Reporting and Concomitant Medication Assessments
Monitor for Non-
serious AE
X
See note in Table 2-2.
Monitor for SAE
X
See note in Table 2-1.
Concomitant 
Medication 
Assessments
X
Efficacy Assessments
Body Imaging
X
Xb
See Section 9.1.
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anti-ICOS
Table 2-5:
Additional Treatment Follow-up Procedural Outline (CA021002)
Procedure
Safety Follow-upa
Survival/Response Long-term Follow-up
FU 1
30 days
(± 7 days) 
FU 2
60 days
(± 7 days)
FU 3
100 days
(± 7 days)
Begins After Completion of Safety 
Follow-up Q12W (± 2 weeks) Until 2 years 
After Last Dose of Study Treatment
Notes
Brain Imaging
For participants with history of brain metastases, surveillance scans to be done per standard 
of care frequency, or sooner if clinically indicated.
See Section 9.1.
Bone Scan
As clinically indicated.
See Section 9.1.
Assessment of 
Participant Survival 
Status
X
Participant status will be assessed by 
either a clinic visit or a telephone 
contact.
New Anti-cancer 
Therapies
X
X
X
X
Any new anti-cancer therapies 
(including surgery and radiotherapy) 
will be recorded.
a Follow-up visits at Days 30, 60, and 100 (± 7 days) should occur after the last dose or on the date of discontinuation (± 7 days).
b Except for participants who start new anti-cancer therapies, participants with SD, PR, or CR at the EOT visit should undergo tumor assessment via CT/MRI 
scans at least Q12W during the survival follow-up period until progression.
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CBC = complete blood count; CR = complete response; ECOG = Eastern Cooperative Oncology 
Group; EOT = end of treatment; FU = follow-up; PE = physical examination; PK = pharmacokinetic; PD = pharmacodynamic; PR = partial response; 
Q12W = every 12 weeks; SAE = serious adverse event; SD = stable disease.
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In the event of multiple procedures are required at a single time point, the ECG may be obtained 
up to 15 minutes earlier, vital signs may be obtained up to 10 minutes earlier or later, and clinical 
laboratory sample may be obtained up to 5 minutes earlier than the nominal time point, ensuring 
the PK samples can be collected on time.
3
INTRODUCTION
CA021002 is a Phase 1/2, first-in-human (FIH), ascending, multiple-dose study of BMS-986226, 
an Inducible T-cell - COStimulator (ICOS; cluster of differentiation [CD]278) agonist monoclonal 
antibody (mAb), in humans with advanced/metastatic solid tumors as monotherapy or in 
combination with either nivolumab (programmed death 1 [PD-1] receptor blocking mAb) or 
ipilimumab (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4], an activation-induced T-cell 
surface molecule that binds CD80 and CD86).
This study will evaluate the safety profile, tolerability, pharmacokinetics
(PK), and 
pharmacodynamics (PD) of intravenous (IV) doses of BMS-986226 administered as monotherapy 
or in combination with either nivolumab or ipilimumab in participants with advanced solid tumors, 
including but not limited to, cervical cancer (CC), colorectal cancer (CRC), head and neck 
squamous cell carcinoma (HNSCC), melanoma (MEL), non-small cell lung cancer (NSCLC), 
adenocarcinoma of the prostate (PRC), renal cell carcinoma (RCC), triple negative breast cancer 
(TNBC) and urothelial carcinoma (UCC).
3.1
Study Rationale
Antibody-based therapy for cancer has become established in recent years and is now one of the 
most successful and important strategies for treating patients with hematological malignancies and 
advanced solid tumors.1 Aside from targeting antigens that are involved in cancer cell proliferation 
and survival, antibodies can also function to either activate or inactivate immunological pathways 
that are important in cancer immune surveillance.2 It is now clear that an antigen-specific 
anti-cancer immune response is the result of a complex dynamic interplay between antigen
presenting cells (APCs), T lymphocyte cells (T cells), and the target cancer cells. The critical 
balance of T-cell activity that dictates whether endogenous anti-tumor immune responses will be 
effective are largely understood to be controlled by antigen-specific stimuli sensed by the T-cell 
receptor and by the combined activity of both positive (co-stimulatory) and negative 
(co-inhibitory) T-cell surface molecules.3 Within the past decade, antibodies against these key 
receptors have been designed and evaluated in the clinic with impressive results, heralding the 
onset of immunotherapy as a key pillar of anti-cancer therapy.4
The most extensively studied immunotherapies in cancer target the negative regulatory receptors
CTLA-4 or PD-1.5 Inhibition of these negative regulatory receptors, referred to as immune 
checkpoint blockade, results in the enhanced activation of T-cell responses and potent anti-tumor 
activity in nonclinical models. Studies with CTLA-4 blockade provided the first clinical evidence 
of improvement in overall survival (OS) with immune modulatory anti-cancer therapy in patients 
with metastatic melanoma.6,7 Following that, Topalian et al showed that anti-PD-1 antibody 
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therapy resulted in objective responses in patients with melanoma, NSCLC, and renal cell 
carcinoma (RCC).8
Subsequent to the success of anti-tumor treatment with CTLA-4 and PD-1 pathway-blocking 
agents, the field of tumor immunotherapy is expanding rapidly. In addition to blocking 
co-inhibitory pathways, activating co-stimulatory pathways to potentiate anti-tumor immune 
responses is being considered as a promising approach.9 With recent emerging clinical evidences
of significant anti-tumor activity of single-agent immunotherapies, combination therapies are now 
explored because they could lead to greater depth of response and OS. This has been observed
with the combination therapy of anti-PD-1 and anti-CTLA-4 antibodies in patients with advanced 
melanoma. It also raises the possibility that combining checkpoint blocking antibodies with 
agonistic antibodies targeting T-cell co-stimulatory molecules could be beneficial. Nonclinical 
data evaluating this type of treatment combination in mouse tumor models indicate that 
combination treatment indeed leads
to enhanced anti-tumor activity compared with
single-agent- treatment.
Administration of ipilimumab has been shown to up-regulate ICOS expression on the surface of 
CD4 and CD8 effector T cells in patients with superficial bladder cancer and advanced 
melanoma.10 Patients with ≥2-fold increase in percentage of circulating CD4+ICOShi expression 
that was sustained at Week 12 showed clinical benefit, while patients with < 2-fold increase did 
not, thus suggesting a role for ICOS+ T cells in supporting anti-tumor activity after administration 
of ipilimumab (n = 14). 
Nivolumab treatment results in increased ICOS gene expression in tumor biopsies in patients with 
both RCC and melanoma.11,12 The increase in ICOS expression after both ipilimumab and 
nivolumab treatment suggests that the ICOS pathway is an appealing target for an agonist antibody
in combination with either nivolumab or ipilimumab, alone or as a combination.
ICOS costimulation potently induces T-cell activation and cytokine production, and agonism of 
ICOS on T-effector cells (Teffs) should further enhance antitumor activity. The activity of an ICOS 
agonist may provide the most benefit in combination with checkpoint inhibitors that induce ICOS 
expression (eg, ipilimumab or nivolumab) and in patients whose T cells are not receiving an 
optimal costimulatory signal through ICOS due to low expression of Inducible T-cell 
COStimulator ligand (ICOS-L) at the tumor site. 
In this study, participants with advanced tumors will be treated with BMS-986226 (an agonistic 
antibody targeting ICOS) monotherapy or BMS-986226 in combination with nivolumab (a 
checkpoint blocking antibody [anti-PD-1 antibody]) or ipilimumab (a checkpoint blocking 
antibody [anti-CTLA-4 antibody]) to take advantage of this enhanced anti-tumor effect.
3.1.1
Research Hypothesis
It is anticipated that an anti-ICOS mAb (BMS-986226) administered as a single agent or in 
combination with nivolumab (BMS-936558/MDX1106, anti-PD-1 antibody) or ipilimumab 
(BMS-734016/MDX010, anti-CTLA-4 antibody) demonstrates adequate safety and tolerability, as 
well as a favorable risk/benefit profile, to support further clinical testing.
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anti-ICOS
3.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of BMS-986226 is 
provided in the Investigator’s Brochure (IB).
3.2.1
Indication Background
It is hypothesized that tumors with more frequent ICOS-expressing tumor infiltrating immune cells 
and less frequent or non-proximal ICOS-L-expressing cells will respond to ICOS agonist mAb 
(BMS-986226) therapy. In addition, the presence of FcγRII (CD32), particularly the FcγRIIB 
(CD32B) isoform, will be required for cross-linking and the anti-tumor activity of BMS-986226. 
To explore which tumor types may respond better to ICOS mAb therapy, immunohistochemistry
(IHC) assessment of ICOS, ICOS-L, and CD32B expression using commercial mAbs against these 
proteins was performed on adjacent formalin-fixed paraffin-embedded (FFPE) sections. Several 
tumors were analyzed, including CRC, HNSCC, melanoma, NSCLC-adenocarcinoma type 
(NSCLC-AD), NSCLC-squamous cell type (NSCLC-SQC), PRC, RCC, and UCC. 
As expected, specific ICOS staining was observed in cells morphologically resembling small 
lymphocytes. CD32B staining was observed in cells with a morphology of either a plasma cell or 
a small lymphocyte. While ICOS-expressing and CD32B-expressing cells were primarily 
distributed in tumor stroma, ICOS-L staining was seen in cells with the morphology of a small 
lymphocyte or tumor cells in a subset of cases. Automated image analysis using HALO software 
on whole slide images revealed a relatively high expression of ICOS and CD32B and low 
expression of ICOS-L in HNSCC, melanoma, and NSCLC-AD, and relatively high expression of
ICOS and low ICOS-L and CD32B expression in UCC, but relatively low ICOS and CD32B 
expression and high ICOS-L expression in CRC, PRC, and RCC. NSCLC-SQC demonstrated a 
relatively low ICOS and high ICOS-L and CD32B expression. 
External evaluation of ICOS gene expression in a variety of epithelial solid tumors demonstrated 
similar results, with HNSCC, NSCLC, TNBC, gastric carcinoma and CC exhibiting highest ICOS 
mRNA expression.13 Based on the aforementioned hypothesis, these preliminary datasets support 
initial development of BMS-986226 in multiple advanced tumors, including HNSCC, NSCLC, 
TNBC, CC and MEL. However, ICOS is also known to be upregulated upon treatment with 
ipilimumab.10 Therefore, tumors that have baseline low expression of ICOS, may become more 
favorable to co-stimulation in the presence of anti-CTLA-4 or anti-PD-1 therapy. Given this 
observation, in this study testing of BMS-986226 will be expanded to all advanced epithelial solid 
tumors, including previously identified low-ICOS expressing tumors, such as CRC, PRC, RCC,
and UCC.
3.2.2
BMS-986226
3.2.2.1
Pharmacology of BMS-986226
The nonclinical pharmacology of BMS-986226 was evaluated in vitro, including binding to cells 
characterized by flow cytometry and Scatchard analysis and binding to human FcγRs characterized 
by surface plasmon resonance. In vitro functional assays elevated activation of T cells, antibody-
driven effector function in antibody-dependent cellular cytotoxicity assays, and complement 
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binding assays. Cytokine release from whole blood was not observed following BMS-986226 
treatment. BMS-986226 was evaluated for binding to human and cynomolgus tissues and ICOS 
expression was characterized by flow cytometry on human tumor-infiltrating lymphocytes (TILs). 
BMS-986226 was found to overcome T-regulatory cell (Treg) activity in in vitro suppression 
assays. In vivo, surrogate mouse binding ICOS agonists were evaluated for anti-tumor activity and 
PD effects in syngeneic mouse tumor models.
Further information on the pharmacology of BMS-986226 is detailed in the IB.14
3.2.2.2
Toxicity of BMS-986226
The nonclinical safety of BMS-986226 was evaluated in vitro in a human tissue cross-reactivity 
study and in cytokine-release and lymphocyte-activation assays in human cells. In vivo, 
BMS-986226 was evaluated in exploratory repeat-dose IV toxicity studies in rats and cynomolgus 
monkeys. In addition, an exploratory single- and repeat-dose (2-week) IV toxicity study was 
conducted in mice using BMS-986246, a surrogate anti-mouse ICOS agonistic antibody with 
identical complementarity-determining regions (hamster-derived) as BMS-986226, with mouse Fc 
domains, and with comparable affinity for mouse ICOS. 
In a Good Laboratory Practice (GLP)compliant tissue cross-reactivity study in normal human 
tissues, staining was consistent with known ICOS expression on T cells and demonstrated binding 
of BMS-986226- fluorescein isothiocyanate (FITC) on the membrane of a subset of mononuclear 
cells (consistent with lymphocytes) in lymphoid tissues and other tissues with mononuclear 
infiltrates. BMS-986226 did not induce cytokine release or increase the expression of activation 
markers on human T, B, or natural killer (NK) cells.
The mouse, rat, and cynomolgus monkey were evaluated in toxicology studies because 
BMS-986226 binds to ICOS receptors expressed on activated T cells from mice, rats, and 
cynomolgus monkeys with comparable affinity as ICOS expressed on activated human T cells 
(concentration required for 50% efficacy values of 0.13 nM to 0.87 nM), and is pharmacologically 
active. 
To explore the feasibility of pivotal rodent studies, single-dose (mouse only) and repeat-dose 
exploratory studies in rats with BMS-986226 and in mice with BMS-986246 were conducted. 
BMS-986226 and BMS-986246 resulted in mortality in rats and mice, respectively, after repeated 
administration. These mortalities were considered secondary to anti-drug antibody 
(ADA)-mediated hypersensitivity reactions based on the nature and timing of clinical signs, 
presence of serum ADA in affected animals, and elevated serum cytokine levels and evidence of 
complement activation in rats. Therefore, rodent species were considered not suitable for further 
toxicity assessment in pivotal studies. It should be noted that as described in International 
Conference on Harmonisation (ICH) S6, the induction of ADA formation in animals is not 
predictive of a potential for ADA formation in humans.
In the GLP 1-month IV toxicity study in cynomolgus monkeys, doses of 0, 1.5 mg/kg (every 
3 weeks [Q3W], 2 total doses), and 15 mg/kg or 75 mg/kg (once every week (Q1W), 5 total doses), 
were administered as a slow bolus injection. BMS-986226 was clinically well tolerated at all doses 
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without any adverse effects. No significant irritation or local tolerance issues were observed at the 
injection sites following repeated IV administration of BMS-986226 as a slow bolus injection at 
≤75 mg/kg in cynomolgus monkeys.
BMS-986226-related findings were limited to PD and immunomodulatory effects at all doses that 
included ICOS receptor expression (RE)/receptor occupancy (RO) changes (for CD4 helper 
T cells), suppression of T-dependent antigen response to keyhole limpet hemocyanin, decreased 
levels of T cells (including total T cells, CD4 helper T cells, CD4 Tregs, central memory CD4 T 
cells, and central memory CD8 T cells), decreased CD4 T-cell activation, and decreased 
percentages of antigen-specific CD8 T cells. Many of these changes persisted up to the end of the 
recovery period at ≥15 mg/kg Q1W consistent with continued BMS-986226 exposure throughout 
the recovery period and the subsequent sustained ICOS receptor downregulation at these doses. In 
general, ICOS RE levels inversely correlated with serum BMS-986226 concentrations. Based on 
the lack of adverse findings, the high dose of 75 mg/kg (Q1W, mean sex-combined area under the
concentration-time curve (AUC) from time zero to 168 hours [AUC(0-168h)=452,000 μg•h/mL]) 
was considered the no-observed-adverse-effect level (NOAEL). In addition, for determination of 
the human maximum recommended starting dose (MRSD), 75 mg/kg was also considered the 
highest nonseverely toxic dose (HNSTD). The HNSTD/NOAEL of 75 mg/kg in cynomolgus 
monkeys is 250× higher than the proposed starting dose in humans (0.3 mg/kg) with a 
corresponding plasma AUC multiple of 102× the projected human AUC at the starting dose 
(approximately 4425 μg•h/mL; see Section 5.4.1).
Overall, the nonclinical toxicology assessment of BMS-986226 has demonstrated an acceptable 
safety profile, supporting clinical use in oncology patients. Additional details are provided in the 
BMS-986226 IB.
3.2.2.3
Nonclinical Metabolism and Pharmacokinetics of BMS-986226
This section summarizes the data available from a series of in vivo PK and PD studies that were 
conducted with BMS-986246 (ICOS.4-mIgG1, an anti-mouse surrogate antibody being used as a 
rodent surrogate for BMS-986226) and BMS-986226 in mice and cynomolgus monkeys, 
respectively. 
In mice, following a single IV bolus dose of 1 mg/kg, the serum concentrations of BMS-986246 
exhibited a bi-exponential decline.15 The serum clearance was 1.8 mL/h/kg and the apparent 
terminal half-life in serum (T-HALF) was 0.65 hours. After a single intraperitoneal dose of 0.1, 1, 
or 10 mg/kg, BMS-986246 was slowly absorbed, with a time of maximum observed plasma 
concentration (Tmax) of 6 to 24 hours, and the absolute bioavailability was 38%, > 100%, and 
> 100%, respectively; reasons for the higher bioavailability at higher doses are not known. Over 
this dose range, increases in exposure were more than dose proportional; with a dose ratio of 
1:10:10, respectively, and the maximum observed plasma concentration (Cmax) and AUC from 
time zero extrapolated to infinite time values increased in the proportion of 1:13:177 and 1:33:599, 
respectively.
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After IV dosing to cynomolgus monkeys, the systemic exposure of BMS-986226 increased in a 
dose-proportional manner between 1 and 10 mg/kg.15 Extracellular distribution was limited in both 
mice and cynomolgus monkeys.
No in vitro or in vivo metabolism studies have been conducted with BMS-986226. In accordance 
with the regulatory guidelines for biotechnology-derived pharmaceuticals,16 the expected in vivo 
degradation of mAbs is to small peptides and amino acids via biochemical pathways that are 
generally understood and independent of typical small-molecule, drug-metabolizing enzymes.
In accordance with regulatory guidelines for biotechnology-derived pharmaceuticals,16 no mass 
balance studies with BMS-986226 were conducted in animals.
3.2.2.4
Clinical Pharmacology and Safety
BMS-986226 has been administered to 21 participants between October 2017 and 28-March-2019, 
in doses ranging from 2 mg to 200 mg. All described data are preliminary and subject to change. 
Nineteen of 21 treated participants received BMS-986226 monotherapy. Monotherapy treatment 
was well tolerated. Grade 1/2 infusion reactions have been reported in 7 of 19 participants, and 
have been clinically manageable. A Grade 3 drug-related hypersensitivity was reported for a 
participant in the 80 mg cohort during BMS-986226 infusion after the above data cut-off date. 
Two participants have been treated with BMS-986226 in combination with ipilimumab, with no 
adverse events (AEs) reported as of the 28-March-2019 data cut-off date.
Given the small number of participants treated with BMS-986226, the subsequent more detailed
evaluation of safety is based on information from nonclinical studies, as described in Section 3.2.2, 
as well as preliminary clinical study data.
As described in ICH S6, the induction of ADA formation in animals is not predictive of a potential 
for ADA formation in humans. Since BMS-986226 is a humanized mAb, it is expected to be less 
immunogenic in humans; however, it has the potential to induce the development of ADAs
following administration. Preliminary data suggests that ADAs are formed in participants treated 
with BMS-986226. The relationship between the incidence of infusion reactions and emergence 
of ADAs is currently unknown based on the small number of treated participants. However, most 
infusion reactions are occurring during the first infusion of BMS-986226, while the ADAs are
detected 2-4 weeks following the initial BMS-986226 administration. Additionally, because BMS-
986226 will be evaluated in combination with either nivolumab or ipilimumab, it is possible that 
this combination may increase the development of BMS-986226 ADA versus BMS-986226 
monotherapy. In combination therapy, BMS-986226 may potentiate immune-related adverse 
reactions caused by nivolumab or ipilimumab. Potential safety concerns and recommended 
management guidelines regarding nivolumab- or ipilimumab-induced AEs are summarized in the 
nivolumab IB17 and ipilimumab IB.18
Immuno-modulatory antibodies, which provide activation signals to T cells, also have the potential 
to cause cytokine release. Nonclinical data indicate that BMS-986226 does not induce cytokine 
release when incubated with human peripheral blood mononuclear cells (PBMC). In addition, 
administration of nivolumab and/or ipilimumab monotherapy or combination therapy in clinical 
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studies did not produce AEs related to cytokine release syndrome. There is no evidence that BMS-
986226 will induce cytokine release syndrome when administered in combination.
BMS-986226 did not cause cytokine release or activation of lymphocytes when incubated with 
human PBMCs, and tissue cross-reactivity studies revealed staining of only mononuclear cells in 
various tissues (no off-target binding). Thus, the expected effects are anticipated to be limited to 
activated CD4 and CD8 T lymphocytes and T regs.
3.2.2.5
Pharmacokinetics of BMS-986226
BMS-986226 has been administered to 12 participants to date, at four different doses; therefore, 
insufficient data are available to clearly characterize human pharmacokinetics. Based on 
nonclinical data, the PK of BMS-986226 are expected to be similar to those of other mAbs. The 
predicted PK estimates for total plasma clearance (CL), volume of distribution, and T-HALF of 
BMS-986226 following IV administration are 0.079 mL/h/kg, 0.066 L/kg, and 25 days, 
respectively. All projected human exposures are expected to be less than those exposures deemed 
safe in the nonclinical toxicology studies.
3.2.3
Nivolumab
3.2.3.1
Pharmacology and Mechanism of Action of Nivolumab
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.19,20,21
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor.22 Collectively, these signals govern the 
balance between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA-4, ICOS, and B- and T-lymphocyte attenuator (BTLA). 23 PD-1 signaling has been shown 
to inhibit CD-28-mediated up-regulation of interleukin (IL)-2, IL-10, IL-13, interferon-γ (IFN-γ) 
and Bcl-xL. PD-1 expression also been noted to inhibit T-cell activation and expansion of 
previously activated cells. Evidence for a negative regulatory role of PD-1 comes from studies of 
PD-1 deficient mice, which develop a variety of autoimmune phenotypes.24 These results suggest 
that PD-1 blockade has the potential to activate anti-self T-cell responses, but these responses are 
variable and dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is 
not accompanied by a universal loss of tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands programmed death ligand-1 (PD-L1) and programmed 
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death ligand-2 (IC50 1.04 nM and 0.97 nM, respectively). Nivolumab binds specifically to PD-1 
and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. 
Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement of both 
proliferation and IFN-γ release in the mixed lymphocyte reaction. Using a cytomegalovirus (CMV) 
re-stimulation assay with human PBMC, the effect of nivolumab on antigen specific recall 
response indicates that nivolumab augmented IFN-γ secretion from CMV-specific memory T cells 
in a dose-dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine 
analog of nivolumab enhances the anti-tumor immune response and results in tumor rejection in 
several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).25
3.2.3.2
Clinical Pharmacology and Safety of Nivolumab
The PK of nivolumab were studied in participants over a dose range of 0.1 to 10 mg/kg 
administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The geometric 
mean (coefficient of variation [CV]%) CL was 9.5 mL/h (49.7%), geometric mean volume of 
distribution at steady state was 8.0 L (30.4%), and geometric mean elimination T-HALF was 
26.7 days (101%). Steady-state concentrations of nivolumab were reached by 12 weeks when 
administered at 3 mg/kg every 2 weeks (Q2W), and systemic accumulation was approximately 
3-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 
10 mg/kg administered Q2W. The clearance of nivolumab increased with increasing body weight. 
The population pharmacokinetic (PPK) analysis suggested that the following factors had no 
clinically important effect on the CL of nivolumab: age (29 to 87 years), gender, race, baseline 
lactate dehydrogenase, PD-L1, solid tumor type, baseline tumor size, and hepatic impairment.
Although Eastern Cooperative Oncology Group (ECOG) status, baseline glomerular filtration rate 
(GFR), albumin level, and body weight had an effect on nivolumab CL, the effect was not 
clinically meaningful. When nivolumab is administered in combination with ipilimumab, the CL 
of nivolumab was increased by 24%, whereas there was no effect on the clearance of ipilimumab. 
Additionally, PPK and exposure response analyses have been performed to support use of 240 mg 
Q2W dosing in addition to the 3 mg/kg Q2W regimen. Using the PPK model, exposure of 
nivolumab at a 240-mg flat dose was identical to a dose of 3 mg/kg for participants weighing 
80 kg, which was the approximate median body weight in nivolumab clinical studies.
Full details on the clinical pharmacology aspects of nivolumab can be found in the nivolumab
IB.17
3.2.4
Ipilimumab
3.2.4.1
Pharmacology and Mechanism of Action of Ipilimumab
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin (Ig) superfamily that competes with CD28 for B7. CTLA-4-mediated signals are 
inhibitory and turn off T-cell-dependent immune responses.26 Ipilimumab is a fully human 
monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from human 
and nonhuman primates. The proposed mechanism of action for ipilimumab is interference of the 
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interaction of CTLA-4 with B7 molecules on APCs, with subsequent blockade of the inhibitory 
modulation of T-cell activation promoted by the CTLA-4/B7 interaction.
Additional details are provided in the current version of the ipilimumab IB.18
3.2.4.2
Clinical Pharmacology and Safety
Phase 3 programs are ongoing in melanoma, PRC, and lung cancer. The safety profile of 
ipilimumab is generally consistent across these 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 events 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 addition, a completed, large, Phase 2 study (Study CA184041) has investigated the addition of 
ipilimumab to carboplatin and paclitaxel using 2 different schedules (concurrent and phased) in 
participants with NSCLC or small cell lung cancer.
Ipilimumab offers a clinically meaningful and statistically significant survival benefit to 
participants with pretreated advanced melanoma (as 3 mg/kg monotherapy compared with the 
melanoma peptide vaccine gp100) and previously untreated advanced melanoma (at 10 mg/kg in 
combination with dacarbazine [DTIC] compared with DTIC alone), and there was evidence of 
clinical activity in randomized studies in other tumor types.
The PK of ipilimumab has been extensively studied in participants with melanoma at the 3- and 
10-mg/kg dose administered as an IV infusion. The mean CL (± standard deviation [Std. Dev.]) 
value after IV administration of 10 mg/kg was 18.3 ± 5.88 mL/h, and the mean steady-state 
volume of distribution (± Std. Dev.) value was 5.75 ± 1.69 L. The PPK of ipilimumab was studied 
in participants with advanced melanoma in 4 Phase 2, 1 Phase 3, and 1 Phase 1 studies. The PPK 
analysis demonstrated that the PK of ipilimumab was linear, the exposures were dose proportional 
across the tested dose range of 0.3 to 10 mg/kg, and the model parameters were time invariant, 
similar to those determined by noncompartmental analyses.
Additional details are provided in the current version of the ipilimumab IB.18
3.3
Benefit/Risk Assessment
Participants who have advanced solid tumors have a poor prognosis, few treatment options, and 
the majority will die of disease.
Immunotherapy with ipilimumab or nivolumab has demonstrated clinical activity in a percentage 
of participants with MEL, NSCLC, RCC, HNSCC, and other tumors. Treatment-related AEs 
include those associated with autoimmune activation, such as colitis, pneumonitis, thyroiditis, 
hepatitis, and adrenal insufficiency.
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical studies with no 
MTD reached at any dose tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) AEs 
with relatively few related, high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, 
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severity, or causality of AEs with respect to nivolumab dose level. A pattern of immune-related 
AEs has been defined, for which management algorithms have been developed; these are provided 
in Appendix 6. Most high-grade events were manageable with the use of corticosteroids or 
hormone replacement therapy (endocrinopathies) as instructed in these algorithms. 
Additional details on the safety profile of nivolumab and ipilimumab, including results from other 
clinical studies, are available in the respective IBs.
Preclinical Toxicology
Three anti-ICOS antibodies have entered the clinic for evaluation in humans (NCT02520791, 
NCT02904226, and NCT02723955), however, published safety data are not available. Since no 
anti-ICOS class of compounds has been marketed, and BMS-986226 has never been administered 
to humans, data to inform the safe conduct of FIH studies are mainly based on the toxicology 
studies in monkeys.
The safety of BMS-986226 has been extensively evaluated in nonclinical models. Based on 
nonclinical data in cynomolgus monkeys, administration of single or multiple doses of 
BMS-986226 is expected to be well tolerated at all the doses proposed for this FIH clinical study. 
Efficacy of the anti-ICOS mAb has been evaluated as monotherapy or in combination with either 
anti-PD-1 or anti-CTLA-4 in multiple tumor-bearing mouse models. Based on the nonclinical data, 
the combination of BMS-986226 and nivolumab or ipilimumab is expected to exert anti-tumor 
activity across multiple tumor types.
In the absence of clinical studies with BMS-986226, the evaluation of risk is based on information 
from nonclinical studies with BMS-986226 in cynomolgus monkeys (Section 3.2.2.2), and 
potential effects are based on the proposed mechanism of action and clinical evidence from 
nivolumab or ipilimumab therapy. 
The nonclinical GLP toxicology assessment of BMS-986226 has demonstrated a dose-related 
toxicity profile of immune-related AEs (irAEs) and cytokine-release potential compatible with the 
expected mechanism of action. Overall, there were no adverse findings observed in the nonclinical 
toxicology studies that identify specific safety concerns for using BMS-986226 in the proposed 
clinical study as a single agent. The nonclinical safety of BMS-986226 was evaluated in vitro in a 
human tissue cross-reactivity study and in cytokine-release and lymphocyte-activation assays in 
human cells. In vivo, BMS-986226 was evaluated in exploratory repeat-dose IV toxicity studies 
in rats (≤30 mg/kg) and cynomolgus monkeys (≤75 mg/kg; pivotal study). In addition, an 
exploratory single- and repeat-dose (2-week) IV toxicity study was conducted in mice using 
BMS-986246, a surrogate anti-mouse ICOS agonistic antibody with identical complementarity-
determining regions (hamster-derived) as BMS-986226 with mouse Fc domains, and with 
comparable affinity for mouse ICOS. While toxicities associated with ADA formation limited the 
usefulness of this animal model, the results are not expected to be predictive of human response to 
ADA. As described in ICH S6, the induction of ADA formation in animals is not predictive of a 
potential for ADA formation in humans. A detailed explanation of the nonclinical toxicology 
program for BMS-986226 is described in Section 3.2.2.2 and in the IB.
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Overall Risk/Benefit for Combination with Nivolumab or Ipilimumab
In combination therapy of BMS-986226 and nivolumab or ipilimumab, as observed in the 
combination of ipilimumab and nivolumab, it is possible that a higher incidence of irAEs may 
occur with the combination of the 2 antibodies. The safety profiles of nivolumab and ipilimumab 
monotherapy and the combination of ipilimumab and nivolumab are well defined based on 
experience with more than 12,300 patients evaluated in clinical studies. 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 IBs for nivolumab17 and 
ipilimumab18. Unanticipated side effect events may also occur.
Summary
The proposed clinical study of BMS-986226 has been designed to minimize the overall risk to 
participants; thus, measures will include:
•
A sentinel participant will be utilized for all dose escalation cohorts in monotherapy 
(Preliminary Safety Cohorts and Part A) and all cohorts in combination therapy (Parts B and 
C; see Section 5.1.2).
•
Continuous safety assessments will be utilized by the investigators and Sponsor to determine 
whether dose modification, additional safety measures, or termination of the study is required 
at any time. In addition, AEs and SAEs will be reviewed on an ongoing basis by the Bristol-
Myers Squibb (BMS)
Medical Monitor/Study Director
(or designee) and Global 
Pharmacovigilance and Epidemiology representatives to monitor for any safety signals or 
trends. As BMS-986226 is an experimental agent, it is possible that unforeseen, unknown, or 
unanticipated reactions may occur. However, based on the nonclinical safety profile of 
BMS-986226 and the 250-fold exposure margin (based on the nonclinical HNSTD of 75 mg/kg 
in cynomolgus monkeys) built into the planned starting dose of 25 mg (flat dose), the potential 
safety risks are expected to be minimized. 
•
The administration will occur at infusion centers with medical monitoring and the capability 
to manage infusion reactions or anaphylaxis. Premedications are recommended to be 
administered prior to BMS-986226 infusion, as described in Section 7.1 and 7.3.6. Participants 
will be observed for at least 60 minutes following the completion of BMS-986226 infusion 
due to the potential risk of, and to monitor for, infusion reactions. The protocol provides a 
treatment algorithm for infusion reactions (see Section 7.3.6 and Appendix 6). In addition to 
conventional safety measures for infusion of biologic agents, all participants will undergo 
observation and assessment for signs of infusion reaction post-infusion after all infusions of 
BMS-986226.
•
Furthermore, to assess for potential effects of lymphocyte activation, dose-limiting toxicities 
(DLTs) will be recorded for all the cohorts in monotherapy and in combination with nivolumab 
or ipilimumab. 
•
Management algorithms for nivolumab- and ipilimumab-induced AEs involving GI, renal, 
pulmonary, hepatic, endocrine, skin, and neurologic systems are included in the protocol 
(see Section 7.3.3).
•
Participants who develop irAEs may require prolonged treatment with high-dose 
corticosteroids and other immunosuppressive agents. This could increase the risk of 
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opportunistic infections. IrAE management algorithms in the protocol recommend antibiotic 
prophylaxis against opportunistic infections in such situations.
•
Complete blood counts and chemistry (including liver enzyme) tests will be carried out prior 
to administration of study treatment and on a weekly basis during the first 4 weeks of treatment 
in monotherapy or in combination between BMS-986226 and nivolumab or ipilimumab. In 
addition, a complete physical examination (PE) will be conducted on Cycle 1 Day 1 along with 
weekly symptom-directed targeted PEs during the first 5 to 6 weeks of treatment. Due to the 
potential risk of exaggerated inflammatory response, participants with autoimmune disorders, 
chronic hepatitis, or who are at risk for flare of autoimmunity will be excluded.
In conclusion, there may be no direct benefit to participants treated with BMS-986226, and the 
potential exists for study treatment-related toxicity. However, there may be potential direct benefit 
to participants in this study including the following: both single-agent and combined therapy with 
these investigational agents may result in a greater proportion of participants with stabilization of 
disease, objective response, or increased DOR than those observed with standard therapy or other 
investigational immunotherapy. It is also possible that both single-agent and combined therapy 
may reverse T-cell exhaustion and achieve responses in 1) tumors refractory to anti-PD-1, anti-
PD-L1, or anti-CTLA-4 antibody therapy; and/or 2) tumors with high Treg infiltrate. 
The potential benefit described above supports evaluating BMS-986226 both as single agent and 
in combination with nivolumab or ipilimumab in this Phase 1/2 clinical study with risk mitigation 
and clinical monitoring described above.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
To characterize the safety and tolerability of BMS-986226 administered 
alone and in combination with nivolumab or ipilimumab in participants 
with advanced solid tumors
Incidence of AEs, SAEs, AEs 
meeting 
protocol-defined 
DLT 
criteria, 
AEs 
leading 
to 
discontinuation, and AEs resulting 
in death.
Incidence of clinical laboratory 
test abnormalities
Secondary
To explore the preliminary efficacy of BMS-986226 administered alone 
and in combination with either nivolumab or ipilimumab in participants 
with advanced solid tumors
ORR, mDOR, and PFS rate at 
24 weeksa
To characterize the PK of BMS-986226 when administered alone and in 
combination with nivolumab or ipilimumab in participants with advanced 
solid tumors
PK parameter estimates of 
BMS-986226
To characterize the immunogenicity of BMS-986226 when administered 
alone and in combination with nivolumab or ipilimumab in participants 
with advanced solid tumors
Incidence of ADAs specific for 
BMS-986226
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
To monitor target engagement of BMS-986226 administered alone and in 
combination with either nivolumab or ipilimumab in participants with 
advanced solid tumors
Summary measures of changes
from baseline (% or absolute 
change) in cell surface ICOS 
expression on T cells and ICOS-
ligand+ B cells
a These endpoints will be assessed based on RECIST v1.1 or PCWG3 (prostate only) criteria and will be determined
based on tumor measurements occurring every 8 weeks (± 1 week) during the treatment period and at least every 
12 weeks (± 2 week) in the response and survival follow-up periods. For Part A, scans will be collected centrally 
and may be reviewed by BICR at a later date or at any time during the study. For Parts B, C, D and E, scans will 
be collected centrally to be reviewed in real time by BICR.
Abbreviations: ADA = anti-drug antibody; BICR = blinded independent central review; DLT = dose limiting toxicity; 
DOR = duration of response; 
 mDOR = median duration of response; ORR = objective 
response rate; 
PK = pharmacokinetics; 
 
 RECIST = Response Evaluation Criteria In Solid Tumors; 
TIL = tumor-infiltrating lymphocytes.
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5
STUDY DESIGN
Figure 5-1:
Study Design Schematic
* Note: Arms B2 and C2 will enroll only if additional safety, PK, and PD data are required to inform dose expansion decisions. The dose levels assessed in B2 and 
C2 will not exceed those evaluated in Part A, B1, or C1.
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5.1
Overall Design
This is a Phase 1/2, open-label study of BMS-986226 administered as a monotherapy or in 
combination with either nivolumab or ipilimumab in participants with advanced solid tumors. The 
study will be conducted in 3 parts: 1) dose-escalation monotherapy (Preliminary Safety Cohorts
and Part A); 2) dose-escalation combination therapy with either nivolumab (Part B) or ipilimumab 
(Part C); 3) a dose expansion phase with either nivolumab (Part D) or ipilimumab (Part E).
Monotherapy consists of 2 different parts as follows:
•
Preliminary Safety Cohorts with BMS-986226 administered as monotherapy at 2 mg and 8 mg 
once every 4 weeks (Q4W) for 24 weeks
•
Part A, with BMS-986226 administered at 25 mg, 80 mg, 200 mg, 400 mg, and 800 mg Q4W 
for 24 weeks
Parts B and C consist of different combination cohorts comprising: 
•
B1: BMS-986226 administered every 12 weeks (Q12W) + nivolumab 480 mg Q4W at a 
starting dose level of BMS-986226 one dose level lower than a monotherapy dose (Part A) that 
has cleared the DLT period.
•
B2: BMS-986226 Q4W + nivolumab 480 mg Q4W at a starting dose level of BMS-986226 
tested in part B1.
•
C1: BMS-986226 Q12W + ipilimumab 3 mg/kg Q4W at a starting dose level of BMS-986226 
one dose level lower than a monotherapy dose (Part A) that has cleared the DLT period.
•
C2: BMS-986226 Q4W + ipilimumab 3 mg/kg Q4W at a starting dose level of BMS-986226 
tested in Part C1.
Parts B1 and C1 will enroll concurrently. Parts B2 and C2 will enroll if preliminary data from Part 
A or Parts B1 and C1 suggest a more frequent dose regimen than Q12W and if additional safety, 
PK, or PD data are required to optimize dose and/or schedule selection (see Section 5.1.2.2 [Parts 
B1 and B2] and Section 5.1.2.3 [Parts C1 and C2]). Parts B1/C1 and B2/C2 can enroll concurrently 
and participants will be alternately assigned to all open cohorts. 
The doses of BMS-986226 for Parts B and C (combination with nivolumab or ipilimumab) will be 
determined using all available safety (clinical and laboratory), PK, and target engagement/PD
 data, as well as modeling recommendations within the Bayesian hierarchical modeling 
framework, ie, the BLRM-Copula model, by incorporating single-agent toxicity profiles of both 
BMS-986226 (Preliminary Safety Cohorts and Part A) and nivolumab or ipilimumab18 and any 
available combination toxicity data from Parts B and C (for subsequent doses of BMS-986226 in 
Parts B and C), PK/PD modeling, and will not exceed the maximum administered dose (MAD) of 
BMS-986226 monotherapy in the Preliminary Safety Cohorts and Part A (see Section 5.1.2.1).
At no point will the dose of BMS-986226 administered in combination with nivolumab or 
ipilimumab (Parts B and C) exceed the dose of BMS-986226 that has been demonstrated 
previously to be safe in the monotherapy dose-escalation arm (Part A), nor at any point during 
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combination therapy in Parts B and C will the BMS-986226 dose exceed the highest dose 
determined to be tolerated in the monotherapy dose-escalation arm (Part A). In addition, the 
starting dose level of BMS-986226 used in combination with nivolumab or ipilimumab (Parts B 
and C) will be one dose level lower than a monotherapy (Part A) dose that has cleared the DLT 
period.  
Parts B and C will consist of combination dose escalation cohorts aimed to explore the kinetics of 
ICOS-receptor downmodulation
and re-expression (and/or change
in selected target 
engagement/PD
) following administration of BMS-986226 in the presence of multiple 
doses of nivolumab Q4W (Part B) or ipilimumab (Q4W) (Part C). Up to 3 different doses of BMS-
986226 will be administered in each of Parts B1 and C1 and an additional 6-12 participants will 
be enrolled in up to 3 different dose cohorts in Parts B2 and C2:
•
Doses that induce or are predicted to induce different levels of ICOS receptor downmodulation, 
including at least one dose that induces near-complete receptor downmodulation (and/or 
change in selected target engagement/PD
) for a duration of at least 4 weeks. These
dose levels will allow characterization of the ICOS receptor re-expression kinetics after near-
complete downmodulation for a period of time equal to, less than, and/or exceeding the dosing 
intervals used in Part A. Understanding ICOS receptor kinetics will help inform testing BMS-
986226 dosing intervals in future study(ies). Subsequent doses will also be evaluated by 
BLRM-Copula for toxicity. 
Dose levels will be determined based on all available safety (clinical and laboratory) and PK data, 
as well as changes in peripheral target engagement markers (eg, ICOS down regulation on T cells
and ICOS + B cells) from previous and completed portions of current cohorts and/or the 
BLRM/BLRM-Copula model whenever applicable.
Table 5.1-1:
Study Cohorts per Part
Study Part
Study Treatment
Cohorts
Preliminary Safety 
Cohorts and Part A
BMS-986226 
monotherapy
•
CC
•
CRC
•
HNSCC
•
MEL
•
NSCLC
•
PRC
•
RCC
•
TNBC
•
UCC
•
Other Advanced Epithelial Solid Tumors
Parts B and C
BMS-986226 + 
nivolumab or 
ipilimumab
•
CC
•
CRC
•
HNSCC
•
MEL
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Table 5.1-1:
Study Cohorts per Part
Study Part
Study Treatment
Cohorts
•
NSCLC
•
PRC
•
RCC
•
TNBC
•
UCC
•
Other Advanced Epithelial Solid Tumors
Parts D and E
BMS-986226 + 
nivolumab or 
ipilimumab
•
To be determined based on safety, tolerability, PK, and PD data 
from Parts A, B, and C
For Parts A, scans will be collected centrally and may be reviewed by BICR at a later date or at 
any time during the study. For Parts B, C, D and E scans will be collected centrally to be reviewed 
in real time by BICR.
Physical examinations, vital sign measurements, 12-lead electrocardiogram (ECG), and clinical 
laboratory evaluations will be performed at selected times throughout the dosing interval. 
Participants will be closely monitored for AEs throughout the study. Blood will be collected at 30, 
60, and 100-day follow-up visits (Section 9.5) after study treatment administration for PK analysis.
Participants will complete up to 4 phases of the study: screening, treatment, safety follow-up, and 
response/survival follow-up, as described below. Total duration of participation in the study is 
approximately 4 years.
The study design schematic is presented in Figure 5-1.
5.1.1
Screening
The screening phase will last for up to 28 days and take place prior to the first administration of 
study treatment. During the screening phase, the participant’s initial eligibility will be established,
and written informed consent will be obtained. Tumor biopsies will be collected for all participants 
and sent for central evaluation of ICOS expression by immunohistochemistry, and all participants 
will receive the tetanus booster vaccine 3-7 days prior to Cycle 1 Day 1 of first administration of 
study treatment. Stool will be collected for microbiota composition analysis. Participants will be 
enrolled using the Interactive Response Technology (IRT). The screening assessments are shown 
in Table 2-1.
5.1.2
Treatment Phase
The treatment phase in the Preliminary Safety Cohort and Part A consists of up to six 4-week 
treatment cycles (1 cycle = 28 days). In the Preliminary Safety Cohort and Part A, each treatment 
cycle will consist of BMS-986226 monotherapy for a total of 24 weeks.
Dose levels for Parts B and C will be determined based on all available safety (clinical and 
laboratory) and PK data, as well as changes in peripheral target engagement markers (eg, ICOS 
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downregulation on T cells and ICOS + B cells) from previous and completed portion of current 
cohorts, and will be guided by the BLRM/BLRM-Copula model whenever applicable.
In Parts B1 and C1, 4 week cycles will be used, such that BMS986226 + nivolumab or ipilimumab 
will be administered starting on Cycle 1 Day 1. Nivolumab and ipilimumab will be administered
on Day 1 of each cycle. BMS-986226 will be administered Q12W, or on Day 1 of every third cycle 
(Cycle 1 Day1, Cycle 4, Day1, Cycle 7 Day1, etc.). Participants on Parts B1 and C1 may continue 
treatment for up to a total of 2 years.
The treatment phase in Parts B2 and C2 will consist of BMS-986226 + nivolumab or ipilimumab 
administered on Day 1 of each cycle and will be enrolled if additional safety, PK, or PD data is 
required to optimize dose and/or schedule selection. In parts B2 and C2 BMS-986226 will be 
administered Q4W and participants may continue treatment for a total of 2 years.
Following each treatment cycle, the decision to treat a participant with additional cycles of study 
treatment
will be based on tumor assessment evaluations performed every 8 weeks
(Q8W ± 1 week) and completed before the first dose in the next cycle. Tumor progression or 
response endpoints will be assessed using Response Evaluation Criteria In Solid Tumors 
(RECIST) v1.1 (Appendix 5) or PCWG3, for prostate only (Appendix 11).
Treatment beyond progression with additional cycles of study treatment may be allowed for up to 
a maximum of 24 weeks for Part A and 2 years for Parts B, C, D, and E in select participants with 
initial RECIST v1.1 or PCWG3 (prostate only) defined progressive disease after discussion and 
agreement between the Principal Investigator and the BMS Medical Monitor/Study Director (or 
designee) that the benefit/risk assessment favors continued administration of the study treatment 
(eg, participants are continuing to experience clinical benefit as assessed by the investigator, 
tolerating treatment, and meeting other criteria specified in Section 8.1.2).
Participants with a response of unconfirmed progressive disease, SD, PR, or CR at the end of a 
given cycle will continue to the next treatment cycle. Participants will generally be allowed to 
continue study treatment until the first occurrence of 1) completion of the maximum number of 
cycles, 2) confirmed progressive disease, 3) clinical deterioration suggesting that no further benefit 
from treatment is likely, 4) intolerability to therapy, or 5) a participant meeting criteria for 
discontinuation of study treatment as outlined in Section 8.1. Individual participants with 
confirmed CR will be given the option to discontinue study treatment on a case-by-case basis after 
specific consultation and agreement between the investigator and BMS Medical Monitor/Study 
Director (or designee) in settings where benefit/risk justify discontinuation of study treatment.
5.1.2.1
Monotherapy Dose Escalation (Preliminary Safety Cohorts and Part A)
Up to approximately 34 participants may be treated during the monotherapy dose escalation 
(Preliminary Safety Cohorts and Part A).
Expected dose levels for monotherapy dose escalation (Preliminary Safety Cohorts and Part A) are 
provided in Table 5.1.2.1-1. All participants treated with BMS-986226 monotherapy are 
recommended to receive premedications, as described in Section 7.1, in order to reduce the risk of 
infusion-related reactions.
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Preliminary Safety Cohorts
The Preliminary Safety Cohorts will evaluate the safety of BMS-986226 following monotherapy 
administration of 2 dose levels, 2 mg and 8 mg.
A single new participant per cohort will be administered an IV BMS-986226 as follows:
•
BMS-986226 2 mg Q4W in 4-week cycles for up to 24 weeks of study treatment
•
BMS-986226 8 mg Q4W in 4-week cycles for up to 24 weeks of study treatment
For the purpose of guiding dose escalation, dose-limiting toxicities (DLTs) will be defined based 
on the incidence, intensity, and duration of AEs for which no clear alternative cause is identified. 
The DLT period will be 28 days (4 weeks) in the Preliminary Safety Cohorts. Any toxicities that 
occur beyond the 4-week DLT period will also be considered in dose-level decisions. For the 
purpose of participant management, any AE that meets DLT criteria (Section 7.3.2), regardless of 
the cycle in which it occurs, will lead to discontinuation of study treatment. Participants who 
discontinue study treatment during the 4-week DLT evaluation period for reasons other than a 
DLT may be replaced with a new participant at the same dose level. AEs will be graded according 
to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v4.0327.
Once the safety (during the 4 weeks DLT period) of 2 mg and 8 mg of BMS-986226 has been 
established in a single, independent participant per dose, Part A will start.
Additional participants may be enrolled in the Preliminary Safety Cohorts per dose level as early 
as 5 days after the first participant is treated at each dose level to gather additional information on 
the safety, PK, and PD profile.
Intra-participant dose escalation is only allowed in the Preliminary Safety Cohorts as follows:
•
Once the observation period of 4 weeks for 8 mg is completed, participant(s) treated at 2 mg 
may be offered the possibility to dose escalate at 8 mg.
•
Once the DLT period of 5 weeks for 25 mg is completed, participant(s) treated at 2 mg that 
escalated to 8 mg or participant(s) treated with 8 mg may be offered the possibility to dose 
escalate at 25 mg
The decision to dose escalate may be allowed in select participants after discussion and agreement 
with the BMS Medical Monitor/Study Director (or designee), as long as the participant is tolerating 
treatment.
The decision to treat a participant with additional cycles of study treatment (up to a maximum of 
24 weeks), will be based on safety, tolerability, and tumor assessment Q8W (± 1 week) prior to 
dose administration in the next cycle.
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Part A
Dose escalation decisions in Part A of the study will be guided by Bayesian Logistic Regression 
Model (BLRM). Each participant will be administered IV doses of BMS-986226 per the cohort 
assignment as follows: 
•
25 mg flat dose Q4W in 4-week cycles for up to 24 weeks of study treatment
•
80 mg flat dose Q4W in 4-week cycles for up to 24 weeks of study treatment
•
200 mg flat dose Q4W in 4-week cycles for up to 24 weeks of study treatment
•
400 mg flat dose Q4W in 4-week cycles for up to 24 weeks of study treatment
•
800 mg flat dose Q4W in 4-week cycles for up to 24 weeks of study treatment
A sentinel participant will be used for all cohorts of monotherapy in Part A and combination 
therapy in Parts B and C. The first participant in each cohort will receive the Cycle 1 Day 1 dose 
of study treatment and be observed for 5 days before additional participants (ie, Participant 2
onward) in that cohort receive study treatment.
The decision to treat a participant with additional cycles of study treatment (up to a maximum of 
24 weeks), will be based on safety, tolerability, and tumor assessment Q8W (± 1 week) prior to 
dose administration in the next cycle.
Planned dose levels may be modified or intermediate dose levels added guided by the BLRM 
analysis with consideration of all available safety, PK, and PD data. 
Once the safety (during the DLT evaluation) of a dose level has been established, additional 
participants (up to a total of 12) may be added at that dose level to better characterize the safety, 
PK, and PD profile. 
Dose Escalation Decisions for Part A
The dose-escalation phase of the study will evaluate the safety and tolerability of BMS-986226
monotherapy based on DLTs using a BLRM model.
During the dose-escalation phase, a set of approximately 3 participants will be treated initially 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 5-week DLT period will be accounted for in making 
dose level decisions and/or dose level modifications.
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 re-assessment of 
dose recommendation, by BLRM in the monotherapy escalation phase, will be carried out for each 
dose level. Planned dose levels for dose escalation are provided in Table 5.1.2.1-1. Planned dose 
levels may be modified, or additional intermediate dose levels added, based upon the BLRM 
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analysis. Once the safety (during the DLT evaluation) of a monotherapy dose level has been 
established (Preliminary Safety Cohorts and Part A), additional participants (up to 12 total) may 
be added at that dose level to better characterize the safety, PK, and PD profile.
Table 5.1.2.1-1:
Dose Escalation (Preliminary Safety Cohorts and Part A)
Dose Level
BMS-986226
1
2 mg (Preliminary Safety Cohorts)
2
8 mg (Preliminary Safety Cohorts)
3
25 mg (Part A)
4
80 mg (Part A)
5
200 mg (Part A)
6
400 mg (Part A)
7
800 mg (Part A)
Dose-limiting Toxicities in Part A
For the purpose of guiding dose escalation, DLTs will be defined based on the incidence, intensity, 
and duration of AEs for which no clear alternative cause is identified. The DLT period will be 
35 days (5 weeks) in Part A. Any toxicities that occur beyond the 5-week DLT period will also be 
considered in dose-level decisions.
For the purpose of participant management, any AE that meets DLT criteria (Section 7.3.2), 
regardless of the cycle in which it occurs, will lead to discontinuation of study treatment. 
Participants who withdraw from the study during the DLT evaluation period for reasons other than 
a DLT may be replaced with a new participant at the same dose level. The incidence of DLT(s) 
during the DLT evaluation period will be used in dose escalation decisions in Part A and guide 
dose recommendations in Parts B and C. AEs occurring after the 5-week DLT evaluation period 
will be considered for the purposes of defining any BLRM recommended dose upon agreement 
between the Sponsor, Medical Monitor/Study Director (or designee), and investigators, if the AEs 
are determined to have no clear alternative cause and are not related to disease progression.
AEs will be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03.27
5.1.2.2
BMS-986226 and Nivolumab Combination Therapy Cohort (Parts B1 and 
B2)
The purpose of combination cohort with nivolumab is to gather safety, tolerability, PK, and PD
information regarding the administration of BMS-986226 in combination with nivolumab 480 mg 
flat dose Q4W. Part B1 aims to determine the kinetics of ICOS receptor downmodulation and re-
expression (and/or change in selected target engagement/PD
) following administration 
of BMS-986226 Q12W in combination with nivolumab 480 mg administered Q4W for a duration 
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of 2 years. Continuous evaluation of toxicity events in the combination cohort will be performed 
throughout the enrollment. All participants treated with BMS-986226 in combination with
nivolumab are recommended to receive premedications, as described in Section 7.1, in order to 
reduce the risk of infusion-related reactions.
Up to 3 different dose levels of BMS-986226 will be tested in Part B1, as determined by safety, 
PK and PD data. The starting dose level used in combination with nivolumab (Part B) will be one 
dose level lower than a monotherapy (Part A) dose that has cleared the DLT period. At each dose 
level, approximately 6 evaluable participants will be treated. A sentinel participant will be enrolled 
in Part B1 (BMS-986226 Q12W + nivolumab 480 mg Q4W) and observed for 5 days before 
additional participants in Parts B1 at the same dose level receive study treatment. 
Part B2 (BMS-986226 Q4W + nivolumab 480 mg Q4W) will be opened at dose levels evaluated
in at least one participant in Part B1. Approximately 6-12 evaluable participants will be treated per
cohort, if enrolled, to better characterize safety, PK, and PD of the combination. For instance, Part 
B2 will begin enrollment if the re-expression of ICOS on circulating T cells is observed 4 weeks 
after the first dose of BMS-986226 in Parts A or B1. Part B2 would therefore be utilized to provide 
a more granular assessment of safety and PD of BMS-986226. More than 1 dose level (no more 
than 3 different dose levels) may be enrolled, should additional safety, PK, and PD data be needed. 
Once the safety (during the DLT evaluation) of a combination of BMS-986226 and nivolumab has 
been established and a recommended BMS-986226 dose regimen has been selected for Part D, 
then additional participants (up to 6 additional evaluable participants) may be treated at the 
recommended dose to better characterize the safety, PK, and PD profile.
5.1.2.3
BMS-986226 and Ipilimumab Combination Therapy Cohort (Parts C1 
and C2)
The purpose of combination cohort with ipilimumab is to gather safety, tolerability, PK, and PD
information regarding the administration of BMS-986226 in combination with ipilimumab at 
3 mg/kg Q4W. Part C1 aims to determine the kinetics of ICOS receptor downmodulation and re-
expression (and/or change in selected target engagement/PD
) following administration 
of BMS-986226 Q12W in combination with ipilimumab administered Q4W for a duration of 2 
years. Continuous evaluation of toxicity events in the combination cohort will be performed 
throughout the enrollment. All participants treated with BMS-986226 in combination with 
ipilimumab are recommended to receive premedications, as described in Section 7.1, in order to 
reduce the risk of infusion-related reactions.
Up to 3 different dose levels of BMS-986226 will be tested in Parts C1, as determined by safety, 
PK and PD data. The starting dose level used in combination with ipilimumab (Part C) will be one 
dose level lower than a monotherapy (Part A) dose that has cleared the DLT period. At each dose 
level, approximately 6 evaluable participants will be treated, where a sentinel participant will be 
enrolled in Part C1 (BMS-986226 Q12W + ipilimumab 3mg/kg Q4W and observed for 5 days 
before additional participants in Parts C1 at the same dose level receive study treatment.  
Part C2 (BMS-986226 Q4W + ipilimumab 3 mg/kg Q4W) will be opened at dose levels evaluated
in at least one participant in Part C1. Approximately 6-12 evaluable participants will be treated per 
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dose cohort, if enrolled, to better characterize safety, PK, and PD of the combination. For instance, 
Part C2 will begin enrollment if the re-expression of ICOS on circulating T cells is observed 4 
weeks after the first dose of BMS-986226 in Part A or C1. Part C2 would therefore be utilized to 
provide a more granular assessment of safety and PD of BMS-986226. More than 1 dose level (no 
more than 3 different dose levels) may be enrolled, should additional safety, PK, and PD data be 
needed.
Once the safety (during the DLT evaluation) of a combination of BMS-986226 and ipilimumab 
has been established and a recommended BMS-986226 dose regimen has been selected for Part E, 
then additional participants (up to 6 additional evaluable participants) may be treated at the 
recommended dose to better characterize the safety, PK, and PD profile.
Dose-limiting Toxicities in Combination Cohorts (Parts B and C)
For the purpose of ensuring safety, DLTs will be defined based on the incidence, intensity, and 
duration of AEs for which no clear alternative cause is identified. The DLT period will be 35 days 
(5 weeks) in Parts B and C.
For the purpose of participant management, any AE that meets DLT criteria (Section 7.3.2), 
regardless of the cycle in which it occurs, will lead to temporary hold of study treatment. 
Participants who withdraw from the study during the DLT evaluation period for reasons other than 
a DLT may be replaced with a new participant at the same dose level. 
Re-challenge of participants experiencing a DLT will be evaluated on a case-by-case basis, once 
the AE returns to baseline or Grade 1, after specific consultation and agreement between the 
investigator and BMS Medical Monitor/Study Director (or designee) in settings where benefit/risk 
justify re-administration of study treatment (see Section 7.3.5).
AEs will be graded according to the NCI CTCAE v4.03.27
5.1.2.4
Combination Expansion Arms (Parts D and E)
The purpose of the cohort expansion is to gather additional safety, tolerability, preliminary 
efficacy, PK, and PD information regarding BMS-986226 in combination with either nivolumab 
(Part D) or ipilimumab (Part E). Continuous evaluation of toxicity events in the cohort expansions 
will be performed throughout enrollment in the expansion cohorts. All participants treated with 
BMS-986226 in combination with either nivolumab or ipilimumab are recommended to receive 
premedications, as described in Section 7.1, in order to reduce the risk of infusion-related 
reactions. If, at any time, the aggregate rate of treatment-related toxicities meeting DLT criteria 
exceeds 33% across all participants treated the findings will be discussed and further enrollment 
will be interrupted. Depending on the nature and grade of the toxicity, and after assessing the 
risk/benefit ratio, a new dose for all cohorts may be initiated at a lower dose level.  
The dose and schedule of BMS-986226 in Parts D and E will be determined based on all available 
safety, tolerability, efficacy, PK, and PD data from Parts A, B, and C. Parts D and E will be 
implemented following the revised protocol to define dose, schedule, and population. 
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Approximately 40 participants will be enrolled in each of Parts D and E. Safety, efficacy, PK, and 
PD data will be used to determine the precise patient population that will be enrolled in the 
expansion arms.
Participants with a response of unconfirmed progressive disease, stable disease, partial response, 
or complete response, at the end of a given cycle will continue to the next treatment cycle. 
Participants will be allowed to continue study treatment until the first occurrence of any of the 
following:
•
Completion of the maximum number of cycles
•
Confirmed progressive disease
•
Clinical deterioration suggesting that no further benefit from treatment is likely
•
Intolerability to therapy
•
Participant meets the criteria for discontinuation of study treatment as shown in Section 8.2.
5.1.3
Follow-up
5.1.3.1
Safety Follow-up
Upon completion of 24 weeks of study treatment for Part A (or up to a maximum of 48 weeks if 
applicable) or 2 years for Parts B, C, D, and E, once the decision is made to discontinue the 
participant from study treatment (e.g., at end of treatment [EOT]), all participants will enter the 
safety follow-up period.
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 and the start of the Week 1 safety follow-up 
visit. For participants who do not complete all scheduled cycles of study treatment, the EOT visit 
will be the most recent on-treatment visit (with all available safety and response data), does not 
need to be repeated, and will be considered the start of the safety follow-up visit.
After the EOT visit, all participants will be evaluated for any new AEs for at least 100 days after 
the last dose of study treatment. Follow-up visits to monitor for AEs should occur at Days 30, 60, 
and 100 after the last dose or on the date of discontinuation (± 7 days). All participants will be 
required to complete the 3 clinical safety follow-up visits regardless of whether or not they start 
new anti-cancer treatment, except those participants who withdraw consent for study participation.
5.1.3.2
Survival Follow-up
After completion of the safety follow-up visits, all participants treated with monotherapy and 
combination therapy will enter the survival follow-up period. Participants will be followed 
approximately every 3 months (12 weeks) until death, loss to follow-up, withdrawal of consent, or 
conclusion of the study, whichever comes first. The duration of this phase is up to 2 years from 
the last dose of study treatment, although a longer follow-up period could be considered in selected 
cases if an efficacy signal is apparent.
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5.1.3.3
Response Follow-up
After completion of the Safety Follow-up period, participants with ongoing SD, PR, or CR at the 
EOT visit will enter the Response Follow-up period. This period will occur simultaneously with 
the Survival Follow-up period for the mentioned participants. Participants will continue to have 
radiologic and clinical tumor assessments approximately every 3 months (12 weeks) until death, 
loss to follow-up, withdrawal of consent, or conclusion of the study, whichever comes first. 
Radiological tumor assessments for participants who have ongoing clinical benefit may continue 
to be collected after participants complete the survival phase of the study. Participants who have 
disease progression following initial course of study treatment will not be evaluated for response 
beyond the EOT visit and will be allowed to receive other tumor-directed therapy as required. If 
the participant discontinues treatment for any reason other than progressive disease, radiological 
follow-up will continue until the participant receives additional treatment.
5.1.4
Treatment with Additional Cycles 
All participants will be treated for 24 weeks of monotherapy or for 2 years for combination therapy 
unless criteria for study treatment discontinuation are met earlier. Only participants completing 
treatment in the monotherapy (Part A) cohort, with ongoing disease control (CR, PR, or SD), or 
unconfirmed progressive disease, may be eligible for an additional 24 weeks of study treatment on 
a case-by-case basis after careful evaluation and discussion with the BMS Medical Monitor/Study 
Director (or designee) to determine whether the risk/benefit ratio supports administration of further 
study treatment. Upon completion of the additional study treatment period all participants will 
enter safety follow-up period.
5.1.5
Treatment Beyond Progression
Treatment beyond progression may be allowed in select participants with initial RECIST v1.1 or 
PCWG3 (prostate only) defined progressive disease after discussion and agreement with the BMS 
Medical Monitor/Study Director (or designee) that 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 specified in 
(Section 8.1.2).
Participants must be re-consented with an informed consent form (ICF) addendum to continue 
treatment beyond progression. Treatment beyond progression will require continued tumor 
assessments.
5.1.6
Data Monitoring Committee and Other External Committees
As this is an early stage, first-in-human study, a data monitoring committee will not be used.
BMS has developed a multi-layered process to ensure safety monitoring through close 
collaboration of study site investigators, the BMS study team, and the BMS Global 
Pharmacovigilance and Epidemiology (GPVE)-led Medical Surveillance Team. Study safety will 
be evaluated continuously in real time by representatives of BMS GPVE, who operate 
independently from the clinical team and monitor safety across all BMS protocols. AEs will be 
monitored continuously by the medical monitor(s) and GPVE. Safety, PK, and PD data are
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reviewed during teleconferences between investigators and the BMS clinical team, which will be 
held regularly. The decision to escalate or expand the dose will be based on the aforementioned 
review with investigators.
5.2
Number of Participants
The number of participants for this study will be approximately 234. Up to approximately 34 of 
these participants may be treated with monotherapy (Preliminary Safety Cohorts and Part A); 
approximately 6 evaluable participants may be treated at each dose level for Parts B1 and C1; 
approximately 6-12 evaluable participants may be treated at each dose level for Parts B2 and C2;
up to 6 additional evaluable participants may be treated in Parts B and/or C, at a recommended 
BMS-986226 dose regimen for Parts D and/or E to better characterize the safety, PK, and PD
profile; approximately 80 participants will be treated in combination expansion arms, Parts D and 
E.
Additional information on sample size determination can be found in Section 10.1.
5.3
End of Study Definition
The start of the study is defined as the first visit for the first participant screened. 
The end of study is defined as the last visit or scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last participant. Study completion is defined as the final date on which 
data for the primary endpoint were or are expected to be collected if they are not the same.
5.4
Scientific Rationale for Study Design
5.4.1
Rationale for BMS-986226 First-in-Human Dose (Preliminary Safety 
Cohorts and Part A Monotherapy)
The selection of the BMS-986226 starting dose is based on the pivotal repeat-dose IV toxicology 
study in cynomolgus monkeys and the mouse CT26 colon adenocarcinoma tumor efficacy model. 
These approaches reflect the goal of adequately ensuring patient safety while limiting the number 
of advanced-stage cancer patients from receiving sub-pharmacologically active doses.
In the pivotal repeat-dose (5 doses/week) IV toxicity study, the dose of 75 mg/kg 
(AUC[0-168h] ≤452,000 μg•h/mL) was considered to be the NOAEL and was also considered 
the HNSTD to determine potential MRSD as per ICH S9.28 Using a standard milligram per 
kilogram conversion to the human equivalent dose and a safety factor of 6-fold, the potential 
MRSD was calculated to be 12.5 mg/kg. 
The anti-tumor efficacy of hamster anti-mouse ICOS agonist mAb (BMS-986246) was studied in 
the mouse CT26 colon adenocarcinoma model as a single agent or in combination with an anti-
mouse PD-1 mAb.29 In this study, improved anti-tumor efficacy of BMS-986246 was noted in 
combination with an anti-murine PD-1 mAb relative to single-agent treatment. The AUC and 
percent tumor growth inhibition (%TGI) relationship in this study was used to project human 
starting and efficacious doses. Peak %TGI was reached at 3 mg/kg dose of BMS-986246 in 
combination with anti-mPD1 (corresponding Cmax at first week of 84 μg/mL and AUC from 0 to 
1 week of 450 μgday/mL). Accordingly, the 4.6-mg/kg dose of BMS-986226 (368 mg assuming 
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80 kg human body weight) is projected to achieve these targeted exposures in humans and is 
considered the targeted efficacious dose. Negligible anti-tumor activity (no improvement over 
anti-murine PD-1 mAb alone) in mice was noted at 0.3 mg/kg. To achieve comparable systemic 
exposures as the 0.3 mg/kg dose in mice, 25 mg was selected as the first dose level for Part A. The 
projected exposures (eg, AUCs) following administration of 25 mg are 102-fold lower than the 
exposures observed in cynomolgus monkeys at the NOAEL dose.
Other considerations to select the starting dose included ICOS expression in humans and 
comparisons of the projected concentrations relative to those used in the in vitro cytokine-release 
assay. Unlike high-risk targets, eg, CD28 receptor, which is constitutively expressed, normal ICOS 
expression is limited, with the majority of high-expressing cells found to be activated T cells.30
The dose of BMS-986226 that is projected to result in approximately 80% to 85% ICOS binding 
to activated T cells at Cmax is 2 mg. This dose would be expected to engage ICOS in activated 
T cells, but not expected to have appreciable clinical activity and thus will be used as the starting 
dose in the Preliminary Safety Cohorts.
Collectively, these data support using a starting dose of 2 mg BMS-986226 in the Preliminary 
Safety Cohorts to allow safe administration of BMS-986226 at a dose projected to not have 
appreciable clinical activity. The first dose level in Part A is 25 mg BMS-986226, as it is expected 
to have pharmacologic activity and reasonable safety in the cancer patient population.
5.4.2
Rationale For Treatment Duration
5.4.2.1
Rationale for 24-week Duration of BMS-986226 Monotherapy
While immunotherapies are rapidly making great strides in the treatment of cancer, the optimal 
duration of treatment to obtain and maintain deep and durable responses is a matter of ongoing 
clinical investigation. Emerging clinical data on time to response with immunotherapies in cancer 
suggest that a majority of participants who responded did so within the first 24 weeks on treatment. 
5.4.2.2
Rationale for 2-year Duration of BMS-986226 in Combination with 
Nivolumab or Ipilimumab
The optimal duration of immunotherapy is an important question and continues to be investigated. 
In study CA209153, patients with previously treated advanced NSCLC who completed 1 year of 
nivolumab therapy were randomized to either continue or stop treatment, with the option of
retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 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 patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (i.e., 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.31 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 patients with previously 
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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.32 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).33
Taken together, the data suggest shorter duration of nivolumab of only 1 year was associated with 
increased risk of progression in previously treated patients with NSCLC, suggesting that treatment 
beyond 1 year is likely needed. 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.
Although there is no data available for 2 year treatment regimen of ipilimumab, the mechanism of 
action of the negative regulators of T cell activation is similar to that of nivolumab. Therefore, 
CA021002 will evaluate the safety and tolerability of ipilimumab (Q4W) in combination with 
BMS-986226 for up to 2 years. 
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore in 
study CA021002, treatment with BMS-986226 in combination with nivolumab or ipilimumab will 
not be extended beyond 2 years. 
5.4.3
Rationale for Treatment Beyond Progression
Immunotherapeutic agents produce atypical clinical response patterns that are not usually observed 
in 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 SD. 
Two distinct nonconventional patterns have been reported: 1) a reduction in target tumor burden 
despite the appearance of new lesion(s) and 2) a transient increase in target tumor burden in an 
initial phase followed by subsequent tumor shrinkage.
This phenomenon was observed in the Phase 2 study of nivolumab (Study CA209003) in solid 
tumor patients. Two hypotheses explain this phenomenon. First, enhanced inflammation within 
tumors could lead to an increase in tumor size, which would appear as enlarged index lesions and 
as newly visible small non-index lesions. Over time, both the malignant and inflammatory portions 
of the mass may then decrease, leading to overt signs of clinical improvement. Alternatively, in 
some individuals, the kinetics of tumor growth may initially outpace anti-tumor immune activity. 
With sufficient time, the anti-tumor activity will dominate and become clinically apparent. 
Therefore, it is important to avoid premature discontinuation of the study treatment that might 
induce a nonconventional response pattern in some participants.
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The decision to continue treatment beyond investigator-assessed progression should be discussed 
with the BMS Medical Monitor/Study Director (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.
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5.5
Justification for Dose and Schedules for BMS-986226, Nivolumab, and 
Ipilimumab
5.5.1
Rationale for BMS-986226 Flat Dosing and Schedule
Therapeutic mAb doses have been routinely calculated on a body size basis with a perception that 
this approach may reduce inter-participant variability in drug exposure compared with a flat dose 
approach. However, recent analyses of marketed experimental mAbs have demonstrated that body 
weight-based dosing did not always offer advantages over flat dosing in reducing exposure 
variability. Because the magnitude of the impact of body weight on the human PK of BMS-986226 
is not yet determined and it is unknown if body size-based dosing would increase or decrease 
inter-participant variability, this study will utilize a flat dose in the escalation and combination
phases as a more convenient approach and which is more likely to reduce the potential for dosing 
errors.
The starting dose of BMS-986226 in combination with either nivolumab 480 mg Q4W or 
ipilimumab 3 mg/kg Q4W will be determined based on the expected activity at this dose range and 
the expected tolerability and safety profile of BMS-986226 in the monotherapy dose escalation 
(Part A). At no point will the dose of BMS-986226 administered in combination with nivolumab 
or ipilimumab- exceed doses of BMS-986226 that have been demonstrated previously to be 
tolerated in the monotherapy dose escalation arm (Part A). Accordingly, additional intermediate 
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or lower doses or less frequent dosing of BMS-986226 may be tested, if none of the planned 
doses/schedule is found to be tolerated when combined with nivolumab or ipilimumab.
The BMS-986226 dose for Parts B and C will be based on evaluating the most up-to-date data 
available in all dosed participants, including clinical and laboratory safety assessments as well as 
PK, PD, and efficacy data from all treated participants at each dose level up to the MAD.
For the Preliminary Safety Cohorts and Parts A, B2 and C2, BMS-986226 will be administered at 
a dose schedule of Q4W. This schedule is based on predicted human PK using nonclinical data. 
The projected T-HALF for BMS-986226 in humans is 25 days (Section 3.2.2.5), allowing for 
dosing at an interval of 4 weeks. 
Parts B1 and C1 will be conducted to help inform safety and possible alternative dosing schedules 
by utilizing PK and target engagement/PD markers, including but not limited to ICOS 
downregulation and re-expression. In Parts B1 and C1, participants will be administered BMS-
986226 Q12W at the dose that induces or is predicted to induce near-complete receptor 
downregulation (and/or change in selected target engagement/PD
) in the presence of 
nivolumab Q4W or ipilimumab Q4W. PK and PD data will be generated and analyzed to 
understand the duration of effect of BMS-986266 on the kinetics of ICOS downregulation and re-
expression, and/or the kinetics of other appropriate PD markers.
5.5.2
Rationale for Nivolumab Dose Selection
Currently, nivolumab 240 mg Q2W or nivolumab 3 mg/kg Q2W are approved in various regions 
for the treatment of melanoma, NSCLC, RCC, classical Hodgkin’s lymphoma, and UCC.
The safety and efficacy of the nivolumab 480 mg Q4W flat dose are expected to be similar to the 
approved nivolumab dose of 240 mg or nivolumab 3 mg/kg Q2W. The nivolumab dose of 480 mg 
Q4W was selected based on clinical data and modeling and simulation approaches using PPK and 
exposure-response analyses of data from studies in multiple tumor types (melanoma, NSCLC, and 
RCC) where body weight-normalized dosing (mg/kg) has been used. The PPK analyses have 
shown that exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 
10 mg/kg administered Q2W, and no clinically meaningful differences in PK across ethnicities 
and tumor types were observed. Nivolumab clearance and volume of distribution were found to 
increase as body weight increases but less than proportionally with increasing weight, indicating 
that milligram-per-kilogram dosing represents an over-adjustment for the effect of body weight on 
nivolumab PK. Using the PPK model, the overall distributions of average nivolumab steadystate 
exposures are comparable after treatment with either nivolumab 3 mg/kg Q2W or nivolumab 
480 mg Q4W, although the flat dose regimen of 480 mg Q4W is predicted to result in 
approximately 40% higher steadystate peak concentration (-Cmaxss-) and approximately 20% 
lower steady-state trough concentrations compared to the reference regimen of 3 mg/kg Q2W. 
Across the various tumor types in the clinical program, nivolumab has been shown to be safe and 
well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab exposure 
produced by 3 mg/kg and efficacy and safety has been found to be relatively flat. Although 
nivolumab Cmaxss is predicted to be higher following 480 mg Q4W, these exposures are predicted 
to be lower than or within the exposure ranges observed at doses up to 10 mg/kg Q2W used in the 
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nivolumab clinical program and are not considered to put participants at increased risk. The 
exposures predicted following administration of nivolumab 480 mg Q4W are on the flat part of 
the exposure response curves for previously investigated tumors (melanoma and NSCLC) and are 
not predicted to affect efficacy. Based on these data, nivolumab 480 mg Q4W is expected to have 
similar efficacy and safety profiles to nivolumab- 3 mg/kg Q2W.
5.5.3
Rationale for Ipilimumab Dose Schedule
Ipilimumab 3 mg/kg Q4W will be tested in combination with BMS-986226 during the study in 
Parts C1 and C2. Ipilimumab is currently approved in the US for administration in unresectable or 
metastatic melanoma following monotherapy administration and in combination with nivolumab 
at a dose of 3 mg/kg Q3W for a total of 4 doses. Ipilimumab is also approved in the US for the 
treatment of adjuvant melanoma at a dose of 10 mg/kg Q3W for 4 doses, followed by 10 mg/kg 
Q12W for up to 3 years or until documented disease recurrence or unacceptable toxicity.37 Finally, 
ipilimumab is being studied in combination with nivolumab at various doses, including 1 and 
3 mg/kg, and at dosing intervals up to Q12W. Benefit may be gained from dosing ipilimumab for 
a longer duration than the dosing interval of Q3W dosing for a total of 4 doses. Further, in the 
combination setting, less frequent dosing has shown to be beneficial to the tolerability and response 
profile of ipilimumab.38 While ipilimumab Q4W dosing has not been tested previously, it may 
offer benefit to enhance the tolerability of ipilimumab versus Q3W dosing, and to allow for 
prolonged dosing duration versus the 4-dose schedule when administered in combination with 
BMS-986226.
5.5.4
Rationale for Dose-escalation Phase Design
The BLRM with an overdose control principle escalation was selected as an appropriate design for 
this study. It offers more accuracy and efficiency in determining the true MTD/MAD compared to 
rule-based methods (such as 3 + 3 design) by incorporating external information from nonclinical 
studies as well as historical clinical studies. The escalation with overdose control (EWOC) 
principle limits the risk of exposing participants in the next cohort to an unsafe or toxic dose. 
Hence, it ensures that safety is not compromised during dose escalation. Simulation results 
demonstrate that BLRM allows fast escalation when the expected toxicity is very low and with 
participants treated at sub-therapeutic doses, which is attributed to the adaptive Bayesian learning 
from previous doses. In addition, BLRM has greater applicability to the combination therapy 
setting compared to other model-based methods. All available treatment related adverse events
obtained from the monotherapy phase (Preliminary Safety Cohorts and Part A) will be 
characterized and incorporated as prior knowledge into the drug combination phase of the study 
(Parts B, C, D, and E) or used in future studies.
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.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
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a) The participant must sign the ICF prior to the performance of any study-related
procedures that are not considered part of standard of care.
b) The participant must sign the consent for pretreatment and on-treatment tumor biopsy 
samples at acceptable clinical risk, as judged by the investigator.
i)
Participants will be eligible to receive treatment upon completion of pre-treatment 
biopsy collection and confirmation that the biopsy sample has been sent for central 
analysis.
ii) The solid tumor tissue specimen must be a core needle, excisional, or incisional biopsy. 
 
 Biopsies of bone lesions that do not 
have a soft tissue component or decalcified bone tumor samples are also not acceptable.
iii) Biopsied lesions should be distinct from index lesion(s) being evaluated for 
radiological response.
iv) An FFPE (block) sample must be sent for central analysis. 
 
 
v) If a participant had a biopsy in the preceding 90 days with no intervening anti-cancer 
therapy, participants can be enrolled without needing a repeat biopsy after discussion 
with the BMS Medical Monitor/Study Director (or designee) and upon confirmation of 
the availability of FFPE blocks. Participants will be required to undergo on-treatment 
biopsies at acceptable clinical risk as judged by the investigator in all arms.
2) Type of Participant and Target Disease Characteristics
a) Participants must be at least 18 years old and have histological or cytological confirmation 
of metastatic and/or unresectable malignancy, including but not limited to CC, CRC, 
HNSCC, MEL, NSCLC, PRC, RCC, TNBC, and UCC with measureable disease per 
RECIST v1.1 (see Appendix 5) or PCWG3 (prostate only) (see Appendix 11) and have at 
least 1 lesion accessible for biopsy in addition to the target lesion.
b) Presence of at least 1 lesion with measurable disease as defined by RECIST v1.1 or 
PCWG3 (prostate only) for solid tumors for response assessment. Participants with lesions 
in a previously irradiated field as the sole site of measurable disease will be permitted to 
enroll provided the lesion(s) have demonstrated clear progression and can be measured 
c) Participants must have received, and then progressed or been intolerant to, at least 
1 standard treatment regimen in the advanced or metastatic setting, if such a therapy exists, 
and have been considered for all other potentially efficacious therapies prior to enrollment.
Participants who are ineligible for standard therapy (due to medical factors such as co-
morbid illness, age, etc.) will be allowed to enroll provided the reason for their ineligibility 
is documented in their medical records.
d) Participants with prior exposure to therapy with any agent specifically targeting checkpoint 
pathway inhibition (such as anti-PD-1, anti-PD-L1, or anti-CTLA-4) are permitted after a 
washout period of any time greater than 4 weeks from the last treatment.
e) For all parts (A, B1, B2, C1, C2, D, and E):  
i)
Participants with CC, CRC, HNSCC, MEL, NSCLC, PRC, RCC, TNBC, and UCC will 
be permitted. Participants with other solid tumor histologies may be considered and 
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eligibility should be discussed with BMS Medical Monitor/Study Director (or 
designee). 
f)
For all parts (A, B1, B2, C1, C2, D, and E)
i)
The participant must consent for pretreatment and sequential treatment (2 weeks after 
first dose of study treatment and 12 weeks after first dose) tumor biopsy samples.
ii) The pretreatment and sequential biopsy samples should be from the same lesion, if 
possible. Thus, lesion that is > 3 cm at baseline should be considered for collecting 
biopsy samples. A different lesion may be used to collect on-treatment biopsies should 
the original lesion not be available.
g) As per revised protocol 02 this criteria is now combined with criteria f).
h) Participants who experienced prior Grade 1 to 2 immunotherapy therapy-related immune-
mediated AEs must have confirmed recovery from these events at the time of study entry, 
other than endocrinopathies treated with supplementation, as documented by resolution of 
all related clinical symptoms, abnormal findings on physical examination, and/or 
associated laboratory abnormalities. Where applicable, these participants must also have 
completed steroid tapers for treatment of these AEs by a minimum of 14 days prior to 
commencing treatment with study treatment.
i)
Eligibility of participants with prior Grade ≥3 checkpoint therapy-related immune AEs 
will be considered on a case-by-case basis after discussion with the BMS Medical 
Monitor/Study Director (or designee) (eg, asymptomatic isolated Grade 3 lipase elevations 
without clinical or radiological features of pancreatitis will be permitted to enroll).
j)
“Not applicable as per revised protocol 02” In an effort to limit confounding factors, for 
all cohorts where applicable, no more than 5 participants previously found to be “rapid 
progressors” (time to treatment failure ≤2 months) on anti-PD-1, anti-PD-L1, or anti-
CTLA-4 therapy should be enrolled per cohort.
k) ECOG performance status ≤2
l)
Prior palliative radiotherapy must have been completed at least 2 weeks prior to the first 
dose of the study treatment. Participants with symptomatic tumor lesions at baseline that 
may require palliative radiotherapy within 4 weeks of the first dose of study treatment are 
strongly encouraged to receive palliative radiotherapy prior to enrollment.
3) The following tumor types will be explored:
a) CRC
i)
Participants must have histologically confirmed CRC that is metastatic or recurrent 
with documented disease progression.
ii) Document microsatellite instability (MSI), mismatch repair (MMR), KRAS, and 
BRAF status if known. 
iii) Prior therapy requirement: Participants must have received at least 1, but no more than 
3, prior systemic therapies for metastatic and/or unresectable disease (or have 
progressed within 6 months of adjuvant therapy).
iv) Participant must have incurable metastatic disease (ie, participants with disease that is 
potentially curable by surgical resection are not eligible for treatment).
v) Participants must have been offered and/or have received or refused at least 1 prior 
approved immune therapy regimen, that is considered standard of care for their disease 
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stage and condition, in the country where they are receiving treatment, if such a 
regimen exists. Reason(s) for refusal should be documented.
b) HNSCC (oral cavity, pharynx, larynx)
i)
Participants must have histologically confirmed incurable, locally advanced, recurrent, 
or metastatic HNSCC (oral cavity, pharynx, larynx), Stage III or IV and not amenable 
to local therapy with curative intent (surgery or radiation therapy with or without 
chemotherapy).
ii) Participants should have documented HPV status (can be inferred by p16 staining) and, 
if known, subtype (HPV16/18).
iii) “Not applicable as per revised protocol 03” Participants must have received and then 
progressed or have been intolerant or refractory to at least 1 but no more than 2 prior 
systemic therapies (eg, platinum-based chemotherapy) regimen for the treatment of 
metastatic or locally advanced unresectable disease.
iv) Prior curative radiation therapy must have been completed at least 4 weeks prior to 
study treatment administration. Prior focal palliative radiotherapy must have been 
completed at least 2 weeks before study treatment administration.
v) Participants must have been offered and/or have received or refused at least 1 prior 
approved immune therapy regimen, that is considered standard of care for their disease 
stage and condition, in the country where they are receiving treatment, if such a 
regimen exists. Reason(s) for refusal should be documented.
vi) Participants must have received and then progressed or have been intolerant or 
refractory to at least 1 but no more than 3 prior systemic therapies (eg, platinum-based 
chemotherapy) regimen for the treatment of metastatic or locally advanced 
unresectable disease
c) NSCLC 
i)
Participants must have histologic or cytologic confirmation of NSCLC (per the seventh 
International Association for the Study of Lung Cancer [IASLC]) with squamous or 
nonsquamous histology that is advanced (metastatic and/or unresectable).
ii) “Not applicable as per revised protocol 03” Participants must have had at least 1, but 
not more than 2, prior systemic therapies for NSCLC. Maintenance, adjuvant, or 
neoadjuvant (chemotherapy or chemoradiation) therapy do not count as an additional 
line of treatment.
iii) Participants should have been offered a platinum-based chemotherapy for NSCLC. The 
platinum-based chemotherapy may have been in the adjuvant, neoadjuvant, or 
chemoradiation setting. Participants with recurrent/metastatic disease that has recurred 
within 6 months of completing such treatment are considered eligible for study 
treatment. Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last 
administration of the prior regimen occurred at least 4 weeks prior to enrollment.
iv) Prior definitive chemoradiation for locally advanced disease is also permitted as long 
as the last administration of chemotherapy or radiotherapy (whichever was given last) 
occurred at least 4 weeks prior to enrollment.
v) Participants with known EGFR mutations or ALK rearrangements must have received 
EGFR or ALK inhibitors, respectively. EGFR, ALK, KRAS, and ROS1 mutational 
status must be documented, if known.
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vi) Participants must have been offered and/or have received or refused at least 1 prior 
approved immune therapy regimen, that is considered standard of care for their disease 
stage and condition, in the country where they are receiving treatment, if such a 
regimen exists. Reason(s) for refusal should be documented.
vii)Participants must have had at least 1, but not more than 3 prior systemic therapies for 
NSCLC. Maintenance, adjuvant, or neoadjuvant (chemotherapy or chemoradiation) 
therapy do not count as an additional line of treatment.
d) PRC
i)
Participants must have histologic or cytologic confirmation of adenocarcinoma of the 
prostate.
ii) “Not applicable as per revised protocol 02” Participants have been treated by 
orchiectomy or are receiving a luteinizing hormone-releasing hormone analog, and 
have a testosterone level ≤50 ng/dL.
iii) “Not applicable as per revised protocol 02” Metastatic disease by any 1 of the 
following modalities: computerized tomography (CT), magnetic resonance imaging 
(MRI), and bone scan.
a.
Participants with bone-only disease should have progression confirmed as per 
PCWG3 criteria and require confirmatory scans.  
iv) Participants must have received abiraterone or enzalutamide.
v) “Not applicable as per revised protocol 02” Progression during hormonal treatment. 
For eligibility purposes, progressive disease is defined as:
(1).Rising prostate-specific antigen values at a minimum of 1-week intervals and a 2.0-
ng/mL minimum starting value OR;
(2).Progression per bone scan: the appearance of 2 or more new lesions, OR;
(3).Progression per target lesions/measurable disease: nodal progression, per modified 
RECIST v1.1. Only lymph nodes > 2 cm will be considered to assess a change in 
size qualifying for disease progression.
vi) Anti-androgens (bicalutamide, flutamide, nilutamide) or adrenal androgen production 
inhibitors (aminoglutethamide or ketoconazole) should be discontinued 28 days prior 
to starting study treatment. Note: bicalutamide or nilutamide must be discontinued 
within 6 weeks of study arm assignment.
(1).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, and must 
demonstrate progression.
(2).For participants who 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 treatment.
vii)Evidence of M1 metastatic disease on previous bone, CT, and/or MRI scan. 
viii) Ongoing ADT with a gonadotropin-releasing hormone (GnRH) analogue or 
bilateral orchiectomy (ie, surgical or medical castration) confirmed by testosterone 
levels of 1.73 nmol/L (≤50 ng/dL) at the screening visit. Castrate levels of 
testosterone must be maintained by surgical or medical means (leuteinizing 
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hormone-releasing hormone (LHRH / GnRH analogues) throughout the conduct of 
the study.
ix) Documented prostate cancer progression as per PCWG3 criteria39 (see Appendix 11) 
with one of the following:
(1).PSA progression* defined by a minimum of 2 rising PSA levels with an interval of 
≥1 week between each determination with either (a) soft tissue disease progression 
or (b) bone disease progression or both (a) and (b). The PSA value at the screening 
visit should be ≥2μg/L (2 ng/mL).
(2).Soft tissue disease progression defined by RECIST v1.1. Participants whose disease 
spread is limited to regional pelvic lymph nodes will be considered eligible.
(3).Bone disease progression with 2 or more new lesions on bone scan.
*Participants who received an anti-androgen must have progression after 
withdrawal (≥4 weeks since last flutamide administration or ≥6 weeks since last 
bicalutamide or nilutamide administration)
x) Participants with bone-only disease may not be eligible if a soft tissue fresh pre-
treatment and on-treatment tumor biopsies cannot be provided.
xi) “Not applicable as per revised protocol 03” Participants must have received 1 but not 
more than 2 prior regimens for castration-resistant disease. If docetaxel chemotherapy 
is used more than once, this will be considered as one regimen.
xii)Participants must have received 1 but not more than 3 prior regimens for castration-
resistant disease. If docetaxel chemotherapy is used more than once, this will be 
considered as one regimen.
xiii)
Participants must have been offered and/or have received or refused at least 1 prior 
approved immune therapy regimen, that is considered standard of care for their disease 
stage and condition, in the country where they are receiving treatment, if such a 
regimen exists. Reason(s) for refusal should be documented.
e) UCC
i)
Participants must have histological or cytological evidence of metastatic or surgically 
unresectable transitional cell carcinoma of the urothelium involving the bladder, 
urethra, ureter, or renal pelvis. Minor histologic variants (< 50% overall) are 
acceptable.
ii) Participants must have metastatic or surgically unresectable disease.
iii) Participants must have progression or recurrence after treatment:
(1).“Not applicable as per revised protocol 03” With at least 1 platinum-containing 
chemotherapy regimen (if platinum eligible) but no more than 2 for metastatic or 
surgically unresectable locally advanced urothelial cancer, or
(2).Within 12 months of peri-operative (neo-adjuvant or adjuvant) treatment with a 
platinum agent in the setting of cystectomy for localized muscle-invasive urothelial 
cancer. 
(3).With at least 1 platinum-containing chemotherapy regimen (if platinum eligible) 
but no more than 3 for metastatic or surgically unresectable locally advanced 
urothelial cancer.
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iv) Sequential chemotherapy given as a planned sequence to optimize response will count 
as 1 regimen.
v) Participants must have been offered and/or have received or refused at least 1 prior 
approved immune therapy regimen, that is considered standard of care for their disease 
stage and condition, in the country where they are receiving treatment, if such a 
regimen exists. Reason(s) for refusal should be documented.
f)
CC
i)
Participants must have histologically confirmed CC that is unresectable, metastatic, or 
recurrent with documented disease progression.
ii) Document tumor HPV status if known. If tumor HPV status is unknown, participants 
must consent to allow their submitted archived tumor tissue sample (block or unstained 
slides) to be tested.
iii) Participants must have been offered and/or have received or refused at least 1 prior 
platinum-based therapy for metastatic and/or unresectable disease. Reason(s) for 
refusal should be documented.
iv) Participants must have not received more than 3 prior systemic therapies.
v) Concurrent chemotherapy administered with primary radiation and adjuvant 
chemotherapy given following completion of radiation therapy do not count as 
systemic therapies, though participants who progressed less than 6 months from 
primary platinum-based therapy are eligible.
vi) Participants must have been offered and/or have received or refused at least 1 prior 
approved immune therapy regimen, that is considered standard of care for their disease 
stage and condition, in the country where they are receiving treatment, if such a 
regimen exists. Reason(s) for refusal should be documented.
g) MEL
i)
Participants must have histologically confirmed recurrent or metastatic melanoma not 
amenable to local therapy with curative intent (surgery with or without chemotherapy) 
ii) Participants must have known BRAF and NRAS mutation status.
iii) Participants must have received and progressed/been intolerant of at least 1 but no more 
than 3 prior systemic therapies for metastatic and/or unresectable disease and have been 
considered for all other potentially efficacious therapies.
iv) Participants must have been offered and/or have received or refused at least 1 prior 
approved immune therapy regimen, that is considered standard of care for their disease 
stage and condition, in the country where they are receiving treatment, if such a 
regimen exists. Reason(s) for refusal should be documented.
h) RCC
i)
Participants must have histologically confirmed advanced or metastatic RCC with a 
clear cell component, not amenable to curative surgery.
ii) Must have received at least 1 but not more than 3 prior systemic therapies in the 
advanced or metastatic setting. Systemic therapies may include anti-angiogenic therapy 
regimens (including but not limited to sunitinib, sorafenib, pazopanib, axitinib, 
tivozanib, and bevacizumab), cytokine therapy (eg, IL-2, IFN-α), vaccine therapy, or 
treatment with cytotoxics.
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iii) Participants must have evidence of progression on or after the last treatment regimen 
received and within 6 months prior to study enrollment.
iv) Participants must have been offered and/or have received or refused at least 1 prior 
approved immune therapy regimen, that is considered standard of care for their disease 
stage and condition, in the country where they are receiving treatment, if such a 
regimen exists. Reason(s) for refusal should be documented.
i)
TNBC
i)
Participants must be women with histologically or cytologically confirmed breast 
carcinoma.
ii) Tumor must be “triple receptor negative” defined as ER/progesterone negative per local 
lab and HER-2 negative defined as HER-2 0 or 1+ by IHC, or IHC 2+ and ISH not 
amplified, or ISH-non amplified.
iii) Participants must have progression or refractory disease. 
iv) Participants must have had at least 1 and not more than 3 systemic chemotherapeutic, 
targeted or investigational regimens for the treatment of metastatic or locally advanced 
and unresectable disease.
v) Participants may refuse chemotherapy for their disease. Participants actively refusing 
chemotherapy must have had best response of stable disease, or progression or 
refractory disease to other treatment options such as radiotherapy, targeted agents, or 
investigational therapy prior to starting study treatment. The participant’s refusal must 
be thoroughly documented. The investigator will discuss each individual participant 
refusing chemotherapy with the sponsor’s Medical Monitor/Study Director (or 
designee) to confirm eligibility.
vi) Participants must have been offered and/or have received or refused at least 1 prior 
approved immune therapy regimen, that is considered standard of care for their disease 
stage and condition, in the country where they are receiving treatment, if such a 
regimen exists. Reason(s) for refusal should be documented.
4) Physical and laboratory test findings
a) Adequate hematologic function
i)
White blood cells ≥2,000/μL
ii) Neutrophils ≥1,500/μL (stable off any growth factor within 4 weeks of first study 
treatment administration)
iii) Platelets ≥100× 103/μL (transfusion to achieve this level is not permitted within 
2 weeks of first study treatment administration)
iv) Hemoglobin ≥9.0 g/dL (transfusion to achieve this level is not permitted within 
2 weeks of first study treatment administration)
b) Adequate hepatic function
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)
c) Normal thyroid function or stable on hormone supplementation per investigator assessment
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d) Serum creatinine ≤1.5× ULN or creatinine clearance (CrCl) ≥40 mL/min (measured using 
the Cockcroft Gault formula below):
Female CrCl = (140 - age in years) × weight in kg × 0.85
72 × serum creatinine in mg/dL
Male CrCl = (140 - age in years) × weight in kg × 1.00
72 × serum creatinine in mg/dL
e) Ability to comply with treatment, PK and PD sample collection, and required study 
followup.
f)
Participant re-enrollment: This study permits the re-enrollment of a participant who has 
discontinued the study as a pretreatment failure (eg, participant has not been treated). If 
re-enrolled, the participant must be re-consented.
5) Age and Reproductive Status
a) Males and females, ages ≥18 years at the time of informed consent.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity of 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 for the duration 
of study treatment with nivolumab or ipilimumab and 5 months after the last dose of study 
treatment (ie, 30 days [duration of ovulatory cycle] plus the time required for the 
investigational drug to undergo approximately 5 half-lives).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab or 
ipilimumab and 7 months after the last dose of study treatment (ie, 90 days [duration of 
sperm turnover] plus the time required for the investigational drug to undergo 
approximately five half-lives). In addition, male participants must be willing to refrain 
from sperm donation during this time.
f)
Due to potential presence of study drugs in seminal fluid, azoospermic males who are 
sexually active must use condoms for all sexual activity during study treatment. 
Additionally, condoms must continue to be used for 4 months after the participants’ final 
treatment. WOCBP who are continuously not heterosexually active are also exempt from 
contraceptive requirements, and still must undergo pregnancy testing as described in this 
section.
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. 
Investigators shall advise on the use of highly effective methods of contraception 
(see Appendix 4), which have a failure rate of < 1% when used consistently and correctly.
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6.2
Exclusion Criteria
1) Target Disease Exceptions
a) Participants with active central nervous system (CNS) metastases, untreated CNS 
metastases, or with the CNS as the only site of disease are excluded. However, 
participants with controlled brain metastases 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), off steroids for at least 2 weeks, and no new or progressive 
neurological signs and symptoms.
b) Participants with carcinomatous meningitis.
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 treatment.
b) Non-cytotoxic agents, unless at least 4 weeks or 5 half-lives (whichever is shorter) have 
elapsed from the last dose of prior anti-cancer therapy and the initiation of study 
treatment. If 5 half-lives is shorter than 4 weeks, agreement with the Sponsor/Medical
Monitor/Study Director (or designee) is mandatory.
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 
treatment.
d) Prior therapy with any agent specifically targeting T-cell co-stimulation pathways, such 
as anti-OX40 antibody, anti-CD137, anti-GITR antibody, and anti-CD27.
e) Prior therapy with anti-ICOS antibody.
f)
No prior adverse reaction to tetanus toxoid-containing vaccines.
g) Participants with known allergies to egg products, neomycin, or tetanus toxoid are also 
considered ineligible
3) Medical History and Concurrent Diseases
a) Prior malignancy active within the previous 2 years except for locally curable cancers 
that have been apparently cured, such as basal or squamous cell skin cancer, superficial 
bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
b) Prior organ allograft.
c) Toxicity (except for alopecia) related to prior anti-cancer therapy and/or surgery, unless 
the toxicity is either resolved, returned to baseline or Grade 1, or deemed irreversible.
i)
Any active neuropathy Grade > 2 (NCI CTCAE v4.0327).
d) 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.
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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.
e) History of life-threatening toxicity related to prior immune therapy (eg, anti-CTLA-4
or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting
T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely
to re-occur with standard countermeasures (eg, hormone replacement after adrenal
crisis).
f)
Interstitial lung disease that is symptomatic or that may interfere with the detection or 
management of suspected drug-related pulmonary toxicity.
g) 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 ≤10 mg 
daily prednisone equivalent in the absence of active autoimmune disease.
ii) Treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating
study treatment is permitted.
h) Uncontrolled or significant cardiovascular disease including, but not limited to, any
of the following:
i)
Myocardial infarction or stroke/transient ischemic attack within the past 6 months.
ii) Uncontrolled angina within the past 3 months.
iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia,
ventricular fibrillation, or torsades de pointes).
iv) History
of
other
clinically
significant
heart disease
(eg, myocarditis, 
cardiomyopathy, congestive heart failure with New York Heart Association
functional classification III to IV [Appendix 9], pericarditis, or significant
pericardial effusion).
v) Cardiovascular disease-related requirement for daily supplemental oxygen therapy.
vi) QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation 
> 480 msec, except for right bundle branch block.
i)
History of chronic hepatitis as evidenced by the following:
i)
Any positive test result for hepatitis B virus or hepatitis C virus indicating presence 
of virus, eg, hepatitis B surface antigen (Australia antigen) positive, or hepatitis C 
antibody positive (except if hepatitis C ribonucleic acid [RNA] negative).
j)
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).
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k) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome.
Note: Testing for HIV-1 and HIV-2 must be performed at sites where mandated by
local requirements.
l)
Any major surgery within 4 weeks of the first dose of study treatment. Participants 
must have recovered from the effects of a major surgery or significant traumatic injury 
at least 14 days before the first dose of study treatment.
i)
Participants who have received a 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.
m) Receipt of packed red blood cells or platelet transfusion within 2 weeks of the first
dose of study treatment.
n) Any known or underlying medical or 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.
o) WOCBP who are pregnant or breastfeeding.
4) Allergies and Adverse Drug Reaction
a) History of allergy to study treatment 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 
physical (eg, infectious disease) illness.
c) Participants with serious or uncontrolled medical disorders
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) intravenously.
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/included in the analysis population. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
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participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements (see Appendix 8), and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any SAEs.
6.4.1
Retesting During Screening
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 within any single 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 because it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1 may be repeated in an 
effort to find all possible well-qualified participants. Consultation with the BMS Medical 
Monitor/Study Director (or designee) may be needed to identify whether repeat testing of any 
particular parameter is clinically relevant.
7
TREATMENT
Study treatment is defined as any investigational treatment(s) or marketed product(s) intended to 
be administered to a study participant according to the study randomization or treatment allocation.
Study treatment includes IPs/investigational medicinal products (IMPs) and non-IPs/IMPs and can 
consist of the following:
•
BMS-986226
•
Nivolumab
•
Ipilimumab
•
Tetanus Vaccine
An IP, also known as IMP in some regions, is defined as a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical study, including products 
already with a marketing authorization but used or assembled (formulated or packaged) differently 
from the authorized form, used for an unauthorized indication, or when used to gain further 
information about the authorized form.
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.
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Table 7-1:
Study Treatments for CA021002
Product Description / 
Dosage Form
Potency
IP/NonIMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage Conditions
(per Label)
BMS-986226-01
Solution for Injection
10 mg/mL
IP
Open
Vial
2 to 8 °C, Protect from 
light  
Nivolumab
Solution for Injection
10 mg/mL
IP
Open
Vial
2 to 8 °C, Protect from 
light and freezing
Ipilimumab
Solution for Injection 
5 mg/mL
IP
Open
Vial
2 to 8 °C, Protect from 
light and freezing
Tetanus vaccine
Per locala
IP
Open
Various 
packaging 
configuration
Refer to the label on 
container and/or 
pharmacy manual
Abbreviations: IP = investigational product
a Tetanus vaccine (Tdap preferred, Td or equivalent after discussion with the Medical Monitor/Study Director or 
designee) will be obtained as local commercial product in countries if allowed by local regulations or through 
investigating sites standard prescribing procedures.
7.1
Treatments Administered
The selection and timing of dose for each participant are presented in Table 7.1-1.
Table 7.1-1:
Selection and Timing of Dose per Part
Study Treatment
Dose Level
Frequency of 
Administration
Route of 
Administration
Infusion time 
(Minute)
Preliminary Safety Cohorts and Part A
BMS-986226
2, 8, 25, 80, 200, 400, 
800 mg
Q4W
IV
30
Part B1
Nivolumab
480 mg
Q4W
IV
30
BMS-986226
3 Doses evaluated by 
BLRM-copula, PK/PD
Q12W
30
Part B2
Nivolumab
480 mg
Q4W
IV
30
BMS-986226
3 Doses evaluated by 
BLRM-copula, PK/PD
Q4W
IV
30
Part C1
Ipilimumab
3 mg/kga
Q4W
IV
30
BMS-986226
3 Doses evaluated by 
BLRM-copula, PK/PD
Q12W
30
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Table 7.1-1:
Selection and Timing of Dose per Part
Study Treatment
Dose Level
Frequency of 
Administration
Route of 
Administration
Infusion time 
(Minute)
Part C2
Ipilimumab
3 mg/kga
Q4W
IV
30
BMS-986226
3 Doses evaluated by 
BLRM-copula, PK/PD
Q4W
30
Part D
Nivolumab
480 mg
Q4W
IV
30
BMS-986226
PK/PD from Part B
TBD
30
Part E
Ipilimumab
3 mg/kga
Q4W
IV
30
BMS-986226
PK/PD from Part C
TBD
IV
30
a Weight collected at baseline/screening should be used to calculate ipilimumab dose unless weight has changes more 
than +/- 10% from baseline on C1D1
Note: In Parts B, C, D, and E a 30-minute infusion of either nivolumab or ipilimumab will be followed by a 30-minute 
observation period, followed by a 30-minute infusion of BMS-986226. In all parts, participants will be observed for 
at least 60 minutes following the completion of BMS-986226 infusion due to the potential risk of, and to monitor for, 
infusion reactions.
In order to reduce the risk of infusion-related reactions, participants enrolled in all study parts are 
recommended to receive premedication 30 minutes prior to initiation of study treatment. 
Recommended premedications include a H1 histamine antagonist, such as diphenhydramine
50 mg (or equivalent), and an antipyretic, such as acetaminophen/paracetamol 325 to 1000 mg (or
equivalent). Premedication should be administered prior to infusion of any study drug, and should 
comply with the permitted medications and dosing described in Section 7.6. Any alternative 
premedication regimen must be discussed with, and approved by the BMS Medical Monitor/Study 
Director prior to administration of any study treatment. Medical management of any infusion 
reactions occurring irrespective of whether premedication was administered, remain at the 
discretion of the investigator. Guidelines for management of infusion reactions are described in 
Section 7.3.6.
7.1.1
Method of Treatment Assignment
This is an open-label study. All participants must be assigned a participant number upon providing 
signed written informed consent. Based on the rate of participant enrollment, the Sponsor will 
implement an IRT to assign participant numbers, study treatment group, and dose level, as well as 
manage drug supply. During the screening visit, the investigative site will register the participant 
by an IRT designated by BMS for assignment of a 5-digit participant number that will be unique 
across all sites. Enrolled participants, including those not dosed, will be assigned sequential 
participant numbers 
.
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The participant identification number (PID) will ultimately be composed of the site number and
participant number. For example, the first participant screened (e.g., enrolled) at site number 1, 
will have a PID 
. Specific instructions for using the IRT will be provided to the
investigational sites in a separate instruction manual.
Once it is determined that the participant meets the eligibility criteria following the screening visit, 
the assigned treatment group and dose level will be provided to the site study team through the 
IRT prior to the first study treatment administration. The participant will be informed of one of the 
following:
•
Assigned to a part (Preliminary Safety Cohorts and Part A) and dose cohort in the dose 
escalation portion of the study.
•
Assigned to a part (Part B1, B2, C1, or C2) in the combination portion of the study. 
•
Assigned to the expansion portion of the study (Parts D and E)
During dose escalation, all participants will be assigned to the Preliminary Safety Cohorts, then 
Part A until the decision is made to start the combination with either nivolumab or ipilimumab. If 
there are no openings available in the part to which the participant would be assigned by this 
algorithm, then the participant will be assigned to the next open part/cohort. In the event that 
multiple cohorts are open in Parts B and/or C simultaneously, participants will be assigned to those 
cohorts in an alternating fashion.
During dose escalation (Preliminary Safety Cohorts and Part A), participants who are not evaluable 
for DLT determination may be replaced (see Section 5.1.2.1). Replacement participants will be 
assigned to the same part (Part A) and dose, but will be assigned a new participant number. Please 
refer to the IRT manual for complete details on replacement of participants.
Participants in Parts A, B and C may be replaced if adequate paired pretreatment and on-treatment 
biopsy specimens are not obtained. The replacement participant will receive the same treatment as 
that for the participant being replaced, but a new participant number will be assigned (see
Section 5.1.2.2 and 5.1.2.3).
7.2
Blinding
This is a non-randomized, open-label study; blinding procedures are not applicable.
7.3
Dosage Modification
With the exclusion of the Preliminary Safety Cohorts, intra-participant dose escalation or reduction 
of BMS-986226, 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.
7.3.1
Treatment Delay
Participants who experience a DLT must have the study treatment held. Participants who are 
required to permanently discontinue both study treatments are listed in Section 8.1. In addition, all 
Grade 2 hepatic, pulmonary, renal, GI, and neurological AEs should be evaluated and managed 
per the toxicity management algorithms (Appendix 6). Participants not meeting guidelines for 
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permanent discontinuation will be permitted to resume study treatment based on the criteria 
specified below in Section 8.1.1. Participants eligible to resume study treatment will resume study 
treatment at the visit following their last received dose.
In all cohorts, if there is a delay in dosing of BMS-986226 alone or in combination with nivolumab 
or ipilimumab, between 1 and 12 days, the procedures at the original scheduled visit should be 
performed as soon as possible. If the delay is more than 12 days, the visit and dose will be 
considered missed; the procedures at the next scheduled visit should be performed, and subsequent 
BMS-986226 doses will follow every 4 weeks.
Extensions to the period of dose delays may be granted for individual participants on a 
case-by-case basis after specific consultation and agreement between the investigator and BMS 
Medical Monitor/Study Director (or designee) in settings where benefit/risk may justify continued 
study treatment (eg, participant deriving clinical benefit who requires prolonged steroid taper for 
the management of non-DLT -drug-related- AEs or experiences delays for the management of a 
nondrug-related AE).
The end of cycle tumor assessments (ie, CT/MRI, PET, etc) will continue on a Q8W schedule 
relative to the participant’s first dose regardless of any study treatment delay incurred.
7.3.2
BMS-986226 Dose-limiting Toxicities
For the purpose of guiding dose escalation, DLTs will be defined based on the incidence, 
intensity, and duration of AEs for which no clear alternative cause is identified. The DLT period 
will be 35 days (5 weeks).
In the Preliminary Safety Cohorts, participants who have received 1 dose of BMS-986226 and 
have completed, or who discontinued due to a DLT in the 4-week DLT period, will be considered 
as DLT-evaluable participants for BMS-986226 monotherapy.
In Part A, participants who have received 2 doses of BMS-986226 and have completed, or who 
discontinued due to a DLT in the 5-week DLT period, will be considered as DLT-evaluable 
participants for BMS-986226 monotherapy. 
In Parts B, C, D and E, participants receiving either 1 dose of BMS-986226 or 2 doses of either 
nivolumab or ipilimumab, 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 doses for reasons other than a DLT in the monotherapy (Part A) 
or 1 dose in combination therapy (Parts B, C, D, E), will not be considered as DLT-evaluable 
participants and may be replaced with a new participant at the same dose level. Participants in 
Part A, who are dose delayed during the DLT evaluation period for reasons other than a DLT could 
be considered as DLT-evaluable participants if they receive at least 2 doses of therapy.
For the purpose of participant management, any AE that meets DLT criteria, regardless of the
cycle in which it occurs, will lead to discontinuation of study treatment (except as defined in 
Section 7.3.5). Participants who withdraw from the study during the 5-week DLT evaluation
period for reasons other than a DLT may be replaced with a new participant at the same dose
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level. The incidence of DLT(s) during the 5-week DLT evaluation period will be used in dose
escalation decisions through application of the BLRM/BLRM-Copula model. AEs occurring after
the DLT period will be considered to enhance the robustness of BLRM/BLRM-Copula 
prediction, upon agreement between the Sponsor, Medical Monitor/Study Director (or 
designee), and investigators.
Participants experiencing a DLT will enter the safety follow-up period of the study. DLTs
occurring after the 4-week DLT observation period for the Preliminary Safety Cohorts or 5-week
DLT observation period for Parts A, B and C will be accounted for in determining the MAD for 
the combination part.
AEs will be graded according to the NCI CTCAE v4.0327, as listed below:
A. Hepatic Non-hematological DLT
Any one of the following study treatment-related events will be considered a hepatic DLT:
•
Any Grade ≥3 elevation of AST, ALT, or total bilirubin.
•
Grade 2 AST or ALT with symptomatic liver inflammation (eg, right upper quadrant 
tenderness, jaundice, pruritus).
•
AST or ALT > 3× ULN and concurrent total bilirubin > 2× ULN without initial findings of 
cholestasis (elevated serum alkaline phosphatase [ALP] [eg, findings consistent with Hy’s law 
or FDA definition of potential drug-induced liver injury or potential drug-induced liver injury 
[p-DILI]). Note that this special category of DLT uses ULN rather than Common Toxicity 
Criteria (CTC) grade for definition.
B. Non-hepatic Non-hematological DLT
Any of the following events will be considered a non-hepatic non-hematological DLT:
•
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity ≤2 weeks or requires systemic treatment.
•
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, myocarditis, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction of any duration will require discontinuation.
•
Any 
Grade 
3 
or 
greater 
nondermatologic, 
nonhepatic 
nonhematological
study 
treatment-related toxicity will be considered a DLT, with the following specific exceptions:
−
Grade 3 or Grade 4 electrolyte abnormalities that are not complicated by associated clinical 
adverse experiences, last ≤72 hours, and either resolve spontaneously or respond to 
conventional medical intervention
−
Grade 3 nausea, vomiting, or diarrhea that lasts less than 72 hours (without steroid therapy) 
and either resolves spontaneously or responds to conventional medical intervention
−
Isolated Grade 3 elevation of amylase or lipase not associated with clinical or radiographic 
evidence of pancreatitis
−
Isolated Grade 3 fever not associated with hemodynamic compromise (eg, hypotension, 
clinical or laboratory evidence of impaired end-organ perfusion or with other symptoms of 
infusion-related reactions that returns to ≤Grade 1 with standard treatment in ≤1 hour
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−
Grade 3 endocrinopathy that is well controlled by hormone replacement
−
Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or 
suspected tumor)
−
Grade 3 fatigue for ≤7 days
−
Grade 3 infusion reaction that returns to Grade 1 in ≤1 hour
C. Dermatologic DLT
•
Grade 3/4 rash if no improvement (ie, resolution to Grade ≤1) after a 1-week to 2-week 
infusion delay. Participants who have not experienced a Grade 3 drug-related skin AE may 
resume treatment in the presence of Grade 2 skin toxicity.
•
Grade 4 rash of any duration
D. Hematologic DLT
•
Grade 4 neutropenia ≥5 days in duration
•
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant bleeding 
or any requirement for platelet transfusion
•
Grade 4 anemia not explained by underlying disease
•
Grade 4 febrile neutropenia
•
Grade 3 febrile neutropenia that lasts > 48 hours
•
Grade ≥3 hemolysis (i.e., requiring transfusion or medical intervention such as steroids)
7.3.3
Management Algorithms for Immuno-oncology Agents
Immuno-oncology (I-O) agents are associated with irAEs that can differ in severity and duration
from AEs caused by other therapeutic classes. BMS-986226, nivolumab, and ipilimumab 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 I-O agents to assist investigators in assessing and managing the 
following groups of irAEs:
•
GI
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
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The clinical nature of AEs noted with BMS-986226 will determine the role of the algorithms for
use in toxicities related to its use in this study. The algorithms recommended for the management 
of irAEs in this protocol are in Appendix 6.
7.3.4
Dose Delays Due To Toxicity
Participants who experience the following must have all study treatment(s) withheld:
•
Potential DLTs, until DLT relatedness is defined.
•
Select AEs and laboratory abnormalities:
−
Grade ≥1 pneumonitis
−
Grade ≥2 abnormality in AST, ALT, or total bilirubin
−
Grade ≥2 abnormality in creatinine
−
Grade ≥2 diarrhea or colitis
−
Grade ≥2 neurological AE
−
AE, laboratory abnormality, or concurrent illness that, in the judgment of the investigator, 
warrants delaying study treatment administration.
Criteria for participants who are required to permanently discontinue both study treatments are
listed in Section 8.1. Participants not meeting guidelines for permanent discontinuation will be 
permitted to resume therapy based on the criteria specified below in Section 7.3.5. Participants 
eligible to resume study treatment will resume study treatment at the nominal treatment visit 
following their last received study treatment dose.
The end of cycle tumor assessments, such as CT, MRI, or positron emission tomography (PET), 
will continue on a once Q8W schedule relative to the participant’s first dose, regardless of any 
treatment delay incurred.
7.3.5
Exceptions to Permanent Discontinuation Criteria
Any drug-related AE occurring at any time that meets DLT criteria as outlined in Section 7.3.2
will require permanent discontinuation. Exceptions to permanent discontinuation are listed in 
Section 8.1.
Study treatment may be re-initiated in participants experiencing non-life-threatening AEs that meet 
DLT criteria and that have been resolved to Grade 1 or baseline. Consideration to resume treatment 
will be made on a case-by-case basis in a discussion between the investigator and BMS Medical 
Monitor/Study Director (or designee) and approval of the sponsor, taking into account the overall 
benefit/risk ratio for the individual participant and the following factors:
•
A 2-week washout period is required after completing the immune suppressive treatment used 
to manage the AE (eg, steroids). The AE should not recur/worsen during the washout period.
•
Evidence for clinical or radiographic benefit must be present, which can include improvement 
of physical symptoms (eg, ECOG status, shortness of breath), symptomatic improvement in 
combination with assessment of SD, or radiographic response.
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In the event of recurrence of the AE that met the DLT criteria, study treatment will be permanently 
discontinued for the participant.
Additionally, consideration to permanently discontinue study treatment for participants with any 
severe Grade 3 drug-related AE that recurs will be made on a case-by-case basis in a discussion 
between the investigator and BMS Medical Monitor/Study Director (or designee).
All participants who discontinue IP should comply with protocol-specified follow-up procedures 
as outlined in Section 5.1.3. 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 or 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.
7.3.6
Management of Drug-related Infusion Reactions
BMS-986226 is a humanized mAb and has the potential to induce hypersensitivity reactions 
following administration. As of 28-March-2019, 7 of 19 (36.8%) participants treated with 
BMS-986226 monotherapy experienced a Grade 1 or Grade 2 infusion-related reaction. One 
participant experienced Grade 3 hypersensitivity during BMS-986226 infusion after the data cut-
off date of 28 March 2019. When such reactions occur, they may manifest with fever, chills, rigors, 
headache, flushing, rash, urticaria, pruritus, arthralgia, hypotension, hypertension, bronchospasm, 
or other allergic-like reactions. All Grade 3 or 4 infusion reactions should be reported within 
24 hours to the BMS Medical Monitor/Study Director (or designee) and reported as an SAE. 
Infusion reactions should be graded according to NCI CTCAE v4.0327 guidelines.
Premedications are recommended as per section 7.1.
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.
•
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 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 
(eg, 
antihistamines, 
nonsteroidal-anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, or IV fluids); 
prophylactic medications indicated for ≤24 hours.
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•
Remain at the bedside and monitor participant until resolution of symptoms. Monitor 
participant closely.
•
Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the 
participant with diphenhydramine 50 mg IV (or equivalent) and acetaminophen/paracetamol 
325 to 1,000 mg.
•
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. 
•
If the infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be
increased to 100% of the original infusion rate. The amount of study treatment infused must 
be recorded on the CRF.
•
If symptoms recur, then no further BMS-986226, nivolumab, or ipilimumab will be 
administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and 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 or 4 symptoms: Severe reaction, Grade 3: prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (eg, renal impairment or
pulmonary infiltrates); Grade 4: life-threatening; pressor or ventilatory support indicated.
•
Remain at bedside and monitor participant until recovery of the symptoms.
•
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 intramuscular or 
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. 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.4
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that the IP is only dispensed to study participants. The IP must be 
dispensed only from official study sites by authorized personnel according to local regulations.
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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 including all processes 
required to ensure that treatment is accurately administered. This includes documentation of drug 
storage, administration, and, as applicable, storage temperatures, reconstitution, and use of 
required processes (eg, required diluents and administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 and the pharmacy manual.
7.4.1
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
7.5
Treatment Compliance
Study treatment will be administered in the clinical facility by trained medical personnel. 
Treatment compliance will be monitored by drug accountability as well as by recording 
BMS-986226, nivolumab, and ipilimumab administration in participants’ medical records and in 
the CRF.
7.6
Concomitant Therapy
7.6.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to study treatment administration in the study 
are described below. Medications taken within 4 weeks prior to study treatment administration 
must be recorded on the CRF.
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Immunosuppressive agents (except as stated in Section 7.6.2)
•
Concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy (except where 
otherwise indicate), immunotherapy, extensive, non-palliative radiation therapy, or standard 
or investigational agents) Herbal prescriptions including, but not limited to, cannabis and other 
recreational drugs
•
Any live / attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella (MMR) during treatment and until 100 days post last dose.
No concomitant medications (prescription, over-the-counter or herbal) are to be administered 
during the study unless they are prescribed for the treatment of specific clinical events. Any 
concomitant therapies must be recorded on the CRF.
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7.6.1.1
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 or not they should receive contrast and, if so, what type and dose of contrast are
appropriate. MRI contrast should not be given to participants with severe renal insufficiency 
(eg, estimated GFR < 30 mL/min/1.73 m2) because of increased risk of nephrogenic systemic 
fibrosis in this participant population. In these participants, alternative imaging tests or MRI 
without gadolinium should be considered. In addition, participants should be excluded from MRI 
if they have uncontrollable claustrophobia, metallic implants, pacemakers, and so on.
The ultimate decision to perform MRI in an individual participant in this study rests with the site 
radiologist, the investigator, and the standard set by the local Ethics Committee (EC).
7.6.2
Permitted Therapy
Participants are permitted the use of the following treatments:
•
Topical, ocular, intra-articular, intra-nasal, and inhalational corticosteroids (with minimal 
systemic absorption).
•
Adrenal replacement steroid doses ≤10 mg daily prednisone equivalent.
•
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).
•
Bisphosphonates and RANKL directed-therapies for bone metastases are permitted.
Systemic immunosuppressive agents and the use of systemic corticosteroids are permitted in the 
context of treating AEs. Participants receiving corticosteroids for treatment of drug-related AEs 
must be receiving < 10 mg/day prednisone equivalent for < 5 days up to 7 days prior to re-initiation 
of study treatment. Participants may continue to receive hormone replacement therapy.
7.6.3
Palliative Local Therapy
Palliative and supportive care for disease-related symptoms may be offered to all participants on 
the study after the DLT evaluation period. Limited radiation therapy or surgery to control isolated 
lesions is permitted for participants who have investigator-assessed clinical benefit following 
consultation with the BMS Medical Monitor/Study Director (or designee).
Participants should not receive study treatment during radiation, as the potential for overlapping 
toxicities with radiotherapy and BMS-986226 or BMS-986226 in combination with nivolumab or
ipilimumab is currently not known. Anecdotal data suggest that radiotherapy administered to 
participants while receiving nivolumab or ipilimumab therapy is tolerable. However, because 
concurrent radiotherapy and immunotherapies in cancer have not been formally evaluated, in cases 
where palliative radiotherapy is required for a tumor lesion, BMS-986226 alone or in combination
with nivolumab or ipilimumab should be withheld for at least 1 week before, during, and 1 week 
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after radiation. Participants should be closely monitored for any potential toxicity during and after 
receiving radiotherapy, and AEs related to radiotherapy should resolve to Grade 1 prior to 
resuming study treatment.
Participants who have received palliative local therapy will be documented as having had disease 
progression for the purpose of efficacy analyses.
7.7
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants must discontinue IP (and non-IP at the discretion of the investigator) for any of the 
following reasons:
•
Participant’s request to stop study treatment
•
Any clinical AE, laboratory abnormality, or intercurrent illness that, 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 BMS
•
Loss of ability to freely provide consent through imprisonment or involuntary 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.)
•
Pregnancy
•
Documented and confirmed disease progression as defined by RECIST v1.1 (see Appendix 5) 
or PCWG3 (prostate cancer only) (see Appendix 11) unless participant meets criteria for 
treatment beyond progression (Section 8.1.2)
•
Clinical deterioration while receiving active study treatment that, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant
•
Discretion of the investigator
•
Inability to comply with the protocol requirements
•
Individual participants with confirmed CR will be given the option to discontinue study 
treatment on a case-by-case basis after specific consultation and agreement between the 
investigator and BMS Medical Monitor/Study Director (or designee) in settings where 
benefit/risk justifies discontinuation of study treatment
•
Any Grade 4 drug-related AE or laboratory abnormality (including, but not limited to,
creatinine, AST, ALT, or total bilirubin), except for the following events that do not require 
discontinuation:
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−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia, leukopenia, or asymptomatic amylase or lipase abnormalities
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy AEs, such as hyperthyroidism or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor/Study Director (or designee).
•
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage study treatment-related AEs 
are allowed 
−
Dosing delays lasting > 6 weeks from the previous dose that occur for nondrug-related 
reasons may be allowed if approved by the BMS Medical Monitor/Study Director (or 
designee).
•
The assessment for discontinuation of nivolumab or ipilimumab should be made separately 
from the assessment made for discontinuation of BMS-986226. Although there is overlap 
among the discontinuation criteria, if discontinuation criteria are met for BMS-986226 but not 
for nivolumab or ipilimumab, treatment with nivolumab or ipilimumab may continue even if 
BMS-986226 is discontinued.
•
If a participant in any of the nivolumab or ipilimumab/BMS-986226 combination arms meets 
criteria for discontinuation and the investigator is unable to determine whether the event is 
related to both or 1 of the study treatments, the participant should discontinue both nivolumab 
or ipilimumab and BMS-986226 and should be taken off the treatment phase of the study.
Refer to the Schedule of Activities (Section 2) for the data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 5.1.3. The only exception to this requirement is when a 
participant withdraws consent for all study procedures, including posttreatment study follow-up,
or loses the ability to consent freely (eg, imprisonment, involuntarily incarceration for the 
treatment of either a psychiatric or a physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate CRF page.
8.1.1
Criteria to Resume Treatment 
Subsequent dosing with the study treatment may resume once drug-related DLT AEs resolve to 
Grade 1 or baseline.
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In agreement with the Sponsor, after evaluation of the risk/benefit ratio, participants with selected 
drug-related AE that meet DLT criteria may resume treatment once the AE is resolved to Grade ≤1
or baseline value (see Section 7.3.5).
Participants who experience AEs and do not meet the criteria for permanent discontinuation as 
outlined in Section 8.1 may resume study treatment 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 7.3.2) must resolve to baseline prior to resuming study treatment.
•
For participants with Grade 2 AST, ALT, or total bilirubin elevations, dosing may resume 
when laboratory values return to baseline and management with corticosteroids (if needed) is 
complete.
−
Participants with combined Grade 2 AST/ALT and total bilirubin values meeting DLT 
criteria (Section 7.3.2) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with, and 
approved by, the BMS Medical Monitor/Study Director (or designee).
•
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment.
If the criteria to resume treatment are met, the participant should restart treatment at the next 
nominally scheduled time point per protocol.
Even if the criteria to resume treatment are met, the consideration to re-initiate study treatment 
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 BMS Medical 
Monitor/Study Director (or designee) to determine the risks and benefits of continuing on the 
treatment following resolution versus discontinuing therapy permanently.
If study treatment is delayed > 6 weeks, the participant must be permanently discontinued from 
study treatment, except as specified in Section 7.3.5.
8.1.2
Treatment Beyond Disease Progression
As described in Section 5.4.3, accumulating evidence indicates that a minority of participants with 
solid tumors treated with immunotherapy may derive clinical benefit despite initial evidence of 
progressive disease. Participants will be permitted to continue on study treatment beyond initial 
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RECIST v1.1 defined progressive disease (see Appendix 5) or PCWG3 (prostate cancer only) (see 
Appendix 11) 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 prior to receiving any additional BMS-986226, 
nivolumab, or ipilimumab treatment using an ICF describing any reasonably foreseeable risks 
or discomforts, or other alternative treatment options 
The assessment of clinical benefit should take into account whether the participant is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. If the investigator 
feels that the participant continues to achieve clinical benefit by continuing treatment with the 
study treatment, the participant should remain on the study and continue to receive monitoring 
according to the Schedule of Activities (see Section 2). All decisions to continue treatment beyond 
initial progression must be discussed with the BMS Medical Monitor/Study Director (or designee),
and an assessment of the risk/benefit of continuing with study treatment must be documented in 
the study records. Participants will be re-consented to explain the rationale for this ongoing 
treatment.
8.1.3
Discontinuation Due to Further Progression (Confirmed Progression)
Participants will continue to receive monitoring according to the on-treatment assessments in 
Section 2. Radiographic assessment by CT (preferred) or MRI (described in Section 9.1) is 
required when participants continue post-progression study treatment and should be performed at 
each scheduled tumor assessment 4 to 6 weeks following initial disease progression to determine 
whether there has been continued progressive disease or not. Participants should discontinue study 
treatment upon evidence of further progression, defined as an additional 10% or greater increase 
in tumor burden volume from the time of initial progression (including all target lesions and new 
measurable lesions). 
The tumor burden volume from the time of initial progression should be used as the reference 
baseline for comparison with the post-progression assessment. 
Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore must be included in the tumor burden measurement as follows: 
•
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). 
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For statistical analyses that include the investigator-assessed progression date, participants who 
continue treatment beyond initial investigator-assessed, RECIST v1.1 or PCWG3 (prostate cancer 
only) defined progression will be considered to have investigator-assessed progressive disease at 
the time of the initial progression event.
For participants who discontinue post-progression study treatment, no additional radiographic 
assessments will be required.
8.1.4
Post-study Treatment Study Follow-up
Post-study follow-up is of critical importance and is essential to preserving participant safety and 
the integrity of the study. Participants who discontinue study treatment must continue to be 
followed up for the collection of outcome and/or survival follow-up data as required and in line 
with Section 5 until death or the conclusion of the study.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the -defined window (Section 2). At the time of this request, each participant will be contacted to 
determine his or her survival status unless the participant has withdrawn consent for all contacts 
or is lost to follow-up.
Participants who discontinue study treatment may continue to be followed up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed up for protocol-specified follow-up procedures, as indicated in Section 5.1.3. The 
only exception to this is when participants specifically withdraw consent for any further contact 
with them or persons previously authorized by participants to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The investigator should explain the withdrawal of consent in detail in the medical records and 
enter on the appropriate CSR page 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; this 
explanation should be 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.
8.3
Lost to Follow-up
Guidelines for participants lost to follow-up include the following:
•
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 for contact.
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•
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 
1 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 -retained third-party representative to assist site staff with obtaining the 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, 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 (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 (Section 2), is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities (Section 2).
Additional measures, including non-study-required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug-
induced liver enzyme evaluations) will be monitored during the follow-up phase via on-site/local 
laboratories until all study treatment-related toxicities resolve, return to baseline, or are deemed 
irreversible.
If a participant shows pulmonary-related signs (hypoxia or fever) or symptoms (eg, dyspnea, 
cough, or fever) consistent with possible pulmonary AEs, the participant should be immediately 
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evaluated to rule out pulmonary toxicity according to the suspected pulmonary toxicity
management algorithm in the ipilimumab IB.18
Some of the assessments referred to in this section may not be captured as data in the CRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the Schedule of Activities in Section 2.
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
Methods of Assessment
CT and MRI are essential parts of the work-up to establish recurrence. The following imaging 
assessments should be performed at prespecified intervals: CT of the chest and CT or MRI of the 
abdomen, pelvis, and other known/suspected sites of disease. 
•
CT scans should be acquired with a slice thickness of 5 mm or less with no intervening gap 
(continuous).
•
Should a participant have a contraindication for CT IV contrast, a non-contrast CT of the chest 
and a contrast-enhanced MRI of the abdomen and pelvis and other known/suspected sites of 
disease may be obtained. MRIs should be acquired with a slice thickness of 5 mm or less with 
no gap (continuous).
•
Every attempt should be made to image each participant using an identical acquisition protocol 
on the same scanner for all imaging time points. 
•
PET alone will not be considered for the disease assessment. Complementary CT and/or MRI 
or biopsy must be performed in such cases. 
−
Note: Use of CT component of a PET/CT scanner: Combined modality scanning, such as 
with fluorodeoxyglucose (FDG)-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 corrections
of the CT portions of a combined FDG-PET/CT are of limited use in anatomically based
efficacy assessments, and it is, therefore, suggested that they should not be substituted for 
dedicated diagnostic contrast enhanced CT scans for anatomically based RECIST v1.1 (see 
Appendix 5) or PCWG3 (prostate cancer only) (see Appendix 11) measurements. 
However, if a site can document that the CT performed as part of an FDG-PET/CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the FDG-PET/CT can be used for RECIST v1.1 measurements. Note, however, 
that the FDG-PET portion of the CT introduces additional data that may bias an 
investigator if it is not routinely or serially performed. 
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•
Histology or cytological evidence of recurrence should be attempted in all cases except for 
brain metastases. Cytology and/or histology are mandatory to confirm recurrence in solitary or 
in equivocal lesions, any new lesions occurring in the kidney, and lymph nodes unless the 
lesion is too small to biopsy or the risk of biopsy is substantial (eg, inter-aortal node with risk 
of bleed after biopsy because of close proximity to the aorta and inferior vena cava), in which 
case, the recurrence must be confirmed with a repeat scan 4 weeks later.
Disease assessment with CT and/or MRI, as appropriate, will be performed at baseline and 
approximately Q8W (± 1 week) during the treatment phase (prior to dosing at Cycles 3, 5 and 7) 
until progressive disease per RECIST v1.1 (see Appendix 5) or PCWG3 (prostate cancer only) 
(see Appendix 11), or until confirmed progressive disease for participants treated beyond 
progression (defined as an additional 10% or greater increase in tumor burden volume from time 
of initial progression [including all target lesions and new measurable lesions]), or withdrawal 
from study. Tumor assessments at other time points may be performed if the investigator is 
concerned about tumor progression. Tumor response will be assessed by the investigator according 
to RECIST v1.1 (see Appendix 5) or PCWG3 (prostate cancer only) (see Appendix 11) for 
participants with solid tumors.
For participants with prostate cancer, bone lesions should be assessed using Technetium-99m 
(Tc-99m) based radionuclide bone scans. Anterior and posterior whole body planar images should 
be acquired. Additional (including spot views and SPECT) images should be submitted if acquired. 
Assessments should be performed at baseline and at the time points described per PCWG3 criteria 
until disease progression per PCWG3 criteria (see Appendix 11), or discontinuation of study 
treatment, whichever occurs later. Tumor assessments at other time points may be performed if 
clinically indicated and should be confirmed at least 4 weeks after initial response. Changes in 
tumor measurements and tumor responses will be assessed by the investigator per study design 
using PCWG3 criteria. Investigators will also report the number and size of new lesions that appear 
while on study. For participants who are treated beyond PCWG3-defined progression, tumor 
assessments will continue to be performed until discontinuation of study treatment (typically upon 
evidence of further progression). Any additional imaging that may demonstrate tumor response or 
progression (including scans performed at unscheduled time points and/or at an outside institution 
should be collected for PCWG3 tumor assessment and submitted to the BICR.
Images will be submitted to an imaging core laboratory. Sites should be trained prior to scanning 
the first study participant. Image acquisition guidelines and submission process will be outlined in 
the Imaging Manual to be provided by the core laboratory.
For Part A, images will be collected centrally and may be reviewed by BICR at a later date, or at 
any time during the study per BMS request. For Parts B, C, D and E, images will be collected 
centrally and reviewed by BICR.
9.1.2
Primary Efficacy Assessments
Not applicable.
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9.1.3
Secondary Efficacy Assessments
The secondary efficacy assessments will include the objective response rate (ORR; eg, PR + CR), 
mDOR, and progression-free survival rate (PFSR) at 24 weeks based on assessment of tumor 
response using RECIST v1.1 or PCWG3 (prostate cancer only).
ORR is defined as the proportion of all treated participants whose best overall response (BOR) is 
either a CR or PR. BOR is defined as the best response designation over the study as a whole, 
recorded between the dates of first dose and the date of first objectively documented tumor 
progression per RECIST v1.1 (or PCWG3) or the date of subsequent therapy, whichever occurs 
first. CR or PR determinations included in the BOR assessment must be confirmed by a second 
scan performed no less than 4 weeks after the criteria for response are first met. A Best Overall 
Response of SD requires a minimum of 49 days on study from the date of first dose to the date of 
the first imaging assessment. For those participants who have surgical resection, only pre-surgical 
tumor assessments will be considered in the determination of BOR.
mDOR, computed for all treated participants 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 disease 
progression per RECIST v1.1 (or PCWG3) or death, whichever occurs first.
PFSR at 24 weeks is defined as the proportion of treated participants remaining progression free 
and surviving at 24 weeks. The proportion will be calculated by the Kaplan-Meier estimate, which 
takes into account censored data.
For prostate cancer, the consensus guidelines of the PCWG3 have been taken into consideration 
for the determination of radiographic disease progression assessment. All target and non-target 
sites of disease identified on the baseline assessment should be reassessed with the same imaging 
modality at subsequent assessments. Bone lesions should be assessed with Tc-99m based bone 
scans.  
For prostate cancer disease progression, at each disease assessment, progressive disease will be 
determined using the criteria based on PCWG3. 
Radiographic progression in soft tissue lesions (prostate only) is described in Table 9.1.3-1. See 
Appendix 11 (PCWG3) for additional information.
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Table 9.1.3-1:
Definition of Radiographic Progression
Parameter
Progression
Date of Progression
Soft tissue lesions (target, non-
target lesions with CT or MRI)
Progression of soft tissue lesions 
(target, non-target, new lesions with 
CT or MRI)
Date of first unequivocal 
progression of soft tissue lesion 
(target, non-target, or new lesions) 
as per PCWG3a
Bone lesions on radionuclide bone 
scan per PCWG3
At least 2 new lesions on the first 
post-treatment bone scan, 
confirmed on the next scan 
(performed at least 6 weeks later) 
AND with at least 2 additional 
lesions as compared to the first 
post-treatment bone scan
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
a RECIST v1.1 criteria are modified for assessing soft tissue lesions per PCWG3. See Appendix 11.
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
Immune-mediated adverse events (IMAEs) are AEs consistent with an immune-mediated 
mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection 
or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology, 
which were exacerbated by the induction of autoimmunity. Information supporting the assessment 
will be collected on the participant’s CRF.
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, are considered related to the study treatment or the study, or caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting are specified in Appendix 3.
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9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE information should begin at the initiation of study treatment until 
100 days of the last dose of study treatment, at the time points specified in the Schedule of 
Activities (Section 2). 
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 SAEs that occur during the screening period and within 100 days of the last dose of study 
treatment must be collected. If applicable, SAEs that relate to any later protocol-specified 
procedure (eg, a follow-up skin biopsy) must be collected. For participants assigned to treatment 
and never treated with study treatment, SAEs should be collected for 30 days from the date of 
treatment assignment.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study 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 the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of this being 
available.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study treatment, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in
the context of known adverse events, when appropriate for the program or protocol.
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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 will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the participant is lost to follow-up (as 
defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
All SAEs that occur during the screening period and within 100 days of the last dose of study 
treatment must be collected. For participants randomized/assigned to treatment and never treated 
with study treatment, SAEs should be collected for 30 days from the date of 
randomization/treatment assignment.
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the IB and will notify the Institutional Review Board/EC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting AEs to regulatory authorities and EC according to local 
applicable laws including European Directive 2001/20/EC and FDA Code of Federal Regulations 
21 CFR Parts 312 and 320. A 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 BMS 
Medical Monitor/Study Director (or 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.
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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 BMS Medical Monitor/Study 
Director (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. 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.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE CRF 
page or electronic SAE Report Form, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that, wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a p-DILI event. All occurrences of p-DILIs, meeting the defined 
criteria, must be reported as SAEs (see Section 9.2.4 and Appendix 3 for reporting details).
p-DILI is defined as: 
1) Aminotransaminases (AT) (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, preexisting chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
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The key responsibilities for investigators during p-DILI assessment include the following: 
•
Early detection, medical evaluation (including the exclusion of other potential causes), and 
rapid laboratory confirmation of liver-related abnormalities
•
BMS notification of p-DILI cases via SAE forms
Following the gathering and assessment of relevant clinical information, BMS is responsible for: 
•
Timely evaluation and triaging of p-DILI cases
•
Expedited reporting of p-DILI cases 
•
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 event 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, nonexhaustively and 
by way of example only, infectious diseases (such as active hepatitis A, B, and C), congenital 
diseases (such as Gilbert’s syndrome), neoplastic diseases (such as hepatocellular carcinoma), 
autoimmune diseases (such as primary biliary cirrhosis), and the use of concomitant hepatotoxic 
medications (such as antibiotics, the oral contraceptive pill, and herbal medicines). All 
investigations to exclude potential causes of liver function abnormalities or hepatic signs and/or 
symptoms should be guided by relevant factors such as the participant’s age, gender, clinical 
history, and signs and symptoms.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, x-ray 
filming, and any other potential safety assessment required or not required by protocol should also 
be recorded as a non-serious AE or SAE, 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-986226, 
nivolumab and/or ipilimumab, that is greater than the assigned dose, and considered excessive and 
medically important by the investigator, will be considered an overdose.
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In the event of an overdose, the investigator/treating physician should:
1) Contact the Medical Monitor/Study Director (or designee) immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 125 days)
3) Obtain a plasma sample for PK analysis within 125 days from the date of the last dose of study 
treatment if requested by the Medical Monitor/Study Director (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 will be made by the investigator in 
consultation with the Medical Monitor/Study Director (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).
9.4.1
Physical Examinations
Refer to the Schedule of Activities for the timing of assessments (Section 2).
9.4.2
Vital Signs
Refer to the Schedule of Activities for the timing of assessments (Section 2).
9.4.3
Electrocardiograms
Refer to the Schedule of Activities for the timing of assessments (Section 2).
 
 
 
For the purposes of monitoring participant safety, the investigators will review the 
12lead ECGs using their site’s standard ECG machines throughout the study. 
 
9.4.4
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
•
A central/local laboratory will perform the analyses and will provide reference ranges for these 
tests.
•
Results of clinical laboratory tests performed on Day -1 must be available prior to dosing.
•
The clinical tests that will be performed 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 
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units. Any abnormal laboratory test result considered clinically significant by the investigator 
must be recorded on the appropriate AE page of the CRF (see Section 9.2.6).
Table 9.4.4-1:
Clinical Laboratory Tests
Hematology
Prothrombin time, activated partial thromboplastin time, and international normalized ratio (at screening only)
Platelet count
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Serum Chemistry
Aspartate aminotransferase
Alanine aminotransferase
Total bilirubin
Direct bilirubin (reflex only)
Alkaline phosphatase
Lactate dehydrogenase
Creatinine
Blood urea nitrogen
Glucose (Fasting required at screening only)
Gamma glutamyl transferase (reflex only)
Lipase
Testosterone (PRC only)
C-reactive protein
Total protein
Albumin
Sodium
Potassium
Chloride
Carbon Dioxide
Calcium
Phosphorus
Magnesium
Creatine kinase
Creatinine clearance- screening only
Thyroid stimulating hormone
Free T3 and T4 (screening and reflex only)
Amylase
Urinalysis
Protein
Blood
Glucose
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if positive 
for blood, protein, or leukocytes esterase on dipstick
Serology
Serum for hepatitis C antibody (If hepatitis C antibody is positive reflex to hepatitis C RNA) or hepatitis C RNA, 
hepatitis B surface antigen.
Testing for HIV-1 and HIV-2 must be performed at sites only where mandated by local requirements. (Screening 
Only) 
Viral Status HNSCC and CC only: Sites should submit and document prior HPV status and subtype, particularly 
HPV16 and HPV18, within 28 days of dosing. 
Tetanus booster (administered 3-7 days prior to Cycle 1 Day 1 at screening; a tetanus booster does not have to 
be administered if the participant received a tetanus booster within 6 weeks of starting study drug)
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Table 9.4.4-1:
Clinical Laboratory Tests
Other Analyses
Pregnancy test (women of childbearing potential only: screening, pre-dose, discharge).
Follicle-stimulating hormone (screening only for women 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 as per standard 
medical/clinical judgment. 
9.5
Pharmacokinetic and Immunogenicity Assessments
Samples for PK and immunogenicity assessments will be collected for all participants receiving 
BMS-986226, 
 as described in Table 9.5-1 through Table 9.5-4. 
Immunogenicity samples will be analyzed for anti-BMS-986226 antibodies, 
 by validated immunoassays.
All pre-dose samples should be taken within 30 minutes prior to the start of the infusion of first 
drug. End-of infusion (EOI) samples should be taken immediately prior to the stopping of the drug 
infusion (in monotherapy) or to the stopping of the second drug infusion (in combination 
therapy), preferably within 2 minutes prior to the end of infusion. 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 pre-dose sample should be collected just 
prior to the delayed dose. However, if a pre-dose sample is collected but the dose is subsequently 
delayed, an additional pre-dose sample should not be collected. Further details of sample 
collection, processing, and shipment will be provided in the Laboratory Manual.
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Table 9.5-1:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-986226 (Preliminary Safety 
Cohorts and Part A)
Study Day of Sample 
Collection (1 Cycle = 
4 Weeks)
Event
Time (Relative to Start of 
BMS-986226 Infusion)
Hour:Min
BMS-986226
Blood Sample
BMS-986226 Immunogenicity 
Sample
Treatment Cycles
Cycle 1 Day 1 (C1D1)a
Pre-dose
0:00
X
X
EOIb
0:30
X
4:00
X
C1D2
24:00
X
C1D4
72:00
X
C1D8 (+/- 1 day)
168:00
X
C1D15 (+/- 1 day)
336:00
X
X
C1D22 (+/- 1 day)
504:00
X
C2D1
Pre-dose
0:00
X
X
EOIb
0:30
X
4:00
X
C2D2
24:00
X
C2D8 (+/- 1 day)
168:00
X
C2D15 (+/- 1 day)
336:00
X
C2D22 (+/- 1 day)
504:00
X
C3D1
Pre-dose
0:00
X
X
EOIb
0:30
X
C3D2
24:00
X
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Table 9.5-1:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-986226 (Preliminary Safety 
Cohorts and Part A)
Study Day of Sample 
Collection (1 Cycle = 
4 Weeks)
Event
Time (Relative to Start of 
BMS-986226 Infusion)
Hour:Min
BMS-986226
Blood Sample
BMS-986226 Immunogenicity 
Sample
C3D8 (+/- 1 day)
168:00
X
C3D15 (+/- 1 day)
336:00
X
C3D22 (+/- 1 day)
504:00
X
C4D1
Pre-dose
0:00
X
X
EOIb
0:30
X
C5D1
Pre-dose
0:00
X
X
C6D1
Pre-dose
0:00
X
X
Adverse Event
Grade 3/4 Hypersensitivity 
Reactionc
X
X
End of Treatment and Follow-up Period
EOT
X
X
30-Day FU
X
X
60-Day FU
X
X
100-Day FU
X
X
a Participants taking 2 or 8 mg of BMS-986226 in the Preliminary Safety Cohorts will follow the same sampling schedule as in Part A. In the event that participants 
taking 2 or 8 mg of BMS-986226 should be permitted to intra-dose escalate up to 8 and/or 25 mg, the sampling schedule should be restarted at Cycle 1 Day 1 at 
each dose escalation.
b This sample should be taken immediately prior to the stopping of the BMS-986226 drug infusion (in monotherapy), preferably within 2 minutes prior to the end 
of infusion. If the end of infusion is delayed beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly. EOI samples 
may not be collected from the same IV access as the drug was administered.
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c Samples will be taken as directed when drug-related adverse event, Grade 3/4 infusion reaction, or hypersensitivity reaction is confirmed.
Abbreviations: C = Cycle; D = Day; EOI = end of infusion; EOT = end of treatment; FU = follow-up.
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Table 9.5-2:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-986226
 
(Parts B1 and C1)
Study Day of 
Sample Collection
(Cycle = 4 weeks)
Event
Time (Relative to 
Start of Nivolumab or
Ipilimumab Infusion)
Hour:Min
BMS-986226
Blood Sample
BMS-986226 
Immunogenicity 
Sample
Treatment Cycles
Cycle 1 Day 1 
(C1D1)
Pre-dosea
00:00
X
X
EOIb
00:30
X
04:00
X
C1D2
24:00
X
C1D4
72:00
X
C1D8 (+/- 1 day)
168:00
X
C1D15 (+/- 1 day)
336:00
X
C1D22 (+/- 1 day)
504:00
X
C2D1
Pre-dose
0:00:00
X
X
C2D8 (+/- 1 day)
168:00
X
C2D15 (+/- 1 day)
336:00
X
C3D1
Pre-dose
0:00
X
X
C4D1
Pre-dose
0:00
X
X
EOIb
0:30
X
4:00
X
C4D2
24:00
X
C4D8 (+/- 1 day)
168:00:00
X
C4D15 (+/- 1 day)
336:00:00
X
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Table 9.5-2:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-986226
 
 (Parts B1 and C1)
Study Day of 
Sample Collection
(Cycle = 4 weeks)
Event
Time (Relative to 
Start of Nivolumab or
Ipilimumab Infusion)
Hour:Min
BMS-986226
Blood Sample
BMS-986226 
Immunogenicity 
Sample
C4D22 (+/- 1 day)
504:00:00
X
C5D1
Pre-dose
0:00
X
C5D8 (+/- 1 day)
168:00
X
C5D15 (+/- 1 day)
336:00
X
C6D1
Pre-dose
0:00
X
X
C7D1
Pre-dose
0:00
X
X
C7D1
EOIb
0:30
X
C8D1 
Pre-dose
0:00
X
C10D1
Pre-dose
0:00
X
X
EOIb
0:30
X
Every 3 Cycles 
starting with 
C13D1 (example: 
C16D1, C19D1, 
etc)
Pre-dose
0:00
X
X
Adverse Event
Grade 3/4 
Hypersensitivity 
Reactionc
X
End of Treatment and Follow-up Period
EOT
X
X
30-Day FU
X
X
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Table 9.5-2:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-986226
 
 (Parts B1 and C1)
Study Day of 
Sample Collection
(Cycle = 4 weeks)
Event
Time (Relative to 
Start of Nivolumab or
Ipilimumab Infusion)
Hour:Min
BMS-986226
Blood Sample
BMS-986226 
Immunogenicity 
Sample
60-Day FU
X
X
100-Day FU
X
X
a All pre-dose samples for BMS-986226 
 should be taken prior to the start of nivolumab/ipilimumab infusion (preferably within 
30 minutes).
b This sample should be taken immediately prior to the stopping of the second drug infusion (in combination therapy), preferably within 2 minutes prior to the 
end of infusion. If the end of infusion is delayed beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly. EOI 
samples may not be collected from the same IV access as the drug was administered.
c Samples will be taken as directed when drug-related adverse event, Grade 3/4 infusion reaction, or hypersensitivity reaction is confirmed.
Abbreviations: C = Cycle; D = Day; EOI = end of infusion; EOT = end of treatment; FU = follow-up.
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Table 9.5-3:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-986226
 
 (Parts B2 and C2)
Study Day of 
Sample Collection
(1 Cycle = 
4 Weeks)
Event
Time (Relative 
to Start of 
BMS-986226 
Infusion)
Hour:Min
BMS-986226
Blood Sample
BMS-986226 
Immunogenicity Sample
Treatment Cycles
Cycle 1 Day 1 
(C1D1)
Pre-dosea
00:00
X
X
EOIb
00:30
X
04:00
X
C1D2
24:00
X
C1D4
72:00
X
C1D8 (+/- 1 day)
168:00
X
C1D15 (+/- 1 day)
336:00
X
C1D22 (+/- 1 day)
504:00
X
C2D1
Pre-dose
00:00
X
X
EOIb,
00:30
X
4:00
X
C2D2
24:00
X
C2D8 (+/- 1 day)
168:00
X
C2D15 (+/- 1 day)
336:00
X
C2D22 (+/- 1 day)
504:00
X
C3D1
Pre-dose
00:00
X
X
EOIb
00:30
X
4:00
X
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Table 9.5-3:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-986226
 
 (Parts B2 and C2)
Study Day of 
Sample Collection
(1 Cycle = 
4 Weeks)
Event
Time (Relative 
to Start of 
BMS-986226 
Infusion)
Hour:Min
BMS-986226
Blood Sample
BMS-986226 
Immunogenicity Sample
C3D2
24:00
X
C3D8 (+/- 1 day)
168:00
X
C3D15 (+/- 1 day),
336:00
X
C3D22 (+/- 1 day)
504:00
X
C4D1
Pre-dose
00:00
X
X
C5D1
Pre-dose
00:00
X
X
C7D1
Pre-dose
00:00
X
X
Every 3 Cycles 
starting with C10D1 
(example: C13D1, 
C16D1, etc)
Pre-dose
00:00
X
X
Adverse Event
Grade 3/4 
Hypersensitivity 
Reactionc
X
X
End of Treatment and Follow-up Period
EOT
X
X
30-Day FU
X
X
60-Day FU
X
X
100-Day FU
X
X
a All pre-dose samples for BMS-986226 
should be taken prior to the start of nivolumab/ipilimumab infusion (preferably within 
30 minutes). 
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b This sample should be taken immediately prior to the stopping of the second drug infusion (in combination therapy), preferably within 2 minutes prior to the 
end of infusion. If the end of infusion is delayed beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly. EOI 
samples may not be collected from the same IV access as the drug was administered.
c Samples will be taken as directed when drug-related adverse event, Grade 3/4 infusion reaction, or hypersensitivity reaction is confirmed.
Abbreviations: C = Cycle; D = Day; EOI = end of infusion; EOT = end of treatment; FU = follow-up.
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Table 9.5-4:
Pharmacokinetic and Immunogenicity Sampling Schedule for BMS-986226
 
(Parts D and E)
Study Day of 
Sample Collection
(Cycle = 4 weeks)
Event
Time (Relative to 
Start of BMS-986226
Infusion)
Hour:Min
BMS-986226
Blood Sample
BMS-986226 
Immunogenicity 
Sample
Treatment Cycles
Cycle 1 Day 1 
(C1D1)
Pre-dosea
00:00
X
X
EOIb
00:30
X
C2D1
Pre-dose
00:00
X
X
C3D1
Pre-dose
00:00
X
X
C4D1
Pre-dose
00:00
X
X
C7D1
Pre-dose
00:00
X
X
Every 3 Cycles 
starting with 
C10D1 (example: 
C13D1, C16D1, 
etc)
Pre-dose
0:00
X
X
Adverse Event
Grade 3/4 
Hypersensitivity 
Reactionc
X
End of Treatment and Follow-up Period
EOT
X
X
30-Day FU
X
X
60-Day FU
X
X
100-Day FU
X
X
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a All pre-dose samples for BMS-986226 
should be taken prior to the start of nivolumab/ipilimumab infusion (preferably within 
30 minutes).
b This sample should be taken immediately prior to the stopping of the second drug infusion (in combination therapy), preferably within 2 minutes prior to the 
end of infusion. If the end of infusion is delayed beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly. EOI 
samples may not be collected from the same IV access as the drug was administered.
c Samples will be taken as directed when drug-related adverse event, Grade 3/4 infusion reaction, or hypersensitivity reaction is confirmed.
Abbreviations: C = Cycle; D = Day; EOI = end of infusion; EOT = end of treatment; FU = follow-up
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The serum samples will be analyzed for drug (BMS-986226 
) and 
ADA (BMS-986226 antibodies and/or anti-nivolumab or anti-ipilimumab antibodies) by validated 
immunoassays.
 
 
 Serum samples designated for PK 
 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).
 
Labeling and Shipping of Biological Samples: Detailed instructions for the PK and PD blood 
collection, labeling, processing, storage, and shipping will be provided to the site in the procedure 
manual.
9.6
Pharmacodynamics
Details on the PD biomarker assessments are included 
.
9.7
Pharmacogenomics
Not applicable.
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9.9
Health Economics or Medical Resource Utilization and Health 
Economics
Health Economics or Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
10.1.1
Preliminary Safety Cohorts and Dose Escalation (Part A)
Two single participants will be treated at BMS-986226 2 mg and 8 mg, respectively, in the 
Preliminary Safety Cohorts. Additional participants may be enrolled in the Preliminary Safety 
Cohorts at each dose level to gather additional information on the safety, PK, and PD profile. 
Approximately 3 participants will be treated at the starting dose levels of BMS-986226 in Part A. 
During the dose-escalation phase, an adaptive dose-escalation scheme (BLRM for monotherapy 
and BLRM-Copula for combination therapy) employing the escalation with overdose control 
(EWOC) principle will be used. The method is fully adaptive, makes use of all the information 
available at the time of each dose assignment, not just data from the current dose level, and directly 
addresses the ethical need to control the probability of overdosing. The targeted toxicity rate in 
this study is in the range of 16% to 33%. The boundary is similar to the toxicity boundary used by 
a rule-based design (ie, 3 + 3 design) in that a minimum is set at 16% (approximately 1 in 6) DLT 
rate and at a maximum at 33% (approximately 2 in 6) DLT rate. The use of the EWOC principle 
limits the risk of exposing participants in the next cohort to an unsafe dose by ensuring the posterior 
probability of the DLT rate exceeding 33% at any dose is capped at 30%. 
Due to the nature of the dose escalation process, the exact number of participants to be treated at 
each dose level cannot be precisely determined. The maximum number of participants to be treated 
in Part A will be approximately 30 for dose escalation. However, simulation studies with various 
scenarios show that the expected number of DLT-evaluable participants is approximately 
20 participants or less (Appendix 10).
While the BLRM/BLRM-Copula will use DLT information from the DLT period only, clinical 
assessment will take into consideration the totality of available data, including PK/PD from all 
treated participants encompassing monotherapy and combination therapy, in assigning a dose level 
for the next cohort of 3 participants. At most, 12 DLT-evaluable participants will be treated at each 
dose level. Additional participants (up to a total of 12) may be treated at or any dose level below 
the estimated MTD for further evaluation of safety, PK, or PD parameters as required.
The model-recommended MTD is the dose that satisfies the following 3 conditions:
1) The empirical posterior probability that the “DLT rate of 16% to < 33%” is greater than a 
prespecified value (ie, 50%);
2) This probability needs to be the largest among the dose levels that satisfy the EWOC condition 
(ie, the probability that the “DLT rate > 33%” must be less than 30%);
3) The minimum number of participants (ie, 6 participants) was treated at this dose level.
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The final recommended MTD/RP2D will be based on the recommendation from the 
BLRM/BLRM-Copula and the overall assessment of all available safety, PK/PD, and efficacy 
data. Lower doses of BMS-986226 may be tested if none of the planned doses are found to be 
tolerable as monotherapy or in combination with either nivolumab or ipilimumab. Such decisions 
will be made after discussion and agreement between the investigators and the BMS Medical 
Monitor/Study Director (or designee).
10.1.2
BMS-986226 and Nivolumab or Ipilimumab Combination Therapy 
Cohorts (Parts B and C)
The purpose of the combination cohort phase of the study is to gather safety, tolerability, preliminary 
efficacy, PK, and PD information regarding BMS-986226 in combination with either nivolumab (Parts 
B) or ipilimumab (Parts C). For each dose level of the Parts B1 and C1, approximately 6 evaluable 
participants will be treated. This sample size also provides each dose level in Parts B1 and C1 with 
about 80% probability to detect any AE with an event rate of 24%. Approximately 6-12 evaluable 
participants may be treated at each dose level for Parts B2 (BMS-986226 + nivolumab) and C2 
(BMS-986226 + ipilimumab) if additional safety, PD, or PD data is required to optimize dose 
and/or schedule selection. With up to 12 evaluable participant in each of Parts B2 and C2, it 
provides each dose level with up to 96% probability to detect any AE with an event rate of 24%.
Once the safety (during the DLT evaluation) of a combination of BMS-986226 and nivolumab 
(ipilimumab) has been established and a recommended BMS-986226 dose regimen has been 
selected for Part D (E), additional participants (up to 6 additional evaluable participants for each 
of nivolumab and ipilimumab in combination with BMS-986226) may be treated at the 
recommended dose to better characterize the safety, PK, and PD profile.
During this part of the study, the BLRM-Copula model, incorporating single-agent toxicity profiles 
of both BMS-986226 (Part A) and nivolumab or ipilimumab, as well as any available information 
from the combination cohorts, will be used to guide any potential dose recommendation. Details 
regarding the BLRM-Copula model are given in Appendix 10.
10.1.3
Combination Expansion Arms (Parts D and E) 
Approximately 40 evaluable participants will be treated in each of Parts D and E. This sample size 
provides each cohort with about 87% probability to detect any AE with an event rate of 5%. 
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who have signed an ICF and are registered into the IRT
Treated
All participants who received any dose of study treatment
Response-evaluable
All treated participants with measurable disease at baseline and 1 of the 
following: (1) at least 1 postbaseline tumor assessment, (2) clinical 
progression, or (3) death.
Pharmacokinetic
All treated participants who have evaluable concentration-time data.
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Population
Description
Immunogenicity
All treated participants who have a baseline and at least 1 postbaseline
immunogenicity measurement.
Abbreviations: ICF = informed consent form; IRT = Interactive Response Technology.
Analyses of safety, extent of exposure, 
 PK, efficacy, and immunogenicity will be 
based on all treated participants.
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock. Below is a 
summary of planned statistical analyses of the primary and secondary endpoints. In general, 
summaries will be performed by cohort. If sufficient data are not available such that adequate 
interpretation of the result is not warranted, some summaries may not be performed and only 
listings will be presented. Efficacy analyses will be performed using the RECIST v1.1 (all 
indications except prostate) or PCWG3 criteria (prostate). Details on censoring scheme on time-
to-event endpoints such as DOR, PFS, and OS will be described in the SAP. A description of the 
participant population will be included in the statistical output reported, including subgroup of age, 
gender, and race.
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
ORR is defined as the proportion of all treated 
participants whose BOR is either CR or PR.
BOR for a participant will be assessed per 
RECIST v1.1 or PCWG3 (for prostate cancer) 
by investigator
Estimate of ORR and corresponding 2-sided exact 
95% CI using the Clopper-Pearson method 
mDOR
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 / PCWG3 or death, 
whichever occurs first.
mDOR using the Kaplan-Meier method and 
corresponding two 2-sided 95% CI using Brookmeyer 
and Crowley methodology (using log-log 
transformation), if appropriate
PFSR at 24 weeks
PFS for a participant is defined as the time 
from the first dosing date to the date of first 
objectively documented disease progression 
or death due to any cause, whichever occurs 
first. 
Estimate by the Kaplan-Meier method and 
corresponding 95% CI will be derived based on 
Greenwood formula
Abbreviations: BOR = best overall response; CI = confidence interval; CR = complete response; DOR = duration of 
response; mDOR = median duration of response; ORR = objective response rate; PCWG = Prostate Cancer Working 
Group;
PFS = progression free survival; PFSR = progression free survival rate; PR = partial response; 
RECIST = Response Evaluation Criteria In Solid Tumors.
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10.3.2
Safety Analyses
All safety analyses for will be performed on the treated population.
Endpoint
Statistical Analysis Methods
Incidence of AEs, SAEs, AEs meeting 
protocol-defined DLT criteria, AEs leading to 
discontinuation, deaths
AEs will be graded according to CTCAE 
v4.0327.
DLT rate by dose level; frequency distribution of 
treated participants with AE using the worst CTC 
grade. Participants will only be counted (1) once at the 
preferred term (PT) level, (2) once at the system organ 
class (SOC) level, and (3) once in the ‘Total 
participant’ row at their worst CTC grade, regardless 
of SOC or PT.
Laboratory abnormalities
Laboratory values will be graded according to 
CTCAE v4.0327.
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; SOC = system 
organ class.
10.3.3
Pharmacokinetic Analyses
The PK parameters to be assessed, if data permit, include:
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(0-T)
Area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration
AUC(TAU)
Area under the concentration-time curve in 1 dosing interval
The PK parameters that may be assessed, if data permit and if deemed necessary, include:
Cmin
The minimum observed concentration within a dosing interval (eg, occurring no 
matter when over the dosing interval)
CLT
Total body clearance
Css-avg
Average concentration over a dosing interval (AUC[TAU]/tau)
AI
Accumulation index; ratio of an exposure measure at steady-state to that after 
the first dose (exposure measure includes AUC[TAU], Cmax, and 
concentrations at the end of dosing interval (Ctau).
T-HALF
Apparent terminal half-life in serum
T-HALFeff
Effective elimination half-life that explains the degree of accumulation 
observed for a specific exposure measure (exposure measure includes 
AUC[TAU], Cmax, and Ctau)
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The following PK parameter will be reported as a separate listing, summary, and plot:
•
Ctrough: Trough observed plasma concentrations (this includes pre-dose concentrations and 
Ctau)
Individual participant PK parameter values will be derived by noncompartmental methods by a 
validated PK analysis program. Actual times will be used for the analyses.
Endpoint
Statistical Analysis Methods
Cmax, AUC(0-T), AUC(TAU), Ctau, CLT, 
Css-avg, AI_AUC, AI_Cmax, AI-Ctau, 
THALFeff_AUC, THALFeff_Cmax
Summary statistics: geometric means and coefficients 
of variation
Tmax
Summary statistics: medians and ranges
Ctrough
Summary statistics to assess attainment of steady state: 
geometric means and coefficients of variation; plots vs 
time by dose
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10.3.4
Immunogenicity Analyses
Endpoint
Statistical Analysis Methods
Incidence of ADA to BMS-986226
Baseline ADA-positive participant is defined 
as a participant who has an ADA-detected 
sample at baselinea. 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
a Baseline sample is the last sample before initiation of the treatment.
Abbreviations: ADA = anti-drug antibody.
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11
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Schaer DA, Hirschhorn-Cymerman D, Wolchok JD. Targeting tumor-necrosis factor receptor 
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10 Carthon B, Wolchok JD, Yuan J, et al. Pre-operative CTLA-4 blockade: tolerability and 
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11 Choueiri, TK, Fishman MN, Escudier B, et al. Immunomodulatory Activity of Nivolumab in 
Metastatic Renal Cell Carcinoma. Clin Cancer Res 2016;22(22):5461-71.
12 Riaz N, Havel JJ, Makarov V et al. Tumor and Microenvironment Evolution during 
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13 Hirsch HA, Reeves JW, Zi, T et al. Genomics based studies of gastric tumors identify ICOS 
as potential target for therapeutic intervention. Poster presented at American Association for 
Cancer Research Annual Meeting; 2018 Apr 11-14; Chicago, Illinois, USA. Abstract #1685.
14 Anti-ICOS mAb (BMS-986226) Investigator Brochure Version 1. Bristol-Myers Squibb 
Company; 2017. Document Control No. 
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15 Nonclinical evaluation of the pharmacokinetics and pharmacodynamics of BMS-986226 
(Study NCPK302). Bristol-Myers Squibb Company; 2017. Document Control No. 
16 ICH Guideline Topic S6(R1): preclinical safety evaluation of biotechnology-derived 
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17 Nivolumab (BMS-936558) Investigator Brochure Version 16. Bristol-Myers Squibb 
Company; 2017. Document Control No. 
18 Ipilimumab (BMS-734016) Investigator Brochure Version 19. Bristol-Myers Squibb 
Company; 2016. Document Control No. 
19 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol 
2003;21:807-39.
20 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol 2006;6:715-27.
21 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
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22 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2004;23:515-48.
23 Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a 
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24 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
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25 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20.
26 Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: releasing the restraints 
on anti-tumor immunity for patients with melanoma. Cancer J 2012;18:153-9.
27 Common Terminology Criteria for Adverse Events Version 4.03, National Institute of Health, 
National Cancer Institute; 2010.
28 Guidance for Industry S9: Nonclinical evaluation for anticancer pharmaceuticals. US 
Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER); 2010.
29 Characterization of the Antitumor Effects of Anti-ICOS Antibody Isotypes Alone or Combined 
with Anti-PD-1 in a CT26 Tumor Model (Experiment No. 1804-010 and BDX1804-102).
30
BMS-986226: Nonclinical Pharmacology Study Report (BDX-1804-010). Bristol-Myers 
Squibb Company; 2016. Document Control No. 
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31 Spigel DR, et al. Randomized results of continuous vs 1-year fixed-duration in patients with 
advanced non-small cell lung cancer. Oral presentation at the European Society of Medical 
Oncology Annual Meeting. 2017 Sep 8-12; Madrid, Spain. Abstract 1297O
32 Brahmer J, et al. Five-year follow-up from the CA209-003 study of nivolumab in previously 
treated advanced non-small cell lung cancer: clinical characteristics of long-term survivors. 
Oral presentation presented at: American Association for Cancer Research (AACR) Annual 
Meeting; April 1-5, 2017; Washington, DC, USA.
33 Felip E et al., Three-year follow-up from Checkmate 017/057: Nivolumab versus docetaxel in 
patients with previously treated advanced non-small lung cancer (NSCLC). Poster discussion 
presentation at the European Society of Medical Oncology Annual Meeting. 2017 Sep 8-12; 
Madrid, Spain. Poster 1301PD
37 Ipilimumab (Yervoy) US Prescribing Information. Bristol-Myers Squibb Company; Revised 
Oct 2015.
38 BMS-936558: A Multi-arm Phase I Safety Study of Nivolumab in Combination with 
Gemcitabine/Cisplatin, 
Pemetrexed/Cisplatin, 
Carboplatin/Paclitaxel, 
Bevacizumab 
Maintenance, Erlotinib, Ipilimumab, or as Monotherapy in Subjects with Stage IIIB/IV Non-
small Cell Lung Cancer (NSCLC), (Study CA209012). Bristol-Myers Squibb Company; 2016. 
Document Control No. 
 
39 Scher HL, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant 
Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials 
Working Group 3. J Clin Oncol 2016;34:1402-18
 
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
5-FU
5-fluorouracil
AE
adverse event
ADA
anti-drug antibody
ADT
androgen deprivation therapy
AI
accumulation index
AIDS
acquired immunodeficiency syndrome
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANC
absolute neutrophil count
APC
antigen presenting cell
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(0-xh)
area under the concentration-time curve from time zero to x hours
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
BICR
blinded independent central review
β-HCG
beta-human chorionic gonadotrophin
BID
bis in die, twice daily
BLRM
Bayesian Logistic Regression Model
BLRM-RD
Bayesian Logistic Regression Model-Recommended Dose
BMS
Bristol-Myers Squibb
BOR
best overall response
BSC
best supportive care
BTLA
B- and T-lymphocyte attenuator
BUN
blood urea nitrogen
C
Cycle
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Term
Definition
CA19-9
cancer antigen 19-9
Css-avg
average concentration over a dosing interval (AUC[TAU]/tau)
CBC
complete blood count
CC
cervical cancer
CD
cluster of differentiation
CEA
cancer embryonic antigen
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
CL
total plasma clearance
CLT
total body clearance
Cmax
maximum observed plasma concentration
Cmaxss
steady state peak concentration
Cmin
minimum observed plasma concentration
CMV
cytomegalovirus
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
Case Report Form, paper or electronic
CRP
C-reactive protein
CT
computerized tomography
Ctau
concentrations at the end of dosing interval
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyte-associated antigen-4
Ctrough
trough observed plasma concentration
CV
coefficient of variation
D
day
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Term
Definition
DLT
dose-limiting toxicity
DMC
Data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DTIC
dacarbazine
EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
GFR
glomerular filtration rate
EGFR
epidermal growth factor receptor
EOI
end of infusion
EOT
end of treatment
eSAE
electronic serious adverse event
EU
European Union
EWOC
escalation with overdose control
F
bioavailability
FcγRs
Fc gamma receptors
FDA
Food and Drug Administration
FDG-PET
fluorodeoxyglucose-positron emission tomography
FFPE
formalin-fixed paraffin embedded
FIH
first-in-human
FITC
fluorescein isothiocyanate
FNR
false-negative rate
FPR
false-positive rate
FSH
follicle-stimulating hormone
FU
Follow-up
GGT
gamma-glutamyl transferase
GI
gastrointestinal
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Term
Definition
GLP
Good Laboratory Practice
GPVE
Global Pharmacovigilance and Epidemiology
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HLA-DR
human leukocyte antigen - antigen D related
HNSCC
head and neck squamous cell carcinoma
HNSTD
highest non-severely toxic dose
HPV
human papillomavirus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation 
ICOS
Inducible T-cell COStimulator
ICOS-L
Inducible T-cell COStimulator ligand
IFN-γ
interferon gamma
Ig
immunoglobulin
IHC
immunohistochemistry
IL
interleukin
IMAE
immune-mediated adverse event
IMP
investigational medicinal product
I-O
immuno-oncology
Ipi
ipilimumab
IP
investigational product
irAE
Immune-related adverse event
irPR
immune-related partial response
irSD
immune-related stable disease
IRT
Interactive Response Technology
IV
intravenous
IVRS
Interactive Voice Response System
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Term
Definition
KLH
keyhole limpet hemocyanin
KRAS
Kirsten rat sarcoma
LDH
lactate dehydrogenase
mAb
monoclonal antibody
MAD
maximum administered dose
MAD-1
one dose level below the maximum administered dose
mCRPC
metastatic castration-resistant prostate cancer
mDOR
median duration of response
MEL
melanoma
MMR
mismatch repair
mOS
median overall survival
MRI
magnetic resonance imaging
MRSD
maximum recommended starting dose
MSI
microsatellite instability
MTD
maximum tolerated dose
mWHO
modified World Health Organization
N
number of participants or observations
N1 + I3
nivolumab 1 mg/kg + ipilimumab 3 mg/kg
N3 + I1
nivolumab 3 mg/kg + ipilimumab 1 mg/kg 
N/A
not applicable
NaF
sodium fluoride
NCI
National Cancer Institute
NK
natural killer
NOAEL
no-observed-adverse-effect level
NSCLC
non-small cell lung cancer
NCSLC-AD
non-small cell lung carcinoma-adenocarcinoma cell type
NSCLC-SQC
non-small cell lung carcinoma, squamous cell type
ORR
objective response rate
OS
overall survival
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Term
Definition
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PD
pharmacodynamics
PD-1
programmed death-1
p-DILI
potential drug-induced liver injury
PD-L1
programmed death ligand-1
PE
physical examination
PET
positron emission tomography
PFS
progression-free survival
PFSR
progression-free survival rate
PID
participant identification number
PK
pharmacokinetic(s)
PPK
population pharmacokinetics
PR
partial response
PRC
adenocarcinoma of the prostate
PSA
prostate-specific antigen
PT
preferred term
Q1W
once every week
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q8W
every 8 weeks
Q12W
every 12 weeks
R&D
Research and Development
RCC
renal cell carcinoma
RD
recommended dose
RE
receptor expression
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Term
Definition
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
RO
receptor occupancy
RP2D
Recommended Phase II dose
R/R
resistant/recurrent
RT-qPCR
quantitative real-time polymerase chain reaction
SAE
serious adverse event
SD
stable disease
SOC
system organ class
SPECT
single photon emission computed tomography
Std. Dev.
standard deviation
T3
triiodothyronine
T4
thyroxine
TBD
to be determined
T-cell
T lymphocyte cell
Teff
T-effector cell
TGI
tumor growth inhibition
T-HALF
apparent terminal half-life in serum
T-HALFeff
effective elimination half-life that explains the degree of accumulation 
observed for a specific exposure measure (exposure measure includes 
AUC[TAU], Cmax, and Ctau)
TIL
tumor-infiltrating lymphocytes
TKI
tyrosine kinase inhibitor
Tmax
time of maximum observed plasma concentration
TNBC
triple-negative breast cancer
Treg
T-regulatory
TSH
thyroid-stimulating hormone
T-VEC
talimogene laherparepvec
UCC
urothelial carcinoma
ULN
upper limit of normal
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Term
Definition
US
United States
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the CRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviations, etc) that is likely to 
affect to a significant degree one or more of the following: (1) the physical, safety, or mental 
integrity of one or more subjects/participants; (2) the scientific value of the 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, consent form, participant
recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects/participants. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects/participants and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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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 for 
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects/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.
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.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the 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.
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.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
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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.
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 (e.g., 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 sites 
stock or 
commercial supply, or a specialty 
pharmacy)
The investigator or designee accepts responsibility 
for documenting traceability and study drug integrity 
in accordance with requirements applicable under 
law and the SOPs/standards of the
sourcing 
pharmacy.   
These records should include:
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If
Then
•
label identification number or batch number 
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form.
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 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects/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 subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
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account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (e.g., 
cytotoxics or biologics).
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If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., 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.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
Participant recruitment (e.g., among the top quartile of enrollers)
•
Involvement in trial design
•
Other criteria (as determined by the study team)
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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 (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
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
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 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
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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: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.*
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
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Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
Hormonal methods of contraception including vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
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 chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception*
•
Male condoms (except in setting of azoospermic male participants) 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
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•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
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 end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
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 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study 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.
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2.2
Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (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.
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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.
•
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. 
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•
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.
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: 
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−
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. 
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 
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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 
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
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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
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 
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.
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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 
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.
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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.
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).
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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
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS
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 (I-O) 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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Refer to http://livertox.nih.gov/ for a compendium of agents that may cause liver injury
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APPENDIX 7
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS
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APPENDIX 8
CONSORT PUBLISHING REQUIREMENTS
The Consolidated Standards of Reporting Trials (CONSORT) encompasses various initiatives 
developed by the CONSORT Group to alleviate the problems arising from inadequate reporting 
of randomized controlled trials.
The CONSORT Statement
The main product of CONSORT is the CONSORT Statement, which is an evidence-based, 
minimum set of recommendations for reporting randomized trials. It offers a standard way for 
authors to prepare reports of trial findings, facilitating their complete and transparent reporting, 
and aiding their critical appraisal and interpretation. CONSORT 2010 is the current version of 
the statement and supersedes the 2001 and 1996 versions.
The CONSORT Statement comprises a 25-item checklist and a flow diagram. The checklist 
items focus on reporting how the trial was designed, analyzed, and interpreted. The flow diagram 
displays the progress of all participants through the trial. The checklist and flow diagram are 
freely available for viewing and downloading at the CONSORT website (http://www.consort-
statement.org/consort-2010). The CONSORT Statement is endorsed by general medical journals, 
specialty medical journals, and leading editorial organizations. CONSORT is part of a broader 
effort, to improve the reporting of different types of health research, and indeed, to improve the 
quality of research used in decision-making in healthcare.
CONSORT 2010 Guideline
The CONSORT (CONsolidated Standards of Reporting Trials) 2010 guideline is intended to 
improve the reporting of parallel-group randomized controlled trial (RCT), enabling readers to 
understand a trial's design, conduct, analysis and interpretation, and to assess the validity of its 
results. This can only be achieved through complete adherence and transparency by authors. 
CONSORT 2010 was developed through collaboration and consensus between clinical trial 
methodologists, guideline developers, knowledge translation specialists, and journal editors 
(see CONSORT group ). CONSORT 2010 is the current version of the guideline and supersedes 
the 2001 and 1996 versions.
CONSORT “Explanation and Elaboration” Document
The CONSORT “Explanation and Elaboration” document explains and illustrates the principles 
underlying the CONSORT Statement, and should preferably be used in conjunction with the 
CONSORT Statement. In addition, extensions of the CONSORT Statement have been developed 
to give additional guidance for RCTs with specific designs, data and interventions. The
CONSORT website (http://www.consort-statement.org/consort-2010) contains the current 
definitive version of the CONSORT 2010 Statement and up-to-date information on extensions.
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APPENDIX 9
NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION
Heart failure is usually classified according to the severity of their symptoms. The table below 
describes the most commonly used classification system, the New York Heart Association 
(NYHA) Functional Classification. It places patients in one of four 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, dyspnea (shortness of 
breath).
II
Slight limitation of physical activity. Comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, 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 10
STATISTICAL METHODOLOGY
STATISTICAL DETAILS FOR BAYESIAN LOGISTIC REGRESSION MODEL AND 
PRIORS FOR DOSE ESCALATION AND SAFETY MONITORING
1
MODEL SETUP FOR BMS-986226 MONOTHERAPY
1.1
Monotherapy Methodology Description 
An adaptive 2-parameter Bayesian Logistic Regression Model (BLRM) guided by the escalation 
with overdose control (EWOC) principle1,2,3 will be used to guide the dose escalation of 
BMS-986226 monotherapy in the monotherapy phase, providing dose recommendation during 
dose escalation. 
The BLRM will be fitted on the dose-limiting toxicity (DLT) data during the first 5 weeks of 
treatment accumulated throughout the dose escalation to model the dose-toxicity relationship of 
BMS-986226 in the monotherapy dose escalation phase. 
The dose-toxicity relationships for BMS-986226 monotherapy is assumed to follow a logistic 
model:
݈݋݃݅ݐሺ݌௜ሻൌ݈݋݃ሺߙଵሻ൅ߚଵ݈݋݃ሺ݀ଵ௜݀ଵ
∗
൘ሻ, 
where ݌௜is the probability of toxicity at dose level ݀ଵ௜. Note that the ߙଵand ߚଵparameters are 
assumed positive, and ݀ଵ
∗is the reference dose for BMS-986226 (please refer to the meaning of 
ߙଵand ߚଵin Section 1.2 for detailed implementation).
1.2
Prior Specification for BMS-986226 Monotherapy
The Bayesian approach requires the specification of prior distributions for model parameters,
which include parameters (ߙଵ, ߚଵ) for BMS-986226. The prior distributions for BMS-986226
single agent activity were derived using a weakly informative prior, as well as discussion with the 
Bristol-Myers Squibb (BMS) clinical team. Details are provided below.
Weakly Informative Prior
•
The median DLT rate at the reference dose (BMS-986226 at 800 mg every 4 weeks) was 
assumed to be 30%, that is, mean (log(ߙଵ)) = logit (0.3) = log(0.3/(1-0.3)) = -0.847.
•
A doubling in dose was assumed to double the odds of DLT, that is, mean (log(ߚଵ)) = 0.
The standard deviation (sd) of log(ߙଵ) was set to 1.53 using the following steps:
•
If the toxicity probability range was set to be [1%, 99%], then the toxicity interval would be 
logit (0.99)-logit (0.01) = 9.19.
•
To cover 99.7% of the variance, the toxicity interval will cover 6×sd (log(ߙଵ)), which gives us 
sd (log(ߙଵ)) = 9.19/6 = 1.53.
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Correspondingly, the standard deviation of log(ߚଵ) was set to 1, which allows for considerably 
larger prior uncertainty for the dose toxicity.
1) The correlation between log(ߙଵ) and log(ߚଵ) was set to 0.
2) Log(ߙଵ) and log(ߚଵ) follow a bivariate normal distribution.
Through those steps, the prior obtained is given in Table 1.2-1. 
Table 1.2-1:
Prior Distribution for Model Parameters for BMS-986226
Parameter
Means
Standard Deviations
Correlation
log(ߙଵ), log(β1)
(-0.847, 0)
(1.53, 1)
0
This prior will be fitted into EAST® v6.3.1 Dose Escalation Module by Cytel for the Monotherapy 
Escalation of BMS-986226 as stated in model setup section.
2
DECISION RULE FOR DOSE ESCALATION AND SIMULATION
Dose escalation recommendations for BMS-986226 monotherapy will be based on the inference 
from the Bayesian posterior and the probability that the true DLT rate for each dose lies in 1 of the 
following categories:
•
[0%, 16%) under-dosing
•
[16%, 33%) targeted toxicity
•
[33%, 100%] excessive toxicity
Note: “[“ or “]“ is inclusive of the respective endpoint, and “(“ or “)”exclusive of the respective 
endpoint.
These boundaries are similar to the toxicity boundaries used by a rule-based design (ie, 3 + 3 
design) in that a minimum is set at 16% (~ 1 in 6) DLT rate and a maximum at 33% (~ 2 in 6) DLT 
rate. Following the principle of EWOC, dose recommendations for the next cohort will be based 
on the Bayesian model after DLT information becomes available during the DLT period, 
accounting for all of the available data from the administered doses, and the candidate doses are 
the ones fulfilling the overdose criterion that there is less than 30% chance of excessive toxicity. 
Only the candidate doses will be considered for the next cohort. While the Bayesian model will 
use DLT information from the DLT period only, clinical assessment will take into consideration 
of the totality of available data including pharmacokinetics (PK)/pharmacodynamics from all 
treated participants.
Stopping Rules:
The following is the general stopping rules of BLRM (-Copula) during Dose Escalation:
•
If all of 30 DLT evaluable participants are treated.
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•
If all of the current pre-specified doses are considered intolerable according to the pre-specified 
cutoff (ie, EWOC criteria), then the model will recommend stopping the current dose level and
a new dose level lower than the current lowest dose level will need to be identified.
•
The maximum number of DLT-evaluable participants in a dose level will be 12. This limit is 
set to avoid instances in which the model could recommend adding subjects indefinitely to a 
specific dose level due to uncertainty in the tolerability profile. 
•
If, for a specific dose level, 6 subjects have been treated and the chance of determining that the 
dose level to be the “target” dose is > 50%, then the model will suggest to stop and declare the 
current dose level to be the maximum tolerated dose (MTD).
Model-recommended MTD:
The MTD is the dose that satisfies the following 3 conditions: 
1) The empirical posterior probability that the ‘DLT rate of 16% -< 33%’ is greater than 50%.
2) This probability needs to be the largest among the dose levels that satisfy the EWOC condition 
(ie, the probability that ‘DLT rate ≥33%’ must be less than 30%).
3) Minimum number of participants (ie, 6) were treated at this dose level.
Final MTD:
The final recommended MTD in Part A will be based on the recommendation from the BLRM and 
overall clinical assessment of all available safety, PK/pharmacodynamics, and efficacy data. 
Lower doses of BMS-986226 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 
BMS Medical Monitor.
2.1
Simulation Parameters 
One thousand trial simulations will be used for each scenario. All simulations will be run using 
EAST v6.3.1 software for BLRM model for the BMS-986226 monotherapy. The number of 
subjects to be treated in each cohort in a specific dose level and the stopping rules used to declare 
MTD are defined as:
•
Fixed cohort size: 3
•
Probability of overdosing: < 30% 
•
Probability of achieving the target toxicity: > 50%
•
Maximum number of participants treated: 30
•
Minimum number of participants treated at a given dose level in order to declare MTD: 6
•
Maximum number of participants at a dose:12
The provisional dose levels for BMS-986226 monotherapy are 25 mg, 80 mg, 200 mg, 400 mg, 
and 800 mg.
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2.2
Operating Characteristics
Section 2.2.1 demonstrates operating characteristics of BLRM for monotherapy.
2.2.1
Operating Characteristics of BLRM for Monotherapy
Five scenarios were investigated by selecting (1) dose-DLT relationship derived by prior, (2) dose-
DLT curve flatter than the one by the prior; (3) narrow safety window in order to explore how 
EWOC limits the risk of exposing participants from a toxic dose level, (4) all doses below the 
target toxicity, and (5) all doses above the target toxicity. Simulations were performed using EAST 
v6 BLRM which allows dose skipping.
For scenario (1), the % DLT by prior was derived using the model solving for the probability, p୧
at the ith dose.
logitሺ݌௜ሻൌlogሺߙଵሻ൅ߚଵlogሺdଵ୧dଵ
∗
൘ሻ
The model can be re-written as follows.
݌௜ൌ
1
1 ൅exp ቀെlogሺߙଵሻെߚଵlogሺdଵ୧dଵ
∗
൘ሻቁ
Using the estimates in Section 1.2, ie, logሺߙଵሻൌെ0.847 and ߚଵൌ1, ݀ଵ
∗ൌ800 mg, the prior 
probability of DLTs at dose 25, 80, 200, 400, and 800 mg is 0.01, 0.04, 0.1, 0.18, and 0.30, 
respectively.
Table 2.2.1-1:
Simulation Results of BLRM for Monotherapy
Scenario
BMS-
986226
Dose
(mg)
25
80
200
400
800
MTD 
Not 
Selected 
(%)
Fitted 
Median
MTD 
Toxicity 
Observed 
(%)
Avg 
No. of
Patients
By prior
% DLT
1
4
10
18
30
% MTD
0
0.9
9.9
61
28.2
0
698.7
17.3
18.2
# Pts
3.1
0.5
2.0
8.2
4.4
# DLTs
0
0
0.2
1.5
1.4
Flatter than 
the one by 
the prior
% DLT
10
15
20
25
30
% MTD
3.9
11.9
22.2
38.5
16.9
6.6
510.4
22.4
17.4
# Pts
4.1
2.0
2.7
5.8
2.7
# DLTs
0.4
0.3
0.6
1.4
0.8
Narrow 
safety 
window
% DLT
3
7
18
31
80
% MTD
0.4
7.9
40.7
49.8
0.2
1
443.4
23.2
18.3
# Pts
3.4
1.9
4.9
7.1
1.1
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Table 2.2.1-1:
Simulation Results of BLRM for Monotherapy
Scenario
BMS-
986226
Dose
(mg)
25
80
200
400
800
MTD 
Not 
Selected 
(%)
Fitted 
Median
MTD 
Toxicity 
Observed 
(%)
Avg 
No. of
Patients
# DLTs
0.1
0.1
0.9
2.2
0.9
All low
% DLT
1
5
10
15
20
% MTD
0.1
0.8
5.4
39.2
54.3
0.2
925.1
13.9
18.4
# Pts
3.1
0.3
1.3
7.0
6.8
# DLTs
0
0
0.1
1.0
1.3
All high
% DLT
45
50
60
75
80
% MTD
11.6
2.6
0.7
0.1
0
85
10.7
57.8
7.0
# Pts
5.2
1
0.26
0.6
0
# DLTs
2.3
0.5
0.1
0.5
0
% DLT, true DLT rate; % MTD, proportion of the dose selected as the MTD; # Pts, average number of participants 
by assuming 3 participants for skipped dose level where the true toxicity rate is below the target rate; # DLTs, average 
number of DLTs by assuming no DLT for skipped dose level where the true toxicity rate is below the target rate; 
Fitted MTD: fitted MTD at 30% as the target toxicity rate; % toxicity observed, average proportion of DLTs given 
the doses were tried
The average sample size in this simulation was observed to be no more than 20 participants. The 
results for the scenarios of narrow safety window and all high show how the EWOC principle 
limits the risk of exposing participants from a toxic dose level. Overall, the scenarios illustrated 
above demonstrate that the model performs well in the hypothetical scenarios investigated.
3
INTERIM MONITORING CASE STUDY TO ILLUSTRATE PROVISION OF 
DOSE RECOMMENDATIONS DURING DOSE-ESCALATION
In order to provide a comprehensive view of the dynamics of the models, different hypothetical 
scenarios exploring all possibilities are examined. For the simplicity of illustration purposes, a 
static cohort size of 3 subjects is applied for dose levels 25 mg, 80 mg, 200 mg, 400 mg, and 800 
mg in the BMS-986226 monotherapy. This cohort size could vary during the actual clinical trial, 
and the BLRM models are designed to fit various different cohort sizes, adaptively. In general, 
there are 4 possible scenarios for a specific dose level, which are 0 DLT observed in 3 total subjects 
in that cohort (denoted as 0/3), 1 DLT observed in 3 subjects (1/3), 2 DLTs observed in 3 subjects 
(2/3), and 3 DLTs observed in 3 subjects (3/3).
During interim monitoring, posterior probabilities will be updated when there is new DLT 
information available. The following three visualization plots will be produced to reflect the real 
time dose-DLT relationship, to quantify benefit (in the form of target dosing) and risk (in the form 
of overdosing and underdosing) during model’s recommendation process, and to facilitate clinical 
team’s interpretation of the model recommendations for the final decision making:
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•
Dose-DLT profile for the doses ranging between 0 mg and 800 mg (Figure 3-1).
•
Stacking histograms displaying predictive probabilities on DLT rates classified into 3 different 
categories (Underdosing, Target dosing, and Overdosing) (Figure 3-2).
•
Box plots summarizing the Markov Chain Monte Carlo samples of predicted DLT rates for the 
5 pre-specified dose levels (Figure 3-3).
In the following illustrations, Figure 3-1 to Figure 3-3 are produced using a hypothetical example 
assuming 0/3 DLTs observed in the 25-mg cohort and 1/3 DLTs observed in the 80-mg cohort.
Figure 3-1:
Updated Dose-DLT Profile After Incorporating Prior Information 
and All Previous DLT Information up to 80 mg
Abbreviations: DLT = dose-limiting toxicity; L = low boundary; U = upper boundary.
Interpretation and usage of Figure 3-1:
Figure 3-1 is a snapshot of an updated dose-DLT profile with DLT information available at dose 
level 80 mg. The dose-DLT profile is captured with a continuous dose spectrum ranging from 0 mg 
to 800 mg. For each dose within the range, there is a corresponding distribution of the predicted 
DLT rates calculated from the posterior samples of the model parameters. This figure will be 
updated each time when new DLT information becomes available. 
In Figure 3-1, there are 3 different quantiles (2.5%, 50%, and 97.5%) plotted to characterize the 
current trend of the toxicity profile (as shown by the 50% quantile), as well as the variation of the 
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dose-DLT profile (as shown by the 2.5% percentile and the 97.5% percentile), according to the 
accumulation of DLT data from all previous and current dose levels. The toxicity boundaries (low 
boundary 0.16 and high boundary 0.33) are illustrated in two dotted horizontal lines to benchmark 
the way, in which the dose-DLT profile is trending. 
Intermediate dose levels can be identified using different boundary cutoffs. For example, using the 
50% percentile curve (green highlight), which represents the nearly average DLT distribution for 
each dose level, the 100 mg could be a potential intermediate dose level corresponding to the lower 
pre-specified DLT rate boundary of 0.16, and the 450 mg could be a fitted MTD dose level 
associated with the upper boundary of 0.33. 
Moreover, if all of the current pre-specified doses are considered intolerable (overdosing 
probabilities > 0.3, a case not shown on the current Figure 3-1), the model will recommend to stop 
the current dose level, and the clinical team can leverage the current updated dose-DLT curve to 
pinpoint a new dose, which is lower than pre-specified lowest dose (25 mg) by using the DLT rate 
boundaries.
Figure 3-2:
Updated Stacking Histogram after Incorporating Prior Information 
and All Previous DLT Information up to 80 mg Monotherapy Data to 
Classify Predicted DLT Rates Into 3 Categories (Under Target, 
Target Interval and Over Target)
Interpretation and usage of Figure 3-2:
Figure 3-2 is a snapshot of stacking histogram with DLT information available at dose level 80 mg 
for the combination studies. This figure will be updated each time when new DLT information 
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becomes available in the combination setting. Similar graphs will also be produced for the 
BMS-986226 monotherapy.
When recommending the next dose level, the model will first exclude doses that are intolerable 
(with overdosing probabilities > 30%, the rate that has been specified for BMS-986226 in 
combination with ipilimumab). Among those qualified candidate doses that are considered 
“tolerable”, the model will select the dose that maximizes the probability of being within the target 
toxicity range (DLT rate of 16% up to 33%). 
As illustrated in Figure 3-2, when there is 0 DLT observed out of 3 subjects for the dose level 
25 mg and 1 DLT out of 3 subjects for the dose level 80 mg, the distribution of predicted DLT 
rates will be characterized into possibilities falling into 3 different categories. First, dose levels of 
400 mg and 800 mg for BMS-986226 are excluded according to the higher-than-cutoff (0.3 for 
mono therapy) overdosing probabilities. Among the remainder of tolerable dose levels (25, 80, 
and 200 mg), the BLRM-Copula model recommends the dose that maximizes the probability of 
being within the target dosing interval. Therefore, the model’s recommendation would be to 
escalate to 200 mg, which is associated with the highest target dosing probability of 
0.372 compared with that of 80 mg (0.311).
Similarly (although not shown on Figure 3-2), according to the rules specified above, the model 
could possibly recommend to de-escalate to a lower dose level than current treated dose level, 
extend the current dose level, or even recommend to stop and identify a new dose level lower than 
80 mg, the lowest pre-specified dose level. Please refer to description of Figure 3-1 for details on 
how to specify the new dose levels.
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Figure 3-3:
Updated Box Plot after Incorporating Prior Information and All 
Previous DLT Information up to BMS-986226 80 mg for Pre-specified 
Dose Levels 
Interpretation and usage of Figure 3-3:
Figure 3-3 is a snapshot with DLT information available at dose level 80 mg for the combination 
setting. The dose-DLT distributions calculated from the posterior samples of the model parameters 
are characterized in the format of boxplots for the pre-specified dose levels. This figure will be 
updated each time when there is new DLT information available. Similar graphs will also be 
produced for the BMS-986226 monotherapy.
This plot supplements the information provided in Figure 3-1. It allows for a more in-depth and 
focused visualization of general trend of dose-DLT relationship, as well as the magnitude and 
variability in the DLT rates for each pre-specified dose level.
3.1
Example of the BLRM using  BMS-986226 Monotherapy Dose 
Escalation 
According to safety consideration and clinical judgement, the dose level 25 mg is recommended 
as the starting dose for BMS-986226 monotherapy. With the current BMS-986226 prior specified 
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in the Section 1.2 and all available DLT information up to 80 mg, a corresponding decision tree 
illustrating various models’ recommendations under all possible scenarios (for dose levels of 
200 mg and 400 mg) is provided in Figure 3.1-1.
Tracing a branch of the decision tree in Figure 3.1-1 illustrates the decision making process. Taking 
the left-most branch of the tree as an example, starting at 25 mg, there were 0 DLT observed at 
25 mg in the real clinical trial, the model recommended to escalate to 80 mg (The BLRM actually 
recommends escalating to dose level 400 mg, but since this is a 16-fold increase of dose and this 
type of dose skipping is not allowed, the dose level 80 mg is selected), one level above the current 
treated dose level according escalation rules per protocol. Additionally, if there was 0 DLT 
observed at 80 mg in real data, the model recommended to escalate further one dose level to 
400 mg. 
As illustrated in Figure 3.1-1, there are 6 potential decision paths for dose levels 80 mg and moving 
onwards up to 200 mg. During the actual clinical study, the tree would be narrowed or deepened 
based on actual DLT. The clinical team will be able to leverage this decision tree to preview 
decisions at each interim monitoring step and to plan proactively.
Figure 3.1-1:
The BLRM Model Hypothetical Decision Tree for BMS-986226
Monotherapy during Dose Escalation (up to 400 mg)
Abbreviations: DE = de-escalation; E = escalation; S = stay.
4
BLRM-COPULA MODEL SETUP FOR BMS-986226 AND NIVOLUMAB OR 
IPILIMUMAB COMBINATION
For Parts B and C of this study, the BLRM-Copula model will be used to evaluate the starting dose 
and to guide the subsequent doses of BMS-986226 in combination with nivolumab or ipilimumab. 
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The BLRM-Copula model incorporates the latest information, including monotherapy information 
from Part A and any available toxicity information in completed portion of Parts B and C, available 
at the time of dose recommendation. In other words, the model concept covers both the starting 
doses and any subsequent doses of BMS-986226 in combination with nivolumab or ipilimumab in 
Parts B and C. Specifically, the starting dose of BMS-986226 in Parts B and C will be guided using 
the BLRM-Copula model, incorporating available single-agent toxicity profiles of BMS-986226 
from the preliminary safety cohorts and Part A and nivolumab or ipilimumab. Any subsequent 
dose of BMS-986226 in Parts B and C will be evaluated using the BLRM-Copula model, 
incorporating single-agent toxicity profiles of BMS-986226, nivolumab or ipilimumab and any 
available combination toxicity profiles from on-going Parts B and C. 
In any case, the dose of BMS-986226 in combination with nivolumab or ipilimumab in Parts B 
and C will not exceed the maximum administered dose for BMS-986226 monotherapy in Part A. 
In summary, the doses of BMS-986226 in Parts B and C (combination with nivolumab or 
ipilimumab) will be determined using all available safety (clinical and laboratory), PK, and target 
engagement
 data, and the modelling recommendation using the 
BLRM-Copula model. The toxicity profiles of both BMS-986226 monotherapy and nivolumab or 
ipilimumab monotherapy, to be incorporated in the BLRM-Copula model, will be discussed in 
upcoming subsections. We introduce briefly the technical background of the BLRM-Copula model 
in the following paragraph.
A copula-type model can be used to cover all general combination cases, including additive and 
synergistic effects. The combination of the 2 treatments will be explored using a Bayesian 
hierarchical model by utilizing the toxicity profiles of the single agents as prior marginal profiles 
for the combination. The following copula-type model4 will be used to describe the probability ݌௜௝
of toxicity when dose level ݅of agent A and dose level ݆of agent B are administered in 
combination:
݌௜௝ൌ1 െ݁ݔ݌ሺെ൤ሼെ݈݋݃ሺ1 െ݌௜
௠ሻሽ
ଵఊభ
ൗ
൅൛െ݈݋݃ሺ1 െݍ௝
௡ሻൟ
ଵఊభ
ൗ൨
ఊభ
ሻ,
where ݌௜is the prespecified best guess toxicity probability for agent A, ݍ௝is the prespecified best 
guess toxicity probability for agent B, ݉and ݊characterize the individual drug effect, and 
ߛଵcharacterizes the drug-drug interactive effect.
The joint toxicity framework models the toxicity rates of both agents as well as their interaction 
effects in a 7-parameter hierarchical model, where each monotherapy dose-toxicity relationship 
will be characterized by a 2-parameter BLRM model (see Section 1.1). There are 3 additional 
parameters for the copula-type model, 1 for each agent (݉and ݊) as well as 1 for the interaction 
term (ߛଵ). A dose-toxicity surface will be characterized for different dose combinations of these 
2 agents.
As there are currently no historical data or prior knowledge to indicate how much information is 
to be borrowed for each of the single agents, parameters ݉and ݊are both set to be 1, meaning 
borrowing 100% of the information from the 2 agents. The above formula is then simplified into 
a 5-parameter model as follows:
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݌௜௝ൌ1 െ݁ݔ݌ሺെ൤ሼെ݈݋݃ሺ1 െ݌௜ሻሽ
ଵఊభ
ൗ
൅൛െ݈݋݃൫1 െݍ௝൯ൟ
ଵఊభ
ൗ൨
ఊభ
.
In each cohort of the study, since only a fixed nivolumab dose (in Part B1) or ipilimumab dose (1 
mg/kg in Part B2, 3mg/kg in Part B3) will be used in the combination with BMS-986226, this 
surface will be simplified into a 2-dimensional dose-toxicity curve. Posteriors for the 
corresponding 5 parameters (2 logistic regression parameters [ߙଵ, ߚଵ] for BMS-986226 and 2 
logistic regression parameters [ߙଶ, ߚଶ] for nivolumab or ipilimumab, as well as 1 interaction 
parameter for the copula-type model [ߛଵ, which will be discussed in detail in the following 
section]) will be fitted into the in-house developed model. It implements the above-described 
theoretical setup.
4.1
Prior Specification for Combination Therapy
In this section, we illustrate the prior specification of parameters in the BLRM-copula model for 
combination therapies. While we give prior examples for illustration purposes, all of those 
specifications may be subject to change when new data of monotherapies are available. 
4.1.1
Marginal Prior for BMS-986226
Posterior information on log(α1) and log(β1) from the monotherapy part of the study will be used 
as marginal BMS-986226 prior for combination with ipilimumab. This prior information is not 
prespecified and will be continuously updated when additional DLT information from the 
monotherapy is available. In the simulation (see Section 3, the prior of BMS-986226 as described 
in Section 1.2 (Table 1.2-1) is used for illustration purposes because no real-time DLT data are 
available at this time.
4.1.2
Marginal Prior for Nivolumab Parameters (log(α2),log(β2)) 
Similar to BMS-986226 monotherapy in the lead-in phase, the logistic model for nivolumab is as 
follows:
݈݋݃݅ݐ൫ݍ௝൯ൌ݈݋݃ሺߙଶሻ൅ߚଶ݈݋݃ሺ݀ଶ௝
݀ଶ
∗
൘
ሻ, where ܽଶ, ߚଶ  > 0.
Note that the ߙଶand ߚଶparameters are assumed positive, and ݀ଶ
∗is the reference dose for 
nivolumab. 
The toxicity profile of nivolumab has been studied in several studies. A bivariate normal prior for 
the nivolumab model parameters (log(α2), log(β2)) was obtained by extracting a posterior of 
nivolumab using incidence of treatment-related Grade 3 to 4 AEs from a Phase 1 dose-escalation 
study and several Phase 3 nivolumab studies, which are used later as the MAP prior for nivolumab. 
These include a Phase 1 dose-escalation study of nivolumab (Study CA209003, N=306 in doses 
of 0.1, 0.3, 1, 3, and 10 mg/kg across multiple tumor types), a randomized Phase 3 study in 
advanced melanoma participants progressing post anti-CTLA-4 therapy (Study CA209037, N=268 
in a dose of 3 mg/kg), a Phase 3 study in previously treated participants with squamous cell NSCLC 
(Study CA209017, N=131 in a dose of 3 mg/kg), a Phase 3 study in previously treated participants 
with non-squamous cell NSCLC (Study CA209057, N=287 in a dose of 3 mg/kg), and a Phase 3 
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study in previously treated participants with clear-cell RCC (Study CA209025, N=406 in a dose 
of 3 mg/kg). The results from the simulation of nivolumab flat dose exposures, the corresponding 
exposure-response analyses, and review of nivolumab safety support nivolumab flat dose and the 
overall distributions of nivolumab exposures are comparable after treatment with either 3 mg/kg 
Q2W or 240 mg Q2W nivolumab. 
 
The MAP prior for the model parameters (log(α2), log(β2)) was obtained in the following steps.
First, a prior distribution for nivolumab was developed:
•
The median DLT rate at the reference dose (3 mg/kg every 2 weeks) was assumed to be 10%, 
that is, mean (log(α2)) = logit(0.10) = log(0.1/0.9) = -2.197.
•
A doubling in dose was assumed to double odds of DLT, that is, mean(log(β2)) = 0.
•
The standard deviation of log(α2) was set to 2, and the standard deviation of log(β2) to 1, which 
allows for considerable prior uncertainty for the dose-toxicity profile.
•
The correlation between log(α2),and log(β2) is assumed to be 0 (assuming independence of 
log(α2) and log(β2)).
•
In addition, heterogeneity between the historical study and current study was incorporated 
using a MAP by defining between-trial standard deviations τ1 and τ2 for log(α2) and log(β2), 
respectively. The between-trial variability is assumed to be moderate. Therefore, τ1 and τ2 were 
set to follow a log-normal distribution with mean log(0.25) and log(0.125), respectively, with 
a common standard deviation log(2)/1.96.
With this prior, the clinical trial data below were used to generate the posterior for nivolumab, 
which is then used as the MAP prior for this study. 
Table 4.1.2-1:
Data from Nivolumab Studies
Nivolumab Flat Dose (mg), 
Q4W
Dose of Nivolumab (mg/kg)
Q2W
Toxicitya
0.1
29% (5/17)
0.3
17% (3/18)
160
1
14% (12/86)
480
3
13% (150/1146)
10
16% (21/131)
a % of participants with treatment-related Grade 3-4 AEs
Abbreviation: Q2W = every 2 weeks; Q4W - every 4 weeks.
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Table 4.1.2-2:
Marginal Prior Distribution for Model Parameters for Nivolumab 
(ie, Posterior from MAP Method)
Parameter
Means
Standard Deviations
Correlation
log(α2), log(β2)
(-1.856, -2.131)
(0.404, 0.546)
-0.009
Note: Nivolumab prior information was based on mg/kg dosing instead of flat dosing. If real pharmacokinetic (PK) 
data from this study show difference from mg/kg assumption, the nivolumab prior will be revisited and modified 
accordingly.
4.1.3
Marginal Prior Derivation for Ipilimumab Parameters (log(α3), log(β3))
Similar to BMS-986226 monotherapy in the monotherapy phase, the logistic model for ipilimumab 
is as follows:
݈݋݃݅ݐ൫ݍ௝൯ൌ݈݋݃ሺߙଷሻ൅ߚଷ݈݋݃ሺ݀ଷ௝
݀ଷ
∗
൘
ሻ, 
where ݍ௝is the probability of toxicity at dose level ݀ଷ௝. Note that the α3 and β3 parameters are 
assumed positive, and ݀ଷ
∗is the reference dose for ipilimumab. 
Since DLT information from ipilimumab studies was not available, incidence of treatment-related 
Grade 3 to 4 adverse events (AEs) from various Phase 2 to 3 ipilimumab studies at Bristol-Myers 
Squibb (BMS) in participants with previously treated or untreated advanced melanoma was used 
in lieu of DLT rate in order to derive the prior for the BLRM parameters corresponding to the 
effect of ipilimumab, (log(α3), log(β3)). Specifically, a bivariate normal MAP prior for the 
ipilimumab model parameters (log(α3), log(β3)) was obtained by extracting a posterior of 
ipilimumab using DLT and safety data from Phase 2 and 3 ipilimumab studies in BMS and the 
meta-analytical-predictive approach. Finally, a mixture prior with both MAP and weakly 
informative components will be generated for BLRM parameters of ipilimumab.
The MAP prior for the model parameters (log(α3), log(β3)) was obtained in the following steps.
First, a weakly informative prior for ipilimumab was developed: 
•
The median toxicity rate at the ipilimumab reference dose (10 mg/kg every 3 weeks) was 
assumed to be 30%, ie, mean (log(α3)) = logit(0.30)= -0.847.
•
A doubling in dose was assumed to double the odds of DLT, ie, mean (log(β3)) = 0.
•
The standard deviation of log(α3) was set to 2, and the standard deviation of log(β3) was set to 
1, which allows for considerable prior uncertainty for the dose-toxicity profile.
•
The correlation between log(α3) and log(β3) was assumed to be 0 (assuming independence of 
log(α3) and log(β3)).
With this prior, the clinical trial data below (Table 4.1.3-1), including: 
•
Phase 3 study of ipilimumab administered at 3 mg/kg vs 10 mg/kg (Study CA184169, N=360 
per arm)
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•
Phase 2 study of multiple doses of ipilimumab monotherapy (Study CA184022, N=71 per arm)
•
Phase 3 study in HLA-A*0201 positive participants (Study MDX010-20, ipilimumab 3 mg/kg 
monotherapy arm with N=131)
•
Data from other various Phase 2 studies (N=111 for pooled 3 mg/kg; N=325 for pooled 
10 mg/kg, from Clinical Overview of a Common Technical Document for ipilimumab)
were used to generate the posterior for ipilimumab. The generation of the posterior uses the meta-
analytic predictive approach, such that heterogeneity between the historical study and the current 
study was incorporated, by defining between-trial standard deviations τ1 and τ2 for log(α3) and 
log(β3), respectively. The between-trial variability is assumed to be moderate. Therefore, τ1 and 
τ2 were set to follow a log-normal distribution with mean log(0.25) and log(0.125) respectively 
with a common standard deviation log(2)/1.96. This leads to the MAP prior in Table 4.1.3-2.
To obtain the mixture prior, 50% weight is assigned to the MAP component, and 50% weight is 
assigned to the weakly informative component. The mixture prior is also presented in Table 4.1.3-
2. Note that the prior of Ipilimumab is derived using mg/kg-based Q3W historical data, and the 
reference dose was selected to be 10 mg/kg Q3W. Since the DLT-evaluation period is 5 weeks and 
to be conservative, we will keep the reference dose as is when evaluating Ipilimumab as Q4W in 
our current study. In other words, we conservatively assume that the DLT toxicity profile in the 
DLT-evaluation period from Ipilimumab Q4W is similar to that for the Ipilimumab Q3W from 
historical studies.
Table 4.1.3-1:
Data from Phase 2 and 3 Ipilimumab Studies at BMS in 
Participants with Previously Treated or Untreated Advanced 
Melanoma
Source
Dose of 
Ipilimumab (mg/kg*)
Toxicity (percentage [number of 
participants/total participants])a
Phase 3 study MDX010-20
3
20.6% (27/131)
Phase 2 Studies Pooled
3
14.4% (16/111)
10
30.5% (99/325)
CA184169
3
18.2% (66/362)
10
34.1% (124/364)
CA184022
0.3
9.7% (7/72)
3
14.1% (10/71)
10
26.8% (19/71)
a % of participants with treatment-related Grade 3-4 AEs
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Table 4.1.3-2:
Prior Distribution for Model Parameters of Ipilimumab
Parameter: (log(α3), log(β3))
Means
Standard 
Deviations
Correlation
Prior for Ipilimumab
(-0.827, -0.289)
(1.444, 0.787)
0.009
MAP component
(-0.805, -0.578)
(0.276, 0.232)
0.263
Weakly Informative Prior
(-0.847, 0)
(2, 1)
0
Note: Ipilimumab prior information was based on mg/kg Q3W dosing.
4.1.4
Prior for Interaction Parameters for Joint Toxicity of BMS-986226 and 
Nivolumab or Ipilimumab Combination
A gamma prior distribution for the interaction parameter γଵis derived to reflect the current 
uncertainty about the toxicity profile of the combination of BMS-986226 and nivolumab or 
ipilimumab. Although no PK drug-drug interaction is expected, the possibility of a significant 
positive interaction between BMS-986226 and nivolumab or ipilimumab cannot be totally 
excluded. The interaction parameter γଵwas chosen accordingly but with a degree of uncertainty 
to allow for the possibility that the interaction may be positive or negative. Therefore, the following 
assumptions are made for the interaction parameter:
•
γଵfollows a gamma distribution and with a mean centered at 1.2, which means the combination 
of 2 agents is likely to have only a small synergistic effect.
•
The standard deviation of ߛis 0.5 such that there is a 61% prior probability that ߛis larger than 
1. 
This model assigns the highest probability to there being small synergistic interaction and also 
allows for the potential of larger synergism of the toxic profiles. It also does not completely ignore 
the possibility of antagonism because there is a 39% prior probability that γଵis less than 1.
5
DOSE RECOMMENDATION BY BLRM-COPULA FOR BMS-986226 IN 
COMBINATION COHORTS
Similar to the dose escalation recommendation for BMS-986226 monotherapy, any recommended 
dose by BLRM Copula (for Parts B and C, and not to exceed the maximum administrated dose of 
the BMS-986226 monotherapy in Part A) and any potential dose recommendation for the 
combination cohorts will be based on the inference from the Bayesian posterior and the probability 
(obtained from the BLRM-Copula model) that the true DLT rate for each dose lies in 1 of the 
following categories:
•
[0%, 16%) under-dosing
•
[16%, 33%) targeted toxicity
•
[33%, 100%] excessive toxicity
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While the Bayesian model will use DLT information of all available data from the DLT period 
only, clinical assessment will take into consideration of the totality of available data including 
PK/PD from all treated participants.
BLRM-Copula Model-Recommended Dose:
At any time a dose recommended by BLRM-Copula model for BMS-986226, using all available 
data to date and time, is the dose that satisfies the following conditions: 
1) Not to exceed the maximum administrated dose of BMS-986226 in Part A, ie., the 
BMS-986226 monotherapy phase 
2) This probability of the true DLT rate falling into the targeted toxicity interval, i.e., [16%, 33%), 
needs to be the largest (or be comparable to numerically the largest with negligible practical 
difference) among the dose levels that satisfy the EWOC condition (ie, the probability that 
‘DLT rate ≥33%’) must be less than 30%; 
Final BLRM-Copula Recommended Dose:
Any final recommended BLRM-Copula recommended dose will be based on the recommendation 
from the BLRM-copula and overall clinical assessment of all available safety, PK/PD, and efficacy 
data. Also, note that the dose recommendation by BLRM-Copula is a real-time on-going process, 
and can be done whenever new DLT information is available.
6
REFERENCES
1
Babb J, Rogatko A, Zacks S. Cancer Phase I clinical trials: efficient dose escalation with 
overdose control. Stat Med 1998;17:1103-20.
2
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to Phase 
I cancer trials. Stat Med 2008;27:2420-39.
3
Neuenschwander B, Capkun-Niggli G, Branson M, et al. Summarizing historical information 
on controls in clinical trials. Clin Trials 2010;7:5-18.
4
Yin G, Yuan Y. Bayesian dose finding in oncology for drug combinations by copula 
regression. J R Stat Soc Ser C Appl Stat 2009;58(2):211-24.
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APPENDIX 11
PROSTATE CANCER WORKING GROUP 3 (PCWG3)
GUIDELINES (WITH MODIFIED RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS (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 
PCWG31.
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.
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Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above.
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (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 
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default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression (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 
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disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: 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 
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, with at least 2 additional lesions on 
the next scan (performed at least 6 weeks later) as compared to first posttreatment 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 
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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.
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
(eg, CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of 
a previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1
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 12
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 03, 02-Dec-2018
This protocol has been revised in several ways to improve access to study treatment for participants
with incurable cancer, while enhancing the scientific knowledge gained from each enrolled 
participant. The inclusion criteria in the protocol was modified in order to expand the study 
population that could potentially benefit from BMS-986226 by adding additional tumor types, as 
well as increasing the number of prior therapies allowed for participants enrolled on study. The 
requirement for confirmation of ICOS expression by IHC on pre-treatment biopsy samples was 
removed, in order to expedite the treatment of participants on the study. The integrity of the biopsy 
sample will be ensured through a new requirement for the provision of the FFPE block obtained 
from the core-needle pre-treatment and on-treatment biopsies. The exact timing of tetanus booster 
administration, to be used as a surrogate measure of antigen-specific immune activation, was 
defined, in order to synchronize the post-booster immune response in the treatment cohorts. 
Additionally, changes were made in the content and timing of clinical, PK, PD
 
analysis, including stool collection for pre-treatment microbiota content analysis, in order to 
enhance the robustness and interpretability of the scientific data gathered from every participant
enrolled on the study.
Sections in the synopsis have been updated to align with the protocol section changes listed below.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 3 Introduction
Section 3.2.1: Indication 
Background
Table 5.1-1: Study Cohorts per 
Part
Section 5.1.2.4: Combination 
Expansion Arms (Parts D and E)
Section 6.1: Inclusion Criteria
Appendix 1: Abbreviations and 
Trademarks
New tumor types were added and 
discussed:
cervical cancer (CC), melanoma
(MEL), renal cell carcinoma (RCC), and 
triple negative breast cancer (TNBC).
Up to three courses of prior systemic 
therapy are permitted in HNSCC, 
NSCLC, PRC and UCC tumor types, 
which has been changed from two prior 
courses.
Modifications were made to 
expand the study population to 
include additional disease types 
and patient cohorts that could 
potentially derive benefit from 
ICOS agonist therapy, based on 
recently published literature.
Table 2.1: Screening Procedural 
Outline.
Section 6.1 Inclusion Criteria
Fresh Pretreatment Tumor Biopsy 
procedures were modified as follows:
The requirement for central assessment of 
tumor content and ICOS expression prior 
to Day 1 of study treatment 
administration (Cycle 1 Day 1) was 
removed.
A requirement for pretreatment biopsy 
collection and shipment for analysis has 
been added.
Modification was made to 
expedite the time-between 
enrollment and first treatment, 
as well as to reduce the 
potential risk of re-biopsy for 
participants who had recently 
undergone the procedure for 
confirmation of disease 
progression.
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Table 2.1: Screening Procedural 
Outline
Section 5.1.1: Screening
Timing for tetanus booster administration 
between Days -7 to -3, prior to dosing 
was added.
The timing of tetanus booster 
administration was narrowed in 
order to synchronize the 
antigen specific immune 
response within each treatment 
cohort.  
Section 2.2: On-treatment 
Procedural Outline
Chemistry and CBC with Differential and 
Platelets were added to list of laboratory 
tests performed on Cycle 2 Day 2 and 
Cycle 2 Day 8.  Additionally, all 
laboratory tests were specified to be 
performed on Day 1 of each cycle.
Modification was made to 
improve clinical monitoring of 
hematologic and metabolic 
effects of BMS-986226 
therapy.
Pharmacokinetic and 
Immunogenicity Tables 9.5-1 
through Table 9.5-4
Sampling time points were adjusted 
and/or tables removed 
The tables in this section were 
modified to support more 
robust assessment for PK and 
immunogenicity while aligning 
with clinical 
 
assessment. 
Table 2-4: Additional Treatment 
Procedural Outline
(Former Table 2-4: Retreatment 
Day 0 Procedural Outline)
Table 2-5: Additional Treatment 
Follow-up Procedural Outline 
(Former Table 2-5: Retreatment 
and Extended Treatment 
Procedural Outline)
Former Table 2-6: Retreatment 
and Extended Treatment Follow-
up Procedural Outline
Section 5.1.5.1: Retreatment 
During Response Follow-up
Retreatment was removed as an option 
for patients who have relapsed after 
experiencing CR/PR or SD after 
completing study treatment. All tables 
and text referring to retreatment were 
removed from the protocol.
The option for retreatment of 
participants on the study was 
removed from the protocol as 
there is minimal evidence to 
support retreatment of 
participants who have 
progressed after completing a 
course of experimental therapy.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Appendix 3: Adverse Events and 
Serious Adverse Events: 
definitions and procedures for 
recording, evaluating, follow up 
and reporting
The previous version of Appendix 3 was 
replaced. 
The Appendix was replaced to 
align with latest BMS 
standards. 
Section 1 Synopsis
Section 5.1
Section 10.1.1
Appendix 10 
Clarifications made to the language 
describing the application of 
BLRM/BLRM-Copula.
Reference to BLRM-RD removed from 
protocol.
Language referencing the 
BLRM model was adjusted in 
order to clarify starting dose 
decision algorithms for the 
combination cohorts as well as 
more precisely defining the 
application of BLRM/BLRM-
Copula in dose escalation 
assessments.
Section 3.2.2.4: Clinical 
Pharmacology and Safety.
Section 3.2.2.5: Pharmacokinetics 
of BMS-986226
Sections were updated to describe results 
from dosing of 12 participants to date.
Information was updated to 
provide latest data available on 
the safety of BMS-986226 in 
human subjects.
All
Minor formatting and typographical 
corrections.
Made corrections for clarity 
and consistency within the 
document.
Overall Rationale for the Revised Protocol 02, 03-Apr-2018
This protocol has been revised to modify the combination escalation of BMS-986226 with either 
nivolumab (Part B) or ipilimumab (Part C) to include and prioritize a Q12W dosing schedule that 
will provide pharmacodynamic data to inform dose and schedule. To rapidly inform a combination 
dose and schedule, the protocol was modified to allow Parts B and C to accrue while Part A is still 
open. In addition, on-treatment biopsy collections were changed to the 2W and 12W timepoints to 
more accurately capture pharmacodynamic activity and a tetanus booster will be administered to 
capture pharmacodynamic activity in an antigen-specific context. Finally, treatment duration of 
BMS-986226 in combination with nivolumab or ipilimumab will be 2 years, rather than 24 weeks, 
to align with published data on the efficacy of treatment with nivolumab monotherapy for 2 years.
Sections in the synopsis have been updated to align with the protocol section changes listed 
below. 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-1: Screening Procedural 
Outline (CA021002); 
 
 
Table 9.4.4-1; Clinical 
New information about a 
tetanus booster to be 
administered for all participants 
in Parts A, B, and C
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Laboratory Tests;
 
 
 
 
 
 
Section 4 Objectives and 
Endpoints; Section 5.1.2 
Treatment phase; Section 5.1.5 
Treatment Beyond Progression; 
Section 6.1. Inclusion Criteria; 
Section 8.1 Discontinuation 
from Study Treatment; Section 
8.1.2 Treatment Beyond Disease 
Progression; Section 8.1.3
Discontinuation Due to Further 
Progression (Confirmed 
Progression); Section 9.1 1 
Method of Assessment; Section 
9.1.3 Secondary Efficacy 
Assessments; Section 10.3 
Statistical Analyses; 
Added text to refer to Prostate 
Cancer Working Group 3 
(PCWG 3) efficacy assessment 
criteria for prostate.
Modified efficacy 
assessment criteria to 
include PCWG 3 criteria 
in addition to Response 
Evaluation Criteria in 
Solid Tumors (RECIST) 
v1.1 criteria.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-2 On-treatment 
Procedural Outline (CA021002); 
Table 2-5: Retreatment and 
Extended Treatment Procedural 
Outline (CA021002); Section 5 
Study design; Section 5.1 
Overall Design; Section 5.1.2.2 
BMS-986226 and Nivolumab 
Combination Therapy Cohort 
(Parts B1 and B2); Section 
5.1.2.3 BMS-986226 and 
Ipilimumab Combination 
Therapy Cohort (Parts C1 and 
C2); Section 6.1 Inclusion 
Criteria; Section 7.1 Treatment 
Administered; Section 10.1.2 
BMS-986226 and Nivolumab or 
Ipilimumab Combination 
Therapy Cohorts (Parts B and C)
Revised the study design and 
the text in this section to modify 
the combination escalation of 
BMS-986226 with either 
nivolumab (Part B) or 
ipilimumab (Part C) to include 
and prioritize a Q12W dosing 
schedule that will provide 
pharmacodynamic data to 
inform dose and schedule.
Prioritized BMS-986226 
Q12W cohorts to 
determine optimal dose 
and schedule using 
selected 
 
assays including ICOS 
and ICOS-L expression
Table 2-2 On-treatment 
Procedural Outline (CA021002); 
Table 2-5: Retreatment and 
Extended Treatment Procedural 
Outline (CA021002); Section 5 
Study design; Section 5.1.2.4 
Combination Expansion Arms 
(Parts D and E); Section 5.2 
Number of Participants; Section 
6.1. Inclusion Criteria; Section 
7.1 Treatment Administered; 
Section 10.1.2 BMS-986226 and 
Nivolumab or Ipilimumab 
Combination Therapy Cohorts 
(Parts B and C)
New text has been added or 
modified in these sections 
related to dose expansion phase 
with either nivolumab (Part D) 
or ipilimumab (Part E)
Modification was made 
to align with the revised 
protocol study design. 
The purpose of the 
cohort expansion is to 
gather additional safety, 
tolerability, preliminary 
efficacy, PK, and PD 
information regarding 
BMS-986226 in 
combination with either 
nivolumab (Part D) or 
ipilimumab (Part E)
Section 5.1.3.1 Safety Follow-
up; Section 5.1.5.1 Retreatment 
During Response Follow-up; 
Section 5.4.2.2; 
Modified language to allow 
combination patients to receive 
study therapies for 2 years 
rather than 24 weeks
Modification was made 
to align with published 
data on the efficacy of 
treatment with 
nivolumab monotherapy 
for 2 years
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Section 5.2 Number of 
Participants
Total number of participants in 
this study was increased to 234 
subjects. 
Modification was made 
to fulfill the expected 
number of participants 
per revised study design.
Section 6 Inclusion criteria; 
Criteria 3d) 
Modified inclusion criteria for 
prostate cancer tumor
Modification was made 
to clarify prior hormonal 
and chemotherapies 
allowed and to define 
progression as per the 
PCWG3 criteria.
Section 7.3.2 BMS-986226 Dose 
Limiting Toxicities
The dose-limiting toxicity 
(DLT) period was modified for 
the combination of BMS-
986226 + nivolumab (Part B1) 
or ipilimumab (Part C1) to 
allow patients to be DLT 
eligible after 1 dose of BMS-
986226.
The 5-week DLT period 
for Parts B and C covers 
2 doses of nivolumab 
(Q4W) or ipilimumab 
(Q4W) and 1 dose of 
BMS-986226 (Q12W).
Section 9.5 Pharmacokinetic and 
Immunogenicity Assessments.
PK and immunogenicity sample 
scheduling tables for Parts A, 
B1, B2, C1 and C2 were 
modified to support the revised 
study design. 
Also new PK and 
immunogenicity tables were 
added to support the sample 
collections for participants in 
Parts D and E.
The tables in this section 
were modified and 
added to support 
assessment for PK and
immunogenicity in 
subjects enrolled in 
Parts A, B1, B2, C1, C2, 
D and E. 
Appendix 10 Statistical 
Methodology
Updated
Updated the BLRM-RD 
languages and related 
prior distributions for 
the combination phase 
to align with the 
protocol text.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Appendix 11: Prostate Cancer 
Working Group 3 (PCWG 3) 
Guidelines (with Modified 
Response Evaluation Criteria in 
Solid Tumors (RECIST) Criteria 
for Soft Tissue Lesion 
Assessment)
Added new appendix for 
PCWG 3.
Appendix added to 
support inclusion of 
PCWG 3 criteria for 
efficacy assessments.
All
Minor formatting and 
typographical corrections.
Made corrections for 
clarity and consistency 
within the document.
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Overall Rationale for the Revised Protocol 01, 20-Jul-2017
The primary reason for this amendment is to incorporate the preliminary safety cohorts, 
intra-patient dose escalation, and revised inclusion/exclusion criteria for certain tumor types and 
to align the protocol with respect to these changes.
Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-2: On-treatment 
Procedural Outline 
(CA021002); Table 2-5: 
Retreatment and Extended 
Treatment Procedural 
Outline for Preliminary 
Safety Cohorts and Parts A, 
B1, B2, and B3 Only 
(CA021002); Figure 5-1: 
Study Design Schematic; 
Section 5.1: Overall Design; 
Table 5.1-1:Study Cohorts 
per Part; Section 5.1.2: 
Treatment Phase; 
Section 5.1.2.1: 
Monotherapy Dose 
Escalation (Preliminary 
Safety Cohort and Part A); 
Section 5.1.2.1.1: 
Preliminary Safety Cohort; 
Section 5.1.2.1.2: Part A; 
Table 5.1-2: Dose 
Escalation (Preliminary 
Safety Cohort and Part A); 
Section 5.2; Number of 
Participants; Section 5.4.1: 
Rationale for BMS-986226 
First-in-Human Dose 
(Preliminary Safety Cohort 
and Part A Monotherapy); 
Section 6.1: Inclusion 
Criteria; Table 7.1-1: 
Selection and Timing of 
Dose per Part; 
Section 7.1.1: Method of 
Treatment Assignment; 
Section 7.3: Dosage 
Modification; Section 7.3.1: 
Treatment Delay; 
Section 7.3.2: BMS-986226 
Dose-limiting Toxicities; 
 
Table 9.5-1: 
A preliminary safety cohort of BMS-986226 
administered at 2 mg and 8 mg every 
4 weeks in a single participant with the 
possibility to offer intra-patient dose 
escalation was added to the protocol in all 
applicable areas, including procedural 
outlines, sampling schedules, inclusion 
criteria, study design, number of participants, 
rationale for study design, and rationale for 
dose. 
Modified the starting 
monotherapy dose of 
BMS-986226 based on available 
in vitro and in vivo data.
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Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for BMS-986226, 
Nivolumab, and Ipilimumab 
(Parts A, B1, B2, and B3); 
Table 9.5-4: Additional and 
Retreatment Cycles 
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for BMS-986226, 
Nivolumab, and Ipilimumab 
(Preliminary Safety Cohorts 
and Parts A, B1, B2, and B3 
Only);
 
 
 
 
Section 10.1.1: Preliminary 
Safety Cohort and Dose 
Escalation (Part A)
Section 6.1: Inclusion 
Criteria
The inclusion criteria were modified as 
follows: 
2.c) Edited so that participants in the study 
should have progressed on, or been intolerant 
to, all standard therapies 
Colorectal cancer (CRC)
3.a.iv) Added: Participants must have 
incurable, metastatic disease (ie, patients 
with disease that is potentially curable by 
surgical resection are not eligible for 
treatment).
Non-small cell lung cancer (NSCLC)
3.c.i.2) Edited: Platinum-based 
chemotherapy may have been given in the 
adjuvant, neoadjuvant, or chemoradiation
setting. Participants with recurrent/metastatic 
disease that has recurred within 6 months of 
completing such treatment are considered 
eligible for study treatment.
Adenocarcinoma of the prostate (PRC)
3.d.iii.a) Added: Participants with bone-only 
disease should have progression confirmed 
Modified the eligibility criteria 
to the requirements for target 
disease characteristics and for 
participants with UCC, CRC, 
PRC, and NSCLC.
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Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
as per PCWG2 criteria and require 
confirmatory scans.
3.d.iv) Added: Participants must have 
received abiraterone and enzalutamide.
Urothelial carcinoma (UCC)
3.e.iii) Removed: All participants must have 
measurable disease by CT or MRI per 
RECIST v1.1 criteria.
3.e.iv.1) Edited so that participants with 
UCC must have progression or recurrence 
after treatment with at least 
1 platinum-containing chemotherapy 
regimen (if platinum eligible) but no more 
than 2 regimens for metastatic or surgically 
unresectable locally advanced urothelial 
cancer
3.e.v) Removed: Participants that have 
received more than 2 prior lines of 
chemotherapy must not have liver 
metastases.
Section 7.3.2: BMS-986226 
Dose-limiting Toxicities; 
Section 7.3.5: Exceptions to 
Permanent Discontinuation 
Criteria
1) The following dose limiting toxicity 
(DLT) criteria were edited/added:
Isolated Grade 3 fever not associated with 
hemodynamic compromise (eg, hypotension, 
clinical or laboratory evidence of impaired 
end-organ perfusion) or with other symptoms 
of infusion-related reactions that returns to 
≤Grade 1 with standard treatment in ≤1 hour
Grade 3 infusion reaction that returns to 
Grade 1 in ≤1 hour
2) The following DLT criterion has been 
added:
Grade 4 rash of any duration
3) A 4-week DLT observation period for the 
Preliminary Safety Cohort was added.
4) Consideration to permanently discontinue 
study therapy, on a case-by-case basis, for 
participants with any severe Grade 3 
drug-related adverse event (AE) that recurs 
was added to Section 7.3.5.
Clarified specific requirements 
for DLT criteria, and modified 
the DLT requirements 
consistent with the 
introduction of preliminary 
safety cohort.
Table 2-2: On-treatment 
Procedural Outline 
(CA021002); Section 3.3: 
Benefit/Risk Assessment; 
Table 7.1-1: Selection and 
Timing of Dose per Part
Instructions were added for participants to be 
observed for at least 60 minutes following 
completion of BMS-986226 infusion.
Extended the post-infusion 
observation period to monitor 
for potential infusion-related 
reactions.
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Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-2: On-treatment 
Procedural Outline 
(CA021002); Table 9.5-4: 
Additional and Retreatment 
Cycles Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for BMS-986226, 
 
 
 
 
 
Edits were made to the procedural outline 
table, pharmacokinetic and immunogenicity 
sample schedule table
 
 to clarify which 
procedures and sampling schedules are to be 
followed for additional cycles and that 
participants in Parts C1 and C2 are not 
eligible for additional cycles.
Updated the study procedural 
outline table to align with the 
description of additional cycles 
in Section 5.1.4: Treatment with 
Additional Cycles beyond 24 
Weeks.
Table 2-2: On-treatment 
Procedural Outline 
(CA021002); Table 2-5: 
Retreatment and Extended 
Treatment Procedural 
Outline for Parts A, B1, B2, 
and B3 Only (CA021002); 
Table 9.5-4: Additional and 
Retreatment Cycles 
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for BMS-986226, 
 
 
Edits were made to the procedural outline 
table, pharmacokinetic and immunogenicity 
sampling schedule table
 
 to clarify which 
procedures and sampling schedules are to be 
followed for retreatment cycles and that 
participants in Parts C1 and C2 are not 
eligible for extended treatment.
Updated the study procedural 
outline tables to align with the 
description of retreatment in 
Section 5.1.5.1: Retreatment 
During Response Follow-up.
Table 2-5: Retreatment and 
Extended Treatment 
Procedural Outline for 
Parts A, B1, B2, and B3 
Edits were made to the procedural outline 
table to clarify which procedures are to be 
followed for extended treatment cycles and 
that participants in Parts C1 and C2 are not 
Updated the study procedural 
outline table to align with the 
description of extended 
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Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Only (CA021002); 
Table 2-6: Retreatment and 
Extended Treatment 
Follow-up Procedural 
Outline (CA021002); 
Section 5.1.6: Extended 
Treatment
eligible for extended treatment. Section 5.1.6 
was added.
treatment in Section 5.1.6:
Extended Treatment. 
Added Section 5.1.6 Extended 
Treatment to clarify this phase 
of treatment, which permits 
participants who have 
completed the maximum 
duration of study treatment to 
have an extended treatment up 
to an additional 24 weeks.
Table 9.5-3: 
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for BMS-986226 
(Parts C1 and C2)
Grade 3/4 hypersensitivity reaction sampling 
time point was added for pharmacokinetic 
(PK) and anti drug antibody (ADA) sampling 
in Parts C1 and C2.
Added PK and ADA sampling 
for Grade 3/4 hypersensitivity to 
better evaluate any drug-related 
AEs, infusion reactions, or 
hypersensitivity reactions.
Table 9.5-1: 
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for BMS-986226, 
 
Table 9.5-2: 
Pharmacokinetic and 
Immunogenicity Post-DLT
Period Sampling Schedule 
for BMS-986226, 
 
Table 9.5-3: 
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for BMS-986226 
(Parts C1 and C2); 
Table 9.5-4: Additional and 
Retreatment Cycles 
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for BMS-986226, 
 
Dose delay sample collection timepoints 
were added for PK and ADA sampling in the 
event that a dose is delayed.
Updated the PK and ADA 
sampling tables to align with 
procedural requirements 
described in the body of the 
protocol.
Table 2-3: Follow-up 
Procedural Outline 
(CA021002)
Tumor assessments were added for all 
participants in survival follow-up until 
beginning a new anti-cancer therapy.
Updated the study procedural 
outline table to align with the 
requirements for tumor 
assessments in Section 5.1.3.3:
Response Follow-up.
Table 2-1: Screening 
Procedural Outline 
Oxygen saturation procedure was removed 
from the assessments to be collected.
Updated the study procedural 
outline table to align with 
Revised Protocol No.: 04
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Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
(CA021002); Table 2-4: 
Retreatment Day 0 
Procedural Outline 
(CA021002)
procedural requirements 
described in the body of the 
protocol.
All
Minor formatting and typographical 
corrections.
Made corrections for clarity and 
consistency within the 
document.
Revised Protocol No.: 04
Date: 31-May-2019
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