Phase 1/2a First-In-Human Study of BMS-986218 Monoclonal Antibody Alone and in Combination With Nivolumab in Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study:  
Phase 1/2a First-In-Human Study of BMS-986218 Monoclonal Antibody Alone and in Combination with 
Nivolumab in Advanced Solid Tumors 
 
 
NCT Number: NCT03110107 
Document Date (Date in which document was last revised): July 29, 2021 
 
 
 

Page:
1
Protocol Number:
CA022001
IND Number:
133711
EUDRACT Number
2017-000597-11
Date
14-Feb-2017
Revised Date
29-Jul-2021
Clinical Protocol CA022001
Phase 1/2a First-In-Human Study of BMS-986218 Monoclonal Antibody Alone and in 
Combination with Nivolumab in Advanced Solid Tumors
Short Title:  Phase 1/2a Study of Monoclonal Antibody BMS-986218 Monotherapy and in 
Combination With Nivolumab in Patients With Advanced Solid Tumors
Protocol Amendment Number: 07
Clinical Trial Physician
Bristol Myers Squibb Company
3401 Princeton Pike, Lawrenceville, NJ 08648
Telephone (office):
email:
Clinical Scientist
Bristol Myers Squibb Company
3401 Princeton Pike , Lawrenceville, NJ 08648
Telephone (office): 
email: 
24-hr Emergency Telephone Number
USA:  
International:  
Bristol Myers Squibb Company
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 
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BMS-986218
anti-CTLA4-NF mAb
Protocol Amendment No.: 07
Date: 29-Jul-2021
2
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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CA022001
BMS-986218
anti-CTLA4-NF mAb
Protocol Amendment No.: 07
Date: 29-Jul-2021
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 07
29-Jul-2021
Added Part 2C and Part 2D evaluating the combination of anti-CTLA4-NF 
(BMS-986218) and nivolumab in non-small cell lung cancer (NSCLC) and 
microsatellite stable colorectal cancer (MSS CRC) participants, respectively.
Incorporates Protocol Amendment 01 United States.
Protocol 
Amendment 01 
United States
16-Apr-2021
Added tumor types in the Part 1A pharmacodynamic (PD) cohort: colorectal 
cancer microsatellite stable (CRC MSS), non-small cell lung cancer 
(NSCLC), and squamous cell carcinoma of the head and neck (SCCHN). 
Added dose levels or dose schedules to the PD cohort.
Protocol 
Amendment 06
22-Dec-2020
The changes include revising the protocol in response to feedback from 
Investigators 
around pregnancy testing and 
contraception requirements; adding responses to the COVID-19 pandemic 
and aligning with nivolumab program standards, including updating the 
contraception language for women of child-bearing potential (WOCBP) 
participants and male participants, and their WOCBP partners.
Administrative 
Letter 05
08-Oct-2019
To notify of incorrect notation stating that Sections 3.2.2 and 3.2.3 were 
updated per Investigator’s Brochure (IB). The sections were not updated.
Administrative
Letter 04
03-Oct-2019
Note added to correct and provide clarifying directions to the schedule of 
activities table and only noted change to Table 2-4, when it affects 
Tables 2-2, 2-3, and 2-4
Revised 
Protocol 05
14-Aug-2019
The primary reasons for the changes to the protocol are:
1)
Specify interim dose levels for Part 1A and Part 1B.
2)
Include a subgroup of additional participants with advanced stage 
cutaneous melanoma in Part 1A.
3)
Specify the doses and schedules for expansions in Part 2A and Part 2B.
4)
Update safety information to align with current Investigator Brochure for 
BMS-986218.
Revised 
Protocol 04
25-Dec-2018
The primary reasons for the changes to the protocol are to:
1)
Update pharmacokinetic and immunogenicity assessments sampling 
schedules to add and/or clarify blood and anti-drug antibody samples.
2)
Clarify relevant systemic exposure of study drugs for male participant 
contraceptive guidance.
Revised 
Protocol 03
24-Oct-2018
Updated the study design as follows:  
• Part 1A:  Inclusion of alternative every-2-weeks (Q2W) dosing schedule to 
study BMS-986218 in the context of rapid T-regulatory cell (Treg) depletion 
and recovery.
• Part 1B:  Inclusion of Bayesian Logistic Regression Model (BLRM) using 
the escalation with overdose control (EWOC) principle, and a starting dose 
1 at dose level below the current safety cleared monotherapy cohort (to allow 
initiation of this study part prior to declaring the RP2D and evaluation of 
different doses in combination in select tumor types)
• Part 2A:  Inclusion of several dose levels and/or schedules to study 
BMS-986218 monotherapy and ipilimumab monotherapy in a randomized 
setting in participants with cutaneous melanoma
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anti-CTLA4-NF mAb
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Document
Date of Issue
Summary of Change
• Part 2B:  Inclusion of several dose levels and/or schedules to study 
BMS-986218 monotherapy in a randomized setting in participants with non-
small cell lung cancer (NSCLC).
Other key changes:  
 clarified expectations and timing of scheduled activities; updated 
eligibility criteria; 
Administrative 
Letter 03
07-Aug-2018
Updated study personnel
Administrative 
Letter 02
18-May-2018
Updated study personnel
Revised 
Protocol 02
14-Feb-2018
Expand enrollment in Part 1A to include up to 60 participants, extend the 
treatment period to 2 calendar years, modify eligibility criteria for 
participants with advanced PDAC, permit the use of concomitant palliative 
hormonal therapy, remove the option of re-treatment following progression, 
Revised 
Protocol 01
05-Apr-2017
Incorporates Amendment 01
Amendment 01
05-Apr-2017
Incorporates revisions to the inclusion/exclusion criteria, study schematic, 
timing of pharmacokinetic and pharmacodynamic collection, and rectified 
inconsistencies in cohort sample size and administrative updates.
Original 
Protocol
14-Feb-2017
Not Applicable
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BMS-986218
anti-CTLA4-NF mAb
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07:
The primary purpose of this amendment is to add Part 2C and Part 2D, BMS-986218 administered
in combination with nivolumab in non-small cell lung cancer (NSCLC) and microsatellite stable 
colorectal cancer (MSS CRC) participants, respectively. This cohort expansion will evaluate 
preliminary efficacy and safety of BMS-986218 in combination with nivolumab. This amendment 
also includes the revisions from Protocol Amendment 01 United States which allows the inclusion 
of participants with MSS CRC, non-small cell lung cancer (NSCLC), and squamous cell 
carcinoma of the head and neck (SCCHN) tumor types as well as adding dose levels or dose 
schedules in the Part 1A pharmacodynamic (PD) cohort.
The synopsis has been revised as applicable to align with the protocol changes.
This protocol amendment applies to all participants.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
Synopsis
All changes in the body are included 
in the synopsis as applicable.
To align the changes in the
body with the synopsis.
Section 2: Schedule of Activities;
Table 2-1
Updated the note for Medical History 
and the note for Concomitant 
Medications to include information 
regarding COVID-19 vaccination.
Revised the note for the collection of 
tumor tissue procedure.
To ensure COVID-related 
vaccine history is captured and 
noted as a concomitant 
medication.
To provide clarity on the tissue 
requirements.
Section 2: Schedule of Activities;
Table 2-2 
Added the Combination Cohort 
Expansions (Part 2C and Part 2D) to 
the On-Treatment tables and added 
assessment timepoints as applicable.
To include assessments for
Part 2C and Part 2D.
Section 2: Schedule of Activities;
Table 2-3 
Removed the 12-week tumor imaging 
assessment for the body imaging 
procedure.
Table 2-3 is for Part 1A of the 
study, this assessment applied 
Protocol Amendment No.: 07
Date: 29-Jul-2021
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BMS-986218
anti-CTLA4-NF mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
to Part 2A, therefore it is not 
applicable.
Section 3.2.1: BMS-986218
BMS-986218 Part 1A administration 
was updated to include 100 and 
150 mg doses Q4W and 35 and 50 mg 
doses for Q2W.
To provide updated clinical 
dosing information.
Section 3.2.2: Nivolumab
Removed outdated information and 
added updated data.
To provide updated nivolumab 
clinical information.
Section 3.3: Benefit-Risk Assessment
Revised bullet item 2 regarding 
observation following first 3 infusions 
of BMS-986218.
Updated COVID-19 text.
To clarify the observation 
period for participants after 
each infusion.
To provide guidance on 
COVID-19 testing and 
vaccines.
Section 4: Objectives and Endpoints
Removed laboratory abnormalities 
from the first primary endpoint for 
safety, tolerability and DLTs when 
BMS-986218 is administered as 
monotherapy and in combination with 
nivolumab.
Added a primary safety and efficacy
objective for Part 2B, Part 2C, and 
Part 2D.
Added Part 1A and Part 1B to the 
secondary efficacy objective. 
Laboratory abnormalities are
removed from primary 
endpoint as they will be 
reported as adverse events.
To include objectives for all 
parts of the study.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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CA022001
BMS-986218
anti-CTLA4-NF mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
Section 5.1: Overall Design;
Figure 5.1-1 Study Design Schematic;
Section 5.1.2.1: The BMS- 986218 
Monotherapy Escalation (Part 1A);
Section 5.1.2.4: The Randomized 
BMS-986218 Monotherapy Cohort 
Expansion in Cutaneous Melanoma 
(Part 2A), the BMS-986218 Cohort 
Expansion  Monotherapy (Part 2B), 
and the BMS-986218 Cohort 
Expansion - Combination Therapy 
(Part 2C and Part 2D)
Added MSS CRC, NSCLC, and 
SCCHN tumor types to Part 1A in 
addition to cutaneous melanoma and
named the cohort ͆Part 1A PD 
Cohort.” 
Added language to allow additional 
dose levels and enrollment of more 
participants at the new dose levels or 
dose schedules.
Updated the schematic and text to 
include additional tumor types in Part 
1A PD cohort and Part 2C and Part 
2D. Updated the table notes 
accordingly.
Updated dose selection text for Part 
2C and Part 2D cohorts.
To allow additional 
participants with selected 
tumor types to be enrolled in 
the Part 1A PD cohort.
To include Part 2C and Part 
2D participants to sections as 
appropriate.
To explain how dose selection 
will occur for Part 2C and Part 
2D.
Section 5.1.4: Data Monitoring 
Committee and Other External 
Committees 
Updated the Bristol-Myers Squibb 
(BMS) department name ‘Global 
Pharmacovigilance and Epidemiology 
(GPVE)’ to ‘WorldWide Patient 
Safety (WWPS)’.  Updated the BMS 
department name ‘Medical 
Surveillance Team (MST)’ to ‘Safety 
Management Team (SMT)’.
To align the names to the 
current BMS department 
names.
Section 5.2: Number of Participants
Updated the number of participants for 
each study part.
To provide each study part and 
the corresponding number of 
participants.
Section 5.4 7: Rationale for Tumor 
Selection
Added rationale for including tumor 
type selection in the PD cohort to 
evaluate the potential therapeutic 
effect of BMS-986218.
To provide clarity on rationale 
for selection of tumor types for 
the PD cohort.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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BMS-986218
anti-CTLA4-NF mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
Section 5.5.2: Rationale for Dose 
Selection and Dosing Schedule; 
Table 5.5.2-1 Dosing Schedule by Study 
Part
Updated the table to include the Part 
2C doses for NSCLC and Part 2D 
doses for MSS CRC.
To include doses for Part 2C
and Part 2D.
Section 6.1: Inclusion Criteria 2) Type 
of Participants and Target Disease 
Characteristics c) iv), (1), c) vi) and
added vii)
Section 6.1: Inclusion Criteria 2) Type 
of Participants and Target Disease 
Characteristics k) i), (1)
Inclusion Criteria 2) Type of 
Participants and Target Disease 
Characteristics l)
Removed two criteria; no longer 
applicable per Protocol Amendment 
01 US and added criteria regarding 
previous therapies. 
Updated inclusion criteria of 
transitional cell (urothelial) carcinoma 
(TCC) of urinary bladder to urothelial
carcinoma.
Added NCLSC inclusion criteria for 
Part 2C.
Added MSS CRC inclusion criteria for 
Part 2D participants.
The criteria are now included 
in 2) c) vii.
Criteria was clarified to allow 
all urothelial carcinomas. 
To add criteria for Part 2C and 
Part 2D cohorts.
Section 6.1: Inclusion Criteria 4) Age 
and Reproductive Status c)
Clarified duration of contraception for 
monotherapy and combination therapy 
for women of childbearing potential.
Added a reference to Appendix 4. 
Also clarified that male participants 
receiving monoclonal antibodies 
(mAbs), are not required to practice 
contraception because mAbs do not 
collect in seminal fluid.
For clarification of 
contraception and duration of 
contraceptive requirements 
based on current safety 
information.
Section 6.2: Exclusion Criteria 3)
Medical History and Concurrent 
Diseases h)
Clarified the exclusion for SARS-
CoV-2 vaccines that require 2 doses.
To provide clarification.
Section 7.1: BMS-986218;
Section 7.1.2: Nivolumab;
Section 7.1.3: Ipilimumab
Removed text that is also included in
the pharmacy manual.
To reduce redundant text.
Section 7.3: Schedule of Dose for Each 
Investigational Product 
Table 7.3-1
Clarified the infusion times for each 
study treatment and added Part 2C and 
Part 2D; updated the table note.
The lower doses are now able
to be administered as standard 
IV infusions. To provide clear 
guidance for each study 
treatment and to include Part 
2C and Part 2D.
Section 7.4: Method of Treatment 
Assignment
Added the method of treatment 
assignment for Part 2C and Part 2D.
To include Part 2C and Part 
2D treatment assignment.
Section 8.1 Discontinuation from Study 
Treatment
Removed “Grade 4 amylase or lipase 
elevation.”
To correct an inconsistency in 
the protocol.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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BMS-986218
anti-CTLA4-NF mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
Section 9.2.1: Time Period and 
Frequency for Collecting AE and SAE 
Information
Removed outdated information on 
where to find the Reference Safety 
Information.
Information is outdated and no 
longer applicable.
Section 9.2.5: Pregnancy
Updated to align with male 
participants not required to use 
contraception and removed repetitive 
text.
For clarification of 
contraception and duration of 
contraceptive requirements 
based on current safety 
information.
Section 9.5: Pharmacokinetic and 
Immunogenicity Assessments;
Table 9.5-2: table note ‘b’
Table 9.5-3: table note ‘b’
Table 9.5-4: table note ‘b’
Extended the time of EOI PK sample 
draw from within 5 minutes to within 
15 minutes after the end of the flush.
Removed information on infusion of 
drug without a flush.
EOI PK sampling window 
updated to allow time for ECG 
collection.
Information is not needed.
Table 9.5-5: table title and table note 
‘b’
Added Part 2C and Part 2D to the 
table title and changed the time of EOI 
PK sampling window from within 5 
minutes to within 15 minutes after the 
end of the flush (table note ‘b’).
To include participants in Part 
2C and Part 2D for 
pharmacokinetic sampling.
EOI PK sampling window 
updated to allow time for ECG 
collection.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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BMS-986218
anti-CTLA4-NF mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
Section 10.1.1: Monotherapy Dose 
Escalation (Part 1A);
Section 10.1.2: The Safety Evaluation 
of Combination Doses of BMS-986218 
with Nivolumab (Part 1B);
Section 10.1.3: The Randomized 
BMS-986218 Monotherapy Cohort 
Expansion in Cutaneous Melanoma 
(Part 2A);
Section 10.1.4: The BMS-986218 
Cohort Expansion - Monotherapy (Part 
2B);
Section 10.1.5: The BMS-986218 
Combination - Therapy Cohort 
Expansion in NSCLC (Part 2C);
Section 10.1.6: The BMS-986218 
Combination - Therapy Cohort 
Expansion in MSS CRC (Part 2D)
Section 10.3.1: Efficacy Analyses;
Section 10.3.9: Interim Analysis
Revised the sample size calculation 
for Part 1A and Part 1A PD cohort.
Defined the participants as ‘dose-
limiting toxicity evaluable’ and 
‘response evaluable’ as applicable.
Added the sample size calculation for 
Part 2C and Part 2D .
Added Part 2C and Part 2D.
Added details of the planned interim 
analyses.
To provide updated sample 
size calculations.
To define the ‘evaluable’ 
participants. 
To include the Part 2C and 
Part 2D participants.
To describe the planned 
interim analysis.
Section 10.3.2 Safety Analyses;
Table 10.3.2-1 Safety - Statistical 
Analyses
Replaced ‘Laboratory abnormalities’ 
with ‘Toxicity Changes from 
Baseline’
Laboratory abnormalities are
removed from primary 
endpoint as they will be 
reported as adverse events.
APPENDIX 2: STUDY 
GOVERNENCE CONSIDERATIONS
Information on remote monitoring will 
be included in the monitoring plan.
Removed information on the process 
when on-site drug destruction is not 
allowed.
To address the details of 
remote monitoring if it is 
utilized.
The process is not applicable 
for the sites participating in 
this study.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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BMS-986218
anti-CTLA4-NF mAb
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & Title
Description of Change
Brief Rationale
APPENDIX 4: WOMEN OF 
CHILDBEARING POTENTIAL 
DEFINITIONS AND  METHODS OF 
CONTRACEPTION
Updated information regarding 
hormone replacement therapy, the 
highly effective contraceptive methods 
that are user dependent and 
independent, unacceptable methods of 
contraception and added less than 
highly effective contraceptive methods 
that are user dependent. 
These updates are to align with 
the BMS standards of 
contraceptive methods.
APPENDIX 8: COUNTRY SPECIFIC 
REQUIREMENTS
Updated HIV exclusion language for 
Argentina 
Clarification of a country 
requirement for Argentina .
APPENDIX 11 STATISTICAL 
METHODS
Expanded the BLRM simulation 
results performed at the beginning of 
the study to the additional planned 
doses that were added in Part 1A 
mono therapy escalation and Part 1B 
combo therapy escalation from 
previous protocol amendments. The 
BLRM mono therapy prior was 
slightly updated to reflect the changes 
in expectation for reference dose, and 
the combo therapy prior incorporated 
mono therapy DLT information for 
combo therapy simulations.
To update BLRM simulations 
for the additional doses in Part 
1A and Part 1B from previous 
protocol amendments.
All as applicable
The abbreviation ‘PD’ is now 
‘pharmacodynamic’ not ‘progressive 
disease’. 
Updated the Bristol-Myers Squibb 
(BMS) department name ‘Global 
Pharmacovigilance and Epidemiology 
(GPVE)’ to ‘WorldWide Patient 
Safety (WWPS)’.  Updated the BMS 
department name ‘Medical 
Surveillance Team (MST)’ to ‘Safety 
Management Team (SMT)’.
Minor formatting and typographical 
corrections throughout.
The cohort is named ‘Part 1A 
PD Cohort’ and ‘PD’ 
represents pharmacodynamic.
To update to the current 
department name.
Minor, therefore have not been 
summarized.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.2 Background ....................................................................................................... 
 
3.2.1 BMS-986218 ............................................................................................ 
 
3.2.1.1 BMS-986218 Nonclinical Pharmacology ....................................... 
 
3.2.1.2 BMS-986218 Nonclinical Pharmacokinetics .................................. 
 
3.2.1.3 BMS-986218 Nonclinical Toxicology ............................................. 
 
3.2.2 Nivolumab ................................................................................................ 
 
3.2.3 Ipilimumab ............................................................................................... 
 
3.3 Benefit-Risk Assessment .................................................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Screening Period ...................................................................................... 
 
5.1.2 Treatment Period ..................................................................................... 
 
5.1.2.1 The BMS-986218 Monotherapy Escalation (Part 1A) .................... 
 
5.1.2.2 The Safety Evaluation of Combination Doses of BMS-986218 with 
Nivolumab (Part 1B) ............................................................................. 
 
5.1.2.3 Dose Escalation Decisions for the BMS-986218 Monotherapy 
Escalation (Part 1A) and the Safety Evaluation of Combination Doses 
of BMS-986218 with Nivolumab (Part 1B) ........................................... 
 
5.1.2.4 The Randomized BMS-986218 Monotherapy Cohort Expansion in 
Cutaneous Melanoma (Part 2A), the BMS-986218 Cohort Expansion - 
Monotherapy (Part 2B), and the BMS-986218 Cohort Expansion - 
Combination Therapy (Part 2C and Part 2D) ...................................... 
 
5.1.2.5 Treatment Beyond Progression....................................................... 
 
5.1.3 Follow-up ................................................................................................. 
 
5.1.3.1 Safety Follow-up Period ................................................................. 
 
5.1.3.2 Response Follow-up Period ............................................................ 
 
5.1.3.3 Survival Follow-up Period .............................................................. 
 
5.1.4 Data Monitoring Committee and Other External Committees ................ 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.4.1 Rationale for the BMS-986218 Monotherapy Escalation (Part 1A) and 
the Safety Evaluation of Combination Doses of BMS-986218 with 
Nivolumab (Part 1B) Design ...................................................................... 
 
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Clinical Protocol
BMS-986218
CA022001
anti-CTLA4-NF mAb
Protocol Amendment No.: 07
Date: 29-Jul-2021
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5.4.2 Rationale for BMS-986218 Monotherapy in Participants Previously 
Treated with Anti-PD-1/PD-L1 Immunotherapy ........................................ 
 
5.4.3 Rationale for the Use of Ipilimumab as a Comparator ........................... 
 
5.4.4 Rationale for the Combination of BMS-986218 and Nivolumab ............. 
 
5.4.5 Rationale for Two Years Fixed Duration of Treatment with Checkpoint 
Blockade ...................................................................................................... 
 
5.4.6 Rationale for Treatment Beyond Progression ......................................... 
 
5.4.7 Rationale for Tumor Selection ................................................................. 
 
5.4.8 Rationale for Open-label Design ............................................................. 
 
 
 
5.5 Justification for Planned Dose Selection .......................................................... 
 
5.5.1 BMS-986218 ............................................................................................ 
 
5.5.1.1 BMS-986218 Rationale for Starting Dose in Humans .................... 
 
5.5.2 Rationale for Dose Selection and Dosing Schedule ................................ 
 
5.5.2.1 BMS-986218 ................................................................................... 
 
5.5.2.2 Nivolumab ....................................................................................... 
 
5.5.2.3 Rationale for Ipilimumab and Nivolumab 30-minute Infusions ..... 
 
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 BMS-986218 ............................................................................................ 
 
7.1.2 Nivolumab ................................................................................................ 
 
7.1.3 Ipilimumab ............................................................................................... 
 
7.2 Handling and Dispensing .................................................................................. 
 
7.3 Schedule of Dose for Each Investigational Product ......................................... 
 
7.4 Method of Treatment Assignment .................................................................... 
 
7.5 Blinding............................................................................................................. 
 
7.6 Dosage Modification ......................................................................................... 
 
7.6.1 Dose-limiting Toxicities ........................................................................... 
 
7.6.1.1 Gastrointestinal Dose-limiting Toxicity .......................................... 
 
7.6.1.2 Hepatic Dose-limiting Toxicity ....................................................... 
 
7.6.1.3 Hematologic Dose-limiting Toxicity ............................................... 
 
7.6.1.4 Dermatologic Dose-limiting Toxicity ............................................. 
 
7.6.1.5 Other Dose-limiting Toxicities ........................................................ 
 
7.6.2 Management Algorithms for Immuno-oncology Agents .......................... 
 
7.6.3 Dose Delays Due To Toxicity .................................................................. 
 
7.6.3.1 Criteria to Resume Treatment ......................................................... 
 
7.6.4 Exceptions to Permanent Discontinuation Criteria ................................. 
 
7.6.5 Management of Drug-related Infusion Reactions.................................... 
 
7.7 Preparation/Handling/Storage/Accountability .................................................. 
 
7.7.1 Retained Samples for Bioavailability/Bioequivalence ............................. 
 
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Clinical Protocol
BMS-986218
CA022001
anti-CTLA4-NF mAb
Protocol Amendment No.: 07
Date: 29-Jul-2021
13
8.0
Approved
930111276
8.0
v
Approved
1.0
v

7.8 Treatment Compliance ...................................................................................... 
 
7.9 Concomitant Therapy........................................................................................ 
 
7.9.1 Prohibited and/or Restricted Treatments................................................. 
 
7.9.2 Other Restrictions and Precautions ......................................................... 
 
7.9.3 Permitted Therapy ................................................................................... 
 
7.9.4 Palliative Radiation ................................................................................. 
 
7.9.5 Surgery ..................................................................................................... 
 
7.9.6 Imaging Restriction and Precautions ...................................................... 
 
7.10 Treatment After the End of the Study ............................................................. 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Treatment Beyond Progression ................................................................ 
 
8.1.1.1 Discontinuation Due to Further Progression (Confirmed 
Progression) .......................................................................................... 
 
8.1.2 Post-treatment Follow-up ........................................................................ 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Safety ................................................................................................................ 
 
9.1.1 Physical Examinations ............................................................................. 
 
9.1.2 Vital signs................................................................................................. 
 
9.1.3 Electrocardiograms ................................................................................. 
 
9.1.4 Clinical Safety Laboratory 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 Immune-mediated Adverse Events ........................................................... 
 
9.2.8 Potential Drug-induced Liver Injury ....................................................... 
 
9.2.9 Other Safety Considerations .................................................................... 
 
9.3 Efficacy Assessments ........................................................................................ 
 
9.3.1 Imaging Assessment for the Study............................................................ 
 
9.4 Overdose ........................................................................................................... 
 
9.5 Pharmacokinetic and Immunogenicity Assessments ........................................ 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.7.1 Absorption, Distribution, Metabolism, and Excretion Sampling ............. 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Protocol
BMS-986218
CA022001
anti-CTLA4-NF mAb
Protocol Amendment No.: 07
Date: 29-Jul-2021
14
8.0
Approved
930111276
8.0
v
Approved
1.0
v

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
9.10 Health Economics OR Medical Resource Utilization and Health Economics
........................................................................................................................... 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.1.1 Monotherapy Dose Escalation (Part 1A) .............................................. 
 
10.1.2 The Safety Evaluation of Combination Doses of BMS-986218 with 
Nivolumab (Part 1B) ................................................................................... 
 
10.1.3 The Randomized BMS-986218 Monotherapy Cohort Expansion in 
Cutaneous Melanoma (Part 2A) ................................................................. 
 
10.1.4 The BMS-986218 Cohort Expansion - Monotherapy (Part 2B) ............ 
 
10.1.5 The BMS-986218 Combination-Therapy Cohort Expansion in NSCLC 
(Part 2C) ..................................................................................................... 
 
10.1.6 The BMS-986218 Combination-Therapy Cohort Expansion in MSS CRC 
(Part 2D) ..................................................................................................... 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.3 Pharmacokinetic Analysis for BMS-986218 .......................................... 
 
10.3.4 Immunogenicity ...................................................................................... 
 
 
 
 
 
 
 
 
 
10.3.9 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
12. APPENDICES ........................................................................................................ 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
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Clinical Protocol
BMS-986218
CA022001
anti-CTLA4-NF mAb
Protocol Amendment No.: 07
Date: 29-Jul-2021
15
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8.0
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1.0
v

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 EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ................................................................................... 
 
APPENDIX 7 NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ................................................................................................ 
 
APPENDIX 8 COUNTRY SPECIFIC REQUIREMENTS ......................................... 
 
APPENDIX 9 CONSORT PUBLISHING REQUIREMENTS ................................... 
 
APPENDIX 10 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 4.0 ......................................................................................................... 
 
APPENDIX 11 STATISTICAL METHODOLOGY ................................................... 
 
APPENDIX 12 PROSTATE CANCER WORKING GROUP 3 (PCWG3) 
GUIDELINES (WITH MODIFIED RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (RECIST) CRITERIA FOR SOFT TISSUE LESION 
ASSESSMENT) ...................................................................................................... 
 
APPENDIX 13 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
 
 
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Clinical Protocol
BMS-986218
CA022001
anti-CTLA4-NF mAb
Protocol Amendment No.: 07
Date: 29-Jul-2021
16
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
1
SYNOPSIS
Protocol Title: Phase 1/2a First-In-Human Study of BMS-986218 Monoclonal Antibody Alone and in 
Combination with Nivolumab in Advanced Solid Tumors 
Short Title: Phase 1/2a Study of Monoclonal Antibody BMS-986218 Monotherapy and in Combination With 
Nivolumab in Patients With Advanced Solid Tumors
Study Phase: 1/2a
Rationale:
This is a Phase 1/2a, first-in-human (FIH) study of BMS-986218, a non-fucosylated (NF) variant of the anti-cytotoxic 
T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody (mAb), alone and in combination with nivolumab 
(anti-programmed cell death 1 [PD-1]), in humans with advanced solid tumors.
Anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab) are approved immunotherapies that define the field of 
checkpoint blockade. Ipilimumab is the first immunotherapy to show a survival advantage in late-stage metastatic 
melanoma and has also demonstrated a significant 25% reduction in risk of recurrence or death in the adjuvant 
treatment in melanoma. Blockade of CTLA-4 by ipilimumab has demonstrated anti-tumor activity in other 
malignancies, including lung, prostate cancer, and renal cell carcinoma (RCC). However, no significant activity was 
observed in bladder, colorectal, esophageal, pancreatic, gastric, hepatocellular, or breast cancer. Ipilimumab is also 
currently in clinical development in combination with nivolumab. The combination was associated with a greater 
benefit in melanoma compared to each single agent. Benefit with the combination has also been observed in non-small 
cell lung cancer (NSCLC) and RCC and is currently being evaluated in other tumor types. The activation of a 
pre-existing but attenuated immune response to cancer by checkpoint blockade is associated with an adverse event 
(AE) profile that is inherent to immune activation. Ipilimumab treatment-related AEs can involve multiple organ 
systems (digestive, skin, and endocrine) that require cessation of drug and treatment with steroids, which attenuate the 
AEs but do not maintain anti-tumor responses. The combination regimen is associated with an increased incidence of 
AEs compared to nivolumab monotherapy, but a similar overall AE profile. Developing a new anti-CTLA-4 antibody 
(Ab) with a more manageable AE profile and an increased depth and breadth of response would provide a significant 
improvement to anti-CTLA-4 therapy. 
BMS-986218 (CTLA-4.4g1fa-nf) is a human mAb against CTLA-4. The sequence is derived from the original 
hybridoma 10D1. The amino acid sequence is the same as that of ipilimumab but differs solely in its glycosylation 
pattern. The Ab is expressed in a fucosyltransferase-8 knockout Chinese hamster ovary cell line. Compared to 
ipilimumab, the glycans attached to the heavy chain Ab do not contain fucose. As a consequence, the NF Ab harbors 
a higher affinity for Fcγ receptors and improves antibody-dependent cellular cytotoxicity (ADCC) in addition to the 
CTLA-4 blocking activity of ipilimumab. T-regulatory cells (Tregs) are highly infiltrating in tumors, where they play 
an important role in impairing anti-tumor immune response by dampening effector cytolytic T-cell function. Tregs in 
tumors express higher levels of CTLA-4, and some studies have shown that part of the mechanism of action of 
ipilimumab is related to Treg depletion triggered by ADCC mediation once ipilimumab binds to CTLA-4-positive 
Tregs, but this aspect is controversial and ipilimumab may not be a strong ADCC-mediating Ab. Pre-clinical studies 
with anti-CTLA-4-NF show enhanced ADCC compared to ipilimumab, correlating with more profound Treg depletion 
in the tumor (but not the periphery). Therefore, it is expected that anti-CTLA-4-NF will result in a more efficacious 
therapy by combining CTLA-4 blocking with the depletion of Tregs expressing CTLA-4.
Based on this differentiated mechanism of action, this study will evaluate the safety and preliminary efficacy of 
BMS-986218 alone and in combination with nivolumab in tumors where ipilimumab did not demonstrate sufficient 
clinical activity and in tumors where high Treg infiltration is correlated with worse prognosis (eg, NSCLC, RCC, 
cutaneous melanoma), or in participants with progressive or recurrent disease after prior immunotherapy with an 
anti-PD-1 or anti-programmed death ligand 1 (PD-L1) containing regimen. 
Study Population:
Participants must be at least 18 years old and have histologic or cytologic confirmation of a solid tumor that is 
advanced (metastatic, recurrent, and/or unresectable) with measurable disease per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 or per Prostate Cancer Working Group 3 (PCWG 3) criteria for prostate, and have at 
least 1 lesion 
.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Objectives and Endpoints:
The objectives and endpoints for the primary, secondary, 
 of this study are shown in 
Table 1-1.
Table 1-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To characterize the safety, tolerability, and DLTs and 
to determine the MTD/RP2D of BMS-986218 
administered as monotherapy and in combination with 
nivolumab in participants with advanced solid tumors
•
To evaluate the efficacy and safety of BMS-986218 
monotherapy relative to ipilimumab in participants 
with advanced cutaneous melanoma previously treated 
with anti-PD-1/PD-L1 immunotherapy (Part 2A only)
•
To evaluate the efficacy and safety of BMS-986218 
alone and in combination with nivolumab in NSCLC 
(Part 2B and Part 2C)
•
To evaluate the efficacy and safety of BMS-986218 
alone and in combination with nivolumab in MSS CRC 
(Part 2D)
•
Incidence of AEs, SAEs, AEs meeting 
protocol-defined DLT criteria, AEs leading to 
discontinuation, and death 
•
ORR, mDOR, and PFSR at 24, 36, and 48 weeks 
by RECIST v1.1 
Secondary
•
To evaluate the preliminary efficacy of BMS-986218 
alone and in combination with nivolumab in advanced 
solid tumors (Part 1A and Part 1B)
•
To characterize the PK and immunogenicity of 
BMS-986218 when administered alone and in 
combination with nivolumab 
•
ORR, mDOR, and PFSR at 24, 36, and 48 weeks 
by RECIST v1.1 or PCWG 3
•
Summary measures of PK parameters and 
incidence of ADA to BMS-986218
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 1-1:
Objectives and Endpoints
Objectives
Endpoints
Abbreviations: 
ADA = anti-drug 
antibody; 
BMS = Bristol-Myers 
Squibb; 
DLT = dose-limiting toxicity; 
mDOR = median duration of response; MSS CRC = microsatellite stable colorectal cancer; MTD = maximum 
tolerated dose; NSCLC = non-small cell lung cancer; ORR = objective response rate; 
 PCWG 3 = Prostate Cancer Working Group; PFSR = progression-free survival rate;
 PK = pharmacokinetic(s); 
RP2D = recommended Phase 2 dose; SAEs = serious adverse events; 
Overall Design:
This is a Phase 1/2a, open-label study of BMS-986218, administered as a single agent and in combination with 
nivolumab, in participants with advanced solid tumors. The study is comprised of 2 parts: dose escalation and dose 
expansion.
•
Part 1: The Dose Escalation Phase, where the dose of BMS-986218, given alone or in combination with 
nivolumab, is escalated to determine the maximum tolerated dose/recommended Phase 2 dose (MTD/RP2D).
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
−
The BMS-986218 Monotherapy Dose Escalation (Part 1A) will escalate the dose of BMS-986218 to 
determine the MTD/RP2D. The study will first evaluate the safety and tolerability of BMS-986218 once 
every 4 weeks (Q4W), given alone, based on dose-limiting toxicities (DLTs), using a Bayesian Logistic 
Regression Model (BLRM) employing the escalation with overdose control (EWOC) principle. In addition, 
to further evaluate the safety and tolerability of BMS-986218, an alternative once-every-2-weeks (Q2W) 
dosing schedule will be explored to characterize the safety and PK of BMS-986218. The Q2W dosing 
schedule will start at a total dose level equivalent to a dose that has cleared safety in the Q4W dosing cohort 
(eg, 10 mg Q2W vs 20 mg Q4W). Subsequent Q2W doses will be guided by Q4W equivalent doses that have 
cleared safety, and will continue evaluating higher Q2W doses up to the MTD equivalent of the Q4W dosing 
cohort. Based on the preliminary PK from the Q4W dosing cohorts, at the steady state, the Q2W dosing 
schedule is projected to provide approximately the same AUCtau (tau = 4 weeks) as the Q4W dosing 
schedule, and approximately 70% Cmax as the Q4W dosing schedule. Intra-participant movement between 
treatment regimens/dosing schedules is not permitted. Additionally, participants with advanced stage 
cutaneous melanoma, microsatellite stable colorectal cancer (MSS CRC), NSCLC, or SCCHN will be treated 
with BMS-986218 on a Q2W or Q4W schedule in the Part 1A pharmacodynamic (PD) cohort.
−
The Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab (Part 1B) will evaluate the 
safety and tolerability of doses of BMS-986218 in combination with nivolumab. The combination of 
BMS-986218 with nivolumab will be evaluated using a BLRM employing the EWOC principle. Starting at 
least 1 dose level lower than the current monotherapy dose level of BMS-986218 demonstrating an acceptable 
safety profile, BMS-986218 will be studied in combination with a 480 mg Q4W flat dose of nivolumab. 
Determination of the MTD for the Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B) will be guided by BLRM-copula.
•
Part 2: The Expansion Phase, where the cohort of participants is expanded to gather additional safety, tolerability, 
preliminary efficacy, pharmacokinetic (PK), and pharmacodynamic information in specific patient populations, 
regarding BMS-986218 alone and in combination with nivolumab.
−
The Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A) will 
evaluate the preliminary efficacy of BMS-986218 monotherapy relative to ipilimumab monotherapy in a 
cohort of cutaneous melanoma participants who have received prior immunotherapy with an anti-PD-1 or 
anti-PD-L1 containing regimen and must have progressive or recurrent disease after prior PD-1/PD-L1 
directed therapy. Three dose levels for BMS-986218 from the Part 1A Q4W monotherapy escalation will be 
evaluated that have had at least 6 DLT evaluable participants and meet safety criteria: one at 7 mg Q4W, one 
at 20 mg Q4W, and one at 70 mg Q4W. Evaluating multiple different doses will aid in selecting the regimen 
that will ultimately provide the optimal benefit-risk ratio to future study participants. Participants must not 
have received prior anti-CTLA-4 therapy in the advanced or metastatic setting.
−
The Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B) will evaluate the preliminary 
efficacy of BMS-986218 in tumor types in which a high level of Treg infiltration correlates with poor 
prognosis. The tumor types to be evaluated will include NSCLC; other tumor types may be explored in the 
future. Participants should have received and then progressed on or relapsed/recurrence after 
anti-PD-1/PD-L1 directed therapy in monotherapy or in combination with chemotherapy. Prior anti-CTLA-4 
therapy is allowed for no more than 20% of participants. Participants who have been intolerant to prior 
immunotherapy are excluded. Three dose levels or schedules for BMS-986218 from the Part 1A Q4W 
monotherapy escalation will be evaluated that have had at least 6 DLT evaluable participants and meet safety 
criteria: one at 7 mg Q4W, one at 20 mg Q4W, and one at 70 mg Q4W. The rationale for evaluating multiple 
dose levels is to optimize the benefit-risk ratio for the participant. 
−
In the BMS-986218 Combination Therapy Cohort Expansion in NSCLC (Part 2C), the preliminary efficacy 
and safety of BMS-986218 in combination with nivolumab will be assessed in participants with NSCLC who 
have progressed or relapsed after anti-PD-1/PD-L1 therapy. Participants must not have received prior 
anti-CTLA-4 therapy in the advanced or metastatic setting. One or more doses to be evaluated in Part 2C will 
be selected from the range of doses assessed as tolerable in Part 1B, and which do not exceed the MTD or 
highest dose administered that has cleared safety. These dose(s) will be selected based on the totality of 
available safety, tolerability, efficacy, PK and PD data. The evaluation of efficacy in Part 2C will initially 
occur at one or more dose levels starting with up to 20 participants at each dose level. Additional participants 
up to 40 at a dose level may be evaluated following initial signal assessment. In Part 2C, participants will be 
treated Q4W for up to 2 calendar years regardless of treatment delays.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
In the BMS-986218 Combination Therapy Cohort Expansion in MSS CRC  (Part 2D), the preliminary efficacy and 
safety of BMS 986218 in combination with nivolumab will be assessed in participants with MSS CRC who have 
progressed or relapsed on at least 1 prior standard therapy. Participants must not have received prior anti-CTLA-4 
therapy in the advanced or metastatic setting.. The dose to be evaluated in Part 2D will be selected from the range of 
doses assessed as tolerable in Part 1B, and which do not exceed the MTD or highest dose administered that has cleared 
safety. The dose will be selected based on the totality of available safety, tolerability, efficacy, PK, and PD data. 
Participants will be tested during screening for extended rat sarcoma (RAS) (neuroblastoma rat viral oncogene 
homolog [NRAS] and Kirsten rat sarcoma viral oncogene homolog [KRAS]) and v-raf murine sarcoma viral oncogene 
homolog B1 (BRAF) mutation status. The RAS status evaluation will be conducted with the goal of enrolling 
approximately 20 participants each with either mutation or wild-type with respect to extended RAS status. The 
Sponsor may elect to prioritize enrollment of participants based on mutation status. In Part 2D, participants will be 
treated Q4W for up to 2 calendar years regardless of treatment delays.
•
The duration of the study will be approximately 5 years.
Protocol Amendment No.: 07
Date: 29-Jul-2021
21
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930111276
8.0
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1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
The study design is shown in Figure 1-1. 
Figure 1-1:
Study Design Schematic
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
a If Part 1 is open upon the decision to initiate Part 2, treatment in the 2 parts will occur in parallel. If supported by clinical and safety data, doses higher than 
200 mg may be studied until MTD is reached, and further details will be provided in a subsequent protocol amendment at such time.
b If Part 1 is open upon the decision to initiate Part 2, treatment in the 2 parts will occur in parallel. If supported by clinical and safety data, doses higher than 
100 mg may be studied until MTD equivalent is reached in participants, and further details will be provided in a subsequent protocol amendment at such time.
c If Part 1B is open upon the decision to initiate Part 2C and Part 2D, treatment in the 2 parts will occur in parallel. If supported by clinical and safety data, doses 
higher than 200 mg BMS-986218 may be studied until MTD is reached, and further details will be provided in a subsequent protocol amendment at such time.
d Tumor-specific eligibility criteria are detailed in Section 6.
e Additional participants may be treated or randomized to further evaluate emerging data or subgroups of interest if needed but not to exceed 40 participants per 
dose level in Part 2A and Part 2B.
f Participants will be randomized, which will include ipilimumab monotherapy and BMS-986218 at different dose levels.
g
Participants will be treated or randomized.
h Dose(s) of BMS-986218 selected for Part 2C and Part 2D will be based on the totality of preliminary safety, tolerability, efficacy, PK and PD data.
i The nivolumab dose found to be tolerable in Part1B will be used in Part 2 combination expansions (Part 2C and Part 2D)
Protocol Amendment No.: 07
Date: 29-Jul-2021
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1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Abbreviations: CTLA = cytotoxic T-lymphocyte-associated protein 4; DLT = dose-limiting toxicity; mCRPC = metastatic castration-resistant prostate cancer; MSS 
CRC = microsatellite stable colorectal cancer; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer ; PD = pharmacodynamic; PD-L1 = 
programmed death-ligand 1; Q2W = every 2 weeks; Q3W = every 3 weeks; Q4W = every 4 weeks; R = randomized; SCCHN = squamous cell carcinoma of the 
head and neck; TNBC = triple-negative breast cancer.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Screening: The screening period will be up to 28 days and begins by establishing the participant’s initial eligibility 
and signing of the informed consent form (ICF). Within a given disease type, participants meeting all eligibility criteria 
will be enrolled in the study using an Interactive Response Technology (IRT) according to the part and treatment arm 
availability.
Treatment: The dosing regimens of BMS-986218 are Q4W and Q2W. Participants will be treated with BMS-986218 
Q4W ± nivolumab Q4W for up to 2 calendar years, BMS-986218 Q2W for up to 2 calendar years, and/or ipilimumab 
Q3W for up to a maximum of 4 doses. Each cycle of the treatment period will be 4 weeks in length, with the exception 
of the treatment arms with Q3W dosing of ipilimumab in the Randomized BMS-986218 Monotherapy Cohort
Expansion in Cutaneous Melanoma (Part 2A), for which each cycle of ipilimumab will be 3 weeks in length.
•
BMS-986218 will be infused over 30 minutes during BMS-986218 Monotherapy Dose Escalation (Part 1A),. 
Ipilimumab and nivolumab will be infused over 30 minutes. 
•
When both BMS-986218 and nivolumab are given in combination, nivolumab will be infused first, followed by 
BMS-986218. The BMS-986218 infusion will start at least 30 minutes after completion of the nivolumab 
infusion.
•
BMS-986218 infusions will require a 60-minute observation period following the completion of the infusion for 
the first 3 doses for each participant. 
•
For participants receiving combination doses of BMS-986218 with nivolumab, a 30-minute infusion of nivolumab 
will be followed by a 30-minute observation period, followed by a 30-minute infusion of BMS-986218 and a 
60-minute observation period following the first 3 infusions for each participant.
•
Ipilimumab infusions will require a 30-minute observation period following the completion of the infusion for 
the first 3 doses for each participant.
•
Tumor progression and response endpoints will be assessed using RECIST v1.1 criteria for solid tumors and 
PCWG 3 criteria for prostate.
Follow-up: 
•
Safety Follow-up Period:
−
Upon completion of study therapy (up to a maximum of 2 calendar years for BMS-986218 Q4W ± nivolumab 
Q4W; up to a maximum of 2 calendar years for BMS-986218 Q2W; up to a maximum of 4 doses for 
ipilimumab Q3W), or once the decision is made to discontinue the participant from treatment (ie, 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 visit as the last 
scheduled and completed on-treatment visit, and will be the start of the safety follow-up period. For 
participants who do not complete all scheduled cycles of therapy, the EOT visit will be the most recent 
on-treatment visit (with all available safety and response data), and will not need to be repeated. Accordingly, 
for these participants, this visit will be considered the start of the safety follow-up period.
−
After the EOT visit, all participants will be evaluated for any new AEs for at least 100 days after the last dose 
of study treatment. Follow-up visits should occur at Days 30, 60, and 100 (± 7 days for each visit) after the 
last dose, or the date of discontinuation (± 7 days). All participants will be required to complete the 3 clinical 
safety follow-up visits, regardless of whether new anti-cancer therapy is started, except those participants 
who withdraw consent for study participation.
•
Response Follow-up Period:
−
At the time of the EOT visit or at the time of study treatment discontinuation, all participants will continue 
to have radiologic and clinical tumor assessments every 8 weeks (Q8W; ± 1 week) until subsequent 
tumor-directed therapy is initiated, or until 48 weeks after discontinuation of study treatment/EOT visit, and 
then every 12 weeks (Q12W; ± 2 weeks) for a total of 2 years. Radiologic assessments for participants who 
have ongoing clinical benefit and remain free of subsequent therapy may continue to be collected after 
participants complete the survival follow-up period of the study. Scans will be submitted to an imaging core 
laboratory for review by blinded independent central review (BICR) at a later date or at any time during the 
study at the Sponsor’s discretion.
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anti-CTLA4-NF mAb
•
Survival Follow-up Period:
−
In parallel with the safety follow-up period, all participants will start the survival follow-up period. 
Participants will be followed up by telephone Q12W (± 2 weeks) from EOT for up to 4 years following the 
first dose of study treatment or until death, loss to follow-up, withdrawal of consent, or conclusion of the 
study, whichever comes first. EQ-5D-3L data can be collected by telephone during the Survival Follow-up 
Period. The duration of the survival follow-up is up to 4 years following the first dose of study treatment. 
Additional survival follow-up time may continue for up to 5 years from the first dose of the study drug. 
Tumor assessment scans, for participants who have ongoing clinical benefit beyond the 4-year period 
following first dose of study treatment, may continue to be collected as part of standard-of-care treatment.
Number of Participants: 
The approximate total number of evaluable participants will be up to 684. Up to approximately 284 evaluable 
participants may be treated in the escalation phase, with 200 evaluable participants for the BMS-986218 Monotherapy 
Escalation (Part 1A) and 84 evaluable participants for the Safety Evaluation of Combination Doses of BMS-986218 
with Nivolumab (Part 1B). 
Approximately 20 evaluable participants will be treated in the Part 1A pharmacodynamic (PD) cohorts. In addition, 
in order to evaluate more than one dose level or schedule, up to 40 additional  evaluable participants may be treated 
in the Part 1A PD cohorts (from participants initially planned for other Part 1 cohorts), provided the total number of 
participants in Part 1 is not exceeded.
The remaining 400 evaluable participants represent the potential number of participants in BMS-986218 cohort 
expansions who may be either randomized (Part 2A and Part 2B) or treated (Part 2C and Part 2D). For the Randomized 
BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A), approximately 132 evaluable 
participants may be treated, with 33 participants per arm required. For the BMS-986218 Monotherapy Cohort 
Expansion (Part 2B), approximately 66 evaluable participants with NSCLC may be treated, with 22 evaluable
participants per arm required. In Part 2A and Part 2B, additional participants may be treated or randomized to further 
evaluate emerging data or subgroups of interest if needed, but not to exceed a total of 40 evaluable participants per 
arm. If additional participants are treated or randomized in Part 2A and Part 2B, then up to 160 response-evaluable
participants (= 40 subjects × 4 arms) and 120 response-evaluable participants (= 40 subjects × 3 arms) can be 
randomized in Part 2A and Part 2B, respectively. For the BMS-986218 Combination Therapy Cohort Expansion in 
NSCLC (Part 2C), approximately 40 response-evaluable participants will be treated. If more than one dose level is 
evaluated, additional participants (up to 40 response-evaluable participants per dose level) may be enrolled, up to 80 
response-evaluable participants (= 40  participants × 2 arms). In Part 2D BMS-986218 Combination Therapy Cohort 
Expansion in MSS CRC, approximately 40 response-evaluable participants will be treated, with the goal of treating 
approximately 20 participants each with either mutation or wild-type with respect to extended RAS status.
Study Treatment: 
Table 1-2:
Study Treatment for CA022001
Medication 
Potency 
IP/Non-IP 
BMS-986218 Injection
20 mg/mL
IP
Nivolumab Injection
10 mg/mL
IP
Ipilimumab Injection
5 mg/mL
IP
Abbreviations: IP = investigational product.
Part 1: Escalation Phase:
BMS-986218 Monotherapy Escalation (Part 1A), each participant will be administered intravenous doses of 
BMS-986218 as follows:
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anti-CTLA4-NF mAb
•
The planned flat dose levels for BMS-986218 are 2, 4, 7, 20, 40, 70, 100, 150, and 200 mg Q4W (up to 
approximately 108 DLT-evaluable participants) or 10, 20, 35, 50, 75, and 100 mg Q2W (up to approximately 72
DLT-evaluable participants) per cycle, for up to 2 calendar years. The Q2W dosing schedule will start at a total 
dose level equivalent to a dose that has cleared safety in the Q4W dosing cohort (eg, 10 mg Q2W vs 20 mg Q4W), 
and continue evaluating higher doses up to the MTD equivalent of the Q4W dosing cohort. If supported by clinical 
and safety data, doses higher than 200 mg Q4W may be studied, and will be guided by Q4W equivalent doses 
that have cleared safety until the MTD equivalent of the Q4W dosing cohort is reached. 
•
Additionally, participants with advanced stage cutaneous melanoma, MSS CRC, NSCLC, or SCCHN will be 
treated with BMS-986218 on a Q2W schedule at a starting dose of 20 mg in the Part 1A PD cohort. Based on 
preliminary analysis of Treg count decrease in the tumor microenvironment, using single-cell ribonucleic acid 
(RNA) sequencing gene expression analysis, additional cohorts of participants at higher dose levels may be 
evaluated. For example, if the expected PD activity is not observed after 5 to 10 evaluable participants at the 20
mg dose level, then the next set of 5 to 10 evaluable participants may be enrolled at a higher dose level or Q4W 
schedule. Therefore, more than one dose level may be evaluated based on the pharmacodynamic results 
assessment. Any additional dose levels evaluated in the Q2W schedule of the Part 1A PD cohort will be a dose 
that has been determined to be safe and tolerable in either the Q2W escalation part or a dose equivalent to Q4W 
dose, which has been determined to be safe and tolerable in the Q4W dose escalation part. Approximately 20 
evaluable participants per dose level (per dose schedule) may be treated as part of the PD cohort.
•
Prior to declaring the MTD, and in consultation with Investigators, the Sponsor has the option to expand any dose 
level previously established to be tolerable in order to obtain additional experience or to investigate dose levels 
intermediate to those defined in the protocol. Planned dose levels may be modified, or intermediate dose levels 
added, based upon the BLRM analysis and clinical evaluation of all available safety and PK/pharmacodynamic 
data. Once the tolerability (during the DLT evaluation) of a dose level has been established, additional participants 
may be added at that dose level to better characterize the safety, PK, and pharmacodynamic profiles, for up to 
approximately 200 participants for study Part 1A.
•
Sentinel Participant: During the dose-escalation phase, a staggered dosing (sentinel participant) approach will 
be used. The first participant to be dosed at Cycle 1 Day 1 of each dose level will be observed for 5 days, before 
additional participants (ie, Participant 2 onward in that cohort) receive study treatments in the same dose level. 
Initially, 3 participants will be enrolled at the start of each cohort, in accordance with the sentinel participant 
approach cited above. However, to allow for any unforeseen discontinuations (such as disease progression) before 
the 8-week DLT period (56 days) is completed, extra participants may be enrolled in each dose escalation cohort. 
The Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab (Part 1B): This will be initiated 
starting at 1 dose level below current safety cleared Q4W monotherapy cohort, defined from BLRM and an overall 
assessment of all available safety, PK/pharmacodynamic, and efficacy data of the BMS-986218 Monotherapy 
Escalation (Part 1A). 
•
The starting dose of BMS-986218 was 1 dose level lower than the Q4W 40 mg monotherapy dose level of 
BMS-986218, which had demonstrated an acceptable safety profile and was administered in combination with 
nivolumab at the flat dose of 480 mg Q4W. Dose escalation and determination of MTD for the Safety Evaluation 
of Combination Doses of BMS-986218 with Nivolumab (Part 1B) will be guided by BLRM-copula. Subsequent 
dose selection of the combination will be based on evaluating the recommendation from BLRM-copula and an 
overall assessment of all available safety and PK/pharmacodynamic data. Safety evaluation and tumor assessment 
will be performed Q8W (2 cycles). If toxicity is unacceptable at any combination dose level, additional 
combination dose level(s) may be evaluated using BMS-986218 and/or nivolumab (eg, dose of 240 mg Q4W). 
Selection of dose level for each study drug will be based on the nature and attribution of observed DLTs in 
previously evaluated dose levels. An intermediate dose level of BMS-986218 and/or an intermediate dose level 
of nivolumab Q4W may be evaluated in additional cohort(s). No intra-subject dose escalation or de-escalation of 
BMS-986218 or nivolumab is allowed at any dose level.
•
Up to approximately 84 evaluable participants will be enrolled in Part 1B.
•
Sentinel Participant: The sentinel participant rule will be followed. The first participant to be dosed at Cycle 1 
Day 1 of each dose level will be observed for 5 days, before additional participants (ie, Participant 2 onward in 
that cohort) receive study treatments at the same dose level. Initially, 3 participants will be enrolled at the start of 
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BMS-986218
anti-CTLA4-NF mAb
each cohort, in accordance with the sentinel participant approach cited above; however, to allow for any 
unforeseen discontinuations (eg, disease progression) before the 8-week DLT period (56 days) is completed, extra 
participants may be enrolled in each dose cohort.
Dose Limiting Toxicities: For the purpose of guiding dose escalation, DLTs will be defined based on the incidence, 
intensity, and duration of AEs that are possibly related to study treatment. The DLT period will be 8 weeks (56 days) 
in both the BMS-986218 Monotherapy Dose Escalation (Part 1A) and the Safety Evaluation of Combination Doses 
of BMS-986218 with Nivolumab (Part 1B). Any toxicities that occur beyond the DLT period will be accounted for in 
making final dose level decisions.
Part 2: Expansion Phase
BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A)
•
Part 2A will evaluate the preliminary efficacy of BMS-986218 monotherapy relative to ipilimumab monotherapy 
in a cohort of participants with advanced cutaneous melanoma who have received prior immunotherapy with an 
anti-PD-1 or anti-PD-L1 containing regimen and must have progressive or recurrent disease after prior 
anti-PD-1/PD-L1 directed therapy. Participants must not have received prior anti-CTLA-4 therapy in the 
advanced or metastatic setting. Three dose levels or schedules for BMS-986218 from the Part 1A Q4W 
monotherapy escalation will be evaluated that have had at least 6 DLT evaluable participants and meet safety 
criteria: one at 7 mg Q4W, one at 20 mg Q4W, and one at 70 mg Q4W. Evaluating a number of different doses 
will aid in selecting the regimen that will ultimately provide the optimal benefit-risk ratio to future study 
participants.
BMS-986218 Cohort Expansion - Monotherapy (Part 2B)
•
In Part 2B, the preliminary efficacy of BMS-986218 will be investigated in tumor types where ipilimumab did 
not demonstrate a sufficient level of efficacy in previous studies and tumors in which a high level of Treg 
infiltration correlates with a poor prognosis. The tumor types to be evaluated will include NSCLC 
(adenocarcinoma or squamous cell subtypes only; at least 22 participants required per study arm); other tumor 
types may be explored in the future. Participants should have received and then progressed on or 
relapsed/recurrence after anti-PD-1/PD-L1 directed therapy in monotherapy or in combination with 
chemotherapy. Prior anti-CTLA-4 therapy is allowed for no more than 20% of participants. Three dose levels or 
schedules for BMS-986218 from the Part 1A Q4W monotherapy escalation will be evaluated that have had at 
least 6 DLT evaluable participants and meet safety criteria: one at 7 mg Q4W, one at 20 mg Q4W, and one at 70 
mg Q4W. The rationale for evaluating multiple dose levels is to optimize the benefit-risk ratio for the participant. 
BMS-986218 will be administered for a maximum duration of 2 calendar years regardless of treatment delays.
BMS-986218 Cohort Expansion - Combination Therapy in NSCLC (Part 2C)
In the BMS-986218 Combination Therapy Cohort Expansion (Part 2C), the preliminary efficacy and safety of
BMS-986218 in combination with nivolumab will be investigated in participants whose NSCLC has progressed or 
relapsed after anti-PD-1/PD-L1 therapy. Participants must not have received prior anti-CTLA-4 therapy in the 
advanced or metastatic setting. Any selected BMS-986218 Part 2C dose will not exceed the highest Part 1B 
administered dose that has cleared safety, with a minimum of 6 evaluable participants for Safety Evaluation. More 
than one dose may be evaluated in Part 2C. The dose(s) of BMS-986218 selected for Part 2C will be based on the 
totality of available safety, PK, and pharmacodynamic data from Part 1 and Part 2. The nivolumab dose found to be 
tolerable in Part 1B will be used in Part 2C. In Part 2C, participants will be treated Q4W for a maximum duration of 
2 calendar years regardless of treatment delays.
BMS-986218 Cohort Expansion - Combination Therapy in MSS CRC (Part 2D)
In the BMS-986218 Combination Therapy Cohort Expansion (Part 2D), the preliminary efficacy and safety of 
BMS-986218 in combination with nivolumab will be investigated in participants with MSS CRC who have progressed
or relapsed on at least 1 prior standard therapy. Participants must not have received prior anti-CTLA-4 therapy in the 
advanced or metastatic setting. The selected BMS-986218 Part 2D dose will not exceed the highest Part 1B 
administered dose that has cleared safety, with a minimum of 6 evaluable participants for Safety Evaluation. The 
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anti-CTLA4-NF mAb
dose(s) of BMS-986218 selected for Part 2D will be based on the totality of available safety, PK, and 
pharmacodynamic data from Part 1 and Part 2. The nivolumab dose found to be tolerable in Part 1B will be used in 
Part 2D. In Part 2D, participants will be treated Q4W for a maximum duration of  2 calendar years regardless of 
treatment delays. 
Study Assessments:
•
Safety Assessments: Safety assessments will be based on reported AE reports and the measurement results of 
vital signs, electrocardiograms, physical examinations, and clinical laboratory tests. AEs will be coded using the 
most current version of Medical Dictionary for Regulatory Activities (MedDRA) and the incidence of observed 
AEs will be tabulated and reviewed for potential significance and clinical importance. AEs will be assessed 
continuously during the study and for 100 days after the last dose of BMS-986218 in the case of monotherapy, 
and the last dose of BMS-986218 and nivolumab for combination therapy. Local laboratories will perform the 
clinical laboratory tests and will provide reference ranges for these tests. Both AEs and laboratory tests will be 
graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. 
•
PK Assessments: The PK of BMS-986218 will be derived from serum concentration vs time data. The PK 
parameters that will be assessed include: maximum observed plasma concentration (Cmax), time of maximum 
observed serum concentration, area under the serum concentration-time curve (AUC) from time zero to the time 
of the last quantifiable concentration, AUC in 1 dosing interval, observed serum trough concentration at the end 
of a dosing interval, total body clearance, average serum concentration over a dosing interval at steady state, 
accumulation index for AUC and Cmax, and terminal elimination half-life. Individual participant PK parameter 
values will be derived by noncompartmental methods by a validated PK analysis program. Actual times will be 
used for the final analyses. Sparse ipilimumab and nivolumab serum concentration-time data will be collected 
and may be used in an integrated population PK or exposure-response analysis along with data from other 
ipilimumab and nivolumab studies, which would be the subject of a separate report.
•
Immunogenicity Assessments: Serum samples for BMS-986218, ipilimumab, and nivolumab anti-drug 
antibodies (ADAs) will be collected from all participants at specified timepoints.
•
Efficacy Assessments:
−
Efficacy assessments for the anti-tumor activity of BMS-986218, alone and in combination with nivolumab, 
will be based on tumor measurements, using RECIST v1.1 or per PCWG 3 criteria for prostate, with 
computed tomography and/or magnetic resonance imaging, as appropriate, at baseline and Q8W (± 1 week) 
for the Q4W and Q2W dosing regimens during the treatment period, except the Randomized BMS-986218 
Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A), where tumor assessment in participants 
receiving BMS-986218 or ipilimumab will occur at 12 weeks from first dose (± 1 week), prior to initiating 
the next cycle of treatment. After that, subsequent tumor imaging assessments to be performed Q8W (± 1 
week). Tumor imaging assessments are to be performed prior to initiating next cycle of treatment. 
−
Efficacy assessments for the anti-tumor activity of ipilimumab are to be performed 12 weeks from first dose, 
regardless of dose delays, if any (± 1 week). Tumor imaging assessments are to be performed prior to 
initiating next cycle of treatment. Participants who remain free of subsequent therapy will undergo the second 
tumor imaging assessment at 24 weeks from first dose ± 1 week. After that, participants who remain free of 
subsequent therapy will undergo tumor imaging assessment Q8W (± 1 week) until subsequent tumor-directed 
therapy is initiated or until 48 weeks after discontinuation of study treatment/EOT visit, and then Q12W (±
2 weeks) for a total duration of 2 years. 
−
Images will be submitted to an imaging core lab. Image acquisition guidelines and submission process will 
be outlined in the CA022001 Imaging Manual to be provided by the core laboratory.
Data Monitoring Committee: No.
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 Worldwide Patient Safety (WWPS)-led Safety Management Team 
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anti-CTLA4-NF mAb
(SMT). This collaborative process constitutes the safety monitoring plan for the study. To support safety oversight, 
BMS has established ongoing processes for collection, review, analysis, and submission of individual AE reports and 
their aggregate analyses. Because this is an open-label study, WWPS, the BMS Medical Monitor, and the Investigators 
will have access to all data necessary for safety evaluation.
BMS WWPS is an internal group that operates independently from the clinical team to monitor safety across all BMS 
protocols, and analyze all data in an unblinded fashion. Within BMS, an SMT is established for investigational 
therapies under clinical development, and a member of WWPS chairs this team. In addition, signal detection is 
performed at least monthly and ad hoc throughout the study by the SMT composed, at a minimum, of the WWPS
medical safety assessment physician (Chair of the SMT) and WWPS single case review physician, the Clinical 
Development Lead, the study biostatistician, and epidemiologist; all of whom, analyze the data in an unblinded 
fashion. Furthermore, the SMT routinely monitors for actual or potential issues related to participant safety that could 
result in a change in the medical benefit-risk balance associated with the use of study treatment(s).
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BMS-986218
anti-CTLA4-NF mAb
2
SCHEDULE OF ACTIVITIES
Study assessments and procedures are shown in Table 2-1, Table 2-2, Table 2-3, Table 2-4, and 
Table 2-5.
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Table 2-1:
Screening Schedule of Activities for All Study Parts
Procedure
Screening Visit
(Days -28 to -1)
Notes
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol-specific ICF is signed.
IRT Participant Assignment
X
After the participants meet all eligibility criteria, sites will use IRT for participant number 
assignment. Subsequent visits will be registered into the IRT system for drug supply (see 
Section 5.1.1).
Inclusion/Exclusion Criteria
X
See Section 6.1 and Section 6.2.
Medical History
X
Include any toxicities or allergy related to previous treatments and tumor characteristics 
(eg, mutation status, receptor status, viral status, if available). All medical history relevant to the 
disease under study, and COVID-19 vaccines more than 30 days prior to first study treatment.
Prior Cancer Therapies
X
Concomitant Medications
X
Within 14 days prior to randomization/treatment assignment. Vaccine use within 30 days prior to 
first study treatment.
ECOG Performance Status 
X
Safety Assessments
PE
X
If the screening PE is performed within 72 hours prior to dosing on Day 1, then a single examination 
may count as both the screening and predose evaluation on C1D1.
Physical Measurements
X
Includes height and weight.
Vital Signs
X
Includes body temperature, respiratory rate, and seated/supine blood pressure and heart rate. Blood 
pressure and heart rate should be measured after the participant has been resting quietly for at least 
5 minutes.
Oxygen Saturation
X
Pulse oximetry collected at rest.
ECG
X
ECGs should be recorded after the participant has been supine for at least 5 minutes and prior to 
blood draws. Screening ECG is to be collected as a single reading (see Section 9.1.3).
Laboratory Tests
X
See Clinical Laboratory Assessments in Section 9.1.4 and Table 9.1.4-1. There will be a 
minus-72-hour window from C1D1 during screening for the collection of laboratory tests.
Urinalysis 
X
Microscopic urine reflex only for urinalysis positive for blood/protein/leukocytes.
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Table 2-1:
Screening Schedule of Activities for All Study Parts
Procedure
Screening Visit
(Days -28 to -1)
Notes
Serology
X
Includes hepatitis C Ab, hepatitis B surface antigen, and HIV-1 and HIV-2 Ab (see Section 9.1.4 and 
Table 9.1.4-1).
Pregnancy Test
X
For WOCBP only. Serum to be collected at screening and within 24 hours prior to dosing on Day 1 
of each treatment cycle. Serum pregnancy test may be taken on the first day of treatment, provided 
results are available prior to starting study therapy. If pregnancy test is taken within 24 hours of 
dosing (C1D1), a further pregnancy test is not required.
FSH
X
Women only, as needed to document postmenopausal status.
Adverse Event Reporting
Assessment of Signs/Symptoms/
Clinical Complaints
X
Monitor for SAEs
X
All SAEs must be collected from the date of participant’s written consent until 100 days after 
discontinuation of dosing.
All AEs (SAEs or nonserious AEs) associated with SARS-CoV-2 infection collected from time of 
consent.
Tumor Assessments
Body Imaging
X
Refer to Imaging Assessment details in Section 9.3.1. CT and MRI scans should be acquired with a 
slice thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should be made 
to image each participant using an identical acquisition protocol on the same scanner for all imaging 
timepoints. 
Brain Imaging
X
MRI without and with contrast of the brain required at screening only if participant is symptomatic 
or has history of brain metastasis and has not had brain imaging within 30 days of anticipated first 
study drug administration. CT of the brain without and with contrast may be performed if MRI is 
contraindicated. Refer to Imaging Assessment details in Section 9.3.1. CT and MRI scans should be 
acquired with a slice thickness of 5 mm or less with no intervening gap (contiguous). Every attempt 
should be made to image each participant using an identical acquisition protocol on the same scanner 
for all imaging timepoints. 
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Table 2-1:
Screening Schedule of Activities for All Study Parts
Procedure
Screening Visit
(Days -28 to -1)
Notes
Bone Scan
X
Required for participants with prostate cancer for evaluation of bone disease; otherwise, as clinically 
indicated. Refer to Imaging Assessment details in Section 9.3.1. Every attempt should be made to 
image each participant using an identical acquisition protocol on the same scanner for all imaging 
timepoints.
Clinical Treatment Supplies
Dispense Study Treatment
X
Study treatments (BMS-986218, ipilimumab, and nivolumab) to be supplied by BMS and in 
assigned vials per IRT (see Section 5.1.1, Table 2-2, Table 2-3, and Table 2-4).
Abbreviations:  Ab = antibody; AE = adverse event; BMS = Bristol-Myers Squibb; C1D1 = Cycle 1 Day 1; CT = computed tomography; 
 ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FSH = follicle stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus; ICF = informed consent form; IRT = Interactive Response Technology; MRI = magnetic resonance imaging; 
 PE = physical examination; RNA = ribonucleic acid; SAE = serious adverse events; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 2; WOCBP = women of childbearing potential.
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Table 2-2:
On-Treatment - Schedule of Activities for Q4W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A), Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B), Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), and Combination 
Cohort Expansions (Part 2C and Part 2D)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1
Safety Assessments
ECOG Performance 
Status
X
X
X
X
PE
X
X
X
X
Symptom Directed PE
X
X
X
X
X
X
Weight
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
For BMS-986218, vital signs will be 
obtained within 30 minutes before the 
start of the infusion and then every 
15 minutes (± 5 minutes) from the start 
of the infusion until 60 minutes after 
completion of the infusion for the first 
3 doses of study treatment on C1D1, 
C2D1, and C3D1. For all cycles after 
cycle 3, vital signs and oxygen saturation 
are to be taken before the infusion and at 
the end of each infusion.
For nivolumab, vital signs will be 
obtained within 30 minutes before the 
start of the infusion and then every 
30 minutes (± 5 minutes) from the start 
Protocol Amendment No.: 07
Date: 29-Jul-2021
35
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-2:
On-Treatment - Schedule of Activities for Q4W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A), Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B), Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), and Combination 
Cohort Expansions (Part 2C and Part 2D)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1
of the infusion until completion of the 
infusion. 
If any vital sign is abnormal (based upon 
clinician assessment) at the final check, 
the participant must be observed further 
for a period of time, as clinically 
indicated.
Oxygen Saturation
X
X
X
Oxygen saturation to also be performed 
in conjunction with vital signs 
monitoring on these days. For all cycles 
after Cycle 3, vital signs and oxygen 
saturation are to be taken before the 
infusion and at the end of each infusion. 
ECG
X
X
X
X
ECGs should be recorded after the 
participant has been supine for at least 
5 minutes and prior to blood draws. 
ECGs to be performed in triplicate in 
association with PK sampling, at predose 
and EOI, on Day 1 of both Cycle 1 and 
Cycle 3 for Part 1A only (see 
Section 9.1.3). Single safety ECGs to be 
performed for all other time points.
Protocol Amendment No.: 07
Date: 29-Jul-2021
36
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-2:
On-Treatment - Schedule of Activities for Q4W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A), Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B), Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), and Combination 
Cohort Expansions (Part 2C and Part 2D)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1
Beyond Cycle 3, ECGs must be 
performed every 3 cycles up to EOT.
Laboratory Tests
X
X
X
X
X
X
X
X
X
X
There will be a minus-72-hour window 
for collection of laboratory tests on 
Day 1 of each cycle and a window of 
± 2 days for all other timepoints. 
Coagulation assessment at screening 
only. See Section 9.1.4 and 
Table 9.1.4-1.
Urinalysis 
X
X
As clinically 
indicated; 
microscopic 
urine reflex 
only for 
urinalysis 
positive for 
blood/protein/
leukocyte 
esterase
X
Protocol Amendment No.: 07
Date: 29-Jul-2021
37
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-2:
On-Treatment - Schedule of Activities for Q4W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A), Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B), Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), and Combination 
Cohort Expansions (Part 2C and Part 2D)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1
Pregnancy Test 
(WOCBP only)
X
X
X
X
Serum/urine to be collected within 24 
hours prior to dosing. Pregnancy test may 
be completed on the first day of 
treatment, provided that the results are 
available before the start of study 
therapy. Serum or urine pregnancy test 
must be performed within 24 hours prior 
to administration of study treatment 
(urine pregnancy test:  minimum 
sensitivity 25 IU/L or equivalent units of 
hCG).
Adverse Event Reporting and Concomitant Medication Assessments
Monitor for Non-SAEs
Non-SAEs will be collected starting with the first dose of study medication and 
through 100 days following the last dose of study treatment.
Section 9.2 and Appendix 3.
All AEs (SAEs or nonserious AEs) 
including those associated with 
SARS-CoV-2 infection must be collected 
continuously during the treatment period.
Monitor for SAEs
All SAEs must be collected from the date of the participant’s written consent until 
100 days following the last dose of study treatment.
Section 9.2 and Appendix 3.
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
Protocol Amendment No.: 07
Date: 29-Jul-2021
38
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-2:
On-Treatment - Schedule of Activities for Q4W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A), Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B), Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), and Combination 
Cohort Expansions (Part 2C and Part 2D)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1
PK Assessments
Serial Blood Sampling
See Table 9.5-2 and Table 9.5-5 of the PK and immunogenicity sampling schedule and 
Section 9.5.
Immunogenicity (ADA) 
Assessments
See Table 9.5-2 and Table 9.5-5 of the PK and immunogenicity sampling schedule and 
Section 9.5.
Protocol Amendment No.: 07
Date: 29-Jul-2021
39
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-2:
On-Treatment - Schedule of Activities for Q4W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A), Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B), Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), and Combination 
Cohort Expansions (Part 2C and Part 2D)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1
Imaging Assessments
Body Imaging
Tumor imaging assessment to be performed Q8W from first dose (± 1 week), prior to 
initiating next cycle of treatment (for Part 1A, Part 1B, Part 2B, Part 2C, and Part 2D).
Tumor imaging assessment to be performed at 12 weeks from the first dose, regardless 
of dose delays, if any (± 1 week), prior to initiating the next cycle of treatment, for 
participants in the Randomized BMS-986218 Monotherapy Cohort Expansion in 
Cutaneous Melanoma (Part 2A). After that, subsequent tumor imaging assessments to 
be performed Q8W (± 1 week), prior to initiating the next cycle of treatment. 
Participants who remain free of subsequent therapy will undergo tumor imaging 
assessment Q8W (± 1 week) until subsequent tumor-directed therapy is initiated or 
until 48 weeks after discontinuation of study treatment/EOT visit, and then Q12W 
(± 2 weeks) for a total duration of 2 years. 
The same imaging modality is to be used 
for all assessments, per RECIST v1.1 
(Appendix 5) or per PCWG 3 criteria for 
prostate (Appendix 12). Tumor 
assessment to be performed prior to 
initiating next cycle of treatment. CT and 
MRI scans should be acquired with slice 
thickness of 5 mm or less with no 
intervening gap (contiguous). Every 
attempt should be made to image each 
participant using an identical acquisition 
protocol on the same scanner for all 
imaging timepoints. 
Brain Imaging
Participants with history of brain metastasis will have MRI performed as clinically 
indicated and at the discretion of the Investigator.
MRI without and with contrast of the 
brain should be performed. CT of the 
brain without and with contrast may be 
obtained if MRI is contraindicated. CT 
and MRI scans should be acquired with 
slice thickness of 5 mm or less with no 
intervening gap (contiguous). Every 
attempt should be made to image each 
participant using an identical acquisition 
protocol on the same scanner for all 
imaging timepoints.
Protocol Amendment No.: 07
Date: 29-Jul-2021
40
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-2:
On-Treatment - Schedule of Activities for Q4W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A), Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B), Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), and Combination 
Cohort Expansions (Part 2C and Part 2D)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1
Protocol Amendment No.: 07
Date: 29-Jul-2021
41
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-2:
On-Treatment - Schedule of Activities for Q4W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A), Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B), Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), and Combination 
Cohort Expansions (Part 2C and Part 2D)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1
Protocol Amendment No.: 07
Date: 29-Jul-2021
42
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-2:
On-Treatment - Schedule of Activities for Q4W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A), Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B), Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), and Combination 
Cohort Expansions (Part 2C and Part 2D)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1
Clinical Treatment Supplies
BMS-986218 
Administration
X
X
X
Study treatments, BMS-986218 and 
nivolumab, to be supplied by BMS; vials 
assigned by IRT must be used.
Nivolumab 
Administration (Part 
1B, 2C, and 2D only)
X
X
X
Abbreviations:  ADA = anti-drug antibody; AE = adverse event; BMS = Bristol-Myers Squibb; CXDY = Cycle X, Day Y, as an example; CT = computed 
tomography; D = day; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; 
 EOT = end of treatment; 
 hCG = human chorionic gonadotropin; 
IRT = Interactive Response Technology; MRI = magnetic resonance imaging; PCWG 3 = Prostate Cancer Working Group 3; PE = physical examination; 
PK = pharmacokinetic; Q8W = every 8 weeks; Q12W = every 12 weeks; 
 RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 
WOCBP = women of childbearing potential.
a EOT is defined as the visit where the decision is made to discontinue the participant from treatment. Evaluations will be performed prior to study discharge, or 
for participants who are prematurely discontinued.
b For participants who complete all scheduled cycles of therapy, the EOT visit will be the same as the last scheduled and completed on-treatment visit 
(eg, Cycle 3 Day 21) and the start of the Safety Follow-up period. For participants who do not complete all scheduled cycles of therapy, the EOT visit will be 
the most recent on treatment visit (with all available safety and response data); it does not need to be repeated and will be considered as the start of the Safety 
Follow-up period.
Protocol Amendment No.: 07
Date: 29-Jul-2021
43
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-3:
On-Treatment - Schedule of Activities for Q2W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in 
Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1 & D15
Safety Assessments
ECOG Performance 
Status
X
X
X
X
X
X
PE
X
X
X
X
X
X
Symptom Directed PE
X
X
X
X
Weight
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
For BMS-986218, vital signs will be 
obtained within 30 minutes before the start 
of the infusion and then every 15 minutes 
(± 5 minutes) from the start of the infusion 
until 60 minutes after completion of the 
infusion for the first 3 doses of study 
treatment on C1D1, C1D15, and C2D1. 
For all doses after C2D1, vital signs and 
oxygen saturation are to be taken before 
the infusion and at the end of infusion.
If any vital sign is abnormal (based upon 
clinician assessment) at the final check, the 
participant must be observed further for a 
period of time, as clinically indicated.
Protocol Amendment No.: 07
Date: 29-Jul-2021
44
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-3:
On-Treatment - Schedule of Activities for Q2W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in 
Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1 & D15
Oxygen Saturation
X
X
X
X
X
Oxygen saturation to also be performed in 
conjunction with vital signs monitoring on 
these days. For all infusions after C2D1, 
vital signs and oxygen saturation are to be 
taken before the infusion and at the end of 
each infusion. 
ECG
X
X
X
X
X
X
ECGs should be recorded after the 
participant has been supine for at least 
5 minutes and prior to blood draws. ECGs 
to be performed in triplicate in association 
with PK sampling, at predose and EOI, on 
Day 1 of both Cycle 1 and Cycle 3 for 
Part 1A only (see Section 9.1.3). Single 
safety ECGs to be performed for all other 
time points.
Beyond Cycle 3, ECGs must be performed 
every 3 cycles up to EOT.
Laboratory Tests
X
X
X
X
X
X
X
X
X
X
There will be a minus-72-hour window for 
collection of laboratory tests on Day 1 of 
each cycle and a window of ± 2 days for 
all other timepoints. Coagulation 
assessment at screening only. See 
Section 9.1.4 and Table 9.1.4-1.
Protocol Amendment No.: 07
Date: 29-Jul-2021
45
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-3:
On-Treatment - Schedule of Activities for Q2W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in 
Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1 & D15
Urinalysis 
X
X
X
X
As clinically 
indicated; 
microscopic 
urine reflex 
only for 
urinalysis 
positive for 
blood/protein/
leukocyte 
esterase
X
Pregnancy Test 
(WOCBP only)
X
X
X 
(Day 1 only)
X
Serum/urine for pregnancy test to be 
collected within 24 hours prior to dosing 
on Day 1 of each cycle. Pregnancy test 
may be completed on the first day of 
treatment, provided the results are 
available before the start of study therapy. 
Serum or urine pregnancy test must be 
performed within 24 hours prior to 
administration of study treatment on Day 1 
of each cycle (urine pregnancy test:  
minimum sensitivity 25 IU/L or equivalent 
units of hCG).
Protocol Amendment No.: 07
Date: 29-Jul-2021
46
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-3:
On-Treatment - Schedule of Activities for Q2W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in 
Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1 & D15
Adverse Event Reporting and Concomitant Medication Assessments
Monitor for Non-SAEs
Non-SAEs will be collected starting with the first dose of study medication and 
through 100 days following the last dose of study treatment.
Section 9.2 and Appendix 3.
All AEs (SAEs or nonserious AEs) 
including those associated with 
SARS-CoV-2 infection must be collected 
continuously during the treatment period. 
Monitor for SAEs
All SAEs must be collected from the date of the participant’s written consent until 
100 days following the last dose of study treatment.
Section 9.2 and Appendix 3.
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
PK Assessments
Serial Blood Sampling
See Table 9.5-3 of the PK and immunogenicity sampling schedule and Section 9.5.
Immunogenicity (ADA) 
Assessments
See Table 9.5-3 of the PK and immunogenicity sampling schedule and Section 9.5.
Protocol Amendment No.: 07
Date: 29-Jul-2021
47
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-3:
On-Treatment - Schedule of Activities for Q2W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in 
Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1 & D15
Imaging Assessments
Body Imaging
Tumor imaging assessment to be performed Q8W from the first dose (± 1 week), 
prior to initiating next cycle of treatment in Part 1A. Participants who remain free of 
subsequent therapy will undergo tumor imaging assessment Q8W (± 1 week) until 
subsequent tumor-directed therapy is initiated or until 48 weeks after discontinuation 
of study treatment/EOT visit, and then Q12W (± 2 weeks) for a total duration of 2 
years.
The same imaging modality is to be used 
for all assessments, per RECIST v1.1 
(Appendix 5) or per PCWG 3 criteria for 
prostate (Appendix 12). Tumor assessment 
to be performed prior to initiating next 
cycle of treatment. CT and MRI scans 
should be acquired with slice thickness of 
5 mm or less with no intervening gap 
(contiguous). Every attempt should be 
made to image each participant using an 
identical acquisition protocol on the same 
scanner for all imaging timepoints. 
Brain Imaging
Participants with history of brain metastasis will have MRI performed as clinically 
indicated and at the discretion of the Investigator.
MRI without and with contrast of the brain 
should be performed. CT of the brain 
without and with contrast may be obtained 
if MRI is contraindicated. CT and MRI 
scans should be acquired with slice 
thickness of 5 mm or less with no 
intervening gap (contiguous). Every 
attempt should be made to image each 
participant using an identical acquisition 
protocol on the same scanner for all 
imaging timepoints.
Protocol Amendment No.: 07
Date: 29-Jul-2021
48
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-3:
On-Treatment - Schedule of Activities for Q2W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in 
Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1 & D15
Protocol Amendment No.: 07
Date: 29-Jul-2021
49
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-3:
On-Treatment - Schedule of Activities for Q2W Dosing Schedules in BMS-986218 Monotherapy 
Escalation (Part 1A)
Procedure
Cycle 1 (28 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 (28 Days in Length) 
(Visit Window ± 2 Days)
Cycles 3 
and Beyond 
(Each Cycle 28 
Days in 
Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
DLT Period is Cycles 1 and 2
D1
D8
D15
D22
D1
D8
D15
D22
D1 & D15
Clinical Treatment Supplies
BMS-986218 
Administration
X
X
X
X
X
Study treatment, BMS-986218, to be 
supplied by BMS; vials assigned by IRT 
must be used.
Abbreviations:  ADA = anti-drug antibody; AE = adverse event; BMS = Bristol-Myers Squibb; CXDY = Cycle X Day Y, as an example; CT = computed 
tomography; D = day; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; 
hCG = human chorionic gonadotropin;
IRT = Interactive Response Technology; MRI = magnetic resonance imaging; 
PCWG 3 = Prostate Cancer Working Group 3; PE = physical examination; PK = pharmacokinetic; Q8W = every 8 weeks; Q12W = every 12 weeks; 
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anti-CTLA4-NF mAb
RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 
WOCBP = women of childbearing potential.
a EOT is defined as the visit where the decision is made to discontinue the participant from treatment. Evaluations will be performed prior to study discharge, or 
for participants who are prematurely discontinued.
b For participants who complete all scheduled cycles of therapy, the EOT visit will be the same as the last scheduled and completed on-treatment visit 
(eg, Cycle 3 Day 21) and the start of the Safety Follow-up Period. For participants who do not complete all scheduled cycles of therapy, the EOT visit will be 
the most recent on-treatment visit (with all available safety and response data); it does not need to be repeated and will be considered as the start of the Safety 
Follow-up Period.
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CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-4:
On-Treatment - Schedule of Activities for Q3W Dosing Schedule for Ipilimumab in the Randomized 
BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A)
Procedure
Cycle 1 
(21 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 
(21 Days in Length)
(Visit Window 
± 2 Days)
Cycle 3 and Cycle 4 
(21 Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
D1
D8
D15
D1
D8
D15
D1
D8
D15
Safety Assessments
ECOG Performance 
Status
X
X
X
X
PE
X
X
X
X
Symptom Directed 
PE
X
X
X
X
Weight
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
For ipilimumab, vital signs will be obtained 
within 30 minutes before the start of the 
infusion and then every 30 minutes 
(± 5 minutes) from the start of the infusion until 
completion of the infusion. 
If any vital sign is abnormal (based upon 
clinician assessment) at the final check, the 
participant must be observed further for a 
period, as clinically indicated.
Oxygen Saturation
X
X
X
ECG
X
X
X
X
ECGs should be recorded after the participant 
has been supine for at least 5 minutes and prior 
to blood draws. Single safety ECGs to be done 
prior to each infusion for all treatment cycles. 
ECGs must be performed on Day 1 of each 
cycle and at EOT.
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BMS-986218
anti-CTLA4-NF mAb
Table 2-4:
On-Treatment - Schedule of Activities for Q3W Dosing Schedule for Ipilimumab in the Randomized 
BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A)
Procedure
Cycle 1 
(21 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 
(21 Days in Length)
(Visit Window 
± 2 Days)
Cycle 3 and Cycle 4 
(21 Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
D1
D8
D15
D1
D8
D15
D1
D8
D15
Laboratory Tests
X
X
X
X
X
X
X
X
There will be a minus-72-hour window for 
collection of laboratory tests on Day 1 of each 
cycle and a window of ± 2 days window for all 
other timepoints. Coagulation assessments will 
be performed at screening only. See 
Section 9.1.4 and Table 9.1.4-1.
Urinalysis 
X
X
As clinically indicated; 
microscopic urine 
reflex only for 
urinalysis positive for 
blood/protein/leukocyte 
esterase.
X
Pregnancy Test 
(WOCBP only)
X
X
X
X
Serum/urine to be collected within 24 hours 
prior to dosing. Pregnancy test may be 
completed on the first day of treatment, 
provided the results are available before the start 
of study therapy. Serum or urine pregnancy test 
must be performed within 24 hours prior to 
administration of study treatment (urine 
pregnancy test:  minimum sensitivity 25 IU/L or 
equivalent units of hCG).
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BMS-986218
anti-CTLA4-NF mAb
Table 2-4:
On-Treatment - Schedule of Activities for Q3W Dosing Schedule for Ipilimumab in the Randomized 
BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A)
Procedure
Cycle 1 
(21 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 
(21 Days in Length)
(Visit Window 
± 2 Days)
Cycle 3 and Cycle 4 
(21 Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
D1
D8
D15
D1
D8
D15
D1
D8
D15
Adverse Event Reporting and Concomitant Medication Assessments
Monitor for 
Non-SAEs
Non-SAEs will be collected starting with the first dose of study medication and 
through 100 days following last dose of study treatment.
Section 9.2 and Appendix 3.
All AEs (SAEs or nonserious AEs) including 
those associated with SARS-CoV-2 infection 
must be collected continuously during the 
treatment period
Monitor for SAEs
All SAEs must be collected from the date of the participant’s written consent until 
100 days following the last dose of study treatment.
Section 9.2 and Appendix 3.
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
PK Assessments
Serial Blood 
Sampling
See Table 9.5-4 of the PK and immunogenicity sampling schedule and Section 9.5.
Immunogenicity 
(ADA) Assessments
See Table 9.5-4 of the PK and immunogenicity sampling schedule and Section 9.5.
Imaging Assessments
Body Imaging
Tumor imaging assessment to be performed at 12 weeks from the first dose, 
regardless of dose delays, if any (± 1 week). After that, subsequent tumor imaging 
assessments to be performed Q8W (± 1 week). Participants who remain free of 
subsequent therapy will undergo tumor imaging assessment Q8W (± 1 week) until 
subsequent tumor-directed therapy is initiated or until 48 weeks after discontinuation 
of study treatment/EOT visit, and then Q12W (± 2 weeks) for a total duration of 
2 years. 
The same imaging modality is to be used for all 
assessments, per RECIST v1.1 (Appendix 5). 
CT and MRI scans should be acquired with slice 
thickness of 5 mm or less with no intervening 
gap (contiguous). Every attempt should be made 
to image each participant using an identical 
acquisition protocol on the same scanner for all 
imaging timepoints.
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BMS-986218
anti-CTLA4-NF mAb
Table 2-4:
On-Treatment - Schedule of Activities for Q3W Dosing Schedule for Ipilimumab in the Randomized 
BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A)
Procedure
Cycle 1 
(21 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 
(21 Days in Length)
(Visit Window 
± 2 Days)
Cycle 3 and Cycle 4 
(21 Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
D1
D8
D15
D1
D8
D15
D1
D8
D15
Brain Imaging
Participants with history of brain metastasis will have MRI performed as clinically 
indicated and at the discretion of the Investigator.
MRI without and with contrast of the brain 
should be performed. CT of the brain without 
and with contrast may be obtained if MRI is 
contraindicated. CT and MRI scans should be 
acquired with slice thickness of 5 mm or less 
with no intervening gap (contiguous). Every 
attempt should be made to image each 
participant using an identical acquisition 
protocol on the same scanner for all imaging 
timepoints.
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CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-4:
On-Treatment - Schedule of Activities for Q3W Dosing Schedule for Ipilimumab in the Randomized 
BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A)
Procedure
Cycle 1 
(21 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 
(21 Days in Length)
(Visit Window 
± 2 Days)
Cycle 3 and Cycle 4 
(21 Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
D1
D8
D15
D1
D8
D15
D1
D8
D15
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CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-4:
On-Treatment - Schedule of Activities for Q3W Dosing Schedule for Ipilimumab in the Randomized 
BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A)
Procedure
Cycle 1 
(21 Days in Length)
(Visit Window ± 2 Days, 
except for C1D1)
Cycle 2 
(21 Days in Length)
(Visit Window 
± 2 Days)
Cycle 3 and Cycle 4 
(21 Days in Length)
(Visit Window 
± 2 Days)
EOTa,b
Notes
D1
D8
D15
D1
D8
D15
D1
D8
D15
Clinical Treatment Supplies
Ipilimumab 
Administration
X
X
C3 
and 
C4 
only
Ipilimumab to be administered for up to a 
maximum of 4 doses. Ipilimumab study 
treatment to be supplied by BMS; vials assigned 
by IRT must be used.
Abbreviations:  ADA = anti-drug antibody; AE = adverse event; BICR = blinded independent central review; C = cycle; CXDY = Cycle X Day Y, as an example; 
D = day; DLT = dose-limiting toxicity; ECG = electrocardiogram; 
 EOT = end of treatment; 
 hCG = human chorionic gonadotropin; 
IRT = Interactive Response Technology; MRI = magnetic resonance imaging; 
PCWG 3 = Prostate Cancer Working Group 3; PE = physical examination; PK = pharmacokinetic; 
 Q8W = every 8 weeks; Q12W = every 12 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
a EOT is defined as the visit where the decision is made to discontinue the participant from treatment. Evaluations will be performed prior to study discharge, or 
for participants who are prematurely discontinued.
b For participants who complete all scheduled cycles of therapy, the EOT visit will be the same as the last scheduled and completed on-treatment visit 
(eg, Cycle 4 Day 21) and the start of the Safety Follow-up Period. For participants who do not complete all scheduled cycles of therapy, the EOT visit will be 
the most recent on-treatment visit (with all available safety and response data); it does not need to be repeated and will be considered the start of the Safety 
Follow-up Period.
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BMS-986218
anti-CTLA4-NF mAb
Table 2-5:
Follow-up Procedural Outline for All Study Parts (CA022001)
Procedure
Safety Follow-up
Response 
Follow-up
Survival 
Follow-upb
Notes
Follow-up 1
30 Daysa
(± 7 Days) 
Follow-up 2
60 Days 
(± 7 Days)
Follow-up 3
100 Days 
(± 7 Days)
Safety Assessments
PE
X
X
X
Vital Signs
X
X
X
Includes body temperature, seated/supine blood 
pressure, and heart rate.
Laboratory Tests
X
X
X
Laboratory tests also as clinically indicated; See 
laboratory assessments in Section 9.1.4 and 
Table 9.1.4-1. 
Urinalysis
As clinically indicated (see Section 9.1.4).
Pregnancy Test
X
X
X
For WOCBP, serum/urine pregnancy test is to be 
performed (urine pregnancy test:  minimum sensitivity 
25 IU/L or equivalent units of hCG) (see Section 9.2.5).
For additional country-local requirements, refer to 
Appendix 8.
Adverse Event Reporting and Concomitant Medication Assessments
Monitor for 
Non-SAEs
X
X
X
Non-serious AEs will be collected starting with the first 
dose of study medication and through 100 days after 
discontinuation of dosing (Section 9.2 and Appendix 3).
Participants will be followed for all SAEs, and all AEs 
(SAEs and non-serious AEs) associated with confirmed 
or suspected SARS-CoV-2 infection until resolution, the 
condition stabilizes, the event is otherwise explained, 
the event is deemed irreversible, the participant is lost to 
follow-up (as defined in Section 8.3), or for suspected 
cases, until SARS-CoV-2 infection is ruled-out.
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CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-5:
Follow-up Procedural Outline for All Study Parts (CA022001)
Procedure
Safety Follow-up
Response 
Follow-up
Survival 
Follow-upb
Notes
Follow-up 1
30 Daysa
(± 7 Days) 
Follow-up 2
60 Days 
(± 7 Days)
Follow-up 3
100 Days 
(± 7 Days)
Monitor for SAEs
X
X
X
All SAEs must be collected from the date of the 
participant’s written consent until 100 days after 
discontinuation of dosing.
Participants will be followed for all SAEs, non-serious 
AEs of special interest (as defined in Section 9.2.3), and 
all AEs (SAEs and non-serious AEs) associated with 
confirmed or suspected SARS-CoV-2 infection until 
resolution, the condition stabilizes, the event is 
otherwise explained, the event is deemed irreversible, 
the participant is lost to follow-up (as defined in 
Section 8.3), or for suspected cases, until SARS-CoV-2 
infection is ruled-out.
Concomitant 
Medication 
Assessments
X
X
X
Sample Collection
PK Assessments
See Table 9.5-2, Table 9.5-3, Table 9.5-4, and Table 9.5-5 of the PK and immunogenicity sampling schedule and Section 9.5.
Immunogenicity 
(ADA) Assessments
See Table 9.5-2, Table 9.5-3, Table 9.5-4, and Table 9.5-5 of the PK and immunogenicity sampling schedule and Section 9.5.
Efficacy Assessments
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BMS-986218
anti-CTLA4-NF mAb
Table 2-5:
Follow-up Procedural Outline for All Study Parts (CA022001)
Procedure
Safety Follow-up
Response 
Follow-up
Survival 
Follow-upb
Notes
Follow-up 1
30 Daysa
(± 7 Days) 
Follow-up 2
60 Days 
(± 7 Days)
Follow-up 3
100 Days 
(± 7 Days)
Tumor/Response 
Assessments
X
At the time of the EOT visit or at the time of study 
treatment discontinuation, all participants will continue 
to have radiologic and clinical tumor assessments every 
Q8W (± 1 week) until subsequent tumor-directed 
therapy is initiated or until 48 weeks after 
discontinuation of study treatment/EOT visit, and then 
Q12W (± 2 weeks) for a total duration of 2 years.
Radiologic assessments for participants who have 
ongoing clinical benefit and remain free of subsequent 
therapy may continue to be collected after participants 
complete the Survival Follow-up Period of the study. 
Scans will be submitted to an imaging core laboratory 
for review by BICR at a later date, or at any time during 
the study at the Sponsor’s discretion. 
CT and MRI scans should be acquired with slice 
thickness of 5 mm or less with no intervening gap 
(contiguous). Every attempt should be made to image 
each participant using an identical acquisition protocol 
on the same scanner for all imaging timepoints.
Brain Imaging
X
As clinically indicated. CT and MRI scans should be 
acquired with slice thickness of 5 mm or less with no 
intervening gap (contiguous). Every attempt should be 
made to image each participant using an identical 
acquisition protocol on the same scanner for all imaging 
timepoints.
Bone Scan
X
Required for participants with prostate cancer for 
evaluation of bone disease; otherwise, as clinically 
indicated. Every attempt should be made to image each 
participant using an identical acquisition protocol on the 
same scanner for all imaging timepoints.
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CA022001
BMS-986218
anti-CTLA4-NF mAb
Table 2-5:
Follow-up Procedural Outline for All Study Parts (CA022001)
Procedure
Safety Follow-up
Response 
Follow-up
Survival 
Follow-upb
Notes
Follow-up 1
30 Daysa
(± 7 Days) 
Follow-up 2
60 Days 
(± 7 Days)
Follow-up 3
100 Days 
(± 7 Days)
Subsequent 
Treatments 
(Anti-cancer)
X
X
X
X
Assessment of 
Participant Survival 
Status
X
Participant status will be assessed by any documented 
clinic visit or telephone contact Q12W.
Abbreviations:  ADA = anti-drug antibody; AE = adverse event; BICR = blinded independent central review; CR = complete response; EOT = end of treatment; 
 EOT = end of treatment; 
 hCG = human chorionic gonadotropin; 
 PE = physical examination; PR = partial response; PK = pharmacokinetics; 
 Q8W = every 8 weeks; Q12W = every 12 weeks; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; SD = stable disease; WOCBP = women of child bearing potential. 
a Follow-up visits at Days 30 (± 7 days), 60 (± 7days), and 100 (± 7days) should occur relative to the last dose of study treatment or date of discontinuation, 
whichever is later.
b Survival Follow-up will be measured Q12W (± 2 weeks) for up to 4 years from the date of the first dose of study treatment. 
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BMS-986218
anti-CTLA4-NF mAb
In the event that multiple procedures are required at a single time point, the electrocardiogram 
(ECG) may be obtained up to 15 minutes earlier, vital signs may be obtained up to 10 minutes 
earlier or later, and clinical laboratory sample may be obtained up to 5 minutes earlier than the 
nominal timepoint, ensuring that the pharmacokinetics (PK) samples can be collected on time.
3
INTRODUCTION
This is a Phase 1/2a, first-in-human (FIH) study of BMS-986218, a non-fucosylated (NF) variant 
of the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody (mAb), 
alone and in combination with nivolumab (anti-programmed cell death 1 [PD-1]), in humans with 
advanced solid tumors.
3.1
Study Rationale
Anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab) are approved immunotherapies that define 
the field of checkpoint blockade. Ipilimumab is the first immunotherapy to show a survival 
advantage in late-stage metastatic melanoma and has also demonstrated a significant 25% 
reduction in risk of recurrence or death in the adjuvant treatment in melanoma. Blockade of 
CTLA-4 by ipilimumab has demonstrated anti-tumor activity in other malignancies, including 
lung, prostate cancer, and renal cell carcinoma (RCC). However, no significant activity was 
observed in bladder, colorectal, esophageal, pancreatic, gastric, hepatocellular, or breast cancer. 
Ipilimumab is also currently in clinical development in combination with nivolumab. The 
combination was associated with a greater benefit in melanoma compared to each single agent. 
Benefit with the combination has also been observed in non-small cell lung cancer (NSCLC) and 
RCC and is currently being evaluated in other tumor types. The activation of a pre-existing but 
attenuated immune response to cancer by checkpoint blockade is associated with an adverse event 
(AE) profile that is inherent to immune activation. Ipilimumab treatment-related AEs can involve 
multiple organ systems (digestive, skin, and endocrine) that require cessation of drug and treatment 
with steroids, which attenuate the AEs but do not maintain anti-tumor responses. The combination 
regimen is associated with an increased incidence of AEs compared to nivolumab monotherapy, 
but a similar overall AE profile. Developing a new anti-CTLA-4 antibody (Ab) with a more 
manageable AE profile and an increased depth and breadth of response would provide a significant 
improvement to anti-CTLA-4 therapy. 
BMS-986218 (CTLA-4.4g1fa-nf) is a human mAb against CTLA-4. The sequence is derived from 
the original hybridoma 10D1. The amino acid sequence is the same as that of ipilimumab but 
differs solely in its glycosylation pattern. The Ab is expressed in a fucosyltransferase-8 knockout 
Chinese hamster ovary cell line. Compared to ipilimumab, the glycans attached to the heavy chain 
Ab do not contain fucose. As a consequence, the NF Ab harbors a higher affinity for Fcγ receptors 
and improves antibody-dependent cellular cytotoxicity (ADCC) in addition to the CTLA-4 
blocking activity of ipilimumab. T-regulatory cells (Tregs) are highly infiltrating in tumors, where 
they play an important role in impairing anti-tumor immune response by dampening effector
cytolytic T-cell function. Tregs in tumors express higher levels of CTLA-4, and some studies have 
shown that part of the mechanism of action of ipilimumab is related to Treg depletion triggered by 
ADCC mediation once ipilimumab binds to CTLA-4-positive Tregs; however, this aspect is 
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CA022001
BMS-986218
anti-CTLA4-NF mAb
controversial and ipilimumab may not be a strong ADCC-mediating Ab. Pre-clinical studies with 
anti-CTLA-4-NF show enhanced ADCC compared to ipilimumab, correlating with more profound 
Treg depletion in the tumor (but not the periphery). Therefore, it is expected that anti-CTLA-4-NF 
will result in a more efficacious therapy by combining CTLA-4 blocking with the depletion of 
Tregs expressing CTLA-4.
Based on this differentiated mechanism of action, this study will evaluate the safety and 
preliminary efficacy of BMS-986218 alone and in combination with nivolumab in tumors where 
ipilimumab did not demonstrate sufficient clinical activity as referenced in Section 5.1.2.4. 
3.2
Background
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.1,2
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, such as CTLA-4, PD-1, or PD-L1 
inhibition. 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.3
Collectively, these signals govern the balance between T-cell activation and tolerance.
3.2.1
BMS-986218
BMS-986218 is a fully human immunoglobulin G1 (hIgG1) mAb against CTLA-4, an inhibitory 
receptor expressed on activated effector T cells and Tregs. BMS-986218 shares the same amino 
acid sequence and ligand blocking properties as ipilimumab but is produced in cells deficient for 
alpha-(1,6)-fucosyltransferase (Fut8), the enzyme that mediates fucosylation of the Ab 
carbohydrate side chain at N-linked glycopeptides. Therefore, BMS-986218 is an NF version of 
ipilimumab, which has increased affinity for the activating Fcγ receptor, cluster differentiation 
(CD) 16. Increasing the affinity of the Ab for CD16 increases the Ab-dependent cellular 
cytotoxicity of target expressing cells elicited by the Ab. This increase in effector function has 
been shown to mediate specific depletion of immune suppressive Tregs at the tumor site of mouse 
tumor models.4,5 Therefore, BMS-986218 may increase the anti-tumor immune response through 
2 distinct mechanisms of action:  the activation of effector CD4 and CD8 T cells by blocking the 
inhibitory function of CTLA-4, and the depletion of tumor infiltrating Tregs.
This study will evaluate the safety, tolerability, and preliminary efficacy of intravenous (IV) doses 
of BMS-986218, administered as monotherapy and in combination with nivolumab in participants 
with advanced solid tumors, and is expected to determine the maximum tolerated 
dose/recommended Phase 2 dose (MTD/RP2D) of BMS-986218 to be used in future studies as 
monotherapy or in combination with nivolumab.
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CA022001
BMS-986218
anti-CTLA4-NF mAb
As of the date of this protocol, the overall safety experience with BMS-986218 as either a 
monotherapy or in combination is under active investigation and currently emerging. BMS-986218 
monotherapy in Part 1A has been administered Q4W at doses of 2 mg, 4 mg, 7 mg, 20 mg, 40 mg, 
70 mg, 100 mg, and 150 mg. In addition, BMS-986218 has also been administered as monotherapy 
in Part 1A Q2W at 20 mg, 35 mg, and 50 mg. BMS-986218 has also been administered in 
combination with nivolumab at dose of 20 mg BMS-986218 + 480 mg nivolumab. The MTD of 
BMS-986218 as a monotherapy or in combination with nivolumab has not been reached, and dose 
escalation is currently ongoing. Overall, the safety profile of BMS-986218 as a single agent and 
in combination with nivolumab is clinically manageable.
Additional details on the safety and PK profile of BMS-986218 are summarized in the 
BMS-986218 IB.6
It is anticipated that anti-CTLA-4-NF Ab (BMS-986218), administered as a single agent or in 
combination with anti-PD-1 Ab (nivolumab), will demonstrate adequate safety and tolerability, as 
well as a favorable benefit-risk profile, to support further clinical testing. No prospective 
hypotheses are being formally evaluated.
The scientific rationale for the study design is discussed in greater detail in Section 5.4. Additional 
details are summarized in the BMS-986218 Investigator Brochure (IB).6
3.2.1.1
BMS-986218 Nonclinical Pharmacology
BMS-986218 binds to a human CTLA-4-expressing cell line equivalently to ipilimumab, with a 
concentration required for 50% efficacy (EC50) of 1.4 nM. The Ab, however, binds CD16 with 
significantly higher affinity (24- to 30-fold higher, depending on the CD16 polymorphism). Due 
to this increase in CD16 binding, BMS-986218 mediates increased natural killer (NK) 
cell-mediated ADCC of CTLA-4 expressing cells such as activated CD4 or Treg target cells 
compared to ipilimumab. The Ab also induces interleukin (IL)-2 secretion by human peripheral 
blood mononuclear cells (PBMCs) in response to Staphylococcal enterotoxin B (SEB) stimulation 
to a greater extent than ipilimumab.
Murine syngeneic tumor models have validated the anti-tumor efficacy mediated by CTLA-4 
blockade.7 In these models, the activity of a mouse surrogate Ab to murine CTLA-4 (9D9) has 
been shown to be dependent on the ability of the Ab to bind to activating Fcγ receptors.4,5 In order 
to mimic the interactions between human Abs and human FcγRs, 9D9 was produced as either a 
human IgG1 (hIgG1) or an NF hIgG1 (hIgG1-NF). Anti-tumor efficacy was then tested in mice 
that have had mouse Fcγ receptors knocked out, and transgenically express human Fcγ receptors 
instead. The 9D9-hIgG1-NF Ab produced significantly greater anti-tumor efficacy when compared 
to the hIgG1. Maximal tumor growth inhibition (TGI) achieved with the hIgG1-NF Ab was 99% 
compared to 61% for the hIgG1. Immune monitoring of tumor-infiltrating lymphocytes from the 
same experiment indicated that Treg depletion from the tumor site was increased by the hIgG1-NF 
compared with the hIgG1.
Increased activity of BMS-986218 is not restricted to mouse models; in a cynomolgus vaccine 
study, BMS-986218 enhanced the immune response to an Ad5 viral vaccine to a greater extent 
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than ipilimumab. This is evident both through increased CD8 tetramer responses, as well as 
increased Ki-67 expression on CD8 T cells. Consistent with what was seen in mouse models, there 
was no evidence of depletion of peripheral Treg cells after administration of BMS-986218.
The in vitro and in vivo data indicate that BMS-986218 can enhance ADCC activity of ipilimumab 
and improve anti-tumor immune responses, supporting the development of this Ab for the 
treatment of cancer. Additional details are summarized in the BMS-986218 IB.6
3.2.1.2
BMS-986218 Nonclinical Pharmacokinetics
The PK and pharmacodynamic response of BMS-986218 was evaluated in cynomolgus monkeys 
and compared with the PK/pharmacodynamics of ipilimumab. Additional PK/pharmacodynamic 
studies were conducted using anti-mouse CTLA-4 Abs with either hIgG1 (9D9-hIgG1) or NF 
hIgG1 (9D9-hIgG1-NF) as surrogates for ipilimumab and BMS-986218, respectively. In 
cynomolgus monkeys, following a single intravenous (IV) dose of 10 mg/kg of BMS-986218, total 
plasma clearance (CLTp) was low (4 mL/day/kg) and the terminal serum half-life (T-HALF) was 
14 days. Similar PK results in monkeys were obtained with ipilimumab (T-HALF = 14 days and 
CLTp = 3.6 mL/day/kg). After a single 3- or 10-mg/kg intraperitoneal dose of the surrogate mAbs 
9D9-hIgG1-NF and 9D9-hIgG1 to C57BL/6 mice, the T-HALF was approximately 3 to 4 days 
and the exposure (based on area under the concentration-time curve [AUC] vs time curve 
extrapolated to infinity) following dose normalization was similar for the surrogate antibodies 
(68 and 61 μg•day/mL for 9D9-hIgG1-NF and 9D9hIgG1, respectively), suggesting that 
non-fucosylation does not alter the PK of the Ab in human Fc receptor (FcR) knock-in mice. The 
steady-state volume of distribution (Vss) of BMS-986218 in monkeys indicated that BMS-986218 
resides in the extracellular space. Additional details are summarized in the BMS-986218 IB.6 
Prediction of Human Pharmacokinetic and Dose Projection for BMS-986218
The human PK of BMS-986218 is predicted to be the same as that of ipilimumab. This is based 
on their similar PK profiles in cynomolgus monkeys and nearly identical Ab structures. Compared 
to ipilimumab, the lack of the posttranslational fucosylation of BMS-986218 in the hIgG1 Fc 
region is expected to have little impact on the Ab PK.8 Thus, the human clearance (CL), Vss, and 
T-HALF of BMS-986218 are projected to be 4.5 mL/d/kg, 91 mL/kg, and 15 days, respectively.9
The human efficacious dose of BMS-986218 for maximum tumor efficacy is projected to be 
3 mg/kg. At exposures predicted for this dose, the mouse surrogate, 9D9-huIgG1-NF, was able to 
achieve ~90% TGI% in human FcR-transgenic mice bearing MC38 syngeneic tumor. In the same 
mouse tumor model, 9D9-huIgG1-NF appeared to be 10-fold more potent than 9D9-huIgG1, likely 
due to its enhanced Fc effector function (to deplete tumor Treg cells). If similar Fc-mediated 
potency improvement is observed in patients, BMS-986218 may achieve better anti-tumor efficacy 
than ipilimumab at the projected human efficacious dose. 
3.2.1.3
BMS-986218 Nonclinical Toxicology
The cynomolgus monkey was selected as the toxicology species because, like ipilimumab, 
BMS-986218 binds specifically to macaque CTLA-4, but not to homologous CTLA-4 in other 
traditional toxicology species (mouse, rat, rabbit), and has pharmacologic activity only in 
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monkeys. In surface plasmon resonance (SPR) experiments, the binding affinity and on-and-off 
rates of ipilimumab to cyno-CTLA-4 were generally comparable (and/or up to within 4-fold of
each other).10 The enhanced Fc binding and immunostimulatory activity of BMS-986218 resulted 
in a greater incidence and severity of autoimmune/gastrointestinal (GI) toxicity in monkeys than 
was observed previously for ipilimumab.11 The differences in toxicity profile may be explained, 
in large part, by the enhanced potency and the higher doses tested for BMS-986218 vs ipilimumab. 
In a 1-month toxicity study in monkeys (n = 5/sex/group) at weekly doses of 3, 15, or 75 mg/kg 
IV,12 profound enhancement of T-cell activation occurred at all doses following neoantigen 
immunization (keyhole limpet hemocyanin [KLH], necessary and enforcing factor [Nef], and 
glycosaminoglycan [Gag] peptides), consistent with the pharmacology of BMS-986218. 
BMS-986218 was clinically tolerated by monkeys at the low dose of 3 mg/kg/week (mean AUC 
from time zero to 168 hours [AUC(0-168h)] = 11,300 μg•h/mL) with generally mild loose feces 
in some animals and minimal body weight decrease. At higher doses of ≥15 mg/kg/week 
(mean AUC[0-168h] = 32,300 μg•h/mL), BMS-986218 treatment resulted in early euthanasia of 
1 and 6 monkeys at 15 and 75 mg/kg/week, respectively, from Days 22 through 53 due to profound 
clinical toxicity (decreased feeding behavior, liquid feces, blood in feces, thin body condition, 
body weight loss, and/or dehydration). The predominant BMS-986218-related microscopic 
finding was generally dose-related lymphohistiocytic inflammation within a variety of tissues at 
all doses, but with fewer tissues affected and generally minimal findings at the low dose. The GI 
tract (stomach, cecum, and colon) and the kidney were the most severely and consistently affected, 
whereas additional organs were affected at higher doses. BMS-986218 was immunogenic in 57% 
(17/30) of monkeys. Most BMS-986218-related changes were partially or fully reversible, with 
the exceptions of 1 animal at 75 mg/kg/week included above that was euthanatized on Day 53 due 
to unresolved GI toxicity from the dosing period, lymphohistiocytic inflammation that generally 
persisted to the end of the 6-week recovery period, and unchanged or progressive increases in 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at ≥15 mg/kg. Based on 
the tolerability and generally mild severity of lymphohistiocytic tissue inflammation, the highest 
non-severely toxic dose (HNSTD) in this study was considered to be 3 mg/kg/week (mean 
AUC 0-168h = 11,300 μg•h/mL).
Although ipilimumab was not studied in monkeys at doses as high as 75 mg/kg, ipilimumab was 
tolerated without adverse effects at overlapping doses:  up to 30 mg/kg administered every 3 days 
for 
3 doses,13,14,15
at 
10 mg/kg 
administered 
weekly 
for 
1 month 
(mean 
AUC 0-168h = 31,600 μg•h/mL),16 at 1 mg/kg administered weekly for 10 weeks,17 at up to 
10 mg/kg administered approximately monthly for up to 6 months, and at 30 mg/kg administered 
every 3 weeks to pregnant female monkeys (ie, no maternal effects).17,18,19 Of over 100 monkeys 
treated with ipilimumab, only 1 drug-related humane sacrifice occurred due to colitis following 
2 monthly doses of 10 mg/kg in a pharmacology study; and another monkey at 10 mg/kg/month 
in combination with another immunomodulatory Ab and simian immunodeficiency virus DNA 
vaccines developed dermatitis/rash 4 weeks 
following a 3-month dosing period. 
Thus, BMS-986218 appears to have a more potent toxicologic profile than ipilimumab affecting 
greater numbers of monkeys at overlapping exposures. 
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The BMS-986218 HNSTD corresponds to exposure (AUC) multiples of approximately 283-fold 
and 2.8× the projected exposures at the proposed starting FIH dose (2 mg IV, AUC[4-week] 
160 μg•h/mL) and highest projected dose for the FIH study (200 mg IV, AUC[4-week] 
16,008 μg•h/mL), respectively. The HNSTD corresponds to maximum observed plasma 
concentration (Cmax) multiples of approximately 177-fold and 1.8× the projected Cmax at the 
starting FIH dose (2 mg IV, 0.75 μg/mL) and highest proposed doses for the FIH study (200 mg 
IV, 75 μg/mL), respectively. As compared to the ipilimumab efficacious dose of 3 mg/kg (Q3W) 
that is approved for use, the starting dose of BMS-986218 is approximately 0.03 mg/kg or 100-fold 
lower, and the highest projected dose of BMS-986218 is approximately equivalent (3 mg/kg).
In qualitative exploratory in vitro cell activation and cytokine release assays using human 
PBMC,20,21 in vitro incubation of human PBMCs with dry-coated BMS-986218, as well as an 
isotype-matched control mAb (anti-KLH IgG1-NF), led to significant NK cell activation (as 
measured by increased CD25 and CD69 expression) at concentrations ≥1 μg/well. Additionally, 
increased release of IL-1β, IL-6, IL-8, interferon gamma (IFN-γ), and tumor necrosis factor alpha 
(TNF-α) relative to phosphate buffered saline (PBS) control occurred in a majority of donors by 
66 hours of incubation with either dry-coated BMS-986218 or anti-KLH IgG1-NF. Importantly, 
the superagonist positive control mAb TGN 5.11A1 induced activation of both T cells and B cells; 
however, neither BMS-986218 nor isotype control caused activation of either of those cell 
populations following 18 to 66 hours of incubation. Further, incubation with BMS-986218 and 
anti-KLH IgG1 NF did not lead to release of IL-2, IL-5, or IL-10, which was released following 
incubation with the superagonist positive control mAb TGN 5.11A1. Given the similar levels of 
release of specific cytokines and NK cell activation with BMS-986218 and anti-KLH IgG1-NF, 
these findings were not considered to be target mediated. Rather, these results suggest Fc receptor 
engagement of the NF Fc tail of both BMS-986218 and the isotype-matched control Ab. The 
profile of cytokines released, IL-1β, IL-6, IL-8, and TNF-α, are consistent with FcγR engagement, 
primarily on NK cells and monocytes.
Despite the activation and cytokine release observed with BMS-986218 and the isotype control 
under these superphysiologic conditions, clinical trial data from similar NF IgG1 constructs 
indicate that these antibodies do not have significant non-target related cytokine release in humans. 
BMS-986012, an NF hIgG1 that binds to fucosyl-GM1, has been administered in human clinical 
trials without incidence of cytokine-storm like reactions up to 1000 mg/dose, with mean maximal 
serum concentrations up to approximately 376 μg/mL.22 Furthermore, in physiologically relevant 
whole blood assay, clinically relevant concentrations of BMS-986218 in solution induced a modest 
NK cell activation in a few donors at concentrations ≥75 μg/mL, and induced modest cytokine 
release potential similar to that of ipilimumab.14,15,23,24 These findings are also in agreement with 
clinical data indicating that ipilimumab does not elicit adverse cytokine release in humans.25
Overall, BMS-986218 has demonstrated acceptable pharmacologic, nonclinical PK, 
pharmacodynamic, and manageable toxicologic properties that support the transition of 
BMS-986218 into early clinical development. Additional details are summarized in the 
BMS-986218 IB.6
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3.2.2
Nivolumab
Nivolumab is a fully human, IgG4 (kappa) isotype mAb that binds to PD-1 with nanomolar affinity 
(dissociation constant, 3.06 nM) and a high degree of specificity. Nivolumab blocks binding of 
PD-1 to its ligands PD-L1 and programmed death ligand 2 (PD-L2). Nonclinical in vitro testing 
of nivolumab demonstrated that binding to PD-1 results in enhanced T-cell proliferation and 
release of IFN-γ in vitro in mixed lymphocyte reaction and cytomegalovirus assays.
The nonclinical safety of nivolumab was evaluated in a comprehensive toxicology program in 
mice and monkeys and was submitted as part of Biologics License Application 125527.26 Details 
of the in vitro and in vivo nonclinical pharmacology studies conducted to support the development 
of nivolumab can be found in Section 4.1 of the nivolumab IB.27
While nivolumab was well tolerated in cynomolgus monkeys, there is a potential for enhanced 
toxicity when combined with other immunostimulatory agents. However, nonclinical studies with 
nivolumab did not predict clinically relevant adverse effects (eg, no evidence of immune-mediated 
adverse effects was observed in nonclinical toxicology studies with nivolumab). Therefore, 
combination nonclinical toxicology studies with BMS-986218 and nivolumab have not been 
conducted and are not required by the International Conference on Harmonisation S9 Note for 
Guidance on Nonclinical Evaluation for Anticancer Pharmaceuticals.28 The safety of the 
combination will be carefully monitored in the planned clinical trial.
Nivolumab (OPDIVOTM) is approved for the treatment of several types of cancer in multiple 
regions including the United States (US, Dec-2014), the European Union (EU, Jun-2015), and
Japan (Jul-2014).
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including NSCLC, melanoma, RCC, Classical Hodgkin Lymphoma (cHL), small cell 
lung cancer, gastric cancer, squamous cell carcinoma of the head and neck (SCCHN), urothelial 
cancer, hepatocellular carcinoma (HCC), and colorectal cancer (CRC). In confirmatory trials, 
nivolumab as monotherapy demonstrated a statistically significant improvement in overall survival
(OS) as compared with the current standard of care in patients with advanced or metastatic 
NSCLC, unresectable or metastatic melanoma, advanced RCC, or recurrent or metastatic SCCHN. 
Details of the clinical activity in these various malignancies are provided in the USPI and SmPC.
For nivolumab monotherapy, the safety profile is similar across tumor types. The only exception 
is pulmonary inflammation AEs, which may be numerically greater in participants with NSCLC. 
In NSCLC patients, it can be difficult to distinguish between nivolumab-related and 
nivolumab-unrelated causes of pulmonary symptoms and radiographic changes. There is no 
relationship between the incidence, severity, or causality of AEs and the nivolumab dose level. 
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are summarized in the nivolumab IB.27
3.2.3
Ipilimumab
Ipilimumab (BMS-734016, MDX010, and MDX-CTLA-4) is a fully human monoclonal IgG1κ 
specific for human cytotoxic T-lymphocyte antigen 4 (CTLA-4, CD152). CTLA-4 is expressed on 
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a subset of activated T cells on which it acts as a negative regulator of T-cell activity. Ipilimumab 
is a mAb that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. 
Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the 
activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling 
can also reduce Treg function, which may contribute to a general increase in T-cell responsiveness, 
including the anti-tumor response. Ipilimumab has been administered to more than 19,500 subjects 
(total number of participants enrolled in ipilimumab studies) in several cancer types in completed 
and ongoing studies, as well as a compassionate use program. Ipilimumab has been approved for 
use in over 47 countries including the US (Mar-2011), the European Union (Jul-2011), and 
Australia (Jul-2011).
The focus of the monotherapy clinical program has been in melanoma and lung cancer, with 
advanced melanoma and adjuvant melanoma being the most comprehensively studied indications. 
Ipilimumab is being investigated in combination with other modalities, such as chemotherapy, 
radiation therapy, and other immunotherapies in multiple tumor types. 
In melanoma, 2 completed Phase 3 studies (MDX010-20 and CA184024) demonstrated a 
clinically meaningful and statistically significant survival benefit in pretreated advanced 
melanoma and previously untreated advanced melanoma, respectively.
The safety profile of ipilimumab is generally consistent across studies, with a) the majority of AEs 
being inflammatory in nature, which is consistent with the proposed mechanism of action of 
ipilimumab; b) the same types of such immune-mediated AEs in the GI tract, skin, liver, and 
endocrine system being reported; and c) most of these events being manageable with immune 
suppressive therapies.
In patients with advanced melanoma who received 3 mg/kg ipilimumab monotherapy in a Phase 3 
study (MDX010-20), the most frequently reported adverse reactions (≥ 10% of participants) were 
diarrhea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. The 
majority of AEs were mild to moderate (Grade 1 or 2), and treatment was discontinued for adverse 
reactions in 10% of participants.
Long-term survival benefit of treatment with ipilimumab 3 mg/kg was demonstrated through a 
pooled analysis of OS data from clinical trials in participants with previously treated and treatment 
naïve advanced melanoma (N = 965). The Kaplan-Meier OS curve revealed a plateau beginning 
around year 3 (OS rate = 21% [95% confidence interval (CI):  17 to 24]) that extended up to 
10 years in some participants.
Dose-dependent toxicity and the relative efficacy of ipilimumab 3 mg/kg vs 10 mg/kg were 
established in a Phase 3 study in advanced melanoma (CA184169).
Ipilimumab monotherapy prolongs survival in subjects with pretreated and previously untreated 
advanced melanoma and has demonstrated anti-tumor activity in other malignancies, including 
lung cancer, prostate cancer, and RCC.29
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Additional details on the safety profile and clinical benefit of ipilimumab alone and in combination 
with nivolumab, including results from clinical studies in melanoma, prostate, lung, kidney, 
bladder, or breast tumors are summarized in the ipilimumab and nivolumab IBs.27,29 
3.3
Benefit-Risk Assessment
Subjects who have advanced solid tumors have a poor prognosis and few curative options.
Immunotherapy with ipilimumab or nivolumab has demonstrated clinical activity in subjects with 
melanoma or advanced NSCLC, RCC, SCCHN, and other tumors. Treatment-related AEs include 
those associated with autoimmune activation, such as colitis, pneumonitis, thyroiditis, hepatitis, 
and adrenal insufficiency.
Current clinical experience with BMS-986218 is summarized in Section 3.2.1. Clinical benefit has 
not been established in patients with advanced cancer. 
In the absence of completed clinical studies with BMS-986218, the evaluation of risk is largely 
based on information from nonclinical studies with BMS-986218 in monkeys (Section 3.2.1) and 
potential effects based on the proposed mechanism of action and clinical evidence from 
ipilimumab therapy. 
The nonclinical GLP toxicology assessment of BMS-986218 has demonstrated a dose-related 
toxicity profile of immune-mediated adverse events (imAEs) and cytokine release potential 
compatible with the expected mechanism of action (see Section 3.2.1.3). 
In combination therapy of BMS-986218 and nivolumab, as observed in the combination of 
ipilimumab and nivolumab, it is possible that a higher incidence of imAEs may occur with the 
combination of the 2 antibodies. The safety profile of nivolumab monotherapy and the 
combination of ipilimumab and nivolumab are defined based on experience with more than 
17,700 subjects as either monotherapy or in combination therapy. The frequency and types of 
immune-mediated adverse reactions are similar across multiple types of tumors and are described 
in the Reference Safety Information in the current nivolumab IB.27 Unanticipated side effect events 
may also occur.
The proposed clinical studies of BMS-986218 have been designed to minimize the overall risk to 
participants; measures will include the following:
•
Continuous safety assessments will be utilized by the Investigators and Sponsor to determine 
whether additional safety measures or termination of the study is required at any time. In 
addition, AEs and serious adverse events (SAEs) will be reviewed on an ongoing basis by the 
Bristol-Myers Squibb (BMS) Medical Monitor (or designee) and WorldWide Patient Safety 
(WWPS) representatives to monitor for any safety signals or trends. As BMS-986218 is an 
experimental agent, it is possible that unforeseen, unknown, or unanticipated reactions may 
occur. However, based on the nonclinical safety profile of BMS-986218, and the 212-fold 
exposure margin (based on AUC from the nonclinical HNSTD of 3 mg/kg/week in monkeys) 
built into the planned starting dose of 2 mg (flat dose; 0.03 mg/kg administered to a 70-kg 
participant), the potential safety risks are expected to be minimized. 
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•
Study treatment administration will occur at infusion centers with medical monitoring and the 
capability to manage infusion reactions or anaphylaxis. The protocol provides a treatment 
algorithm for infusion reactions. In addition to conventional safety measures for infusion of 
biologic agents, all participants will undergo observation and assessment for signs of infusion 
reaction for 60 minutes post infusion following the first 3 doses of BMS-986218 for each 
participant. Furthermore, to assess for potential effects of lymphocyte activation, a sentinel 
participant will be monitored for 5 days at each dose level. 
•
Management algorithms for ipilimumab/nivolumab-induced AEs involving the GI, renal, 
pulmonary, hepatic, endocrinopathy, skin, neurologic, and cardiac systems are included in the 
protocol (see Section 7.6.2).
•
Participants who develop imAEs may require prolonged treatment with high-dose 
corticosteroids and other immunosuppressive agents. This could increase the risk of 
opportunistic infections. The imAE 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 performed prior 
to administration of study therapy and on a weekly basis during the first 8 weeks of treatment 
in monotherapy and the first 8 weeks of the combination between BMS-986218 and 
nivolumab. In addition, complete physical examinations (PEs) will be conducted on Day 1 of 
each new cycle, along with weekly symptom-directed targeted PEs during the first 8 weeks of 
treatment. Due to the potential risk of exaggerated inflammatory response, participants with 
autoimmune disorders or chronic viral infections, or those who are at risk for flare of 
auto-immunity or immune-related diseases will be excluded.
For the proposed clinical studies of BMS-986218, the overall risk for participating in these trials 
will also be minimized.
•
The amount of blood sampling poses limited risk to the participant and includes discomfort, 
pain, and bleeding. The amount of total blood is reduced to the minimal quantity required to 
address the need of safety monitoring, standard of care, PK/anti-drug antibodies (ADAs), 
 needs and is below the recommended daily limits for each treatment day.
Whether BMS-986218 both as a single agent and in combination with nivolumab administration 
increases the risk for contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection or increases the severity or duration of symptoms is currently unknown. This unknown 
risk must be considered when enrolling a participant. 
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No additional safety monitoring or routine screening tests will be required due to the SARS-CoV-2 
pandemic. Participants with recent or acute infections will be excluded or delay start of treatment 
as defined in Section 6.2. If a participant has a confirmed SARS-CoV-2 infection while on study 
treatment, dose delay or interruption of study treatment is required as described in Section 7.6. 
The study has been designed with study visits that allow for close monitoring of participants’ safety 
throughout the clinical trial (Section 2), and participants are encouraged to contact the investigator 
if an intercurrent illness develops between study visits. Testing for COVID-19 to inform decisions 
about clinical care during the study should follow local standard practice.
Non-live COVID-19 vaccination is considered a simple concomitant medication within the study. 
However, the efficacy and safety of non-live vaccines (including non-live COVID-19 vaccines) in 
participants receiving BMS-986218 is unknown.
In conclusion, the potential direct benefit to participants in this study is that both single-agent and 
combined therapies with these investigational agents may result in a greater proportion of 
participants with stabilization of disease, objective response, progression-free survival, OS, or 
increased duration of response (DOR) than those observed with standard therapy or other 
investigational immunotherapy. It is also possible that both single-agent and combined therapies 
may reverse T-cell exhaustion and achieve responses in 1) tumor types known to be poorly 
responsive to nivolumab or ipilimumab, 2) tumors in relapse after anti-PD-1 or anti-PD-L1 
therapy, and/or 3) tumors where high Treg infiltration correlates with a worse prognosis.
The potential for direct benefit described above warrants evaluating BMS-986218 both as a single 
agent and in combination with nivolumab in this Phase 1 clinical study with risk mitigation 
described above.
4
OBJECTIVES AND ENDPOINTS
The objectives and endpoints for this study are shown in Table 4-1. 
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To characterize the safety, tolerability, and DLTs and 
to determine the MTD/RP2D of BMS-986218 
administered as monotherapy and in combination with
nivolumab in participants with advanced solid tumors
•
To evaluate the efficacy and safety of BMS-986218 
monotherapy relative to ipilimumab in participants 
with advanced cutaneous melanoma previously treated 
with anti-PD-1/PD-L1 immunotherapy (Part 2A only)
•
To evaluate the efficacy and safety of BMS-986218 
alone and in combination with nivolumab in NSCLC 
(Part 2B and Part 2C)
•
Incidence of AEs, SAEs,
AEs meeting 
protocol-defined DLT criteria, AEs leading to 
discontinuation, and death 
•
ORR, mDOR, and PFSR at 24, 36, and 
48 weeks by RECIST v1.1
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To evaluate the efficacy and safety of BMS-986218 
alone and in combination with nivolumab in MSS CRC 
(Part 2D)
Secondary
•
To evaluate the preliminary efficacy of BMS-986218 
alone and in combination with nivolumab in advanced 
solid tumors (Part 1A and Part 1B)
•
To characterize the PK and immunogenicity of 
BMS-986218 when administered alone and in 
combination with nivolumab 
•
ORR, mDOR, and PFSR at 24, 36, and 
48 weeks by RECIST v1.1 or PCWG 3
•
Summary measures of PK parameters and 
incidence of ADA to BMS-986218
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Abbreviations:
DLT = dose-limiting toxicity; DOR = duration of response; 
mDOR = median duration of response; 
MSS CRC = microsatellite stable colorectal cancer; NSCLC = non-small cell lung cancer; ORR = objective response 
rate; 
 PCWG 3 = Prostate Cancer Working Group; 
 PFSR = progression-free survival rate;
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5
STUDY DESIGN
5.1
Overall Design
•
This is a Phase 1/2a, open-label study of BMS-986218, administered as a single agent and in 
combination with nivolumab, in participants with advanced solid tumors. The study is 
comprised of 2 parts, dose escalation and dose expansion.
•
Part 1:  The Dose Escalation Phase, where the dose of BMS-986218, given alone or in 
combination with nivolumab, is escalated to determine the MTD/RP2D.
−
The BMS-986218 Monotherapy Dose Escalation (Part 1A) will escalate the dose of 
BMS-986218 to determine the MTD/RP2D. The study will evaluate the safety and 
tolerability of BMS-986218 once every 4 weeks (Q4W), given alone, based on DLTs, using 
a Bayesian Logistic Regression Model (BLRM) employing the escalation with overdose 
control principle (EWOC). In addition, to further evaluate the safety and tolerability of 
BMS-986218, an alternative once-every-2-weeks (Q2W) dosing schedule will be explored 
to characterize the safety and PK of BMS-986218. The Q2W dosing schedule will start at 
a total dose level equivalent to a dose that has cleared safety in the Q4W dosing cohort 
(eg, 10 mg Q2W vs 20 mg Q4W). Subsequent Q2W doses will be guided by Q4W 
equivalent doses that have cleared safety and will continue evaluating higher Q2W doses
up to the MTD equivalent of the Q4W dosing cohort. Based on the preliminary PK from 
the Q4W dosing cohorts, at the steady state, the Q2W dosing schedule is projected to 
provide approximately the same AUCtau (tau = 4 weeks) as the Q4W dosing schedule, and 
approximately 70% Cmax as the Q4W dosing schedule. Intra-participant movement 
between treatment regimens/dosing schedules is not permitted. Additionally, participants 
with advanced stage cutaneous melanoma, colorectal cancer microsatellite stable (MSS
CRC), NSCLC, or SCCHN will be treated with BMS-986218 on a Q2W or Q4W schedule 
in the Part 1A pharmacodynamic (PD) cohort. The Safety Evaluation of Combination 
Doses of BMS-986218 with Nivolumab (Part 1B) will evaluate the safety and tolerability 
of doses of BMS-986218 in combination with nivolumab. The combination of BMS-
986218 with nivolumab will be evaluated using a BLRM employing the EWOC principle. 
Starting at least 1 dose level lower than the current monotherapy dose level of 
BMS-986218 demonstrating an acceptable safety profile, BMS-986218 will be studied in 
combination with a 480 mg Q4W flat dose of nivolumab. Determination of the MTD for 
the Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab (Part 1B) 
will be guided by BLRM copula.
•
Part 2:  The Expansion Phase, where the cohort of participants is expanded to gather additional 
safety, tolerability, preliminary efficacy, PK, and pharmacodynamic information in specific 
patient populations, regarding BMS-986218 alone and in combination with nivolumab.
−
The Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A) will evaluate the preliminary efficacy of BMS-986218 monotherapy relative to 
ipilimumab monotherapy in a cohort of cutaneous melanoma participants who have 
received prior immunotherapy with an anti-PD-1 or anti-PD-L1 containing regimen and 
must have progressive or recurrent disease after prior PD-1/PD-L1 directed therapy. 
Three dose levels or schedules for BMS-986218 from the Part 1A Q4W monotherapy 
escalation will be evaluated that have had at least 6 DLT evaluable participants and meet 
safety criteria:  one at 7 mg Q4W, one at 20 mg Q4W, and one at 70 mg Q4W. Evaluating 
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multiple different doses will aid in selecting the regimen that will ultimately provide the 
optimal benefit-risk ratio to future study participants. Participants must not have received 
prior anti-CTLA-4 therapy in the advanced or metastatic setting. 
−
The Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B) will evaluate the 
preliminary efficacy of BMS-986218 in NSCLC in participants who have received, and 
then progressed on, relapsed, or have been intolerant to standard systemic therapies with 
proven survival benefit. Additionally, participants must have progressed or have had 
recurrent disease after prior immunotherapy with anti-PD-1/anti-PD-L1 either as 
monotherapy or in combination with other agents. Prior anti-CTLA4 therapy either as 
monotherapy or in combination is not required, but is allowed; however, no more than 
20% of participants are allowed prior anti-CTLA4 therapy. Participants who have been 
intolerant to prior immunotherapy are excluded. Three dose levels or schedules for 
BMS-986218 from the Part 1A Q4W monotherapy escalation will be evaluated that have 
had at least 6 DLT evaluable participants and meet safety criteria:  one at 7 mg Q4W, one 
at 20 mg Q4W, and one at 70 mg Q4W. The rationale for evaluating multiple dose levels 
is to optimize the benefit-risk ratio for the participant.
•
In the BMS-986218 Combination Therapy Cohort Expansion (Part 2C) in NSCLC, the 
preliminary efficacy and safety of BMS-986218 in combination with nivolumab will be 
assessed in participants with NSCLC who have progressed or relapsed after anti-PD-1/PD-L1 
therapy. Participants must not have received prior anti-CTLA-4 therapy in the advanced or 
metastatic setting. One or more doses to be evaluated in Part 2C will be selected from the range 
of doses assessed as tolerable in Part 1B, and which do not exceed the MTD or highest dose 
administered that has cleared safety. These dose(s) will be selected based on the totality of 
available safety, tolerability, efficacy, PK and PD data. The evaluation of efficacy in Part 2C 
will initially occur at one or more dose levels starting with up to 20 participants at each dose 
level. Additional participants up to 40 at a dose level may be evaluated following initial signal 
assessment. In Part 2C, participants will be treated Q4W for up to 2 calendar years regardless 
of treatment delays.
•
In the BMS-986218 Combination Therapy Cohort Expansion in MSS CRC (Part 2D), the 
preliminary efficacy and safety of BMS-986218 in combination with nivolumab will be 
assessed in participants with MSS CRC who have progressed or relapsed on at least 1 prior 
standard therapy. Participants must not have received prior anti-CTLA-4 therapy in the 
advanced or metastatic setting. The dose to be evaluated in Part 2D will be selected from the 
range of doses assessed as tolerable in Part 1B, and which do not exceed the MTD or highest 
dose administered that has cleared safety. The dose will be selected based on the totality of 
available safety, tolerability, efficacy, PK, and PD data. Regardless of whether or not RAS 
mutation status is known, all participants will be tested during screening for extended RAS
(NRAS and KRAS) and BRAF mutation status. Results from this testing at screening is not 
required prior to receiving treatment on study. The RAS status evaluation will be conducted
with the goal of enrolling approximately 20 participants each with either mutation or wild-type 
with respect to extended RAS status. The Sponsor may elect to prioritize enrollment of 
participants based on mutation status. In Part 2D, participants will be treated Q4W for up to 2 
calendar years regardless of treatment delays.
The duration of the study will be approximately 5 years.
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anti-CTLA4-NF mAb
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
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a If Part 1 is open upon the decision to initiate Part 2, treatment in the 2 parts will occur in parallel. If supported by clinical and safety data, doses higher than 
200 mg may be studied until MTD is reached, and further details will be provided in a subsequent protocol amendment at such time.
b If Part 1 is open upon the decision to initiate Part 2, treatment in the 2 parts will occur in parallel. If supported by clinical and safety data, doses higher than 
100 mg may be studied until MTD equivalent is reached in participants, and further details will be provided in a subsequent protocol amendment at such time.
c If Part 1B is open upon the decision to initiate Part 2C and Part 2D, treatment in the 2 parts will occur in parallel. If supported by clinical and safety data, doses 
higher than 200 mg BMS-986218 may be studied until MTD is reached, and further details will be provided in a subsequent protocol amendment at such time.
d Tumor-specific eligibility criteria are detailed in Section 6.
e Additional participants may be treated or randomized to further evaluate emerging data or subgroups of interest if needed but not to exceed 40 participants per 
dose level in Part 2A and Part 2B.
f Participants will be treated or randomized, which will include ipilimumab monotherapy and BMS-986218 at different dose levels.
g
Participants will be treated or randomized.
h Dose(s) of BMS-986218 selected for Part 2C and Part 2D will be based on the totality of preliminary safety, tolerability, efficacy, PK and PD data. Refer to 
Section 5.1.2.4 for additional details.
i The nivolumab dose found to be tolerable in Part1B will be used in Part 2 combination expansions (Part 2C and Part 2D)
Abbreviations: CTLA = cytotoxic T-lymphocyte-associated protein 4; DLT = dose-limiting toxicity; mCRPC = metastatic castration-resistant prostate cancer; MSS 
CRC = microsatellite stable colorectal cancer; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; PD = pharmacodynamic; 
PD-L1 = programmed death-ligand 1; Q2W = every 2 weeks; Q3W = every 3 weeks; Q4W = every 4 weeks; R = randomized; SCCHN = squamous cell carcinoma 
of the head and neck; TNBC = triple-negative breast cancer.
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BMS-986218
anti-CTLA4-NF mAb
A detailed schematic for study period and participant flow is presented in Figure 5.1-2.
Figure 5.1-2:
Study Period and Participant Flow for BMS-986218, Ipilimumab, and 
Nivolumab
Abbreviations:  EOT = end of treatment; Q2W = every 2 weeks; Q3W = every 3 weeks; Q4W = every 4 weeks.
5.1.1
Screening Period
The screening period will be up to 28 days and begins by establishing the participant̓s initial 
eligibility and signing of the informed consent form (ICF). The screening assessments are shown 
in Table 2-1. If a participant exceeds the 28-day screening period due to a study-related procedure 
(eg, 
 waiting for a study-related laboratory value), the participant 
must be re-consented, but does not require a new participant identification number. In this 
situation, the fewest number of procedures from the initial screening should be repeated to qualify 
the participant, while maintaining participant safety and eligibility. Within a given disease type, 
participants meeting all eligibility criteria will be enrolled in the study using an Interactive 
Response Technology (IRT) according to the part and treatment arm availability.
5.1.2
Treatment Period
The dosing regimens of BMS-986218 are Q4W and Q2W. All participants will be treated with 
BMS-986218 Q4W ± nivolumab Q4W for up to 2 calendar years, BMS-986218 Q2W for up to 2 
calendar years, and/or ipilimumab Q3W for up to a maximum of 4 doses. Each cycle of the 
treatment period will be 4 weeks in length, with the exception of the treatment arms with Q3W 
dosing of ipilimumab in the Randomized BMS-986218 Monotherapy Cohort Expansion in 
Cutaneous Melanoma (Part 2A), for which each cycle of ipilimumab will be 3 weeks in length. 
Continuous safety evaluation and tumor assessment for participants receiving BMS-986218 or 
nivolumab will guide the decision to treat a participant with additional cycles of study therapy if 
the participant has confirmed clinical benefit (up to a maximum of 2 calendar years for 
BMS-986218 Q4W ± nivolumab Q4W; or up to a maximum of 2 calendar years for BMS-986218 
Q2W). Tumor assessments will occur every 8 weeks (Q8W) for participants receiving 
BMS-986218 and nivolumab for all study parts, except the Randomized BMS-986218 
Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A), where tumor assessment in 
participants receiving BMS-986218 or ipilimumab will occur at 12 weeks from first dose 
(± 1 week), prior to initiating the next cycle of treatment. After that, subsequent tumor imaging 
assessments to be performed Q8W (± 1 week), prior to initiating the next cycle of treatment. 
Treatment Period
BMS-986218 Q4W ± Nivolumab Q4W 
for up to 2 calendar years;
BMS-986218 Q2W 
for up to 2 calendar years; 
Ipilimumab Q3W
for up to a maximum of 4 doses 
Screening
28 days
Safety Follow-up
Visits on Day 30, 
60, and 100 
(± 7 days) after 
EOT
Response/Survival 
Follow-up
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Participants who remain free of subsequent therapy will undergo tumor imaging assessment Q8W 
(± 1 week) until subsequent tumor-directed therapy is initiated or until 48 weeks after 
discontinuation of study treatment/EOT visit, and then Q12W (± 2 weeks) for a total duration of 
2 years.
Weekly study visits will be performed for the first 8 weeks following the first dose of study 
treatment for the BMS-986218 Monotherapy Escalation (Part 1A), Safety Evaluation of
Combination Doses of BMS-986218 with Nivolumab (Part 1B), the Randomized BMS-986218 
Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A), the Randomized 
BMS-986218 Monotherapy Cohort Expansion (Part 2B), the BMS-986218 Combination Therapy 
Cohort Expansion in NSCLC (Part 2C) and the BMS-986218 Combination Therapy Cohort 
Expansion in microsatellite stable colorectal cancer (MSS CRC) (Part 2D) followed by study visits 
Q4W thereafter. During Cycle 1 and Cycle 3 of the treatment period, additional study visits to 
collect samples for intensive PK, ADA, and cytokine assessments are required. See Section 9.5 for 
further details. 
In the BMS-986218 Monotherapy Escalation (Part 1A), the Randomized BMS-986218 
Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A), and the Randomized 
BMS-986218 Monotherapy Cohort Expansion (Part 2B), BMS-986218 will be administered Q4W. 
An alternative BMS-986218 dosing schedule of Q2W (with dosing on Day 1 and Day 15 of each 
28-day cycle) will also be explored for monotherapy escalation using data obtained from the Q4W 
schedule. BMS-986218 will be infused over 30 minutes, except in the low-dose cohorts where 
infusion times may be shorter. BMS-986218 will require a 60-minute observation period following 
the completion of the infusion for the first 3 doses for each participant. Ipilimumab will be 
administered Q3W and will be infused over 30 minutes.
In the Safety Evaluation of Combination Doses of BMS-986218 with nivolumab (Part 1B), the 
BMS-986218 Combination Therapy Cohort Expansion in NSCLC (Part 2C), and BMS-986218 
Combination Therapy Cohort Expansion in MSS CRC (Part 2D), each combination treatment 
cycle will be comprised of 1 dose of BMS-986218 in combination with 1 dose of nivolumab 
administered Q4W. When both BMS-986218 and nivolumab are given in combination, nivolumab 
will be given first, over 30 minutes, followed by BMS-986218 over 30 minutes, beginning at least 
30 minutes after completion of the infusion of nivolumab. BMS-986218 infusions will require a 
60-minute observation period following the completion of the infusion for the first 3 doses for 
each participant. For participants receiving combination doses of BMS-986218 with nivolumab, a 
30-minute infusion of nivolumab will be followed by a 30-minute observation period, followed by 
an infusion of BMS-986218 and a 60-minute observation period following the first 3 infusions for 
each participant. Ipilimumab infusions will require a 30-minute observation period following the 
completion of the infusion for the first 3 doses for each participant. Additional infusion details for 
nivolumab and ipilimumab are given in the Pharmacy Manual. 
5.1.2.1
The BMS-986218 Monotherapy Escalation (Part 1A)
Up to approximately 108 DLT-evaluable participants will be treated during the BMS-986218 
Monotherapy Escalation (Part 1A) of the study for the Q4W schedule. Each participant will be 
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administered IV doses of BMS-986218 in planned flat dose levels of 2, 4, 7, 20, 40, 70, 100, 150, 
and 200 mg Q4W per cycle, for up to 2 calendar years. If supported by clinical and safety data, 
doses higher than 200 mg may be studied until MTD is reached, and further details will be provided 
in a subsequent protocol amendment at such time.
An alternative dosing schedule of BMS-986218 Q2W will also be explored to further characterize 
the safety, PK, and pharmacodynamics of BMS-986218. Up to approximately 72 DLT-evaluable 
participants will be treated with 10, 20, 35, 50, 75, and 100 mg Q2W during the BMS-986218 
Monotherapy Escalation (Part 1A) of the study for the Q2W schedule. The Q2W dosing schedule 
will start at a total dose level equivalent to a dose that has cleared safety in the Q4W dosing cohort 
(eg, 10 mg Q2W vs 20 mg Q4W), and continue evaluating higher doses up to the MTD equivalent 
of the Q4W dosing cohort. If supported by clinical and safety data, doses higher than 100 mg Q2W 
may be studied, and will be guided by Q4W equivalent doses that have cleared safety until MTD 
equivalent of the Q4W dosing cohort is reached. Based on the preliminary PK from the Q4W 
dosing cohorts, at the steady state, the Q2W dosing schedule is projected to provide approximately 
the same AUCtau (tau = 4 weeks) as Q4W dosing schedule, and approximately 70% Cmax as 
Q4W dosing schedule. 
Additionally, participants with advanced stage cutaneous melanoma, microsatellite stable 
colorectal cancer (MSS CRC), NSCLC, or SCCHN will be treated with BMS-986218 on a Q2W 
schedule at a starting dose of 20 mg in the Part 1A pharmacodynamic (PD) cohort. Based on 
preliminary analysis of Treg count decrease in the tumor microenvironment, using single-cell 
ribonucleic acid (RNA) sequencing gene expression analysis, additional cohorts of participants at 
higher dose levels may be evaluated. For example, if the expected PD activity is not observed after 
5 to 10 evaluable participants at the 20 mg dose level, then the next set of 5 to 10 evaluable 
participants may be treated at a higher dose level or Q4W schedule. Therefore, more than one dose 
level may be evaluated based on the PD results assessment. 
Any additional dose levels evaluated in the Q2W schedule of the Part 1A PD cohort will be a dose 
that has been determined to be safe and tolerable in either the Q2W escalation part or a dose 
equivalent to the Q4W dose, which has been determined to be safe and tolerable in the Q4W dose 
escalation part. Approximately 20 evaluable participants per dose level (per dose schedule) may 
be treated as part of the PD cohort. Each participant will be administered IV doses of BMS-986218 
Q2W or Q4W per cycle, for up to 2 calendar years.
Prior to declaring the MTD, and in consultation with Investigators, the Sponsor has the option to 
expand any dose level previously established to be tolerable in order to obtain additional 
experience or to investigate dose levels intermediate to those defined in the protocol. Planned dose 
levels may be modified, or intermediate dose levels added, based upon the BLRM analysis and 
clinical evaluation of all available safety and PK/pharmacodynamic data. Once the tolerability 
(during the DLT evaluation) of a dose level has been established, additional participants may be 
added at that dose level to better characterize the safety, PK, and pharmacodynamic profiles (not 
to exceed a total of 200 evaluable participants across dose levels and schedules). Additional 
information on DLTs can be found in Section 7.6.1.
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BMS-986218
anti-CTLA4-NF mAb
Sentinel Participant:
During the dose-escalation phase, a staggered dosing (sentinel participant) approach will be used. 
The first participant to be dosed at C1D1 of each dose level will be observed for 5 days, before 
additional participants (ie, Participant 2 onward in that cohort) receive study treatments in the same 
dose level. 
Initially, 3 participants will be enrolled at the start of each cohort, in accordance with the sentinel 
participant approach cited above. However, to allow for any unforeseen discontinuations (such as 
disease progression) before the 8-week DLT period (56 days) is completed, extra participants may 
be enrolled in each dose escalation cohort. 
5.1.2.2
The Safety Evaluation of Combination Doses of BMS-986218 with 
Nivolumab (Part 1B) 
The Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab (Part 1B) will be 
initiated starting at 1 dose level below current safety cleared Q4W monotherapy cohort, defined 
from BLRM and an overall assessment of all available safety, PK/pharmacodynamic, and efficacy 
data of the BMS-986218 Monotherapy Escalation (Part 1A). 
In the Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab (Part 1B), the 
starting dose of BMS-986218 was 1 dose level lower than the Q4W 40 mg monotherapy dose level 
of BMS-986218, which had demonstrated an acceptable safety profile and was administered in 
combination with nivolumab at the flat dose of 480 mg Q4W. Dose escalation and determination 
of MTD for the Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B) will be guided by BLRM-copula. Subsequent dose selection of the combination will be
based on evaluating the recommendation from BLRM-copula and an overall assessment of all 
available safety and PK/pharmacodynamic data. Safety evaluation and tumor assessment will be 
performed Q8W (2 cycles). If toxicity is unacceptable at any combination dose level, additional
combination dose level(s) may be evaluated using BMS-986218 and/or nivolumab (eg, dose of 
240 mg Q4W). Selection of dose level for each study drug will be based on the nature and 
attribution of observed DLTs in previously evaluated dose levels. An intermediate dose level of 
BMS-986218 and/or an intermediate dose level of nivolumab Q4W may be evaluated in additional 
cohort(s). No intra-subject dose escalation or de-escalation of BMS-986218 or nivolumab is 
allowed at any dose level.
At no time will the dose of BMS-986218 in the Safety Evaluation of Combination Doses of 
BMS-986218 with Nivolumab (Part 1B) exceed the highest tolerated dose in the BMS-986218 
Monotherapy Escalation (Part 1A). Dose escalation in each cohort, within the constraints cited 
above, will be enrolled in parallel. Up to approximately 84 DLT-evaluable participants will be 
enrolled in Part 1B. Additional information on DLTs can be found in Section 7.6.1. 
Sentinel Participant:
The sentinel participant rule will be followed. The first participant to be dosed at Cycle 1 Day 1 of 
each dose level will be observed for 5 days, before additional participants (ie, Participant 2 onward 
in that cohort) receive study treatments at the same dose level. Initially, 3 participants will be 
enrolled at the start of each cohort, in accordance with the sentinel participant approach cited 
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anti-CTLA4-NF mAb
above; however, to allow for any unforeseen discontinuations (eg, disease progression) before the 
8-week DLT period (56 days) is completed, extra participants may be enrolled in each dose cohort.
5.1.2.3
Dose Escalation Decisions for the BMS-986218 Monotherapy Escalation 
(Part 1A) and the Safety Evaluation of Combination Doses of BMS-
986218 with Nivolumab (Part 1B) 
The dose-escalation phase of the study will evaluate the safety and tolerability of BMS-986218, 
given alone or in combination with nivolumab, based on DLTs, using a BLRM (for the 
BMS-986218 Monotherapy Escalation [Part 1A]) and a BLRM-copula (for the Safety Evaluation 
of Combination Doses of BMS-986218 with Nivolumab [Part 1B]).
During the monotherapy and combination therapy dose-escalation phase, a set of approximately 
3 participants will be treated at each specified dose level. Cohort tolerability assessment with 
subsequent participant enrollment and dose recommendation will occur when at least 2 evaluable 
participants within a cohort have completed an 8-week DLT period. Any toxicities that occur 
beyond the DLT period will be accounted for in making dose level decisions and/or dose level 
modifications. Additional information on DLTs can be found in Section 7.6.1. 
If the potential DLT occurring in the third evaluable participant regarding the specific dose level 
does not influence the dose recommendation by BLRM or the BLRM-copula, the next dose level 
may proceed without waiting for the third participant to complete the corresponding DLT
observation period, after discussion and agreement between the Sponsor and Investigators. 
Continuous re-assessment of dose recommendation, by BLRM in the BMS-986218 Monotherapy 
Escalation (Part 1A) and BLRM-copula in the Safety Evaluation of Combination Doses of 
BMS-986218 with Nivolumab (Part 1B), will be performed for each dose level. Planned dose 
levels for dose escalation are provided in Table 5.5.2-1. 
Planned dose levels may be modified, or intermediate dose levels added, based upon the BLRM-
copula
analysis for combination and clinical evaluation of all available safety and 
PK/pharmacodynamic data. Once the tolerability (during the DLT evaluation) of a dose level has 
been established, additional participants may be added at that dose level to better characterize the 
safety, PK, and pharmacodynamic profiles.
The monotherapy doses of BMS-986218, selected for the Randomized BMS-986218 Monotherapy 
Cohort 
Expansion 
in 
Cutaneous 
Melanoma 
(Part 2A), 
the 
BMS-986218 
Cohort 
Expansion - Monotherapy (Part 2B), and the combination therapy doses of BMS 986218, selected 
for BMS-986218 Cohort Expansion - Combination Therapy in NSCLC (Part 2C) and 
BMS-986218 Cohort Expansion - Combination Therapy in MSS CRC (Part 2D) will be based on 
evaluating the recommendation from BLRM and an overall assessment of all available safety, 
PK/pharmacodynamic, and efficacy data.
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anti-CTLA4-NF mAb
5.1.2.4
The Randomized BMS-986218 Monotherapy Cohort Expansion in 
Cutaneous Melanoma (Part 2A), the BMS-986218 Cohort Expansion -
Monotherapy (Part 2B), and the BMS-986218 Cohort Expansion -
Combination Therapy (Part 2C and Part 2D) 
The purpose of the BMS-986218 cohort expansions is to gather preliminary efficacy information 
in specific patient populations regarding BMS-986218 alone and in combination with nivolumab. 
 
Continuous evaluation of toxicity events in the BMS-986218 cohort expansions will be performed 
throughout enrollment for all expansion cohorts. If, at any time, the aggregate rate of 
treatment-related toxicities meeting DLT criteria exceeds 33% across all participants treated in 
cohort expansions, the findings will be discussed, and further enrollment will be interrupted. 
Depending on the nature and grade of the toxicity, and after assessing the benefit-risk ratio, a new 
dose for all cohorts may be initiated at a previously tested lower dose level or at a dose level 
intermediate to previously tested lower dose levels.
The Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A) will evaluate the preliminary efficacy of BMS-986218 monotherapy relative to 
ipilimumab monotherapy in a cohort of participants with advanced cutaneous melanoma who have 
received prior immunotherapy with an anti-PD-1 or anti-PD-L1 containing regimen and must have 
progressive or recurrent disease after prior anti-PD-1/PD-L1 directed therapy. Participants must 
not have received prior anti-CTLA-4 therapy. Three dose levels or schedules for BMS-986218 
from the Part 1A Q4W monotherapy escalation will be evaluated that have had at least 6 DLT 
evaluable participants and meet safety criteria:  one at 7 mg Q4W, one at 20 mg Q4W, and one at 
70 mg Q4W, and ipilimumab 3 mg/kg (Q3W, 3-week treatment cycle for up to a maximum of 4 
doses [which are to be completed within 16 weeks of the first dose in case of any delays]). 
In the BMS-986218 Monotherapy Cohort Expansion (Part 2B), the preliminary efficacy of 
BMS-986218 will be investigated in tumor types where ipilimumab did not demonstrate a 
sufficient level of efficacy in previous studies and tumors in which a high level of Treg infiltration 
correlates with a poor prognosis. The tumor types to be evaluated will include NSCLC 
(adenocarcinoma or squamous cell subtypes only; at least 22 participants required per study arm); 
other tumor types may be explored in the future. Participants will be randomized evenly across 
study arms. Three dose levels or schedules for BMS-986218 from the Part 1A Q4W monotherapy 
escalation will be evaluated that have had at least 6 DLT evaluable participants and meet safety 
criteria:  one at 7 mg Q4W, one at 20 mg Q4W, and one at 70 mg Q4W. BMS-986218 will be 
administered for a maximum duration of 2 calendar years when dosed Q4W. Participants should 
have received and then progressed on or relapsed/recurrence after anti-PD-1/PD-L1 directed 
therapy in monotherapy or in combination with chemotherapy. Prior anti-CTLA-4 therapy is 
allowed for no more than 20% of participants.
In the BMS-986218 Combination Therapy Cohort Expansion in NSCLC (Part 2C) , the 
preliminary efficacy and safety of BMS-986218 in combination with nivolumab will be 
investigated in participants whose NSCLC has progressed or relapsed after anti-PD-1/PD-L1 
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therapy. Participants must not have received prior anti-CTLA-4 therapy in the advanced or 
metastatic setting. Any selected BMS-986218 Part 2C dose will not exceed the highest Part 1B 
administered dose that has cleared safety, with a minimum of 6 evaluable participants for Safety 
Evaluation. More than one dose may be evaluated in Part 2C. The dose(s) of BMS-986218 selected 
for Part 2C will be based on the totality of preliminary safety, PK, and PD data from Part 1 and 
Part 2. The nivolumab dose found to be tolerable in Part 1B will be used in Part 2C. In Part 2C, 
participants will be treated Q4W for up to 2 calendar years regardless of treatment delays.
In the BMS-986218 Combination Therapy Cohort Expansion in MSS CRC (Part 2D) the 
preliminary efficacy and safety of BMS-986218 in combination with nivolumab will be 
investigated in participants with MSS CRC who have progressed or relapsed on at least 1 prior 
standard therapy. Participants must not have received prior anti-CTLA-4 therapy in the advanced 
or metastatic setting. Any selected BMS-986218 Part 2D dose will not exceed the highest Part 1B 
administered dose that has cleared safety, with a minimum of 6 evaluable participants for Safety 
Evaluation. The dose of BMS-986218 selected for Part 2D will be based on the totality of 
preliminary safety, PK, and PD data from Part 1 and Part 2. The nivolumab dose found to be 
tolerable in Part 1B will be used in Part 2D. In Part 2D, participants will be treated Q4W for up to 
2 calendar years regardless of treatment delays.
In all study parts, participants with unconfirmed progressive disease, stable disease (SD), partial 
response (PR), or complete response (CR) at the end of a given cycle will continue to the next 
treatment cycle. Participants will be allowed to continue study treatment until the first occurrence 
of any of the following:
•
Completion of the maximum duration of study therapy (up to 2 calendar years for 
BMS-986218 Q4W ± nivolumab Q4W; up to 2 calendar years for BMS-986218 Q2W; up to a 
maximum of 4 doses for ipilimumab Q3W).
•
Confirmed progressive disease defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 (Appendix 5) or per Prostate Cancer Working Group (PCWG 3) criteria for 
prostate (Appendix 12) unless participants meet criteria for treatment beyond progression 
(Section 8.1.1).
•
Clinical deterioration suggesting that no further benefit from treatment is likely.
•
Intolerability to therapy.
•
Participant meets criteria for discontinuation of study treatment as shown in Section 8.1.
5.1.2.5
Treatment Beyond Progression
Tumor progression and response endpoints will be assessed using RECIST v1.1 criteria for solid 
tumors (Appendix 5) or per PCWG 3 criteria for prostate (Appendix 12). Treatment beyond 
progression may be allowed in selected participants with initial RECIST v1.1/PCWG 3-defined 
progressive disease following discussion and agreement with the BMS Medical Monitor (or 
designee), if the benefit-risk assessment favors continued administration of study treatment (eg, 
participants are continuing to experience clinical benefit as assessed by the Investigator, tolerating 
treatment, and meeting other criteria, see Section 8.1.1).
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5.1.3
Follow-up
5.1.3.1
Safety Follow-up Period
Upon completion of study therapy (up to a maximum of 2 calendar years for BMS-986218 Q4W ±
nivolumab Q4W; up to a maximum of 2 calendar years for BMS-986218 Q2W; up to a maximum 
of 4 doses for ipilimumab Q3W), or once the decision is made to discontinue the participant from 
treatment (ie, 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 visit 
as the last scheduled and completed on-treatment visit and will be the start of the Safety Follow-up 
Period. For participants who do not complete all scheduled cycles of therapy, the EOT visit will 
be the most recent on-treatment visit (with all available safety and response data) and will not need 
to be repeated. Accordingly, for these participants, this visit will be considered the start of the 
Safety Follow-up Period.
After the EOT visit, all participants will be evaluated for any new AEs for at least 100 days after 
the last dose of study treatment. Follow-up visits should occur at Days 30, 60, and 100 (± 7 days 
for all study visits) after the last dose, or the date of discontinuation (± 7 days). All participants 
will be required to complete the 3 clinical Safety Follow-up visits, regardless of whether new 
anti-cancer therapy is started, except those participants who withdraw consent for study 
participation.
5.1.3.2
Response Follow-up Period
At the time of the EOT visit or at the time of study treatment discontinuation, all participants will 
continue to have radiologic and clinical tumor assessments Q8W (± 1 week) until subsequent 
tumor-directed therapy is initiated. Participants who remain free of subsequent therapy will 
continue to receive tumor assessment scans Q8W for the first 48 weeks after discontinuation of 
study treatment/EOT visit and then Q12W (± 2 weeks) for a total duration of 2 years. Subsequently, 
they will continue to receive tumor assessment scans as per standard of care guidelines, or at a 
minimum of every 6 months up to 2 years following the last dose of study treatment, or until new 
tumor-directed therapy initiation/withdrawal of study consent. Radiologic assessments for 
participants who have ongoing clinical benefit may continue to be collected after participants 
complete the survival follow up period of the study. Scans will be submitted to an imaging core 
laboratory for review by blinded independent central review (BICR) at a later date or at any time 
during the study at the Sponsor’s discretion.
5.1.3.3
Survival Follow-up Period
In parallel with the Safety Follow-up Period, all participants will start the Survival Follow-up 
Period. Participants will be followed-up by telephone Q12W (± 2 weeks) from EOT for up to 4 
years following the first dose of study treatment or until death, loss to follow-up, withdrawal of 
consent, or conclusion of the study, whichever comes first. 
 Participants with stable disease (SD), partial response (PR), or 
complete response (CR) will have both the Response Follow-up period and Survival Follow-up 
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Period occur simultaneously during the 2-year follow-up period. The duration of this follow-up is 
up to 4 years following the first dose of study treatment, although a longer follow-up period could 
be considered in selected cases if an efficacy signal is apparent. Tumor assessment scans, for 
participants who have ongoing clinical benefit beyond the 4-year period following the first dose
of study treatment, may continue to be collected as part of standard-of-care treatment. Subsequent 
therapies will also be recorded in this Survival Follow-up Period. 
5.1.4
Data Monitoring Committee and Other External Committees
Based upon the stage of the study and appropriate safety monitoring procedures described below, 
BMS has determined that a Data Monitoring Committee is not necessary for this study. 
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 WorldWide Patient 
Safety (WWPS) led Safety Management Team (SMT). This collaborative process constitutes the 
safety monitoring plan for the study. To support safety oversight, BMS has established ongoing
processes for collection, review, analysis, and submission of individual adverse event reports and 
their aggregate analyses. Because this is an open-label study, WWPS, the BMS Medical Monitor, 
and the Investigators will have access to all data necessary for safety evaluation.
BMS WWPS is an internal group that operates independently from the clinical team to monitor 
safety across all BMS protocols and analyze all data in an unblinded fashion. Within BMS, an 
SMT is established for investigational therapies under clinical development, and a member of 
WWPS chairs this team. In addition, signal detection is performed at least monthly and ad hoc 
throughout the study by the SMT composed, at a minimum, of the WWPS medical safety 
assessment physician (Chair of the SMT) and WWPS single case review physician, the Clinical 
Development Lead, the study biostatistician, and epidemiologist; all of whom, analyze the data in 
an unblinded fashion. Furthermore, the SMT routinely monitors for actual or potential issues 
related to participant safety that could result in a change in the medical risk-benefit balance 
associated with the use of study treatment(s). 
All participants in this study represent individuals with high unmet medical need as the prognosis 
for advanced/metastatic solid tumors is generally very poor.
5.2
Number of Participants
The approximate total number of evaluable participants will be up to 684 as shown below:
•
Part 1 - Dose Escalation Phase: Up to approximately 284 evaluable participants may be treated 
in the escalation phase including:
o
Part 1A - up to approximately 200 evaluable participants for the BMS-986218 
Monotherapy Escalation 

Part 1A Q4W monotherapy - up to approximately 108 DLT-evaluable 
participants will be treated.

Part 1A Q2W monotherapy - up to approximately 72 DLT-evaluable 
participants will be treated.
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
Part 1A PD cohort - approximately 20 evaluable participants will be treated in 
the Part 1 PD cohorts. 
-
In addition, in order to evaluate more than one dose level or schedule, 
up to 40 additional evaluable participants may be treated in the Part 1A
PD cohorts (from participants initially planned for other Part 1 cohorts), 
provided the total number of participants in Part 1 is not exceeded.
o
Part 1B - up to approximately 84 DLT-evaluable participants for the Safety Evaluation 
of Combination Doses of BMS-986218 with Nivolumab. 
•
Part 2 - Dose Expansion Phase: The remaining 400 response-evaluable participants represent 
the potential number of participants in BMS-986218 cohort expansions who may be either
randomized (Part 2A and Part 2B) or treated (Part 2C and Part 2D) including:
o
Part 2A - for the Randomized BMS-986218 Monotherapy Cohort Expansion in 
Cutaneous Melanoma, approximately 132 evaluable participants will be randomized, 
with 33 evaluable participants per arm required. 
o
Part 2B - for the BMS-986218 Monotherapy Cohort Expansion in NSCLC, 
approximately 66 evaluable participants will be randomized, with 22 evaluable 
participants per arm required. 
o
In Part 2A and Part 2B, additional participants may be treated or randomized to further 
evaluate emerging data or subgroups of interest if needed but not to exceed a total of 
40 evaluable participants per arm. If additional participants are treated or randomized 
in Part 2A and Part 2B, then up to 160 response-evaluable participants (= 40 
participants × 4 arms) and 120 response-evaluable participants (= 40 participants ×
3 arms) can be randomized in Part 2A and Part 2B, respectively. 
o
Part 2C - for the BMS-986218 Combination Therapy Cohort Expansion in NSCLC, 
approximately 40 response-evaluable participants will be treated. If more than one dose 
level is evaluated, additional participants (up to 40 response-evaluable participants per 
dose level) may be enrolled, up to 80 response-evaluable participants (= 40 participants 
× 2 arms).
o
Part 2D - for the BMS 986218 Combination Therapy Cohort Expansion in MSS CRC, 
approximately 40 response-evaluable participants will be treated, with the goal of 
treating approximately 20 participants each with either mutation or wild-type with 
respect to extended RAS status.
For additional details on sample size determination, see 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. Similarly, the 
end of the study is defined as the last visit or scheduled procedure shown in the Schedule of 
Activities (see Section 2) for the last participant. Primary study completion is defined as the final 
date on which data for the primary endpoint are expected to be collected.
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5.4
Scientific Rationale for Study Design
BMS-986218 is being investigated in humans with advanced solid tumors; either as monotherapy 
or in combination with nivolumab. The study design includes the following:
•
28-day screening period
•
Up to 2 calendar year treatment period for BMS-986218 Q4W ± nivolumab Q4W, up to 
2 calendar year treatment period for BMS-986218 Q2W, and up to a maximum of 4 doses for 
ipilimumab Q3W
•
Dose escalation phase
•
Cohort expansion phase
•
Safety Follow-up Period
•
Response/Survival Follow-up Period
The rationale for the individual elements of the study design are given below. 
5.4.1
Rationale for the BMS-986218 Monotherapy Escalation (Part 1A) and the 
Safety Evaluation of Combination Doses of BMS-986218 with 
Nivolumab (Part 1B) Design
The safety of BMS-986218 in the BMS-986218 Monotherapy Dose Escalation (Part 1A) will be 
evaluated at different dose levels. Based on the totality of data, select dose levels that have cleared 
safety for at least 6 DLT evaluable participants in Part 1A will be further evaluated in combination 
with nivolumab. The safety of CTLA-4 blockade with ipilimumab has been extensively 
characterized in more than 22,571 subjects with different cancer types (refer to the ipilimumab IB 
for further details29). Modifying the ipilimumab structure to retain affinity for CTLA-4 with 
enhanced ADCC may result to a different dose/effect relationship and AE profile. The flat dose of 
2 mg (0.03 mg/kg) of BMS-986218 in the monotherapy dose escalation is lower than the dose 
safely tested in animals and will allow an accurate evaluation of the tolerability of BMS-986218. 
When ipilimumab and nivolumab are used in combination, there is an increased incidence of AEs,
but the AE profile is similar to those observed with each single agent. The relative contribution of 
ipilimumab and nivolumab to the balance between tolerability and efficacy is not fully 
characterized. Because the dose level of ipilimumab relative to nivolumab that could offer the best 
balance between safety and efficacy is unknown, the combination of BMS-986218 with nivolumab 
will be evaluated using a BLRM employing the EWOC principle. This design will help to identify 
the dose regimen of the combination of BMS-986218 and nivolumab with the optimal benefit-risk 
profile. 
The BLRM with an overdose control principle escalation was selected as an appropriate design for 
this study. It offers more accuracy and efficiency in determining the true MTD compared to 
rule-based methods (such as 3 + 3 design) by incorporating external information from pre-clinical 
studies as well as historical clinical trials. The EWOC principle limits the risk of exposing 
participants in the next cohort to an intolerable or toxic dose. Hence, it ensures that safety is not 
compromised during dose escalation. Simulation results demonstrate that BLRM allows fast 
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escalation when the expected toxicity is very low, and limits participants treated at sub-therapeutic 
doses, which is attributed to the adaptive Bayesian learning from previous doses. In addition, 
BLRM has greater applicability to the combination therapy setting compared to other model-based 
methods. After completing the BMS-986218 Monotherapy Escalation (Part 1A), the drug
associated dose toxicity profiles will be characterized and incorporated as prior knowledge into 
the drug expansion phase of the study, the Safety Evaluation of Combination Doses of 
BMS-986218 with Nivolumab (Part 1B), or used in future studies.
5.4.2
Rationale for BMS-986218 Monotherapy in Participants Previously 
Treated with Anti-PD-1/PD-L1 Immunotherapy
Cancer immunotherapies that target the immunosuppressive checkpoint receptors CTLA-4 or 
PD-1 and its ligand, PD-L1, have changed the landscape of anti-cancer immunotherapy. In 
particular, checkpoint inhibitors targeting PD-1 and PD-L1 have demonstrated unprecedented 
clinical efficacy in more than 15 cancer types, including melanoma, NSCLC, RCC, urothelial 
carcinoma, SCCHN, and Hodgkin’s lymphoma.30 Nevertheless, primary resistance to anti-PD-1 
therapies is common, affecting up to 60% of patients in some cancer types. Furthermore, it is now 
becoming apparent that encouraging initial responses observed among some patients can be 
undone by their development of acquired resistance to anti-PD-1 therapies, leading to disease 
relapse.31 In the current understanding of mechanisms contributing to the development of 
resistance to anti-PD-1 therapy, overexpression of other immune checkpoints (TIM-3, LAG-3, and 
CTLA-4) and influx of Tregs (which co-express these molecules) have been demonstrated to 
promote either primary or acquired resistance to anti-PD-1 therapy.32,33
A transcriptional signature associated with resistance to PD-1 immunotherapy, termed as Innate 
PD-1 RESistance (IPRES) was reported. Notably, over 30% of patients whose melanomas 
expressed the IPRES signature responded to CTLA-4 blockade (ipilimumab), suggesting that the 
IPRES signature does not indicate resistance to every immunotherapy.34
In light of these data, targeting CTLA-4 and depleting Tregs should present a valuable mechanism 
to overcome anti-PD-1 resistance. 
5.4.3
Rationale for the Use of Ipilimumab as a Comparator
Ipilimumab was chosen as the comparator to BMS-986218 in the Randomized BMS-986218 
Monotherapy Cohort Expansion in Cutaneous Melanoma (Part 2A) because both agents share a 
similar Ab structure and affinity for CTLA-4. Modification of the Fc portion is intended to enhance 
the ADCC activity of BMS-986218 compared to ipilimumab. A head-to-head comparison in 
melanoma participants, in which ipilimumab has demonstrated a positive benefit-risk profile, will 
allow a more complete comparison of the Treg depletion potential, an evaluation of the potential 
response benefit of the defucosylation in BMS-986218, as well as a better or comparable safety 
profile. 
The dose and schedule of 3 mg/kg ipilimumab Q3W are based on the approved recommended dose 
in advanced cutaneous melanoma. Continuous treatment of both regimens will be evaluated to 
determine the benefit-risk profile of a recurrent immune stimulation by targeting CTLA-4 and 
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Tregs. There is currently no clinical trial evaluating the efficacy and safety of continuous 
administration of ipilimumab in participants who have received prior immunotherapy with an 
anti-PD-1 or anti-PD-L1 containing regimen and have progressive or recurrent disease after prior 
PD-1/PD-L1 directed therapy. The decision to test the activity in participants previously treated 
with anti-PD-1/PD-L1 therapy is based on the potential to re-stimulate the immune response by 
using a different mechanism of action.
5.4.4
Rationale for the Combination of BMS-986218 and Nivolumab
Studies have shown that tumors co-opt some specific immune-checkpoint pathways to engender 
immune resistance, particularly against T cells that are specific for tumor antigens. Co-engagement 
of multiple immune receptors on activated T cells (combination immunotherapy) may result in 
better outcomes as compared to engagement of a single immune receptor. 
This assumption is currently being tested in multiple combination regimens with various agents; 
however, the combination of ipilimumab and nivolumab is the only combination with proven 
clinical activity.
CTLA-4 and PD-1 induce tumor evasion from the immune system through complementary, but 
distinct mechanisms. Nivolumab interferes with the interaction of PD-1 with its ligands PD-L1 
and PD-L2, allowing for activation and proliferation of exhausted or anergic Teff in the tumor. 
Ipilimumab interferes with the interaction of CTLA-4 with CD80 (B7-1) and CD86 (B7-2) 
molecules expressed on antigen presenting cells, allowing for T-cell activation through 
engagement of the costimulatory receptor CD28, which binds to these same B7 ligands. 
In pre-clinical models, combined pathway blockade increased proliferation of effector CD8+ and 
CD4+ T cells and decreased intratumoral Tregs compared to single pathway blockade.
The combination of ipilimumab and nivolumab is approved in the US for the treatment of advanced 
melanoma. Information regarding safety and efficacy can be found in the nivolumab IB.27 The 
combination of nivolumab and ipilimumab is currently under evaluation in various doses, 
schedules of administration, and other tumor types. Results showed promising activity with higher, 
but tolerable toxicity than ipilimumab or nivolumab alone. Different doses and schedules of 
administration were evaluated with different outcomes in terms of safety, tolerability, and efficacy 
depending on tumor type. 
Based on the described synergy between ipilimumab and nivolumab, the current study will 
evaluate the combination of BMS-986218 with nivolumab to generate more information about the 
safety, tolerability, and efficacy of the combination with the rationale that the addition of Treg 
depletion and ADCC-triggered inflammation could increase the synergy between both agents. 
5.4.5
Rationale for Two Years Fixed Duration of Treatment with Checkpoint 
Blockade
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long-term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in participants with previously treated advanced solid tumors 
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(including 129 participants with NSCLC), specified a maximum treatment duration of 2 years. 
Among 16 participants with non-small cell lung cancer (NSCLC) who discontinued nivolumab 
after completing 2 years of treatment, 12 participants were alive after > 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.35 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% and 18% for squamous and non-squamous NSCLC, 
respectively).36
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated participants with NSCLC, suggesting that treatment beyond 
1 year is likely needed. In CA209153, participants with previously treated advanced NSCLC who 
completed 1 year of nivolumab therapy were randomized to either continue or stop treatment, with 
the option of retreatment upon progression. Among 163 participants still on treatment at 1 year 
and without progression, those who were randomized to continue nivolumab had significant 
improvement in PFS compared to those who were randomized to stop treatment, with median PFS 
(post-randomization) not reached vs 10.3 months, respectively; HR = 0.42 (95% CI:  0.25, 0.71). 
With a median follow-up of 14.9 months post-randomization, there also was a trend for 
participants on continued treatment to live longer (OS HR = 0.63 [95% CI:  0.33, 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (ie, 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.37
Collectively, these data suggest that there is minimal if any benefit derived from continuing 
immuno-oncology (I-O) treatment beyond 2 years in advanced tumors. However, even though 
immunotherapy can be well tolerated, participants will be at risk for additional toxicity with 
longer-term treatment. 
5.4.6
Rationale for Treatment Beyond Progression
Immunotherapeutic agents produce atypical clinical response patterns that are not usually observed 
with conventional chemotherapy. Accumulating clinical evidence indicates that some participants 
treated with immune system stimulating agents may develop disease progression by the 
conventional response criteria before demonstrating clinical objective responses and/or SD.
Two distinct non-conventional patterns have been reported:  1) a reduction in target tumor burden 
despite the appearance of new lesion(s), and 2) a transient increase in target tumor burden in an 
initial phase, followed by subsequent tumor shrinkage.
These phenomena were observed in the BMS Phase 2 study (CA209003) of nivolumab in patients 
with solid tumors. Two hypotheses potentially explain these phenomena. First, enhanced 
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inflammation within tumors could lead to an increase in tumor size, which would appear as 
enlarged index lesions and as newly visible small non-index lesions. Over time, both the malignant 
and inflammatory portions of the mass may then decrease, leading to overt signs of clinical 
improvement. Alternatively, in some individuals, the kinetics of tumor growth may initially 
outpace anti-tumor immune activity. With sufficient time, the anti-tumor activity will dominate 
and become clinically apparent. Therefore, it is important to avoid premature discontinuation of 
the study treatment that might induce a non-conventional response pattern in some patients.
5.4.7
Rationale for Tumor Selection
Specific tumors were selected to evaluate the potential therapeutic effect of BMS-986218 based 
on the following rationale:
•
Previously demonstrated efficacy of ipilimumab in cutaneous melanoma.
•
Tumor types where ipilimumab has shown some sign of activity but with no significant 
improvement in survival, such as NSCLC, RCC, triple-negative breast cancer (TNBC), and 
gastric adenocarcinoma; see the ipilimumab IB29 for additional details.
•
Participants with tumors who have received prior immunotherapy with an anti-PD-1 or 
anti-PD-L1 containing regimen and must have progressive or recurrent disease after prior 
PD-1/PD-L1 directed therapy (eg, cutaneous melanoma, NSCLC, RCC) will be evaluated to 
determine if targeting CTLA-4 and/or depleting Tregs might be an interesting strategy to 
re-stimulate the immune system, based on their potential contribution to the resistance to 
anti-PD-1 therapy.32,33
•
Tumors for which high Treg infiltration has been correlated with worse prognosis and for 
which current immunotherapies have not demonstrated efficacy, such as TNBC38,39 or 
advanced stage pancreatic ductal adenocarcinoma (PDAC).40,41
•
Tumors such as NSCLC, SCCHN, MSS CRC, and cutaneous melanoma for which high Treg 
or T-cell infiltration has been observed by flow cytometry (undisclosed in house data), 
compared to other tumor types and the depletion of such Treg cells, could be evaluated 
5.4.8
Rationale for Open-label Design
This study will use an open-label design to ensure that immune-related toxicities in participants
receiving immunotherapy are promptly identified and managed.
For all study parts, Investigator-reported best overall response will be used to determine response-
related endpoints. Scans will be submitted to an imaging core laboratory for review by BICR at a 
later date or at any time during the study at the Sponsor’s discretion.
 
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5.5
Justification for Planned Dose Selection
5.5.1
BMS-986218
5.5.1.1
BMS-986218 Rationale for Starting Dose in Humans
Introduction
Four methods were used to assess the starting dose of BMS-986218:  1) nonclinical toxicology 
data, 2) pharmacology using anti-tumor efficacy data for a mouse surrogate (9D9-hIgG1-NF), 
3) clinical safety data from an ipilimumab exposure-response (ER) of safety analysis, and 4) in
vitro cytokine release data. The method with the lowest starting dose determined selection of the
starting dose in the FIH study. The toxicology-based approach for the starting dose selection
utilized the HNSTD identified from a 1-month repeat-dose toxicity study in cynomolgus monkeys.
The pharmacology-based method leveraged anti-tumor efficacy data from a mouse surrogate
(9D9-hIgG1-NF) to project the human efficacious dose and the starting dose. The third approach
was based on the clinical safety data of ipilimumab, because BMS-986218 is the NF form of
ipilimumab, and toxicity for this class of molecules is often associated with exaggerated
pharmacology. Furthermore, data from an in vitro cytokine release assay were considered as part
of the FIH starting dose selection by targeting the in vitro no-effect level as the Cmax value of the
starting dose. As a result, the lowest dose (ie, 0.03 mg/kg [2-mg flat dose]) among these approaches
was recommended as the FIH starting dose of BMS-986218. The details of each of these
approaches are discussed below. Collectively, the proposed FIH starting dose represents the intent
of ensuring adequate participant safety while limiting the number of cancer participants receiving
sub-therapeutic doses.
Starting Dose Calculated From the HNSTD in Monkeys12
BMS-986218 contains an NF hIgG1fa Fc. Its constant of dissociation (Kd) for the human V158 
and F158 isotypes was 9.5 and 190 nM, respectively, whereas the Kd value for monkey CD16a 
was 7.5 nM.42 These results suggest that the cynomolgus monkey is a relevant toxicology species 
for BMS-986218. In a GLP 1-month repeat-dose toxicity study, BMS-986218 exhibited 
dose-related GI toxicity at all dose levels (3, 15, and 75 mg/kg/week) and resulted in early 
euthanasia in some animals at 15 and 75 mg/kg/week. BMS-986218 also exhibited dose-related, 
minimal to moderate, lymphohistiocytic inflammation within a variety of organs and tissues. As a 
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result, the 3-mg/kg/week dose was considered as the HNSTD, and the no observed adverse effect 
level was not established in the study. Based on the predicted steady-state exposure at the HNSTD 
(AUC[0-168h] 11,300 μg•h/mL obtained after the last dose of 3 mg/kg/week) and the predicted 
human clearance (4.5 mL/d/kg), the FIH starting dose range of BMS-986218, after applying a 
safety factor of 6-fold, was calculated to be 0.33 (exposure based) to 0.5 mg/kg (dose based). 
Starting Dose Selection Based on Pharmacologic Activity in Human CTLA-4 Knock-in Mice 
Bearing MC38 Syngeneic Tumor43
The anti-mouse CTLA-4 Ab (9D9), with a binding affinity similar to its human counterpart, 
reformatted with either regular or NF hIgG1 (9D9-hIgG1 and 9D9-hIgG1-NF) was used as the
mouse surrogates of ipilimumab and BMS-986218, respectively. These molecules were studied 
for anti-tumor efficacy in human FcR knock-in mice bearing MC38 syngeneic tumors. The 
relationship between systemic exposure (AUC from 0 to 21 days [AUC (0-21d)]) and anti-tumor 
efficacy (the percentage of tumor growth inhibition [%TGI]) was explored to project a human 
efficacious dose and subsequently the FIH starting dose (Figure 5.5.1.1-1). Based on the 
exposure-efficacy analysis, 9D9-hIgG1-NF appeared to be 10-fold more potent than 9D9-hIgG1 
(eg, a 10-fold lower dose is needed to achieve the same efficacy).
Figure 5.5.1.1-1:
Exposure and Efficacy Relationship of 9D9-hIgG1 and 9D9-hIgG1NF 
in Human CTLA4 KnockIn MC38 Mouse Tumor Model
AUC_21d = area under the curve from time zero to 21 days; EAUC50 = area-under-the-concentration-time curve 
producing 50% of the maximum effect; Emax = maximum effect.
At the exposure (AUC[0-21d]) of 588 μg•d/mL, 9D9-hIgG1-NF is expected to reach 90% TGI. 
Targeting the same exposure in humans and assuming that the human PK of BMS-986218 is the 
same as that of ipilimumab (CL of 4.5 mL/d/kg), the human efficacious dose was projected to be 
2.6 mg/kg. Subsequently, targeting the mouse exposure corresponding to 20% TGI, the FIH 
starting dose was predicted to be 0.2 mg/kg. 
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Starting Dose Selection Based on Ipilimumab Clinical Exposure and Response of Safety 
Analysis in Melanoma Patients44
An ER of safety analysis conducted with ipilimumab data from previously treated advanced 
melanoma participants showed that, the probability of Grade 3+ imAEs occurred at 
approximately 3% in participants receiving 0.3 mg/kg.44 The probability of Grade 3+ imAEs 
increased to 11% and 23% at ipilimumab doses of 3 and 10 mg/kg, respectively. Targeting similar 
Grade 3+ imAE rates as ipilimumab at 0.3 mg/kg and considering a 10-fold improvement in 
anti-tumor efficacy of BMS-986218 over ipilimumab (based on anti-tumor efficacy studies using 
mouse surrogates), the FIH starting dose was selected to be 0.03 mg/kg (2-mg flat dose).
Starting Dose Calculated from the In Vitro Cytokine Release Assay20
The in vitro cytokine release of BMS-986218 was tested in both soluble and dry-coated assay 
formats. In the soluble assay, minor NK-cell activation was observed at concentrations 
≥75 μg/mL; therefore, the no-effect level was 7.5 μg/mL. In the dry-coated assay, the no-effect 
level was estimated to be 1 μg/mL (based on the assay format of 0.3 μg BMS-986218 dry-coated 
in the well containing 0.3 mL buffer). At a higher concentration, NK cells were activated 
(ie, increase of %CD69+ and CD25+ NK cells), with an increase in the following cytokines:  IL1β, 
IL6, IL8, IFN-γ, and TNF-α. BMS-986218 did not cause T-cell activation and corresponding IL2 
release, which is a hallmark of TGN1412 superagonistic activity.45 The NK cell activation and 
subsequent cytokine release by the enhanced Fc effector function of immobilized BMS-986218 
indicate a potential increased risk of infusion reactions and cytokine release reactions that are 
common for antibodies with enhanced Fc effector function but manageable clinically.46 To 
mitigate any NK cell activation-related safety risks at the starting dose, a human starting dose 
targeting the Cmax equal to the no-effect level of 1 μg/mL (assuming a plasma volume of 
40 mL/kg) was calculated to be 0.04 mg/kg. At the starting dose, the Cmax is also 7.5-fold lower 
than the no-effect level from the soluble assay (7.5 μg/mL) to ensure the safety at the first dose.
Additional Considerations
Beyond the in vivo anti-tumor efficacy data using mouse surrogates, various in vitro activity 
evaluations also support the potency improvement of BMS-986218 over ipilimumab. Compared 
to ipilimumab, BMS-986218 had an equivalent binding affinity to human CTLA-4 but 
approximately 30-fold higher affinity to human CD16a. For example, the SPR Kd of ipilimumab 
for the human CD16a V158 and F158 isotypes was 310 and 4600 nM, respectively, whereas the 
corresponding Kd for BMS-986218 was 9.5 and 190 nM, respectively. The increased affinity of 
BMS-986218 to human CD16a is also in line with the results from an in vitro ADCC assay 
(concentration-dependent ADCC response with BMS-986218, but no significant ADCC with 
ipilimumab in 3 donors)47 and a SEB-stimulated immune activation analysis (maximum 
response/EC50 of BMS-986218 vs ipilimumab:  average 15-fold in 8 donors).48 Therefore, when 
compared with ipilimumab, a 10-fold potency improvement applied to the FIH starting dose of 
BMS-986218 is well justified.
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Conclusion
In summary, the totality of the nonclinical toxicology and pharmacology data of BMS-986218 as 
well as the clinical safety data of ipilimumab were considered in the selection of the FIH starting 
dose. The starting dose of 0.03 mg/kg (2-mg flat dose), derived from ipilimumab clinical safety 
data at 0.3 mg/kg with a 10-fold activity correction (based on anti-tumor efficacy data generated 
with mouse surrogates), is lowest among the 4 approaches used. This dose is about 6- to 10-fold 
below the starting dose calculated from toxicology- and pharmacology-based methods and is also 
supported by the no-effect level from the in vitro cytokine release assay. Therefore, 0.03 mg/kg 
converted to a flat dose of 2 mg using a body weight of 70 kg, is recommended as the FIH starting 
dose for BMS-986218.
5.5.2
Rationale for Dose Selection and Dosing Schedule
The dosing schedule for each part of Study CA022001 is summarized in Table 5.5.2-1, and the 
rationale for dose selection is presented in the following sections.
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Table 5.5.2-1:
Dosing Schedule by Study Part
Study Part
Tumor Types
Dose
Dose Schedule
Part 1A
all solid tumors
2, 4, 7, 20, 40, 70, 100, 150 and 200 mg
Q4W
select solid tumors
10, 20, 35, 50, 75 and 100 mg
Q2W
Part 1B
select solid tumors
BMS-986218 starting at 20 mg
Q4W
nivolumab 480 mg
Q4W
Part 2A
cutaneous melanomaa
ipilimumab 3 mg/kg
Q3W 
BMS-986218 at 7 mg 
Q4W
BMS-986218 at 20 mg
Q4W
BMS-986218 at 70 mg
Q4W
Part 2B
NSCLCb
BMS-986218 at 7 mg 
Q4W
BMS-986218 at 20 mg
Q4W
BMS-986218 at 70 mg
Q4W
Part 2C
NSCLC
BMS-986218 at doses not to exceed MTDc
Q4W
Nivolumabd
Q4W
Part 2D
MSS CRC
BMS-986218 at doses not to exceed MTDc
Q4W
Nivolumabd
Q4W
a Participants must have received prior immunotherapy with an anti-PD-1 or anti-PD-L1 containing regimen and 
must have progressive or recurrent disease after prior PD-1/PD-L1 directed therapy. Participants must not have 
received prior anti-CTLA-4 therapy.
b Participants must have received prior immunotherapy with an anti-PD-1 or anti-PD-L1 containing regimen. Prior 
anti-CTLA-4 is allowed, but for no more than 20% of participants.
c The dose(s) of BMS-986218 selected for Part 2C and Part 2D will be based on the preliminary safety, tolerability, 
efficacy, PK, and pharmacodynamic data.  Refer to Section 5.1.2.4.
d Nivolumab combination dose to be defined from Part 1B; 1 or 2 combination dose regimens will be tested.
5.5.2.1
BMS-986218
A flat dose (mg) of BMS-986218 will be used in this study instead of a body size-based (ie, body 
weight or body surface area) dose. Therapeutic mAb doses have been routinely calculated on a 
body size basis. This practice assumes that dosing by body size significantly reduces variability in 
therapeutic mAb exposure.49 However, recent analyses of marketed and experimental mAbs have 
demonstrated that body size-based dosing did not always offer advantages over flat dosing in 
reducing exposure variability. Many mAbs are target-specific with a relatively large therapeutic 
window that increases the tolerability of exposure variability. Additionally, patient-specific, 
disease-specific, and physiologic characteristics often contribute to exposure variability, resulting 
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in a generally smaller contribution of body size. Therefore, the dosing paradigm for mAbs should 
be assessed in the context of all of these unique characteristics.
With either dosing strategy, bias with respect to exposure is expected to occur in the extremes of 
the body weight distribution. In general, body size-based dosing could result in higher mAb 
concentrations in the heaviest participants (eg, 90th percentile), whereas flat dosing could lead to 
higher mAb concentrations in the lightest participants (eg, 10th percentile). Body weight 
distribution data from a clinical trial database of over 2500 adults with solid or hematologic cancers 
suggested a log-normal distribution of body weight with median, 10th percentile, and 
90th percentile of 78 kg, 56 kg, and 112 kg, respectively.50 To minimize the potential risk of higher 
exposures in the lowest body weight participants, the flat doses of BMS-986218 will be based on 
a body weight of 70 kg. 
In addition to the above rationale, flat dosing offers practical advantages over body size-based 
dosing, including a convenient approach with respect to pharmacy preparation and clinical
administration, and is also more likely to reduce the potential for dosing errors related to body 
size-based calculations.49 Because the magnitude of the impact of body size on the human PK of 
BMS-986218 is not yet determined, the PK and safety data from the Phase 1/2a study will be 
evaluated to validate the flat dosing approach. If appropriate, based on the totality of the data, the 
Sponsor will consider a revision of the flat dosing strategy.
BMS-986218 will be administered Q4W. This dosing frequency is supported by the projected 
human T-HALF for BMS-986218 of 15 days. In addition, it complements the Q4W dosing 
regimen planned in the Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B) and the BMS-986218 Cohort Expansion - Combination Therapy (Part 2C and Part 2D), 
thereby simplifying study logistics for both participants and Investigators.
In addition to Q4W dosing, an alternative schedule of administration of Q2W will be explored to 
characterize the safety and PK of BMS-986218 in participants with selected tumor types that may 
be more likely to have higher Treg levels at baseline. Q2W dosing may be the more relevant dosing 
frequency to achieve the pharmacodynamic goals of the program, given that Tregs are depleted 
within the first few days of BMS-986218 dosing and recover rapidly during the second week, as 
observed in preclinical models. Based on the PK data obtained from the Q4W dosing schedule, 
Q2W dosing will start at the AUC equivalent of a dose level that has cleared safety in the Q4W 
dosing cohort and continue evaluating higher doses up to the MTD.
Additionally, alternative BMS-986218 schedules of administration may also be explored. The dose 
level for such schedules will be based on the PK data obtained from the Q4W dosing schedule and 
will not exceed the MTD. 
5.5.2.2
Nivolumab
In CA209004, a Phase 1b, open-label study of nivolumab in combination with ipilimumab in 
previously treated and untreated subjects with unresectable Stage III or Stage IV malignant 
melanoma, the following dose levels were evaluated during dose escalation:  nivolumab 0.3 mg/kg 
+ ipilimumab 3 mg/kg, nivolumab 1 mg/kg + ipilimumab 3 mg/kg, nivolumab 3 mg/kg + 
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ipilimumab 1 mg/kg, and nivolumab 3 mg/kg + ipilimumab 3 mg/kg. In CA209004, the nivolumab 
3 mg/kg + ipilimumab 3 mg/kg cohort exceeded the MTD per protocol. Both nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg and nivolumab 3 mg/kg + ipilimumab 1 mg/kg had similar clinical activity 
and acceptable safety. ER of efficacy analyses for nivolumab monotherapy across doses of 1 to 
10 mg/kg revealed similar clinical activity (flat ER relationship), whereas ER of efficacy analyses 
for ipilimumab monotherapy across doses of 0.3, 3, and 10 mg/kg demonstrated increasing activity 
with an increase in dose and exposure. These data suggest that, in combination, a 3-mg/kg dose of 
ipilimumab may be more clinically impactful than a 3-mg/kg dose of nivolumab. However, for 
ipilimumab monotherapy, ER analyses of AEs leading to discontinuation or death and Grade 3+ 
imAEs demonstrated a higher risk of these events with increases in dose and exposure. A dose of 
3 mg/kg of ipilimumab Q3W for 4 doses plus 1 mg/kg of nivolumab Q3W for 4 doses, followed 
by 3 mg/kg nivolumab Q2W until progression, was selected for further development following 
CA209004 and was eventually approved for the treatment of advanced melanoma.
A similar dose finding approach will be undertaken in the current protocol. During combination 
therapy dose escalation (Part 1B), BMS-986218 starting at 1 dose level below the current safety-
cleared dose from the BMS-986218 Monotherapy Escalation (Part 1A) Q4W cohort will be studied 
in combination with nivolumab in order to identify a clinically tolerable combination dosing 
regimen that can be further evaluated in dose expansion. The nivolumab dose will be 480 mg 
Q4W, with de-escalation to 240 mg Q4W permitted in Part 1B, if agreed upon by the Sponsor and 
Investigators. There will be no intra-participant dose reductions of nivolumab allowed. In addition, 
if agreed upon by the Sponsor and the study Investigators, intermediate doses of BMS-986218 
and/or nivolumab may be studied.
A nivolumab flat dose of 240 mg Q2W was approved in the US as monotherapy for unresectable 
or metastatic melanoma, metastatic NSCLC, and advanced RCC, and as maintenance therapy for 
unresectable or metastatic melanoma after induction therapy with nivolumab 1 mg/kg plus 
ipilimumab 3 mg/kg Q3W for 4 doses. Flat dosing of nivolumab was supported using PK and 
exposures characterized by integrated population pharmacokinetic (PPK) analyses of data from 
several Phase 1, 2, and 3 clinical trials of nivolumab monotherapy at doses ranging from 0.1 to 
10 mg/kg. Nivolumab CL and Vss were found to increase with increasing body weight; however, 
these increases were less than proportional, indicating that mg/kg dosing represents an 
over-adjustment for the effect of body weight on nivolumab PK. Using the same PPK model, 
nivolumab exposures for flat (mg) dosing regimens (ie, 240 mg Q2W, 360 mg Q3W, and 480 mg 
Q4W) were simulated and evaluated against exposure data for nivolumab 3 mg/kg Q2W and 
10 mg/kg Q2W doses. At these flat doses, simulated median (90% prediction interval [PI]) average 
steady state concentrations (Cavgss) were predicted to be similar (< 10% difference) to the median 
(90% PI) Cavgss for nivolumab 3 mg/kg Q2W in participants weighing 80 kg, which is the 
approximate median body weight of participants included in the PPK analyses described above. 
The predicted median (90% PI) steady-state peak concentrations were also predicted to be lower 
than those for nivolumab 10 mg/kg Q2W, which has been shown to be well tolerated. Given the 
PK, safety, and efficacy data for nivolumab monotherapy (mg/kg dosing) and the simulated flat 
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dosing exposure data described above, a nivolumab flat dose of 480 mg Q4W will be examined in 
combination with BMS-986218 in this study. 
5.5.2.3
Rationale for Ipilimumab and Nivolumab 30-minute Infusions
Ipilimumab is currently approved for IV administration over 90 minutes. Recently, Momtaz et al. 
retrospectively reviewed computerized pharmacy records at their institution of all patients with 
metastatic solid tumor malignancies who received at least 1 dose of ipilimumab 3 or 10 mg/kg 
over 90 minutes between 01-Apr-2008 and 30-Jun-2013.51 They found a low incidence of 
infusion-related reactions (IRRs):  2.2% and 4.3% for ipilimumab 3- and 10-mg/kg doses, 
respectively (P = 0.22, Fisher’s exact test).51 This finding led the Investigators to prospectively 
evaluate ipilimumab 3 mg/kg administered intravenously over 30 minutes. In the first 120 patients 
evaluated, the incidence of IRR was 5.8%, and the few reactions that were observed occurred at 
the second dose of ipilimumab.51 Two of the 7 IRRs did not occur during the infusion. In addition, 
6 of the 7 IRRs were Grade 2, and in no case were IRRs dose limiting. The Investigators concluded 
that the incidence of IRRs in patients receiving ipilimumab 3 mg/kg intravenously over 30 minutes 
was acceptably low although slightly higher than for the standard 90-minute infusion.51 IRRs were 
managed according to institutional guidelines that included premedication with diphenhydramine 
and/or corticosteroids. It was concluded that ipilimumab 3 mg/kg can be safely infused over 30 
minutes with an acceptable and manageable low incidence of IRRs.51 In addition, after an IRR, 
patients can safely receive additional doses of ipilimumab with premedication.51
Nivolumab is currently approved for IV administration over 60 minutes. The impact of infusion 
time on nivolumab safety was assessed in a substudy conducted as part of an ongoing 
community-based trial (ie, CheckMate 153 [CA209153]) in participants with previously treated 
advanced or metastatic NSCLC.52 In the substudy, 322 participants received nivolumab 3 mg/kg 
IV Q2W as a 30-minute infusion, and 355 participants received the same nivolumab regimen as a 
60-minute infusion.
Overall, the safety profiles between the 30- and 60-minute infusion groups were similar. 
Any-grade treatment-related AEs were reported in 53% and 51% of participants given 30- or 
60-minute infusions, respectively. Grade 3 to 4 treatment-related AEs were reported in 12% of 
participants in each infusion group. Among select AEs of any cause, Grade 3 to 4 events were 
comparable between infusion groups in the pulmonary (3% and 2%), hepatic (2% and 3%), and 
GI (2% and 2%) categories. Hypersensitivity/infusion reactions of any cause were reported in 
8 (2%) and 5 (1%) participants administered 30- and 60-minute infusions, respectively. The 
incidence of Grade 3 to 4 hypersensitivity/infusion reactions was < 1% in each infusion group. 
Hypersensitivity/infusion reactions were managed either through dosing interruptions 
(8 participants given 30-minute infusions and 3 participants given 60-minute infusions), 
discontinuations (1 participant given a 30-minute infusion and 2 participants given 60-minute 
infusions), or administration of systemic corticosteroids (3 participants given 30-minute infusions 
and 1 participant given a 60-minute infusion). In addition, population PK modelling demonstrated 
similar predicted Cmax after the first nivolumab dose and at steady state in both infusion groups, 
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suggesting that a 30-minute infusion does not pose an increased safety risk due to an increase in 
nivolumab Cmax.
In conclusion, ipilimumab and nivolumab can be safely administered as 30-minute infusions, with 
a low incidence of infusion-related AEs. Given these findings, 30-minute infusions are being 
implemented across the ipilimumab and nivolumab development programs, including the FIH 
study CA022001.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met prior to dosing on Day 1. No 
exceptions will be granted. This study permits the re-enrollment of a participant that has 
discontinued the study as a pretreatment failure. If re-enrolled, the participant must be re-consented 
and meet all inclusion/exclusion criteria.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The participant must sign the ICF prior to the performance of any study-related procedures 
that are not considered part of standard of care. 
b)
 
2) Type of Participants and Target Disease Characteristics
a) Participants must be at least 18 years old and have histologic or cytologic confirmation of 
a solid tumor that is advanced (metastatic, recurrent and/or unresectable) with measurable 
disease per RECIST v1.1 (Appendix 5) or per PCWG 3 criteria for prostate (Appendix 12)
and have at least one soft-tissue lesion 
.
b) Eastern Cooperative Oncology Group Performance Status of 0 or 1 (Appendix 6).
c) The BMS-986218 Monotherapy Escalation (Part 1A):  
i)
Not applicable per Revised Protocol 03. All solid tumor histologies will be permitted 
during dose escalation, except for participants with primary central nervous system 
(CNS) tumors or tumors with CNS metastases as the only site of active disease.
ii) Not applicable per Revised Protocol 03. Participants must have received, and then 
progressed, relapsed, or been intolerant to all standard treatment regimens with proven 
survival benefit in the advanced or metastatic setting according to tumor type, if such 
a therapy exists. 
iii) All solid tumor histologies will be permitted during dose escalation in the Q4W dosing 
schedule, except for participants with primary CNS tumors or tumors with CNS 
metastases as the only site of active disease.
iv) In the Q2W dose escalation schedule, select solid tumor histologies will be permitted 
during dose escalation, except for participants with CNS metastases as the only site of 
active disease. The included histologies will be NSCLC (squamous or
adenocarcinoma), gastric adenocarcinoma (including gastroesophageal [GE] junction), 
TNBC, colorectal cancer (CRC; adenocarcinoma), pancreatic adenocarcinoma, 
metastatic castrate resistant prostate adenocarcinoma, urothelial carcinoma, or SCCHN 
(oral cavity, pharyngeal, oropharyngeal, hypopharynx, or laryngeal tumors only). Any 
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other cancers of the head and neck, including salivary gland and neuroendocrine 
tumors, are excluded from enrollment. Histologically confirmed recurrent or metastatic 
carcinoma of the nasopharynx, squamous cell carcinoma (SCC) of the skin of head and 
neck, and non-squamous histologies are not allowed. Additional tumor histologies may 
also be included by the Sponsor.
(1) Not applicable per Protocol Amendment 01 US: An additional group of 
participants with advanced stage cutaneous melanoma will also be enrolled. Other 
types of melanoma (eg ocular, mucosal) are not permitted.
v) Participants, other than those with cutaneous melanoma, must have received, and then 
progressed, relapsed, or become intolerant to, at least 2 standard treatment regimens 
with proven survival benefit in the advanced or metastatic setting according to tumor
type, if such a therapy exists. If the participant refuses or is not eligible for these 
regimens, the reason must be documented in the medical record. For hormone-sensitive 
cancers, all previously received and available hormonal therapies will be considered as 
1 systemic therapy regimen for the purposes of eligibility. For prostate cancer, only 
metastatic castrate resistant prostate cancer is allowed.
vi) Not applicable per Protocol Amendment 01 US: Participants in the Part 1A Q2W 
schedule with advanced stage cutaneous melanoma must have received, and then 
progressed, relapsed or intolerant to at least one standard treatment of proven survival 
benefit in the advanced or metastatic setting. Additionally, participants with cutaneous 
melanoma must have also been offered mutation-directed therapy (including but not 
limited to targeted therapy if BRAF V600 activating mutation) that has proven survival 
benefit if indicated. If a participant refuses such mutation directed therapy, it must be 
documented in the medical record. Only cutaneous melanoma is allowed. All other 
melanoma (eg, ocular, mucosal) are not allowed.
vii)Participants in the Part 1A PD cohort must have advanced stage cutaneous melanoma, 
NSCLC (squamous or adenocarcinoma), MSS CRC, or SCCHN (oral cavity, 
pharyngeal, oropharyngeal, hypopharynx, or laryngeal tumors only). 
Participants with advanced stage cutaneous melanoma must have received, and 
then progressed, relapsed, or become intolerant to at least one standard treatment 
of proven survival benefit in the advanced or metastatic setting. Additionally, 
participants with cutaneous melanoma must have also been offered mutation-
directed therapy (including but not limited to targeted therapy if BRAF V600 
activating mutation) that has proven survival benefit if indicated. If a participant 
refuses such mutation-directed therapy, it must be documented in the medical 
record. Only cutaneous melanoma is allowed. Mucosal and uveal/ocular 
melanomas are not permitted; melanoma with unknown primary site may be 
enrolled if the investigator determines mucosal and uveal/ocular primary sites are 
unlikely. 
Participants with NSCLC (squamous or adenocarcinoma), MSS CRC, or SCCHN 
(oral cavity, pharyngeal, oropharyngeal, hypopharynx, or laryngeal tumors only) 
must have received, and then progressed, relapsed, or become intolerant to at least 
2 standard treatment regimens with proven survival benefit in the advanced or 
metastatic setting according to tumor type, if such therapies exist. If the participant 
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refuses or is not eligible for these regimens, the reason must be documented in the 
medical record.
d) Not applicable per Revised Protocol 03. The Safety Evaluation of Combination Doses of 
BMS-986218 with Nivolumab (Part 1B):
i)
Not applicable per Revised Protocol 03. All solid tumor histologies will be permitted 
during dose escalation, except for participants with primary CNS tumors or tumors with 
CNS metastases as the only site of active disease.
ii) Not applicable per Revised Protocol 03. Participants must have received, and then 
progressed, relapsed, or been intolerant to, all standard treatment regimens with proven 
survival benefit in the advanced or metastatic setting according to tumor type, if such 
a therapy exists.
e) Not applicable per Revised Protocol 03. The Randomized BMS-986218 Monotherapy 
Cohort Expansion in Melanoma (Part 2A):  
i)
Not applicable per Revised Protocol 03. Participants with advanced stage cutaneous 
melanoma who have received all standard therapies with proven survival benefit 
including prior immunotherapy with an anti-PD-1 or anti-PD-L1 containing regimen 
and must have progressive or recurrent disease after prior PD-1/PD-L1 directed 
therapy. Participants must not have received prior anti-CTLA-4 therapy in the 
advanced or metastatic setting. 
f)
Not 
applicable 
per 
Revised 
Protocol 
03.
The 
BMS-986218 
Cohort 
Expansion - Monotherapy (Part 2B):
i)
Not applicable per Revised Protocol 03. Participants must have received, and then 
progressed, relapsed, or been intolerant to, all standard systemic therapies with proven 
survival benefit according to their tumor types in the advanced or metastatic setting, if 
such a therapy exists. The following permitted tumor histologies will be evaluated in 
individual cohorts:  
(1).RCC
(2).Urothelial Carcinoma
(3).Advanced stage PDAC  
g) Not 
applicable 
per 
Revised 
Protocol 
03. 
The 
BMS-986218 
Cohort 
Expansion - Combination Therapy (Part 2C):
i)
Not applicable per Revised Protocol 03. Participants must have received, and then 
progressed, relapsed, or been intolerant to, all standard systemic therapies according to 
their tumor types in the advanced or metastatic setting, if such a therapy exists. 
Participants must be immunotherapy naïve with the exception of tumor types for which 
immunotherapies have proved survival benefits. The following permitted tumor 
histologies will be evaluated in individual cohorts:
(1) NSCLC: all participants with non-squamous histology must have known epidermal 
growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) status. 
Participants with an activating EGFR mutation must have received an EGFR 
tyrosine kinase inhibitor. Participants with an ALK translocation must have 
received an ALK inhibitor.
(2) Gastric adenocarcinoma 
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(3) Urothelial carcinoma
(4) CRC
(5) Participants with advanced stage TNBC 
ii) Not applicable per Revised Protocol 03. Participants with advanced stage cutaneous 
melanoma who have received prior immunotherapy with an anti-PD-1 or anti-PD-L1 
containing regimen and must have progressive or recurrent disease after prior PD-
1/PD-L1 directed therapy. Participants must not have received prior anti-CTLA-4 
therapy in the advanced or metastatic setting. 
iii) Not applicable per Revised Protocol 03. Other tumor types could be considered at the 
time of expansion based on scientific rationale and will be evaluated after the protocol 
has been amended to allow the enrollment in this new tumor specific individual cohort.
h) The Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab (Part 1B):
i)
Select solid tumor histologies will be permitted during dose escalation, except for 
participants with CNS metastases as the only site of active disease. The included 
histologies will be NSCLC (squamous or adenocarcinoma), gastric adenocarcinoma 
(including GE junction), TNBC, CRC (adenocarcinoma), pancreatic adenocarcinoma, 
metastatic castrate resistant prostate adenocarcinoma, urothelial carcinoma, or SCCHN
(oral cavity, pharyngeal, oropharyngeal, hypopharynx, or laryngeal tumors only). Any 
other cancers of the head and neck, including salivary gland and neuroendocrine 
tumors, are excluded from enrollment. Histologically confirmed recurrent or metastatic 
carcinoma of the nasopharynx, SCC or other cancers of the skin of head and neck, and 
non-squamous histologies are not allowed. Additional tumor histologies may also be 
included by the Sponsor.
ii) Participants must have received, and then progressed, relapsed, or been intolerant to at 
least 2 systemic therapy regimens with proven survival benefit in the advanced or 
metastatic setting according to tumor type, where available. If the participant refuses 
or is not eligible for these regimens, the reason must be documented in the medical 
record. However, if anti-PD-1 therapy is approved in a given indication, participants 
are eligible to receive this treatment as part of the combination regimen in this study 
prior to having completed 2 prior systemic therapy regimens after discussion and 
agreement with the Medical Monitor (or designee). For hormone-sensitive cancers, all 
previously received and available hormonal therapies will be considered as 1 systemic 
therapy regimen for the purposes of eligibility. For prostate cancer, only metastatic 
castrate resistant prostate cancer is allowed.
i)
The Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A):  
i)
Participants with advanced stage cutaneous melanoma who have received standard 
therapies with proven survival benefit including prior immunotherapy with an 
anti-PD-1 or anti-PD-L1 containing regimen and must have progressive or recurrent 
disease after prior PD-1/PD-L1 directed therapy. Participants must not have received 
prior anti-CTLA-4 therapy in the advanced or metastatic setting. Additionally, 
participants with cutaneous melanoma must have also been offered mutation-directed 
therapy, if indicated, that has proven survival benefit; if a participant refuses such 
therapy, it must be documented in the medical record. No more than 1 intervening 
therapy is allowed but not required between prior anti-PD-1/anti-PD-L1 containing 
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regimen and BMS-986218. No more than 70% of the randomized participants should 
have had progression of disease within a period of 6 months of start of therapy with 
anti-PD-1/PD-L1 agent. Only cutaneous melanoma is allowed. Mucosal and 
uveal/ocular melanomas are not allowed; melanoma with unknown primary site may 
be enrolled if the investigator determines mucosal and uveal/ocular primary sites are 
unlikely.
j)
The BMS-986218 Cohort Expansion - Monotherapy (Part 2B):
i)
Participants must have received, and then progressed, relapsed, or been intolerant to at 
least 2 standard systemic therapies with proven survival benefit according to their
tumor types in the advanced or metastatic setting, if available. If the participant refuses 
or is not eligible for these regimens, the reason must be documented in the medical 
record. Additionally, participants must have progressed or have recurrent disease after 
prior immunotherapy with anti-PD-1/anti-PD-L1 either by itself or in combination with 
other systemic therapy agents. No more than 1 intervening therapy is allowed but not 
required between prior anti-PD-1/anti-PD-L1 containing regimen and BMS-986218. 
Participants who have been intolerant to prior immunotherapy are excluded. Prior anti-
CTLA4 therapy is allowed for no more than 20% of participants, and details of 
treatment (including dates, doses, and response) must be available.
(1) Lung/NSCLC (adenocarcinoma or squamous cell carcinoma); additionally, for 
NSCLC, all participants with adenocarcinoma must have known EGFR, ALK, and 
ROS-1 status. Participants with an activating EGFR mutation, ALK translocation, 
or ROS-1 mutation must have received appropriate inhibitor therapy.
(2) Other tumor histologies may also be included by the Sponsor.
k) The BMS-986218 NSCLC Cohort Expansion - Combination (Part 2C):
i)
Participants must have received, and then progressed, relapsed, or been intolerant to at 
least 2 standard systemic therapies (including anti-PD-1/anti-PD-L1 therapies) with 
proven survival benefit according to their tumor types in the advanced or metastatic 
setting, if available. If the participant refuses or is not eligible for these regimens, the 
reason must be documented in the medical record. Participants must have progressed 
or have recurrent disease after prior immunotherapy with anti-PD-1/anti-PD-L1 either 
by itself or in combination with other systemic therapy agents. No more than 1 
intervening therapy is allowed but not required between prior anti-PD-1/anti-PD-L1 
containing regimen and BMS-986218. Participants who have been intolerant to prior 
immunotherapy are excluded. Participants must not have received prior anti-CTLA-4 
therapy in the advanced or metastatic setting.
The Sponsor may elect to prioritize enrollment of participants with best overall 
response (BOR) of SD, PR, or CR > than 6 months duration in response to prior anti-
PD-1/anti-PD-L1 treatment.
(1) Lung/NSCLC (adenocarcinoma or squamous cell carcinoma); all participants with 
adenocarcinoma must have known EGFR, ALK, Kirsten rat sarcoma viral 
oncogene homolog (KRAS), and ROS-1 status (when testing is available as per 
country/region standard of care practices), participants with an activating EGFR 
mutation, ALK translocation, or ROS-1 mutation must have received appropriate 
inhibitor therapy (as available per country/region standard of care). Note:  If KRAS 
results are not known, then a sample (tissue of microscopic slides, tissue block,
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) should be sent for testing locally. Circulating
tumor DNA may be used if sequencing or polymerase chain reaction (PCR) results 
are not feasible, with prior Sponsor approval
l)
The BMS-986218 MSS CRC Cohort Expansion - Combination (Part 2D):
i)
Participants must have received and then progressed on or after, or have been intolerant 
or refractory to, at least 1 standard systemic therapy for metastatic and/or unresectable 
disease (or have progressed within 6 months of adjuvant therapy). If the participant 
refuses or is not eligible for these regimens, the reason must be documented in the 
medical record and participant can be enrolled.
(1) Prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan given as single 
regimen or over multiple regimens is required.
(2) Prior treatment with an anti-angiogenic therapy (eg, bevacizumab) is required.
ii) Participants must have known microsatellite instability (MSI) or mismatch repair 
status. Extended RAS (KRAS and NRAS), and BRAF status if known, should be 
documented. 
(1) If known to be RAS wild-type, available treatments with demonstrated benefit (eg,
anti-EGFR therapy) must have been received as prior treatments if consistent with 
approved local standard of care.  
The Sponsor may elect to prioritize enrollment of participants based on mutation 
status to ensure approximately 50 % of patients treated are RAS mutant.
3) Physical and Laboratory Test Findings
a) Adequate hematologic function for participants as defined by the following:
i)
Neutrophils ≥1,500/μL.
ii) Platelets ≥80 × 103/μL (transfusion to achieve this level is not permitted within
2 weeks of first study treatment administration).
iii) Hemoglobin ≥8 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.
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 pharmacodynamic sample collection, and
required study follow-up periods.
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f)
All toxicities attributed to systemic prior anti-cancer therapy other than alopecia must have 
resolved to Grade 1 (National Cancer Institute [NCI] Common Terminology Criteria for 
Adverse Events [CTCAE] version 4.03 [v4.03]) or baseline before administration of study 
drug. 
4) Age and Reproductive Status
a) Males and females aged at least 18 years old.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin) within 24 hours prior to the start of study treatment.
c) WOCBP must agree to follow instructions for method(s) of contraception (Appendix 4) for 
the duration of combination therapy treatment with study treatment BMS-986218 plus 5 
months after the end of study treatment. WOCBP receiving monotherapy treatment with 
BMS-986218 or ipilimumab must agree to follow instructions for method(s) of 
contraception for the duration of monotherapy treatment with BMS-986218, or ipilimumab 
plus 3 months after the end of study treatment. Local laws and regulations may require use 
of alternative and/or additional contraception methods. See Appendix 4.
d) WOCBP who are continuously not heterosexually active are also exempt from 
contraceptive requirements but should still undergo pregnancy testing as described in this 
section.
e) Not applicable per Protocol Amendment 06: Male participants who are sexually active 
with WOCBP must agree to follow instructions for method(s) of contraception 
(Appendix 4) during combination treatment with study treatment BMS-986218 and 
nivolumab, plus 5 half-lives of nivolumab (~ 125 days), plus 90 days (duration of sperm 
turnover), for a total of 215 days post-treatment completion. Males who are sexually active 
with WOCBP must agree to follow instructions for methods of contraception during 
monotherapy treatment with BMS-986218 or ipilimumab plus 5 half-lives (~ 75 days) of 
BMS-986218 or ipilimumab plus 90 days (duration of sperm turnover) for a total of 
165 days post-treatment completion. In addition, male participants must be willing to 
refrain from sperm donation during this time. 
f)
Not applicable per Protocol Amendment 06: Azoospermic males are exempt from 
contraceptive requirements. WOCBP who are continuously not heterosexually active are 
also exempt from contraceptive requirements, but still must undergo pregnancy testing as 
described in this section.
g)
No additional contraceptive measures are required to be used in males.
Investigators shall counsel 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 (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 Exclusions
a) Participants with primary CNS malignancies, or tumors with CNS metastases as the only 
site of disease, will be excluded. Participants with controlled brain metastases; however, 
will be allowed to enroll. Controlled brain metastases are defined as no radiographic 
progression for at least 4 weeks following radiation and/or surgical treatment (or 4 weeks 
of observation if no intervention is clinically indicated), and no longer taking steroids for 
at least 2 weeks prior to first dose of study treatment, and with no new or progressive 
neurological signs and symptoms.
2) Prohibited Treatments
a) Cytotoxic agents, unless at least 4 weeks have elapsed from last dose of prior anti-cancer 
therapy and initiation of study therapy.
b) Non-cytotoxic agents, unless at least 4 weeks or 5 half-lives (whichever is shorter) have 
elapsed from the last dose of prior anti-cancer therapy and the initiation of study therapy. 
If 5 half-lives is shorter than 4 weeks, agreement with the Sponsor/Medical Monitor (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 therapy.
d) Prior participation in an anti-CTLA-4-NF clinical study or therapy. 
e) Participants who have received prior curative radiation therapy must have been completed 
at least 4 weeks prior to study drug administration. Prior focal palliative radiotherapy must 
have been completed at least 2 weeks before study drug administration.
f)
Continued luteinizing hormone-releasing hormone (LHRH)/gonadotropin-releasing 
hormone (GnRH) agonist therapy in men with castration-resistant prostate cancer after 
progression on an initial androgen deprivation regimen is allowed.
g) Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care within 4 weeks prior to 
treatment. If less than 4 weeks have elapsed from the last botanical supplement and the 
initiation of study treatment, the participant can be treated at the Investigator’s discretion 
and after discussion and agreement with the Sponsor/Medical Monitor (or designee). 
i)
Use of marijuana and its derivatives for treatment of symptoms related to cancer or 
cancer treatment are permitted if obtained by medical prescription or if its use (even 
without a medical prescription) has been legalized locally.
3) Medical History and Concurrent Diseases
a) Participants
with
concomitant
second
malignancies
(except
adequately
treated
non-melanomatous skin cancers or in situ urothelial, breast, or cervical cancers) are 
excluded unless a complete remission was achieved at least 2 years prior to study entry,
and no additional therapy is required or anticipated to be required during the study period.
b) Participants with other active malignancy requiring concurrent intervention.
c) Prior organ allograft.
d) Toxicity (except for alopecia) related to prior anti-cancer therapy and/or surgery, unless
the toxicity is either resolved, returned to baseline or Grade 1, or deemed irreversible.
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i)
Any active neuropathy > Grade 2 (NCI Common Terminology Criteria for Adverse 
Events [CTCAE] v4.03).
e) Participants with the following:
i)
Active, known, or suspected autoimmune disease.
(1) Participants with well controlled asthma and/or mild allergic rhinitis (seasonal 
allergies) are eligible.
(2) Participants with the following disease conditions are also eligible:
a.
Vitiligo.
b. Type 1 diabetes mellitus.
c.
Residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement.
d. Euthyroid participants with a history of Grave’s disease (participants with
suspected autoimmune thyroid disorders must be negative for thyroglobulin and 
thyroid peroxidase antibodies and thyroid stimulating immunoglobulin [Ig]
prior to the first dose of study treatment).
e.
Psoriasis not requiring systemic treatment, or conditions not expected to recur
in the absence of an external trigger are permitted to enroll.
ii) History of life-threatening toxicity related to prior immune therapy or any toxicity 
that resulted in permanent discontinuation from prior immune therapy (eg,
anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other Ab or drug specifically
targeting T-cell co-stimulation or immune checkpoint pathways) except those that are
unlikely to re-occur with standard countermeasures (eg, hormone replacement after
adrenal crisis).
iii) Conditions requiring systemic treatment with either corticosteroids > 10 mg daily
prednisone equivalents or other immunosuppressive medications within 14 days of
study treatment administration, except for adrenal replacement steroid doses ≤10 mg 
daily prednisone equivalent in the absence of active autoimmune disease.
(1) Treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating
study treatment is permitted.
iv) Uncontrolled or significant cardiovascular disease including, but not limited, to any
of the following:
(1) Myocardial infarction or stroke/transient ischemic attack within the past 6 months.
(2) Uncontrolled angina within the past 3 months.
(3) Any history of clinically significant arrhythmias (such as ventricular tachycardia,
ventricular fibrillation, or torsades de pointes).
(4) History
of other clinically
significant heart disease
(eg, cardiomyopathy,
congestive
heart
failure
with
New
York
Heart
Association
functional
classification III to IV [Appendix 7], pericarditis, or significant pericardial
effusion).
(5) History of myocarditis, regardless of etiology.
(6) Cardiovascular disease-related requirement for daily supplemental oxygen therapy.
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(7) QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation 
> 480 msec, except for right bundle branch block.
v) History of chronic hepatitis as evidenced by the following:
(1) Positive test for hepatitis B surface antigen.
(2) Positive test for qualitative hepatitis C viral load by polymerase chain reaction 
(PCR).
a.
Participants with positive hepatitis C Ab and negative quantitative hepatitis C
by PCR are eligible. History of resolved hepatitis A virus infection is not an 
exclusion criterion.
b. Additional testing or substitute testing per institutional guidelines to rule out
infection is permitted.
vi) Evidence of active infection that requires systemic antibacterial, antiviral, or
antifungal therapy ≤7 days prior to the first dose of study treatment (except for
viral infections that are presumed to be associated with the underlying tumor type
required for study entry).
vii)Known human immunodeficiency virus (HIV) positive with an acquired 
immunodeficiency syndrome (AIDS) defining opportunistic infection within the last 
year, or a current CD4 count <350 cells/uL. Participants with HIV are eligible if:

they have received antiretroviral therapy (ART) for at least 4 weeks prior to 
treatment assignment as clinical indicated while enrolled on study

they continue on ART as clinically indicated while enrolled on study

CD4 counts and viral load are monitored per standard of care by a local health 
care provider.
Note: Testing for HIV must be performed at sites where mandated by local 
requirements (Appendix 8). HIV-positive participants must be excluded in countries 
where mandated locally. 
viii) Any major surgery within 4 weeks of the first dose of study treatment. Participants
must have recovered from the effects of major surgery or significant traumatic injury
at least 14 days before the first dose of study treatment.
ix) Not applicable per Revised Protocol 03. Receipt of non-oncology vaccines containing
live virus for prevention of infectious diseases within 4 weeks prior to first dose of 
study treatment.
(1) The use of inactivated seasonal influenza vaccines, eg, Fluzone®, will be permitted 
on study without restriction.
x) Receipt of packed red blood cells or platelet transfusion within 2 weeks of the first
dose of study treatment.
xi) Any known or underlying medical, psychiatric condition and/or social reason that, in
the opinion of the Investigator or Sponsor, could make the administration of study 
treatment hazardous to the participants or could adversely affect the ability of the
participant to comply with or tolerate the study.
xii)Participants who have received a live/attenuated vaccine within 30 days of first 
treatment.
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(1) The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted 
on study without restriction.
f)
Women who are pregnant or breastfeeding.
g) Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 
20 days for severe/critical illness prior to C1D1. 
i)
Acute symptoms must have resolved and based on investigator assessment in 
consultation with the medical monitor, there are no sequelae that would place the 
participant at a higher risk of receiving study treatment.
h) Previous SARS-CoV-2 vaccine within 14 days of C1D1. Note: For vaccines requiring more 
than one dose, the full series (eg, both doses of a two-dose series) should be completed 
prior to C1D1 when feasible and when a delay in C1D1 would not put the study participant 
at risk.
i)
Leptomeningeal metastases
4) Allergies and Adverse Drug Reaction
a) History of allergy to study treatment(s) or any of its components.
b) History of severe hypersensitivity reaction to any mAb.
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note:  under specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included as a participant. Strict conditions apply and BMS approval is 
required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
There are no lifestyle restrictions applicable for this study given that the participants will receive 
the study investigational products (IPs) IV. 
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized/entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants; to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements (Appendix 9), as applicable; 
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 that has discontinued the study as a 
pretreatment failure (ie, participant has not been randomized/has not been treated). 
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Retesting of laboratory parameters and/or other assessments during the extended screening period 
will be allowed.
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1 may be repeated in an 
effort to find all possible well-qualified participants. Consultation with the Medical Monitor (or 
designee) may be needed to identify whether repeat testing of any particular parameter is clinically 
relevant.
Testing for asymptomatic SARS-CoV-2 infection by reverse transcription polymerase chain 
reaction (RT-PCR) or viral antigen is not required. However, some participants may develop 
suspected or confirmed symptomatic SARS-CoV-2 infection, or be discovered to have 
asymptomatic SARS-CoV-2 infection during the screening period. In such cases, participants may 
be considered eligible for the study after meeting all inclusion/exclusion criteria related to active 
infection, and after meeting the following criteria: 
•
At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive RT-PCR or viral antigen test result, and
•
At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and
•
Acute symptoms (eg, cough, shortness of breath) have resolved and 
•
In the opinion of the investigator, there are no SARS-CoV-2 infection sequelae that may place 
the participant at a higher risk of receiving investigational treatment.
•
In the instance of a SARS-CoV-2 infection during screening, the screening period may be 
extended beyond the protocol-specified timeframe with Medical Monitor approval. 
•
Any screening tests already performed which could potentially be affected by the SARS-CoV-
2 infection or its complications on an individual basis and agreed upon with the Medical 
Monitor (eg, safety labs, oxygen saturation, chest computed tomography [CT] scan) should be 
repeated.
7
TREATMENT
7.1
Treatments Administered 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.
An IP, also known as investigational medicinal product in some regions, is defined as a 
pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) differently than the authorized form, or used for an unauthorized 
indication, or when used to gain further information about the authorized form.
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Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, are considered as non-IPs.
In this protocol, IPs are the following:  
•
BMS-986218 
•
Nivolumab
•
Ipilimumab
All 3 drugs used in this open label study qualify as IPs, as per previous text, and their description 
and storage information are described in Table 7.1-1.
Table 7.1-1:
Investigational Product Description 
Product 
Description / Class 
and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage Conditions
(per Label)
BMS-986218 for 
injection
200 mg/vial
(20 mg/mL)
IP
Open Label
Vial
Store at 2°C to 8°C, 
protected from light
Nivolumab
(BMS-936558) 
solution for 
injection
100 mg/vial
(10 mg/mL)
IP
Open Label
Vial
2°C to 8°C. Protect from 
light and freezing
Nivolumab 
(BMS-936558) 
solution for 
injection
40 mg/vial
(10 mg/mL)
IP
Open Label
Vial
2°C to 8°C. Protect from 
light and freezing
Ipilimumab 
(BMS-734016) 
solution for 
injection
200 mg/vial
(5 mg/mL)
IP
Open Label
Vial
2°C to 8°C. Protect from 
light and freezing
7.1.1
BMS-986218
There will be no intra-participant dose escalations or reductions of BMS-986218 allowed. 
Participants may be dosed within the window per Table 2-2, Table 2-3, and Table 2-4.
Participants should be carefully monitored for infusion reactions during BMS-986218 
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.6.5.
Doses of BMS-986218 may be interrupted, delayed, or discontinued, depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed.
BMS-986218 injection is to be administered as an IV infusion through a 0.2-micron pore size, 
low-protein binding in-line filter at the protocol-specified doses and infusion times. It is not to be 
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administered as an IV push or bolus injection. Prior to infusion, the BMS-986218 injection is 
diluted with 0.9% sodium chloride injection (normal saline) to required concentrations. 
Detailed instructions for preparation, handling, dilution, and infusion of BMS-986218 injection 
may be provided in the Pharmacy Manual or in the IB.6 Care must be taken to assure sterility of 
the prepared solution, as the product does not contain any antimicrobial preservative or 
bacteriostatic agent.
7.1.2
Nivolumab
No intra-participant dose escalations or reductions of nivolumab are allowed. Participants may be 
dosed within the window per Table 2-2.
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.6.5.
Doses of nivolumab may be interrupted, delayed, or discontinued, depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed.
Nivolumab infusion must be promptly followed by a flush of diluent to clear the line. Care must 
be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. 
7.1.3
Ipilimumab
There will be no intra-participant dose escalations or reductions of ipilimumab allowed. 
Participants may be dosed within the window per Table 2-4.
Participants should be carefully monitored for infusion reactions during ipilimumab 
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.6.5.
Doses of ipilimumab may be interrupted, delayed, or discontinued, depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed.
Ipilimumab is to be administered as a 30-minute IV infusion and may be infused using a volumetric 
pump with a 0.2- to 1.2-micron low-protein binding in-line filter at the protocol-specified dose. At 
the end of the infusion, flush the line with a sufficient quantity of diluent.
Detailed instructions for preparation, handling, dilution, and infusion of ipilimumab injection may 
be provided in the Pharmacy Manual or IB. Care must be taken to assure sterility of the prepared 
solution, as the product does not contain any antimicrobial preservative or bacteriostatic agent.
7.2
Handling and Dispensing
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and BMS should be contacted immediately.
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IP documentation must be maintained that includes all processes required to ensure drug is 
accurately administered. This includes documentation of drug storage, administration and, as 
applicable, storage temperatures, reconstitution, and use of required processes (eg, required 
diluents, administration sets).
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by 
the Sponsor and should be purchased locally if permitted by local regulations.
Please refer to the current version of the IB and/or pharmacy manual for complete storage, 
handling, dispensing, and infusion preparation information for BMS-986218, nivolumab, and 
ipilimumab.
7.3
Schedule of Dose for Each Investigational Product
The dosing schedule for each IP is detailed below in Table 7.3-1 all study parts. 
All participants will be monitored continuously for AEs while on study treatment. Treatment 
modifications (eg, dose delay, reduction, re-treatment, or discontinuation) will be based on specific 
laboratory and AE criteria, as described in Section 7.5. 
Table 7.3-1:
Selection and Timing of Dose for All Study Parts
Study 
Treatment
Flat Dose 
Levels
Frequency of 
Administration
Route of 
Administration
Infusion Time
(Minutes)
BMS-986218
2, 4, 7, 20, 
40, 70, 100, 
150 or 
200 mg
Q4W
IV
Doses administered over
approximately 30 minutes. 
BMS-986218
10, 20, 35, 
50, 75 or 
100 mg
Q2W
IV
Doses administered over
approximately 30 minutes. 
Ipilimumab
3 mg/kga
Q3W 
(up to a maximum 
of 4 doses)
IV
Approximately 30 minutes
Nivolumab
480 mg
Q4Wb
IV
Approximately 30 minutes
a Dosing calculations should be based on the body weight assessed at Cycle 1 Day 1 prior to the first dose of 
ipilimumab. If the participant’s weight on the day of dosing differs by > 10% from the weight used to calculate the 
prior dose, the dose must be recalculated.
b For participants in the Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab (Part 1B) and the 
BMS-986218 Cohort Expansion - Combination Therapy (Part 2C and Part 2D), a 30-minute infusion of nivolumab 
will be followed by a 30-minute observation period, followed by a 30-minute infusion of BMS-986218 and a 
60-minute observation period following the first 3 infusions for each participant.
7.4
Method of Treatment Assignment
During the screening visit, the investigative site will call into the enrollment option of the IRT 
designated by BMS for assignment of a 5-digit participant number that will be unique across all 
sites. Enrolled participants, including those not dosed, will be assigned sequential participant 
numbers 
. The patient identification number 
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(PID) will ultimately be comprised of the site number and participant number. For example, the 
first participant screened (ie, enrolled) at site number 1, will have a PID of 
. Once it is 
determined that the participant meets the eligibility criteria following the screening visit, the 
investigative site will call the IRT to centrally assign the participant into the open dose panel. If 
Part 1 is open upon the decision to initiate Part 2, treatment in the 2 parts will occur in parallel.
In the Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma 
(Part 2A), all participants will be centrally randomized evenly across study arms, which will 
include:  BMS-986218 monotherapy at 7 mg, 20 mg, 70 mg Q4W or ipilimumab 3 mg/kg Q3W 
(maximum of 4 doses).
In the Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B), participants will be 
randomized evenly across study arms, which will include:  BMS-986218 at 7 mg, 20 mg, and 
70 mg Q4W.
In Part 2A and Part 2B, if it is decided based on a preliminary assessment of anti-tumor activity 
that not all arms would need to continue enrollment, randomization would continue only in the 
arm(s) that remain open. In addition, more subjects may be enrolled in selected arm(s) as specified 
in Section 5.2 to better assess an initial signal.
In Part 2C Combination Expansion, multiple doses may be open concurrently. In that case, 
treatment assignments will alternate between the dose levels, with consecutively treated 
participants assigned to different parts through IRT whenever possible. If there are no openings 
available in the dose level to which the participant would be assigned by this algorithm, then the 
subject will be assigned to the next open dose.
In Part 2D Combination Expansion, participants will be assigned to one dose.
In Part 2, BMS-986218 Q4W will be administered for a maximum duration of 2 calendar years, 
and ipilimumab Q3W will be administered for a maximum of 4 doses.
For Part 2, participant replacement will not be allowed for participants who are discontinued after 
dosing. 
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
7.5
Blinding
This is an open-label study and randomized in Part 2. Designated personnel of the Sponsor will 
have access to treatment and/or randomization assignments prior to database lock to facilitate data 
analysis (see Section 10.3.9), as well as the bioanalytical analysis of PK and immunogenicity 
samples. A bioanalytical scientist in the Bioanalytical Sciences department of BMS 
Research & Development (or a designee in the external central bioanalytical laboratory) will have 
access to the randomized treatment assignments in order to minimize unnecessary bioanalytical 
analysis of samples.
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7.6
Dosage Modification
Intra-participant dose escalation/reduction of BMS-986218, 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.
7.6.1
Dose-limiting Toxicities
For the purpose of guiding dose escalation, DLTs will be defined based on the incidence, intensity, 
and duration of AEs that are possibly related to study treatment. The DLT period will be 8 weeks 
(56 days) in both the BMS-986218 Monotherapy Dose Escalation (Part 1A) and the Safety 
Evaluation of Combination Doses of BMS-986218 with Nivolumab (Part 1B). Any toxicities that 
occur beyond the DLT period will be accounted for in making final dose level decisions.
Participants receiving 2 doses of BMS-986218 and have completed or who discontinued due to a 
DLT in the 8-week DLT period will be considered as DLT-evaluable participants for BMS-986218 
monotherapy. Participants receiving either 2 doses each of BMS-986218 and nivolumab, or 
participants who discontinued due to a DLT in the 8-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 both monotherapy and combination therapy will not be considered as 
DLT-evaluable participants and may be replaced with a new participant at the same dose level. 
Participants who have received 2 doses and withdraw from the study during the last week of the 
DLT evaluation period for reasons other than a DLT in both monotherapy and combination therapy 
may be considered as DLT-evaluable. Participants who are dose delayed during the DLT 
evaluation period for reasons other than a DLT in both monotherapy and combination therapy 
could be considered as DLT-evaluable participants if they received 2 doses and completed at least 
2 full cycles of therapy 4 weeks each, with a maximum of 12 weeks for the total duration, including 
delays.
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. Participants who
withdraw from the study during the 8-week DLT evaluation period for reasons other than a DLT
may be replaced with a new participant at the same dose level. The incidence of DLT(s) during
the 8-week DLT evaluation period will be used in dose escalation decisions and to define the
MTD. AEs occurring after the DLT period will be considered for the purposes of defining the
RP2D upon agreement between the Sponsor, Medical Monitor (or designee), and Investigators.
Participants experiencing a DLT will not be re-treated with study treatment and will enter the
Safety Follow-up Period of the study. DLTs occurring after the 8-week DLT observation period
will be accounted for in determining the dose levels for expansion.
AEs will be graded according to the NCI CTCAE v4.03.
7.6.1.1
Gastrointestinal Dose-limiting Toxicity
Any of the following study treatment-related events will be considered a GI DLT:
•
Grade 2 colitis that lasts longer than 5 days.
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Grade ≥3 diarrhea or colitis, regardless of duration.
7.6.1.2
Hepatic Dose-limiting Toxicity
Any of the following study treatment-related events will be considered a hepatic DLT:
•
Grade 4 elevations in serum transaminases (AST and ALT), alkaline phosphatase (ALP), or
total bilirubin.
•
Grade 3 elevations in serum AST, ALT, or ALP that last longer than 5 days or are associated 
with clinical symptoms or bilirubin > 2 × ULN in the absence of cholestasis.
•
Grade 2 elevations in AST or ALT with symptomatic liver inflammation (eg, right upper
quadrant tenderness, jaundice).
•
AST or ALT > 3 × ULN and concurrent total bilirubin > 2 × ULN without initial findings of
cholestasis (elevated ALP; eg, findings consistent with Hy’s law or FDA definition of potential
drug-induced liver injury [p-DILI]). Note that this specific category of DLT uses ULN 
rather than CTCAE grade for definition.
Any of the following study treatment-related events will be considered a hepatic DLT for 
participants with HCC:
•
ALT or AST > 20 × ULN, regardless of duration.
•
ALT or AST > 10 × ULN for greater than 2 weeks.
•
Total bilirubin > 8 × ULN regardless of duration for participants with elevated bilirubin at 
study entry or > 5 × ULN for participants with normal bilirubin at study entry.
•
ALT or AST > 3 × ULN and concurrent total bilirubin > 2 × ULN.
7.6.1.3
Hematologic Dose-limiting Toxicity
Any of the following study treatment-related events will be considered a hematologic DLT:
•
Grade 4 neutropenia ≥7 days in duration.
•
Grade 4 thrombocytopenia.
•
Grade 3 thrombocytopenia with bleeding or any requirement for platelet transfusion.
•
Febrile neutropenia that lasts longer than 48 hours. 
•
Grade 3 hemolysis (ie, requiring transfusion or medical intervention such as steroids).
7.6.1.4
Dermatologic Dose-limiting Toxicity
Any of the following study treatment-related events will be considered a dermatologic DLT:  
•
Grade 4 rash.
•
Grade 3 rash if no improvement (ie, resolution to ≤ Grade 1) after a 1- to 2-week infusion 
delay.
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7.6.1.5
Other Dose-limiting Toxicities
Any of the following events will be considered a DLT:
•
Grade 2 drug-related uveitis, episcleritis, iritis eye pain, or blurred vision that does not respond
to topical therapy and does not improve to Grade 1 severity within the re-treatment period OR 
requires systemic treatment.
•
Grade 3 drug-related uveitis, episcleritis, iritis, pneumonitis, bronchospasm, or neurologic
toxicity.
•
Grade ≥4 hypersensitivity reaction or Grade 3 that does not resolve to Grade 1 in < 6 hours.
•
Other ≥Grade 3 study treatment-related toxicity will be considered a DLT. However, the
following Grade 3 or 4 events will not be considered DLTs:
−
Grade 3 or Grade 4 electrolyte abnormalities that are not complicated by associated clinical 
adverse experiences, last less than 48 hours, and either resolve spontaneously or respond 
to conventional medical intervention. Confirmatory laboratory test is required within 
48 hours.
−
Grade 3 nausea or vomiting that lasts less than 48 hours, and either resolves spontaneously 
or responds to conventional medical intervention.
−
Grade 3 or Grade 4 elevation of amylase or lipase not associated with clinical or 
radiographic evidence of pancreatitis.
−
Grade 3 fever not associated with hemodynamic compromise (eg, hypotension, clinical or 
laboratory evidence of impaired end-organ perfusion).
−
Grade 3 endocrinopathy that is well controlled by hormone replacement.
−
Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or 
suspected tumor).
−
Grade 3 fatigue.
−
Grade 3 infusion reaction that returns to Grade 1 in < 6 hours.
7.6.2
Management Algorithms for Immuno-oncology Agents
I-O agents are associated with imAEs that can differ in severity and duration from AEs caused
by other therapeutic classes. BMS-986218, ipilimumab, and nivolumab are considered I-O agents
in this protocol. Early recognition and management of imAEs associated with I-O agents may 
mitigate severe toxicity. Management algorithms have been developed from extensive experience 
with ipilimumab and nivolumab to assist Investigators in assessing and managing the following 
groups of imAEs:
•
GI
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathies
•
Skin
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Neurological
•
Myocarditis
The clinical nature of AEs noted with BMS-986218 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 imAEs in this protocol are in Appendix 10.
7.6.3
Dose Delays Due To Toxicity
Participants who experience the following due to any cause must have all study treatment(s)
withheld:
•
Potential DLTs, until DLT relatedness is defined.
•
Select AEs and laboratory abnormalities:
−
≥Grade 2 pneumonitis.
−
≥Grade 2 abnormality in AST, ALT, or total bilirubin.
−
≥Grade 2 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.
−
Confirmed SARS-CoV-2 infection.
Criteria for participants who are required to permanently discontinue study treatments is listed in
Section 8.2. Participants not meeting guidelines for permanent discontinuation will be permitted
to resume therapy based on the criteria specified below in Section 7.6.3.1. Participants eligible to 
resume study therapy will resume study therapy at the nominal treatment visit following their last
received study medication dose.
The end of cycle tumor assessments, such as CT, magnetic resonance imaging (MRI), or
positron emission tomography
(PET), will continue on a Q8W schedule relative to the 
participant’s first dose, regardless of any treatment delay incurred.
7.6.3.1
Criteria to Resume Treatment
Subsequent dosing with study therapy may resume once drug-related non-DLT AEs resolve to
Grade 1 or baseline.
Participants experiencing AEs not meeting criteria for permanent discontinuation as outlined in
Section 8.2 may resume treatment with study medication under the following criteria:
•
Participants may resume 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.
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−
Participants who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity.
−
Participants with Grade 2 uveitis, episcleritis, iritis, eye pain, or blurred vision not meeting 
DLT criteria (Section 8.2) must resolve to baseline prior to resuming study therapy.
•
For participants with Grade 2 AST, ALT, or total bilirubin elevations, dosing may resume
when laboratory values return to baseline and management with corticosteroids (if needed) is 
complete.
•
Participants with combined Grade 2 AST/ALT and total bilirubin values meeting DLT criteria 
(Section 7.6.1) 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 re-treatment if discussed with, and
approved by, the BMS Medical Monitor (or designee).
•
Participants with drug-related endocrinopathies adequately controlled with only physiologic
hormone replacement may resume treatment.
•
Participants with confirmed SARS-CoV-2 infection may resume treatment after 1) at least 
10 days (20 days for severe/critical illness) have passed since symptoms first appeared, 
positive RT-PRC test result, or positive viral antigen test result, 2) resolution of acute 
symptoms (including at least 24 hours has passed since last fever without fever reducing 
medications), 3) evaluation by the investigator with confirmation that there are no sequelae 
that would place the participant at a higher risk of receiving investigational treatment, and 
4) consultation by the medical monitor. For suspected cases, treatment may also resume if 
SARS-CoV-2 infection is ruled-out and other criteria to resume treatment are met.
−
Prior to re-initiating on-study treatment in a participant with a dosing delay lasting 8 weeks 
due to SARS-CoV-2 infection, the medical monitor/designee must be consulted.
7.6.4
Exceptions to Permanent Discontinuation Criteria
Any drug-related AE occurring at any time that meets DLT criteria as outlined in Section 7.6.1
will require permanent discontinuation, with the exception of the following:
•
Grade 3, nausea, vomiting, or abdominal pain that returns to Grade 1 or baseline within or 
at 48 hours either spontaneously or with medical intervention. 
•
Grade 3 pruritus or rash that returns to Grade 1 or baseline within 7 days with medical
intervention.
•
Isolated Grade 3 or 4 electrolyte imbalances/abnormalities that are not associated with clinical
sequelae and are corrected with supplementation/appropriate management within 3 days of 
their onset.
•
Grade 4 neutropenia < 7 days in duration.
•
Grade 4 lymphopenia or leukopenia.
•
Grade 3 increase in amylase or lipase that is not associated with clinical or radiographic
evidence of pancreatitis.
•
Grade 3 infusion reactions that return to Grade 1 in < 6 hours.
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•
Grade 3 fever not associated with hemodynamic compromise (eg, hypotension, clinical, or
laboratory evidence of impaired end-organ perfusion).
•
Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or
suspected tumor).
•
Grade 3 fatigue.
•
Grade
3
or
4
drug-related
endocrinopathy
AEs,
such
as
adrenal
insufficiency,
adrenocorticotropic hormone, hyper- or hypothyroidism, or glucose intolerance, which
resolve or are adequately controlled with physiologic hormone replacement (corticosteroids,
thyroid
hormones) or glucose-controlling
agents,
respectively,
may
not require
discontinuation after discussion with and approval from the BMS Medical Monitor 
(or designee).
•
Any event that leads to delay in dosing, lasting > 8 weeks from the previous dose, requires
discontinuation, with the exception of the following:
−
Dosing delays for prolonged steroid tapers to manage drug-related AEs are allowed. Prior 
to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks from the 
previous dose, the BMS Medical Monitor (or designee) must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed. Periodic study visits 
to assess safety and laboratory studies should also continue Q4W, or more frequently if 
clinically indicated, during such dosing delays.
−
Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons may not require discontinuation, if approved by the BMS Medical Monitor 
(or designee). Prior to re-initiating treatment in a participant with a dosing delay lasting 
> 8 weeks, the BMS Medical Monitor (or designee) must be consulted.
•
Any AE, laboratory abnormality, or concurrent illness, which, in the judgment of the
Investigator, presents a substantial clinical risk to the participant with continued nivolumab
dosing.
Even if the criteria to resume treatment are met, the consideration to re-initiate study therapy
under the following exception will be made on a case-by-case basis after considering the overall
benefit-risk profile and in consultation between the Investigator and the Sponsor. Any AE with
clinical risk will be assessed on a case-by-case basis with the Investigator and the BMS Medical
Monitor (or designee), to determine the risks and benefits of continuing on therapy following
resolution vs discontinuing therapy permanently.
All participants who discontinue IP should comply with protocol specified follow-up procedures
as outlined in Section 2 and Section 8.2. The only exception to this requirement is when a
participant withdraws consent for all study procedures including post treatment study follow-up
or loses the ability to consent freely (eg, imprisonment, involuntarily incarceration for the
treatment of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason
for the discontinuation must be documented in the participant’s medical records and entered on
the appropriate case report form (CRF) page.
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7.6.5
Management of Drug-related Infusion Reactions
Since BMS-986218, ipilimumab, and nivolumab contain only human Ig protein sequences, they
are unlikely to induce hypersensitivity reactions. However, based on the non-clinical toxicology 
evaluation of BMS-986218, infusion reactions due to T-cell activation and cytokine release may 
occur in both monotherapy and combination with nivolumab. If such a reaction were to occur, it
might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension,
hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 infusion
reactions should be reported within 24 hours to the BMS Medical Monitor (or designee) and
reported as an SAE. Infusion reactions should be graded according to NCI CTCAE v4.03 
guidelines.
Treatment recommendations for infusion reactions are provided below and may be modified
based on local treatment standards and guidelines, as appropriate.
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not
indicated):
•
Remain at bedside and monitor participant until recovery from symptoms. The following
prophylactic premedications are recommended for future infusions:  diphenhydramine 50 mg
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before
study treatment administrations.
For Grade 2 symptoms (moderate reaction requiring therapy or infusion interruption but
responding
promptly
to
symptomatic
treatment
such
as
antihistamines,
non-steroidal
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids, or prophylactic
medications indicated for ≤24 hours):
•
Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the
participant
with
diphenhydramine
50 mg
IV
(or
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant
until resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50%
of the original infusion rate when symptoms resolve; if no further complications ensue
after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor
participant
closely.
If symptoms recur, then no further BMS-986218, ipilimumab, or 
nivolumab will be administered at that visit.
•
For
future infusions,
the following
prophylactic premedications
are recommended:  
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 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 [ie, not rapidly responsive to
symptomatic medication and/or brief interruption
of
infusion];
recurrence
of
symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal
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impairment, pulmonary infiltrates]; Grade 4:  life-threatening; pressor or ventilatory support
indicated):
•
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 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored
until the Investigator is comfortable that the symptoms will not recur. Study treatment will
be permanently discontinued except for a Grade 3 infusion reaction that returns to Grade 1
in less than 6 hours. Investigators should follow their institutional guidelines for the treatment
of anaphylaxis. Remain at bedside and monitor participant until recovery of the symptoms.
In the 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).
7.7
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the Investigator to ensure that IP is only dispensed to study participants. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed, and study personnel must contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
For study treatments not provided by BMS and obtained commercially by the site, storage should 
in accordance with the product label.
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
Further guidance and information for final disposition of unused study treatment are provided in 
the Pharmacy Manual. 
7.7.1
Retained Samples for Bioavailability/Bioequivalence
Not applicable.
7.8
Treatment Compliance
Not applicable.
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7.9
Concomitant Therapy
7.9.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Immunosuppressive agents.
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.2).
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, immunotherapy, extensive, 
non-palliative radiation therapy, or standard or investigational agents for treatment of cancer). 
Palliative hormonal therapy will be permitted when indicated.
•
Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.
•
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.
•
Administration of investigational SARS-CoV-2 vaccines is not allowed during the study. 
Participants may receive authorized or approved SARS-CoV-2 vaccines while continuing on 
study treatment at the discretion of the investigator. See Section 6.2 Exclusion Criteria.
•
Treatment of active SARS-CoV-2 infections or high risk exposures, including use of 
investigational therapies, is allowed and should be discussed with the medical monitor.
7.9.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization or treatment assignment are excluded. Inhaled or topical steroids, and adrenal 
replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease.
7.9.3
Permitted Therapy
Participants are permitted the use of the following treatments:
•
Topical, ocular, intra-articular, intra-nasal, and inhalational corticosteroids.
•
Adrenal replacement steroid doses ≤10 mg daily prednisone equivalent.
•
A brief (less than 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).
•
Palliative hormonal therapy will be permitted when indicated.
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7.9.4
Palliative Radiation
Palliative radiation for disease-related symptoms may be offered to all participants on the study 
after the DLT evaluation period. Limited radiation therapy to control symptoms from isolated 
lesions is permitted for participants who have Investigator-assessed clinical benefit following 
consultation with the BMS Medical Monitor or designee. Participants should not receive study 
treatment during radiation, as the potential for overlapping toxicities with radiotherapy and 
BMS-986218, ipilimumab, or BMS-986218 in combination with nivolumab is currently not 
known. Anecdotal data suggest that radiotherapy administered to participants while receiving 
nivolumab 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-986218, ipilimumab, and/or nivolumab should be withheld for at least 1 week 
before, during, and 2 weeks 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.
Details of palliative radiotherapy should be documented in the source records and eCRF. Details 
in the source records should include dates of treatment, anatomic site, dose administered and 
fractionation schedule, and AEs. Symptoms requiring palliative radiotherapy should be evaluated 
for objective evidence of disease progression. Participants receiving palliative radiation of target 
lesions will have the evaluation of objective response rate (ORR) just prior to radiotherapy, but 
these participants will no longer be evaluable for the determination of response subsequent to the 
date palliative radiation occurs.
7.9.5
Surgery
Participants undergoing major surgery for any reason while on study should have BMS-986218, 
ipilimumab, and/or nivolumab held for at least 4 weeks after surgery, and these study treatments 
should not be resumed until wound healing has occurred and it is considered safe to do so in the 
assessment of the Investigator.
For participants who need to undergo surgery during the study, it is recommended to hold study 
treatment(s) for at least 2 weeks before (if elective or planned) and 3 weeks after surgery or until 
the participant recovers from the procedure, whichever is longer. Wound healing must be evaluated 
by surgeon prior to resuming study treatment. Prior to resuming study treatment, surgically related 
AEs should resolve to Grade 1 or baseline, and participants must meet relevant eligibility criteria 
as determined by the BMS Medical Monitor (or designee) in discussion with the Investigator. 
7.9.6
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, and renal status), the appropriate imaging modality and 
contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants with renal insufficiency should be assessed as to 
whether they should receive contrast and if so, what type and dose of contrast is appropriate. 
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Specific to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration 
rate < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast 
should not be given to this participant population. In addition, participants are excluded from MRI 
if they have tattoos, metallic implants, pacemakers, etc.
The ultimate decision to perform MRI in an individual participant in this study rests with the site 
radiologist, the Investigator, and the standards set by the local Ethics Committee.
7.10
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 for any of the following reasons:
•
Documented disease progression as defined by RECIST v1.1 (Appendix 5) or per PCWG 3 
criteria for prostate (Appendix 12) unless participants meet criteria for treatment beyond 
progression (Section 8.1.1).
•
Clinical deterioration while receiving active study therapy that, in the opinion of the
Investigator, indicates that continued participation in the study is not in the best interest of the 
participant.
•
Any drug-related AE occurring at any time that meets DLT criteria as outlined in Section 7.6.1
will require permanent discontinuation. Exceptions to permanent discontinuation are listed in 
Section 7.6.4.
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information.
•
Any clinical AE, laboratory abnormality or intercurrent illness 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 involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note:  Under 
specific circumstances, and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)
•
Inability to comply with protocol.
•
Discretion of the Investigator.
•
Pregnancy.
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•
Individual participants with confirmed CR will be given the option to discontinue study therapy 
on a case-by-case basis after specific consultation and agreement between the Investigator and 
BMS Medical Monitor (or designee) in settings where benefit-risk justifies discontinuation of 
study therapy.
•
Any event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays for prolonged steroid tapers to manage drug-related AEs are allowed. 
−
Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor (or designee). 
•
If a participant in any of the nivolumab/BMS-986218 combination arms meets criteria for 
discontinuation, because it is not possible to determine whether the event is related to both or 
1 study treatment, the participant should discontinue both nivolumab and BMS-986218 and be 
taken off the treatment phase of the study.
Refer to the Schedule of Activities (Section 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary, for participant safety). Refer to Section 9.2.5 Pregnancy. 
All participants who discontinue study treatment should comply with protocol-specified follow-up 
procedures, as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
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
Treatment Beyond Progression
As described in Section 5.4.6, accumulating evidence indicates that a minority of patients with 
tumors treated with immunotherapy may derive clinical benefit despite initial evidence of 
progressive disease. Participants will be permitted to continue treatment beyond initial RECIST 
v1.1/PCWG 3-defined progressive disease (see Appendix 5 and Appendix 12), 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. 
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•
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 nivolumab or 
BMS-986218 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 
believes that the participant continues to achieve clinical benefit by continuing treatment with the 
study treatments, then the participant should remain on the trial 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 and agreed upon by the BMS Medical Monitor 
(or designee) prior to treatment beyond progression, and an assessment of the benefit-risk of 
continuing with study therapy must be documented in the study records (see Appendix 2).
8.1.1.1
Discontinuation Due to Further Progression (Confirmed Progression)
Participants will continue to receive monitoring according to the on-treatment assessments in 
Section 2. Radiographic assessment, by CT (preferred) or MRI described in Section 9.3.1, is 
required when participants continue post-progression treatment and should be performed at each 
scheduled tumor assessment, no later than 8 weeks ± 7 days following initial disease progression, 
to determine whether there has been continued progressive disease. If the Investigator believes that 
the participant continues to achieve clinical benefit by continuing treatment, the participant should 
remain on the trial and continue to receive monitoring according to the Schedule of Activities 
(Section 2). Participants should permanently discontinue study therapy upon evidence of further 
progression, defined as an additional 10% or greater increase in tumor burden volume from time 
of initial progression (including all target lesions and new measurable lesions). This includes an 
increase in the sum of diameters of all target lesions and/or the diameters of new measurable 
lesions compared to the time of initial progressive disease.
The tumor burden volume from time of initial progression should be used as the reference baseline 
for comparison with the post progression assessment.
Any new lesion considered non-measurable at the time of initial progression may become 
measurable and, therefore, must be included in the tumor burden measurement. 
If the longest diameter increases to at least 10 mm (except for pathological lymph nodes, which 
must have a short axis of at least 15 mm), a lesion is considered measurable. In situations where 
the relative increase in total tumor burden by 10% is solely due to inclusion of new lesions that 
become measurable, these new lesions must demonstrate an absolute increase of at least 5 mm.
For statistical analyses that include the Investigator-assessed progression date, participants who 
continue treatment beyond initial Investigator-assessed, RECIST v1.1/PCWG 3-defined 
progression will be considered to have Investigator-assessed progressive disease at the time of the 
initial progression event.
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For participants who discontinue post progression treatment with study therapy, additional 
radiographic assessments will be required until a new tumor-directed therapy is initiated.
8.1.2
Post-treatment Follow-up
Post-treatment 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 for collection of outcome and/or survival follow-up data as required and in line with 
Section 2 until death or the conclusion of the study.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the Investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
Investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of 
3 documented phone calls, faxes, or emails, as well as lack of response by participant to 
1 registered mail letter. All attempts should be documented in the participant’s medical 
records.
•
If it is determined that the participant has died, then the site will use permissible local methods 
to obtain date and cause of death.
•
If Investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the Investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
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•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the Investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and timing are summarized in the Schedule of Activities (see Section 2). Protocol 
waivers or exemptions are not allowed.
All immediate safety concerns must be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue treatment.
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria before randomization. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed within the 
timeframe defined in the Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study treatment related toxicities resolve, return to baseline, or are deemed 
irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
and fever) consistent with possible pulmonary AEs, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) IB.27
Some of the assessments referred to in this section may not be captured as data in the electronic 
CRF (eCRF). They are intended to be used as safety monitoring by the treating physician. 
Additional testing or assessments may be performed as clinically necessary or where required by 
institutional or local regulations.
9.1
Safety
Safety assessments will be based on reported AEs and the measurement results of vital signs, ECG, 
PEs, and clinical laboratory tests. AEs will be coded using the most current version of Medical 
Dictionary for Regulatory Activities (MedDRA) and the incidence of observed AEs will be 
tabulated and reviewed for potential significance and clinical importance. AEs will be assessed 
continuously during the study and for 100 days after the last dose of BMS-986218 in the case of 
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monotherapy, and the last dose of BMS-986218 and nivolumab for combination therapy. Local 
laboratory will perform the clinical laboratory tests and will provide reference ranges for these 
tests. Both AEs and laboratory tests will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events v4.03. 
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.1.1
Physical Examinations
Refer to the Schedule of Activities for timing of assessments in Table 2-1, Table 2-2, Table 2-3, 
Table 2-4, and Table 2-5. 
9.1.2
Vital signs
Refer to the Schedule of Activities for timing of assessments in Table 2-1, Table 2-2, Table 2-3, 
Table 2-4, and Table 2-5.
9.1.3
Electrocardiograms
Refer to the Schedule of Activities for timing of assessments in Table 2-1, Table 2-2, Table 2-3, 
and Table 2-4.
The effect of BMS-986218 on the QTc interval will be evaluated by a central reader using ECG 
data collected in triplicate along with time-matched PK during the BMS-986218 Monotherapy 
Dose Escalation (Part 1A) only (eg, 1 ECG test equals 3 consecutive individual 12-lead ECGs 
performed 5 minutes apart). For the purposes of monitoring participant safety, the Investigators 
will review the 12-lead ECGs using their site’s standard ECG machines throughout the study. The 
QTcF will be applied to each ECG reading.
9.1.4
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
•
A local laboratory will perform the analyses and will provide reference ranges for these tests. 
Results of clinical laboratory tests performed on Day -1 must be available prior to dosing.
•
The laboratory tests that will be performed for study participants are shown in Table 9.1.4-1.
•
Results of all laboratory tests required by this protocol must be provided to the Sponsor, 
recorded either on the laboratory pages of the CRF or by another mechanism as agreed upon 
between the Investigator and BMS (eg, provided electronically). If the units of a test result 
differ from those printed on the CRF, the recorded laboratory values must specify the correct 
units. Any abnormal laboratory test result considered clinically significant by the Investigator 
must be recorded on the appropriate AE page of the CRF.
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Table 9.1.4-1:
Clinical Laboratory Assessments
Hematology
Hemoglobin and hematocrit
Total leukocyte count, including differential
Platelet count
Prothrombin time, activated partial thromboplastin time and international normalized ratio (at screening only)
Serum Chemistry
Aspartate aminotransferase 
Alanine aminotransferase 
Total bilirubin
Direct bilirubin (reflex)a
Alkaline phosphatase
Lactate dehydrogenase 
Creatinine
Creatine kinase/ Creatine phosphokinase
C-reactive protein
Blood urea nitrogen 
Uric acid 
Glucose
Lipase
Amylase
Gamma glutamyl transferase (reflex only)b
Thyroid stimulating hormone
Free T3 and T4 (screening and reflex only)c
Total protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatinine clearance (Cockcroft-Gault method)
(screening only)
Troponin
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein, or leukocytes esterase are positive on the dipstick
Serology
Serum for hepatitis C Ab, hepatitis B surface antigen, HIV-1 and HIV-2 Ab (at screening, and as mandated by 
local requirement)
Other Analyses
Pregnancy test (WOCBP only:  screening, predose on Day 1 of each treatment cycle, discharge).
FSH (screening only and women only)
a Reflex testing to be performed only if total bilirubin is abnormal.
b Reflex testing to be performed only if liver function test is abnormal. 
c Reflex testing to be performed only if TSH is abnormal.
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9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting are specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE information should begin at initiation of study treatment until 
100 days after the discontinuation of study treatment administration or until the start of a new 
anti-neoplastic treatment (whichever occurs first), at the timepoints specified in the Schedule of 
Activities (see Section 2). 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
to study treatment or not, 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 after discontinuation of 
dosing must be collected, except in cases where a study participant has started a new anti-
neoplastic treatment. However, any SAE occurring after the start of a new anti-neoplastic 
treatment that is suspected to be related to study treatment by the Investigator should be 
reported as an SAE.
•
The Investigator must report any SAE that occurs after these time periods and that is believed 
to be related to study treatment or protocol-specified procedure.
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•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the CRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of this being 
available.
•
All SAEs, and all AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection must be collected from the date of the participant’s written consent 
until 100 days following last dose of study treatment.
•
With the exception of nonserious AEs related to SARS-CoV-2 infection, all nonserious AEs 
(not only those deemed to be treatment-related) should be collected from the time of first dose 
and continuously during the treatment period and for a minimum of 100 days following last 
dose of study treatment. 
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, then the Investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AEs and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgment in the context of known 
AEs, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs
•
Non-serious AEs should be followed to resolution or stabilization or should be reported as 
SAEs if they become serious (see Appendix 3).
•
Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 All identified non-serious AEs must be recorded and described on the non-serious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and non-serious AEs (as defined in Section 9.1), including 
ones associated with confirmed or suspected SARS-CoV-2 infection, will be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, the event is deemed 
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irreversible, or until the participant is lost to follow-up (as defined in Section 8.3), or for suspected 
cases, until SARS-CoV-2 infection is ruled-out.
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the Investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities 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 Independent Review Board (IRB)/Independent Ethics Committee, if 
appropriate according to local requirements.
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 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 for 5 
months for combination therapy and 3 months for BMS-986218 monotherapy after product 
administration, the Investigator must immediately notify the BMS Medical Monitor/designee of 
this event and complete and forward a Pregnancy Surveillance Form to BMS Designee within 24 
hours of awareness of the event and in accordance with SAE reporting procedures described in 
Appendix 3.
The study treatment will be permanently discontinued in an appropriate manner. Please call the 
BMS Medical Monitor (or designee) within 24 hours of awareness of the pregnancy.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur.
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. Protocol-required procedures for study discontinuation and follow-up must be 
performed on the participant.
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9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
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 vs low hemoglobin value).
9.2.7
Immune-mediated Adverse Events
Immune-mediated
AEs are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. Immune-mediated AEs can include events with an alternate 
etiology that were exacerbated by the induction of autoimmunity. Information supporting the 
assessment will be collected on the participant’s CRF.
9.2.8
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a p-DILI event. All occurrences of p-DILIs meeting the defined 
criteria must be reported as SAEs (see Section 9.1 and Appendix 3 for reporting details).
Potential drug induced liver injury is defined as:  
•
ALT or AST elevation > 3 × ULN
AND
•
Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum ALP)
AND
•
No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic.
The key responsibilities for Investigators during p-DILI assessment include:  (i) Early detection, 
medical evaluation (including the exclusion of other potential causes) and rapid laboratory 
confirmation of liver-related abnormalities; and (ii) BMS notification of p-DILI cases via SAE 
forms. Following the gathering and assessment of relevant clinical information, BMS is 
responsible 
for: 
 
(i)
Timely 
evaluation 
and 
triaging 
of 
p-DILI 
cases; 
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(ii) Expedited reporting of p-DILI cases; and (iii) 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, ALP). Any participant with an abnormal 
Hepatic Laboratory Panel that meets p-DILI criteria is a candidate for study treatment
discontinuation. Any confirmed p-DILI events must be reported (along with a description of the 
clinical findings) to BMS as an SAE within 24 hours of confirmation.
An extensive clinical history, examination and appropriate investigations should be obtained to 
exclude cholestatic and other apparent causes that may explain the observed abnormalities in liver 
function and/or hepatic signs and symptoms. Other apparent causes include, non-exhaustively and 
by way of example only, the following:  infectious diseases (such as active hepatitis A, B, and C), 
congenital diseases (such as Gilbert’s syndrome), neoplastic diseases, autoimmune diseases (such 
as primary biliary cirrhosis), and the use of concomitant hepatotoxic medications (such as 
antibiotics, the oral contraceptive pill and herbal medicines). All investigations to exclude potential 
causes of liver function abnormalities or hepatic signs and/or symptoms should be guided by 
relevant factors such as the participant’s age, gender, clinical history, and signs and symptoms.
9.2.9
Other Safety Considerations
Any significant worsening noted during interim or final PEs, ECG, X-ray filming, or 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
Efficacy Assessments
Efficacy assessments for the anti-tumor activity of BMS-986218, alone and in combination with 
nivolumab, will be based on tumor measurements using RECIST v1.1 or per PCWG 3 criteria for 
prostate with CT and/or MRI, as appropriate, at baseline, and during the treatment period. Tumor 
imaging assessments are to be performed prior to initiating next cycle of treatment. 
Tumor assessments will occur every 8 weeks (Q8W) for participants receiving BMS-986218 and 
nivolumab for all study parts, except the Randomized BMS-986218 Monotherapy Cohort 
Expansion in Cutaneous Melanoma (Part 2A), where tumor assessment in participants receiving 
BMS-986218 or ipilimumab will occur at 12 weeks from first dose (± 1 week), prior to initiating 
the next cycle of treatment. After that, subsequent tumor imaging assessments are to be performed 
Q8W (± 1 week), prior to initiating the next cycle of treatment. Participants who remain free of 
subsequent therapy will undergo tumor imaging assessment Q8W (± 1 week) until subsequent 
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tumor-directed therapy is initiated or until 48 weeks after discontinuation of study treatment/EOT 
visit, and then Q12W (± 2 weeks) for a total duration of 2 years. 
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.
9.3.1
Imaging Assessment for the Study
Images will be submitted to an imaging core lab. Image acquisition guidelines and submission 
process will be outlined in the CA022001 Imaging Manual to be provided by the core lab.
Tumor assessment with contrast-enhanced CT scans acquired on dedicated CT equipment is 
preferred for this study. Contrast-enhanced CT of the chest, abdomen, pelvis, and other 
known/suspected sites of disease should be performed for tumor assessments. 
Should a participant have contraindication for a CT IV contrast, a non-contrast CT of the chest and 
a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of disease 
should be obtained. If the primary tumor is not of lung origin, a contrast-enhanced MRI of the 
chest may be obtained instead of a non-contrast CT of the chest. 
Should a participant have contraindication for both MRI and CT IV contrasts, a non-contrast CT 
of the chest and a non-contrast MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained. If the primary tumor is not of lung origin, a non-contrast MRI of the 
chest, abdomen, pelvis, and other known/suspected sites of disease is also acceptable.
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT IV contrast, a non-contrast CT of the chest, abdomen, pelvis, and other 
known/suspected sites of disease is acceptable.
CT and MRI scans should be acquired with slice thickness of 5 mm or less with no intervening 
gap (contiguous). Every attempt should be made to image each participant using an identical 
acquisition protocol on the same scanner for all imaging timepoints. 
Use of CT component of a PET/CT scanner:  Combined modality scanning such as with 
2-deoxy-2-[18F]fluoro-D-glucose (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 correction 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/PCWG 3 measurements. However, if a site can 
document that the CT performed as part of a 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 which may bias an Investigator if it is not routinely or serially performed.
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At screening, MRI without and with contrast of the brain is required if participant is symptomatic 
or has history of brain metastasis and has not had brain imaging within 30 days of anticipated first 
study drug administration. CT of the brain without and with contrast may be performed if MRI is 
contraindicated. CT and MRI scans should be acquired with a slice thickness of 5 mm or less with 
no intervening gap (contiguous). Participants with a history of brain metastasis should have a 
surveillance MRI if clinically indicated.
Participants with prostate cancer should have bone scans performed for each imaging timepoint. 
Other participants may have bone scans as clinically indicated.
Assessments will be performed at baseline and at the timepoints described per RECIST v1.1 
criteria (see Appendix 5) or per PCWG 3 criteria for prostate (see Appendix 12). At the time of 
the EOT visit or at the time of study treatment discontinuation, all participants will continue to 
have radiologic tumor assessments Q8W (± 1 week) until subsequent tumor-directed therapy is 
initiated or until 48 weeks after discontinuation of study treatment/EOT visit, and then Q12W (±
2 weeks) for a total duration of 2 years. 
Radiologic assessments for participants who have ongoing clinical benefit and remain free of 
subsequent therapy may continue to be collected after participants complete the Survival Follow-
up Period of the study. 
Scans will be submitted to an imaging core laboratory for review by BICR at a later date or at any 
time during the study at the Sponsor’s discretion. 
Tumor assessments at other timepoints may be performed if clinically indicated. Assessments of 
PR and CR must be confirmed at least 8 weeks after initial response. When participants are allowed 
to be treated beyond initial disease progression per RECIST v1.1 criteria, subsequent tumor 
assessment will continue Q8W until confirmation of tumor progression. Thereafter, participants 
will continue tumor assessment as described in the follow-up period. Changes in tumor 
measurements and tumor responses will be assessed by the Investigator per study design using 
RECIST v1.1 criteria or per PCWG 3 criteria for prostate. Investigators will also report the number 
and size of new lesions that appear while on study. The timepoint of tumor assessments will be 
reported on the eCRF based on the Investigator’s assessment using RECIST v1.1 criteria or per 
PCWG 3 criteria for prostate. (See Appendix 5 and Appendix 12 for specifics of RECIST v1.1 
criteria and PCWG 3 criteria to be utilized in this study, respectively.)
9.4
Overdose
For this study, any dose of BMS-986218 greater than the assigned dose will be considered an 
overdose.
All occurrences of overdose must be reported as SAEs (see Section 9.2).
In the event of an overdose the Investigator/treating physician should:
1) Contact the Medical Monitor (or designee) immediately.
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2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities until at least 
5 times the projected elimination half-life of BMS-986218 (75 days), when it is considered 
safe to stop monitoring the participant. 
3) Obtain a serum sample for PK if requested by the Medical Monitor/designee (determined on a 
case-by-case basis).
4) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications secondary to an overdose will be made by 
the Investigator in consultation with the Medical Monitor (or designee) based on the clinical 
evaluation of the participant.
9.5
Pharmacokinetic and Immunogenicity Assessments
The serum samples will be analyzed for BMS-986218 and Anti-BMS-986218 antibodies by two 
validated electrochemiluminescence (ECL) assays, respectively. 
The PK of BMS-986218 will be derived from serum concentration vs time data. The PK 
parameters that will be assessed following serial PK collection, are shown in Table 9.5-1. Sparse 
ipilimumab and nivolumab concentration-time data will be collected and may be used in an 
integrated population PK or ER analysis along with data from other ipilimumab and nivolumab 
studies, which would be the subject of a separate report. Separate samples will be collected for PK 
and ADA assessments. 
Table 9.5-1:
Pharmacokinetic Parameters for BMS-986218
Parameters
Definition
Cmax
Maximum observed plasma serum concentration
Tmax
Time of maximum observed plasma serum concentration
AUC(0-T)
Area under the plasma serum concentration-time curve from time zero to time of last 
quantifiable concentration; may be calculated if concentrations are not quantifiable up to 
TAU across a treatment group
AUC(TAU)
Area under the serum concentration-time curve in 1 dosing interval
Ctau
Observed serum concentration at the end of a dosing interval
Ctrough
Trough observed serum concentrations (this includes predose concentrations [C0] and 
Ctau)
Parameters that May be Assessed Following the Dose Administration in Cycle 3
CLT
Total body clearance 
Css-avg
Average serum concentration over a dosing interval (AUC[TAU]/tau) at steady state
AI
Ratio of an exposure measure at steady state to that after the first dose (exposure measure 
includes AUC[TAU] and Cmax)
T-HALF
Terminal serum half-life if data permit
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Individual participant PK parameter values will be derived by noncompartmental methods using a 
validated PK analysis program. Actual times will be used for all formal analyses.
Table 9.5-2, Table 9.5-3, Table 9.5-4, and Table 9.5-5 list the sampling schedule to be followed 
for the assessment of PK. Detailed instructions for the PK blood collection, labeling, processing, 
storage, and shipping will be provided to the site in the procedure manual.
All predose samples should be taken within 30 minutes before the start of any dose 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 predose sample should be collected just prior to the delayed dose. However, if a predose sample 
is collected but the dose is subsequently delayed, then an additional predose sample should not be 
collected. Following consensus of the Investigator and the BMS Medical Monitor (or designee), a 
PK and ADA sample may be taken in the event of a Grade 3+ infusion reaction or hypersensitivity 
reaction using an ‘Event Kit - GR3+ INF RXN’. 
Table 9.5-2:
Pharmacokinetic and Anti-Drug Antibody (ADA) Sampling 
Schedule for BMS-986218 Q4W Monotherapy in Dose Escalation 
(Part 1A) and Dose Expansion (Part 2A and Part 2B)
Study Day of Sample 
Collection
(1 cycle = 4 weeks)
Event
Time (relative to initiation of 
BMS-986218 dose)
Hour:Minute
BMS-986218 
Blood Sample
BMS-986218 
ADA Samples
C1D1
Predosea
00:00
X
X
EOI
See noteb
X
C1D2
24:00
X
C1D8c
168:00
X
C1D15c
336:00
X
C1D22c
504:00
X
C2D1
Predosea
00:00
X
X
EOI
See noteb
X
C2D8c
168:00
X
C3D1
Predosea
00:00
X
X
EOI
See noteb
X
C3D2
24:00
X
C3D8c
168:00
X
C3D15c
336:00
X
C3D22c
504:00
X
C4D1
Predosea
00:00
X
X
C5D1 
Predosea
00:00
X
X
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Table 9.5-2:
Pharmacokinetic and Anti-Drug Antibody (ADA) Sampling 
Schedule for BMS-986218 Q4W Monotherapy in Dose Escalation 
(Part 1A) and Dose Expansion (Part 2A and Part 2B)
Study Day of Sample 
Collection
(1 cycle = 4 weeks)
Event
Time (relative to initiation of 
BMS-986218 dose)
Hour:Minute
BMS-986218 
Blood Sample
BMS-986218 
ADA Samples
Every fourth cycle after C5 
until EOT (C9D1, C13D1, 
C17D1, etc. until EOT)
Predosea
00:00
X
X
EOT
X
X
30-day follow-up
X
X
60-day follow-up
X
X
100-day follow-up
X
X
Grade 3+ Infusion Reaction
X
X
a Predose:  All predose samples should be taken prior to the start of the infusion.
b EOI PK should be collected when all the study drug has been infused. If a flush is administered to clear the IV lines 
of the drug and to ensure delivery of the entire drug dose, then draw the EOI PK sample within approximately 15 
minutes after end of the flush. Do not draw EOI samples from the same IV access that the drug was administered.
Refer to Table 7.3-1 for infusion duration. If the EOI is delayed to beyond the nominal infusion duration, the 
collection of this sample should also be delayed accordingly. 
c This sample may be collected ± 2 days from timepoint. The actual date and time of sampling must be recorded.
Abbreviations:  C = cycle; D = day; EOI = end of infusion; IV = intravenous; PK = pharmacokinetic.
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Table 9.5-3:
Pharmacokinetic and Anti-Drug Antibody (ADA) Sampling 
Schedule for BMS-986218 Q2W Monotherapy in Dose Escalation 
(Part 1A)
Study Day of Sample 
Collection
(1 cycle = 4 weeks)
Event
Time (relative to initiation of 
BMS-986218 dose) 
Hour:Minute
BMS-986218 
Blood Sample
BMS-986218
ADA Samples
C1D1
Predosea
00:00
X
X
EOI
See noteb
X
C1D2
24:00
X
C1D8c
168:00
X
C1D15
Predose,a
00:00
X
EOI
See noteb
X
C1D16
24:00
X
C1D22c
168:00
X
C2D1
Predosea
00:00
X
X
EOI
See noteb
X
C2D8c
168:00
X
C2D15
Predosea
00:00
X
EOI
See noteb
X
C3D1
Predosea
00:00
X
X
EOI
See noteb
X
C3D2
24:00
X
C3D8c
168:00
X
C3D15c
Predosea
00:00
X
EOI
See noteb
X
C3D16
24:00
X
C3D22c
168:00
X
C4D1
Predosea
00:00
X
X
C5D1 
Predosea
00:00
X
X
Every fourth cycle after C5 
until EOT (C9D1, C13D1, 
C17D1, etc. until EOT)
Predosea
00:00
X
X
EOT
X
X
30-day follow-up
X
X
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Table 9.5-3:
Pharmacokinetic and Anti-Drug Antibody (ADA) Sampling 
Schedule for BMS-986218 Q2W Monotherapy in Dose Escalation 
(Part 1A)
Study Day of Sample 
Collection
(1 cycle = 4 weeks)
Event
Time (relative to initiation of 
BMS-986218 dose) 
Hour:Minute
BMS-986218 
Blood Sample
BMS-986218
ADA Samples
60-day follow-up
X
X
100-day follow-up
X
X
Grade 3+ Infusion 
Reaction
X
X
a Predose:  All predose samples should be taken prior to the start of the infusion.
b EOI PK should be collected when all the study drug has been infused. If a flush is administered to clear the IV lines 
of the drug and to ensure delivery of the entire drug dose, then draw the EOI PK sample within approximately 15 
minutes after end of the flush. Do not draw EOI samples from the same IV access that the drug was administered.
Refer to Table 7.3-1 for infusion duration. If the EOI is delayed to beyond the nominal infusion duration, the 
collection of this sample should also be delayed accordingly. 
c This sample may be collected ± 2 days from timepoint. The actual date and time of sampling must be recorded.
Abbreviations:  C = cycle; D = day EOI = end of infusion; IV = intravenous; PK = pharmacokinetic.
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Table 9.5-4:
Pharmacokinetic and Anti-Drug Antibody (ADA) Sampling 
Schedule for Ipilimumab Q3W Monotherapy in Dose Expansion 
(Part 2A)
Study Day of Sample 
Collection (1 cycle = 
3 weeks)
Event
Time (relative to 
initiation of 
Ipilimumab dose) 
Hour:Minute
Ipilimumab Blood 
Sample
Ipilimumab ADA 
Samples
C1D1
Predosea
00:00
X
X
EOI
See noteb
X
C2D1
Predosea
00:00
X
X
EOI
See noteb
X
C3D1
Predosea
00:00
X
X
EOI
See noteb
X
C4D1
Predosea
00:00
X
X
EOT
X
X
30-day follow-up
X
X
60-day follow-up
X
X
100-day follow-up
X
X
Grade 3+ Infusion 
Reaction
X
X
a Predose:  All predose samples should be taken prior to the start of the infusion.
b EOI PK should be collected when all the study drug has been infused. If a flush is administered to clear the IV lines 
of the drug and to ensure delivery of the entire drug dose, then draw the EOI PK sample within approximately 15 
minutes after end of the flush. Do not draw EOI samples from the same IV access that the drug was administered.
Refer to Table 7.3-1 for infusion duration. If the EOI is delayed to beyond the nominal infusion duration, the 
collection of this sample should also be delayed accordingly. 
Abbreviations:  C = cycle; D = day; EOI = end of infusion; IV = intravenous; PK = pharmacokinetic; Q3W = every 
3 weeks.
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Table 9.5-5:
Pharmacokinetic and Anti-Drug Antibody (ADA) Sampling Schedule 
for BMS-986218 Q4W in Combination with Nivolumab Q4W in Dose 
Escalation (Part 1B) and Dose Expansions (Part 2C and Part 2D)
Study Day of Sample 
Collection
(1 cycle = 4 weeks)
Event
Time (Relative to 
Initiation of 
BMS-986218 and 
Nivolumab Dose)
Hour:Minute
BMS-986218 
Blood 
Sample
Nivolumab 
Blood 
Sample
BMS-986218
ADA
Samples
Nivolumab 
ADA 
Samples
C1D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
C1D2
24:00
X
C1D8c
168:00
X
C1D15c
336:00
X
C1D22c
504:00
X
C2D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
C2D8c
168:00
X
X
C3D1
Predosea
00:00
X
X
X
X
EOI
See noteb
X
X
C3D2
24:00
X
C3D8c
168:00
X
C3D15c
336:00
X
C3D22c
504:00
X
C4D1
Predosea
00:00
X
X
X
X
C5D1
Predosea
00:00
X
X
X
X
Every fourth cycle 
after C5 until EOT 
(C9D1, C13D1, 
C17D1, etc. until 
EOT)
Predosea
00:00
X
X
X
X
EOT
X
X
X
X
30-day follow-up
X
X
X
X
60-day follow-up
X
X
X
X
100-day follow-up
X
X
X
X
Grade 3+ Infusion 
Reaction
X
X
X
X
a Predose:  All predose samples should be taken prior to the start of the infusion.
b
EOI PK should be collected when all the study drug has been infused. If a flush is administered to clear the IV 
lines of the drug and to ensure delivery of the entire drug dose, then draw the EOI PK sample within approximately 
15 minutes after end of the flush. Do not draw EOI samples from the same IV access that the drug was administered.
Refer to Table 7.3-1 for infusion duration. Separate EOI samples should be collected following administration of 
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BMS-986218 and nivolumab and recorded with the same collection time. If the EOI is delayed to beyond the 
nominal infusion duration, the collection of this sample should also be delayed accordingly. 
c This sample may be collected ± 2 days from timepoint. The actual date and time of sampling must be recorded.
Abbreviations:  C = cycle; CXDY = Cycle X Day Y, as an example; D = day; EOI = end of infusion; IV = intravenous; 
PK = pharmacokinetic.
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9.6
Pharmacodynamics
9.7
Pharmacogenomics
Not applicable.
9.7.1
Absorption, Distribution, Metabolism, and Excretion Sampling
Not applicable.
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9.10
Health Economics OR Medical Resource Utilization and Health 
Economics
Health economics/medical resource utilization and health economics parameters will not be 
evaluated in the study at this time.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
10.1.1
Monotherapy Dose Escalation (Part 1A)
Dose escalation during the BMS-986218 Monotherapy Escalation (Part 1A) will be guided by 
BLRM employing the EWOC principle. The BLRM method is fully adaptive, makes use of all the 
information available at the time of each dose assignment, not just data from the current dose level, 
and directly addresses the ethical need to control the probability of overdosing. The targeted 
toxicity rate in this study is in the range of (16%, 33%). The use of the EWOC principle limits the 
risk of exposing patients in the next cohort to an intolerable dose by ensuring the posterior 
probability of the DLT rate at or exceeding 33% at any dose is capped at 35%. 
In order to understand operational characteristics of the BLRM, the total maximum number of 
participants for the simulation will be set to 108. As indicated in Appendix 11, simulation studies 
with various scenarios show that the expected number of DLT-evaluable participants needed for 
BLRM is no more than approximately 29.
For the trial, approximately 3 participants will be treated at the starting dose levels of 
BMS-986218. While the BLRM will use DLT information from the DLT period only, clinical 
assessment will take into consideration of the totality of available data including 
PK/pharmacodynamics from all treated participants in assigning a dose level for the next cohort 
of 3 participants. At least 6 DLT-evaluable participants will be treated at the MTD. Without 
exceeding a total of 200 evaluable participants, across dose levels and schedules, additional 
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participants may be treated at any dose level below or at the estimated MTD for further evaluation 
of safety, PK, or pharmacodynamic 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 
pre-specified 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 no greater than 35%);
3) A minimum number of participants (ie, 6) were treated at this dose level.
The final recommended MTD/RP2D will be based on the recommendation from the BLRM and 
overall clinical assessment of all available safety, PK, pharmacodynamic, and efficacy data. Lower 
doses of BMS-986218 may be tested if none of the planned doses are found to be tolerable as 
monotherapy. Such decisions will be made after discussion and agreement between the 
Investigators and the BMS Medical Monitor (or designee).
In addition, in Part 1A PD cohort, approximately 20 evaluable participants will be treated with 
BMS-986218 Q2W or Q4W monotherapy. Evaluable participants for the PD cohort are 
participants with matching baseline 
in order to evaluate PD changes, and additional safety and PK, in participants with advanced stage 
cutaneous melanoma, MSS CRC, NSCLC, or SCCHN. Assuming that the 
 interest is 
measured as a continuous variable, about 20 participants will be needed to provide ≥80% 
confidence that the estimate of the ratio of on-treatment to baseline values will be within 20% of 
the true value, assuming intra-subject variability of 49% at a specific dose level.
10.1.2
The Safety Evaluation of Combination Doses of BMS-986218 with 
Nivolumab (Part 1B)
In the Safety Evaluation Combination Doses of BMS-986218 with Nivolumab (Part 1B), the 
starting dose of BMS-986218 will be at least 1 dose level lower than the highest monotherapy dose 
level of BMS-986218 demonstrating an acceptable safety profile, and will be administered in 
combination with nivolumab at the flat dose of 480 mg Q4W. Dose escalation and determination 
of MTD for the Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab 
(Part 1B) will be guided by BLRM-copula with EWOC principle. Subsequent dose selection of 
the combination will be based on evaluating the recommendation from BLRM-copula and an 
overall assessment of all available safety and PK/pharmacodynamic data. Safety evaluation and 
tumor assessment will be performed Q8W (2 cycles). BLRM-copula will incorporate historical 
information from ipilimumab and nivolumab studies and the DLT information from the DLT 
period from both combination arms to estimate dose-toxicity surface, and will provide guidance 
for dose adjustment of either drug as needed.
While guided by the BLRM-copula, clinical assessment will take into consideration of the totality 
of available data including PK/pharmacodynamic from all treated participants in assigning a dose 
level for the next cohort of 3 participants. Six to 12 DLT-evaluable participants will be treated at 
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each combination dose. Additional participants may be treated at any dose combination below or 
at the BLRM-copula recommended dose combination for further evaluation of safety, PK, or
pharmacodynamic parameters as required. A combination with a higher dose level of either drug 
may be considered if recommended per BLRM-copula, after consideration of all available safety, 
and PK/pharmacodynamic data. At no time will the dose of BMS-986218 in the Safety Evaluation 
of Combination Doses of BMS-986218 with Nivolumab (Part 1B) exceed the highest tolerated 
dose in the BMS-986218 Monotherapy Escalation (Part 1A). Up to approximately 84 DLT-
evaluable participants will be enrolled in Part 1B. 
10.1.3
The Randomized BMS-986218 Monotherapy Cohort Expansion in 
Cutaneous Melanoma (Part 2A)
The primary purpose of the Randomized BMS-986218 Monotherapy Cohort Expansion in 
Cutaneous Melanoma (Part 2A) is to evaluate preliminary efficacy of BMS-986218 relative to 
ipilimumab 3 mg/kg. One hundred and thirty two response-evaluable participants will be 
randomized to BMS-986218 or ipilimumab evenly across study arms (eg, 33 participants to 
BMS-986218 at 7 mg Q4W; 33 participants to BMS-986218 at 20 mg Q4W; 33 participants to 
BMS-986218 at 70 mg Q4W; and 33 participants to ipilimumab) and stratified by the outcome 
(ie, progressed, relapsed) of previous anti-PD-1/PD-L1 immunotherapy. Additional response-
evaluable participants may be randomized to further evaluate emerging data or subgroups of 
interest if needed but not to exceed 40 response-evaluable participants per arm. If additional 
participants are randomized, up to 160 response-evaluable participants (= 40 participants × 4 arms) 
may be randomized in Part 2A. The ORR of ipilimumab will serve as a control. With 33 treated 
participants in each BMS-986218 arm, the lower limit of the 1-sided 80% confidence interval for 
ORR difference from ipilimumab arm will be 12%, 7.3%, or 2.7%, assuming effect size of 20%, 
15%, or 10%, respectively. 
Although the above assumptions on the response rate were used for the purpose of sample size 
calculation, it should be noted that, to date, there are no anti-tumor response data available in this 
post anti-PD-1/PD-L1 population. The efficacy evaluation criteria may evolve by the time when 
the tumor data from this study are matured for evaluation.
10.1.4
The BMS-986218 Cohort Expansion - Monotherapy (Part 2B)
The purpose of the BMS-986218 Cohort Expansion - Monotherapy (Part 2B) is to gather additional 
safety, tolerability, preliminary efficacy as monotherapy, PK, and pharmacodynamic information. 
However, the sample size calculation will be based on the ORR.
The preliminary efficacy of BMS-986218 as a monotherapy in solid tumors, including NSCLC, in 
participants who have received, and then progressed on, relapsed, or have been intolerant to, at 
least 2 standard systemic therapies with proven survival benefit according to their tumor types for 
metastatic and/or unresectable disease will be evaluated. Sixty-six response-evaluable participants 
will be randomized evenly across study arms (eg, 22 participants to BMS-986218 at 7 mg Q4W; 
22 participants to BMS-986218 at 20 mg Q4W; and 22 participants to BMS-986218 at 70 mg 
Q4W). Additional response-evaluable participants may be randomized to further evaluate 
emerging data or subgroups of interest if needed but not to exceed a total of 40 response-evaluable 
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participants per arm. If additional participants are randomized, up to 120 response-evaluable 
participants (= 40 participants × 3 arms) may be randomized in Part 2B.
With 22 treated participants in each BMS-986218 arm, the lower limit of the 2-sided 80% Clopper 
Pearson confidence interval for ORR estimate will be 8.2%, 5.1%, or 2.4%, assuming ORR 
estimate size of 18%, 13.6%, or 9.1%, respectively. 
10.1.5
The BMS-986218 Combination-Therapy Cohort Expansion in NSCLC
(Part 2C)
The purpose of the BMS-986218 Cohort Expansion - Combination Therapy (Part 2C) is to gather 
additional data including safety, tolerability, preliminary efficacy as combination therapy of 
BMS-986218 with nivolumab, in NSCLC. The sample size calculation will be based on the ORR.
Approximately 40 response-evaluable participants will be treated. Initial evaluation of efficacy 
signal (ORR) will be based on approximately the first 20 response-evaluable participants at a dose 
level, will be descriptive based on a point estimate and an 80% Clopper Pearson CI for ORR. In 
order for an 80% CI to exclude a 5.5% ORR (as reported for ipilimumab with nivolumab in similar 
population), at least 3 responders (15% ORR) will need to be observed in the first 20 participants 
evaluated at this dose. If 4 responders are observed (20% ORR), the 80% confidence interval will 
equal (9.0%, 36.1%). Based on the results of this initial evaluation, additional participants for a 
total of up to 40 participants may be treated at a dose level.
Furthermore, if 40 participants are evaluated at a dose level, there will be approximately 80% 
power to detect a difference between the null hypothesis assuming ORR of 5.5% and the alternative 
assuming ORR of 15%, based on a one group χ2 test with a 0.10 one-sided significance alpha 
level. If more than one dose level is evaluated, up to 80 response-evaluable participants (= 40 
participants × 2 arms) may be treated.
10.1.6
The BMS-986218 Combination-Therapy Cohort Expansion in MSS CRC
(Part 2D)
The purpose of the BMS-986218 Cohort Expansion - Combination Therapy (Part 2D) is to gather 
additional data including safety, tolerability, preliminary efficacy as combination therapy of 
BMS-986218 in combination with nivolumab, in participants with MSS CRC. The sample size 
calculation will be based on the ORR.
Approximately 40 response-evaluable participants will be treated in Part 2D, with the goal of 
treating approximately 20 participants each with either mutation or wild-type with respect to 
extended RAS status. As response to immunotherapy may differ substantially based on tumor 
genomics, ORR will be analyzed separately for participants with mutation and participants with 
wild-type.
With 20 treated participants with either mutation or wild-type, the lower limit of the 2-sided 80% 
Clopper Pearson confidence interval for ORR estimate will be 9%, 5.6%, or 2.7%, assuming ORR 
estimate size of 20%, 15%, or 10%, respectively. 
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10.2
Populations for Analyses
For purposes of analysis, the populations in are defined in Table 10.2-1.
Table 10.2-1:
Population for Analyses
Population
Description
Enrolled 
All participants who sign informed consent and are registered into the IRT
Treated
All participants who take at least 1 dose of study treatment
Randomized
All participants who were randomized to study drug (Parts 2A or 2B)
Response-evaluable
All treated participants with measurable disease at baseline and 1 of the following:  (a) at 
least 1 post baseline tumor assessment, (b) clinical progression, (c) death
Pharmacokinetic
All treated participants who have evaluable concentration-time data
Immunogenicity
All treated participants who have baseline and at least 1 post baseline pre-infusion 
immunogenicity assessment
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock, and below is a 
summary of planned statistical analyses of the primary and secondary endpoints.
A description of the participant population will be included in the statistical output reported, 
including subgroups of age, gender, and race.
10.3.1
Efficacy Analyses
The primary efficacy analyses (Table 10.3.1-1) will be performed on the randomized population 
in Parts 2A, and 2B, and on all treated participants in Part 1A, Part 1B, Part 2C, and Part 2D, for 
the final analysis. Supplemental analysis on All treated population may be provided in Parts 2A 
and 2B; Efficacy analyses based on the response-evaluable population may be performed for 
interim analyses when the minimum follow-up period is less than sufficient to warrant adequate 
interpretation of the result. Details of the censoring scheme on time-to-event endpoints such as 
DOR, progression-free survival rate (PFSR), PID, and overall survival rate (OSR) will be 
described in the Statistical Analysis Plan.
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Table 10.3.1-1:
Efficacy - Statistical Analyses
Endpoint
Statistical Analysis Methods
ORR is defined as the proportion of all treated 
participants whose BOR is either CR or PR by 
Investigator per RECIST v1.1 or per PCWG 3 criteria 
for prostate.
BOR for a participant will be assessed per 
RECIST v1.1 by Investigator, unless otherwise 
specified.
Estimate of ORR and corresponding 2-sided exact 95% 
CI using the Clopper-Pearson method by treatment for 
each tumor type.
For part 2A, estimate of difference in ORR between 
arms (using ipilimumab as reference) and 
corresponding 2-sided exact 95% CI using the Clopper-
Pearson method by BMS treatment arms.
Median DOR 
DOR for a participant with a BOR of CR or PR is 
defined as the time between the date of first response 
and the date of the first objectively documented tumor 
progression per RECIST v1.1 or per PCWG 3 criteria 
for prostate, or death, whichever occurs first.
Estimate by the Kaplan-Meier method and 
corresponding 2-sided 95% CI using Brookmeyer and 
Crowley methodology (using log-log transformation) 
by treatment for each tumor type.
PFSR at 24, 36, and 48 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 PFSR by the Kaplan-Meier method and 
corresponding 2-sided 95% CI using Greenwood 
formula by treatment for each tumor type.
For part 2A, estimate difference in PFSR between arms 
(using ipilimumab as reference) by the Kaplan-Meier 
method and corresponding 2-sided 95% CI using 
Greenwood formula by BMS treatment arms.
Estimate median PFS by the Kaplan-Meier method and 
corresponding 2-sided 95% CI using Greenwood 
formula by treatment for each tumor type.
Abbreviations:  BOR = best overall response; BMS = Bristol Myers Squibb; CI = confidence interval; CR = complete 
response; DOR = duration of response; ORR = objective response rate; PCWG 3 = Prostate Cancer Working Group;
PFSR = progression-free survival rate; PR = partial response; RECIST = Response Evaluation Criteria in Solid 
Tumors.
10.3.2
Safety Analyses
All safety analyses will be performed on the treated population.
Table 10.3.2-1:
Safety - Statistical Analyses
Endpoint
Statistical Analysis Methods
Incidence of DLTs, AEs, SAEs, AEs 
leading to discontinuation, and death.
AEs will be graded according to 
CTCAE v4.03.
DLT rate by dose level, frequency distribution of treated participants 
with AE using the worst CTC grade. Participants will only be counted 
(1) once at the PT level, (2) once at the system organ class level, and 
(3) once in the ‘total participant’ row at their worst CTC grade, 
regardless of system organ class or PT.
Toxicity Changes from Baseline.
Laboratory values will be graded 
according to CTCAE v4.03.
Laboratory shift table using the worst CTC grade on-treatment per 
participant.
Abbreviations:  CTC = common terminology criteria; PT = preferred term.
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10.3.3
Pharmacokinetic Analysis for BMS-986218 
Table 10.3.3-1:
Pharmacokinetic ‑ Statistical Analyses
Endpoint
Statistical Analysis Methods
Cmax, AUC(0-T), AUC(TAU), 
Ctau, CLT, Css-avg, AI_Cmax, 
AI_AUC, and T-HALF
Summary statistics:  geometric means and coefficients of variation
Cmax, AUC(0-T), AUC(TAU)
Scatter plots vs dose for each cycle measured; dose proportionality based on a 
power model and a CI around the power coefficient
Tmax
Summary statistics:  medians and ranges
Ctrough 
Summary statistics to assess attainment of steady state:  geometric means and 
coefficients of variation, by treatment and by day; plots vs time by dose
Abbreviations:  AI_AUC = ratio of an exposure measure at steady state to that after the first dose (exposure measure 
includes AUC[TAU]); AI_Cmax = ratio of an exposure measure at steady state to that after the first dose (exposure 
measure includes Cmax); AUC(0-T) = area under the plasma serum concentration-time curve from time zero to time 
of last quantifiable concentration (may be calculated if concentrations are not quantifiable up to TAU across a 
treatment group); AUC(TAU) = area under the serum concentration-time curve in 1 dosing interval; CLT = total body 
clearance; Css-avg = average serum concentration over a dosing interval (AUC[TAU]/tau) at steady state; 
Ctau = observed serum concentration at the end of a dosing interval; Ctrough = trough observed serum concentrations 
(this includes predose concentrations [C0] and Ctau); T-HALF = terminal serum half-life; Tmax = time of maximum 
observed plasma serum concentration. 
PK serum concentration-time data for BMS-986218, ipilimumab, and/or nivolumab may be pooled 
with data from other studies for integrated population PK and ER analyses, which will be presented 
in a separate report.
10.3.4
Immunogenicity
Endpoint
Statistical Analysis Methods
Incidence of ADA
Baseline ADA-positive participant is defined as a participant who has 
an ADA-detected sample at baselinea,b ADA positive- participant is a 
participant with at least 1 ADA-positive sample relative to baseline 
after initiation of the treatment
Frequency distribution of 
baseline ADA-positive 
participants and ADA-positive 
participants after initiation of the 
treatment
a Baseline sample is the last sample before initiation of the treatment.
b Details of the immunogenicity data analysis, including ADA titers, will be provided in the Statistical Analysis Plan.
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10.3.9
Interim Analyses 
Interim analyses will be performed for administrative purposes, internal decisions, or publications 
and they will be descriptive. No formal inferences requiring any adjustment to statistical 
significance level will be performed.
Preliminary efficacy may be assessed for Part 2 to determine an initial signal, and enrollment may 
be paused, prior to enrolling additional participants. Depending on enrollment rate and preliminary 
data there may not be a pause in enrollment. If an inadequate signal is detected from a preliminary 
analysis, then enrollment may be closed for that cohort.
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11
REFERENCES
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Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting:  from immunosurveillance to 
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BMS-986218; Investigator Brochure Version 3. Bristol-Myers Squibb Company; 2019. 
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7
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 
blockade. Science 1996;271:1734-6.
8
Leabman MK, Meng YG, Kelley RF, et al. Effects of altered FcγR binding on antibody 
pharmacokinetics in cynomolgus monkeys. MAbs 2013;5(6):896-903.
9
Feng Y, Masson E, Dai D, et al. Model-based clinical pharmacology profiling of ipilimumab in 
patients with advanced melanoma. Br J Clin Pharmacol 2014;78(1):106-17.
10 Physicochemical Characterization of MDX-010 (Study MDX-010-011-R); Report. Medarex 
Inc.; 18-Jan-2007. Document Control No. 930020111.
11 Ipilimumab Toxicology Written Summary. Bristol-Myers Squibb Company; 2010. Document 
Control No. 930043843.
12 BMS-986218:  One-Month Intermittent-Dose (QW) Intravenous Toxicity Study in Monkeys 
with a 6-Week Recovery (Study DN16107); Report. Bristol-Myers Squibb Company; 2017. 
Document Control No. 930109559.
13 Repeated-dose toxicity study of anti-CTLA-4/10D1 administered via intravenous injection to 
cynomolgus monkeys (Study 126-002); Report. Redfield Laboratories; 2000. Document 
Control No. 930009967.
14 A 2-week toxicity study of human anti-CTLA-4 administered by intravenous injection to 
cynomolgus monkeys (Study 0919-128); Report. Sierra Biomedical; 2000. Document Control 
No. 930009982.
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15 14-day intravenous toxicity study with mAb 10D1 in cynomolgus monkeys (Study 7114-100); 
Report. Covance Laboratories; 2000. Document Control No. 930009970.
16 BMS-663513 and BMS-734016:  One-month intravenous combination toxicity study in 
monkeys (Study DS06064); Report. Bristol-Myers Squibb Company; 2007. Document Control 
No. 930021064.
17 A repeated dose toxicity and efficacy study of MDX-010 or MDX-010-HYB in combination 
with HBsAg and SKMel vaccines in cynomolgus monkeys (Study 1416-128); Report. Sierra 
Biomedical; 2003. Document Control No. 930009973.
18 An immunogenic study following combined intravenous/ intramuscular administration of 
MAb10D1/HBsAg, respectively, to cynomolgus monkeys (Study 0992-128); Report. Sierra 
Biomedical; 2001. Document Control No. 930009968.
19 MDX-CTLA-4:  A 6-month intravenous toxicity study in cynomolgus monkeys (Study 01-
3460); Report. Huntingdon Life Sciences; 2002. Document Control No. 930009980.
20 BMS-986218:  In vitro cytokine release and lymphocyte activation assessment using whole 
blood in a soluble assay format (Study DN16263); Report. Bristol-Myers Squibb Company;
2017. Document Control No. 930110258.
21 BMS-986218:  In vitro cytokine release and lymphocyte activation assessment using human 
peripheral blood mononuclear cells (Study DN16149); Report. Bristol-Myers Squibb 
Company; 2017. Document Control No. 930109567.
22 BMS-986012:  Anti-fucosyl GM1 Investigator Brochure Version 02. Bristol-Myers Squibb 
Company; 2015. Document Control No. 930073880.
23 BMS-663513 and Ipilimumab:  Exploratory in vitro proliferation and cytokine release 
assessment using human peripheral-blood mononuclear cells. Study Report 930034490. 
Bristol-Myers Squibb Research and Development. 2009. Document Control No. 930034490.
24 Effect of Combined MDX-1106 and Ipilimumab Treatment on Ex Vivo Cytokine Expression 
in Human Peripheral Blood Cells (Study MDX-1106/010-008-R), Report. Medarex, 2009. 
Document Control No. 930036361.
25 Ipilimumab Summary of Clinical Safety. Bristol-Myers Squibb Company; 2010. Document 
Control No. 930028133.
26 Nivolumab (Opdivo) US Prescribing Information. Bristol-Myers Squibb Company; Revised 
May 2016.
27 Nivolumab (BMS-936558) Investigator Brochure Version 18. Bristol-Myers Squibb 
Company; 2019. Document Control No. 930038243.
28 Note 
for 
guidance 
on 
nonclinical 
evaluation 
for 
anticancer 
pharmaceuticals 
EMEA/CHMP/ICH/646107/2008.
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29 Ipilimumab (BMS-734016, MDX0110) Investigator Brochure Version 22. Bristol-Myers 
Squibb Company; 2019. Document Control No. 930017531.
30 Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015;348(6230):56-
61.
31 Restifo NP, Smyth MJ, Snyder A. Acquired resistance to immunotherapy and future 
challenges. Nat Rev Cancer 2016;16(2):121-6.
32 Ngiow SF, Young A, Jazquelot N, et al. A threshold level of intratumor CD8+ T-cell PD-1 
expression dictates therapeutic response to anti-PD-1. Cancer Res 2015;75(18):3800-11.
33 Koyama S, Akbay EA, Li YY, et al. Adaptive resistance to therapeutic PD-1 blockade is 
associated with upregulation of alternative immune checkpoints. Nat Commun 2016;7:10501.
34 Hugo W, Zaretsky JM, Sun L, et al. Genomic and transcriptomic features of response to 
anti-PD-1 therapy in metastatic melanoma. Cell 2016;165(1):35-44.
35 Brahmer J, Horn L, Jackman D, 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.
36 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 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.
38 Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification 
of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 2006;24:5373-
80.
39 Merlo A, Casalini P, Carcangiu ML, et al. FOXP3 expression and overall survival in breast 
cancer. J Clin Oncol 2009;27:1746-52.
40 Hiraoka N, Onozato K, Kosuge T, et al. Prevalence of FOXP3+ regulatory T cells increases 
during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin. 
Cancer Res 2006;12:5423-34. 
41 Ino Y, Yamazaki-Itoh R, Shimada K, et al. Immune cell infiltration as an indicator of the 
immune microenvironment of pancreatic cancer. Br. J. Cancer 2013;108:914-923. 
42
BMS-986218:  Binding Affinity for Human FcγRs by Surface Plasmon Resonance (Study 
Report BDX-010NF-006). Bristol Myers Squibb Company; 2017. Document Control No.
930105087.
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43
BMS-986218:  Validation Report for the Quantification of BMS-986218 in Cynomolgus 
Monkey Serum by Chemiluminescence Enzyme-Linked Immunosorbent Assay (ELISA). 
Bristol-Myers Squibb Company; 2016. Document Control No. 930106252.
44
Ipilimumab Population Pharmacokinetic and Exposure - Response Analyses in Previously 
Treated or Untreated Subjects with Advanced Melanoma. Bristol-Myers Squibb Company;
2014. Document Control No. 930082362.
45
Stebbings R, Eastwood D, Poole S, et al. After TGN1412:  Recent developments in cytokine 
release assays. J of Immunotoxicology 2013;10(1):75–82.
46
Saber H, Gudi R, Manning M, et al. An FDA oncology analysis of immune activating products 
and first-in-human dose selection. Reg Tox and Pharm 2016;81:448-456.
47
BMS-986218:  In Vitro Fc Effector Function of BMS-986218, (Study BDX-010NF-005). 
Bristol-Myers Squibb Company; 2017. Document Control No.930109701. 
48
BMS-986218:  Evaluation of BMS-986218 in Functional Assays (Study BDX-1804-004). 
Bristol-Myers Squibb Company; 2016. Document Control No. 930109403.
49 Wang DD, Zhang S, Zhao H, et al. Fixed dosing versus body size-based dosing of monoclonal 
antibodies in adult clinical trials. J Clin Pharmacol 2009;49(9):1012-1024.
50 Bai S, Jorga K, Xin Y, et al. A guide to rational dosing of monoclonal antibodies. Clin
Pharmacokinet 2012;51(2):119-135.
51 Momtaz P, Park V, Panageas KS, et al. Safety of infusing ipilimumab over 30-minutes. J Clin 
Oncol 2015;33(30):3454-3458.
52 Waterhouse D, Horn L, Reynolds C, et al. Safety Profile of Nivolumab Administered as 30-
Minute Infusion:  Analysis of Data from CheckMate 153. ASCO poster #3059.
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12.
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
Ab
antibody
ADA
anti-drug antibody
ADCC
antibody-dependent cellular cytotoxicity
AE
adverse event
AI
accumulation index
AI_AUC
accumulation index ratio of AUC at steady state to that after the first dose
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
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 1 dosing interval
Avg
average
BLRM
Bayesian Logistic Regression Model
BMS
Bristol-Myers Squibb
BOR
best overall response
BRAF
v-raf murine sarcoma viral oncogene homolog B1
BUN
blood urea nitrogen
C
cycle
Cavg
average concentration
Cavgss
average steady state concentration
CD
cluster differentiation
cHL
classical Hodgkin Lymphoma
CI
confidence interval
CL
clearance
CLT
total body clearance
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Term
Definition
CLTp
total plasma clearance
Cmax
maximum observed plasma concentration
CNS
central nervous system
COVID-19
Coronavirus Disease 2019
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
case report form
Css-avg
average concentration over a dosing interval (AUC[TAU]/tau) at steady 
state
CT
computed tomography
CTAg
Clinical Trial Agreement
Ctau
observed concentration at the end of a dosing interval
CTC
common terminology criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
trough observed plasma concentration
D
day
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
EAU50
area-under-the-concentration-time curve producing 50% of the maximum 
effect
EC50
concentration required for 50% efficacy
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EGFR
epidermal growth factor receptor
EMAX
maximum effect
EOI
end of infusion
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Term
Definition
EOT
end of treatment
ER
exposure response
EWOC
escalation with overdose control
FcR
Fc receptor
FDA
Food and Drug Administration
FDG
2-deoxy-2-[18F]fluoro-D-glucose
FIH
first-in-human
FNR
false negative rate
FPR
false positive rate
FSH
Follicle stimulating hormone
GI
gastrointestinal
GE
gastroesophageal
GnRH
gonadotropin-releasing hormone
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
hIgG1
human immunoglobulin G1
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
IB
Investigator Brochure
ICF
informed consent form
IFN-γ 
interferon gamma
Ig
immunoglobulin
IL
interleukin
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Term
Definition
IMP
investigational medicinal product
IND
Investigational New Drug
I-O
immuno-oncology
IP
investigational product
IPRES
Innate PD-1 RESistance
irAE
immune-related adverse event
IRR
infusion-related reaction
IRT
Interactive Response Technology
IV
intravenous
Kd
constant of dissociation
KRAS
Kirsten rat sarcoma viral oncogene homolog
LHRH
luteinizing hormone releasing hormone
mAb
monoclonal antibody
MAP
meta-analytic predictive
mCRPC
metastatic castration-resistant prostate cancer
mDOR
median duration of response
MRI
magnetic resonance imaging
MSS
microsatellite stable
MTD
maximum tolerated dose
NF
non-fucosylated
NK
natural killer (cell)
NRAS
neuroblastoma rat viral oncogene homolog
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OSR
overall survival rate
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
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Term
Definition
PCWG 3
Prostate Cancer Working Group 3
PD
pharmacodynamic
PD-1
programmed cell death 1
PDAC
pancreatic ductal adenocarcinoma
PD-L1
programmed death ligand 1
PD-L2
programmed death ligand 2
p-DILI
potential drug-induced liver injury
PE
physical examination
PET
positron emission tomography
PrEE
probability of early efficacy
PrET
probability of early termination
PFS
progression-free survival
PFSR
progression-free survival rate
PI
prediction interval
PID
patient identification number
PK
pharmacokinetic/s
PPK
population pharmacokinetics
PR
partial response
PT
preferred term
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q8W
every 8 weeks
Q12W
every 12 weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RAS
rat sarcoma
RCC
renal cell carcinoma
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Term
Definition
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RP2D-1
1 dose level below the recommended Phase 2 dose of BMS 986218
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCC
squamous cell carcinoma
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SMT
Safety Management Team
SPR
surface plasmon resonance
T3
triiodothyronine
T4
thyroxine
TGI
tumor growth inhibition
T-HALF
terminal serum half-life
Tmax
time of maximum observed concentration
TNBC
triple-negative breast cancer
TNF-α
tumor necrosis factor alpha
Treg
T-regulatory cell
TSH
thyroid stimulating hormone 
ULN
upper limit of normal
US
United States
Vss
steady-state volume of distribution
WOCBP
women of childbearing potential
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Term
Definition
WWPS
Worldwide Patient Safety
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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:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 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 deviation, 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. 
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The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted as soon 
as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects/participants currently enrolled in the study if they are affected by the amendment; and (3) 
the new form must be used to obtain consent from new subjects/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
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 by 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. 
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Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
•
Provide a copy of the consent form and written information about the study, in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects’/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA
Authorization.
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 
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devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its 
vendors):
Records or logs must comply with applicable regulations and 
guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each participant, including 
unique participant identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, if applicable 
•
dates and initials of person responsible for Investigational 
Product dispensing/accountability, as per the Delegation of 
Authority Form.
Sourced by site, and not 
supplied by BMS or its 
vendors 
(examples 
include IP sourced from 
the 
sites 
stock,
or 
commercial supply, or a 
specialty pharmacy)
The investigator or designee accepts responsibility for documenting 
traceability and study treatment integrity in accordance with 
requirements applicable under law and the SOPs/standards of the 
sourcing pharmacy. 
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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 
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. 
Monitoring  details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
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requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities 
and promptly forward copies of inspection reports to the 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, institution 
procedures, or for the period specified by BMS or designee, whichever is longer. The investigator 
(or head of the study site in Japan) must contact BMS prior to destroying any records associated 
with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor, or sourced by the investigator),
such as partially used study treatment containers, vials, and syringes, may be destroyed on site. 
If
Then
Study 
treatments 
supplied 
by 
BMS 
(including its vendors)
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety or to 
meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
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If
Then
Study treatments sourced by site, not 
supplied by BMS (or its vendors) (examples 
include study treatments sourced from the 
site’s stock or commercial supply, or a 
specialty pharmacy)
It is the investigator’s or designee’s responsibility 
to dispose of all containers according to the 
institutional guidelines and procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor,
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non-study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
STUDY AND SITE START AND CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed. The investigator may initiate 
study-site closure at any time, provided there is reasonable cause and sufficient notice is given in 
advance of the intended termination. Reasons for the early closure of a study site by the Sponsor 
or investigator may include, but are not limited to:
•
Failure of the investigator to comply with the protocol,  the requirements of  the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
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•
Inadequate recruitment of participants by the investigator
•
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criterion will be used to select the signatory 
investigator:
•
Study steering committee chair or their designee
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [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 CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors.  No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
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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).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.8 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see Section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint; if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 
hours to BMS (or designee) using the same procedure used for transmitting the initial SAE 
report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be 
reported to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the 
electronic data capture (EDC) system is unavailable/not functioning for 
transmission of the eCRF to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted 
via email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 4 provides general information and definitions related to Woman of Childbearing 
Potential and methods of contraception that can be applied to most clinical trials. For information 
specific to this study regarding acceptable contraception requirements for female and male 
participants, refer to Section 6.1 of the protocol. Only the contraception methods as described in 
Section 6.1 are acceptable for this study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age
45 years in the absence of other biological or physiological causes. In addition, females
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. Suggested 
guidelines for the duration of the washout periods for HRT tryes are presented below. Investigators 
should use their judgement in checking serum FSH levels.
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
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Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the timepoint where the Investigational Medicinal Product 
(IMP) or any active major metabolites have decreased to a concentration that is no longer 
considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in 
context of safety margins from the no-observed-adverse-effect level or the time required for 5 half-
lives of the IMP to pass.
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 3 months after the end of study 
treatment for monotherapy treatment with BMS-986218 or with monotherapy with ipilimumab,
and 5 months after completion of combination therapy treatment with BMS-986218 and 
nivolumab.* Less than highly effective contraception methods are not acceptable.
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation. (This method of contraception can only be used by WOCBP participants 
in studies where hormonal contraception is permitted by the study protocol). b
−
oral (birth control pills)
−
intravaginal (rings)
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulation
(This
method of contraception can only be used by WOCBP participants in studies where hormonal 
contraception is permitted by the study protocol).b 
−
oral 
−
injectable
Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of study therapy.
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation/and or implantation. (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol).b
•
Intrauterine device (IUD)
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•
Intrauterine hormone-releasing system (IUS) (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol). b,c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP, and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective contraception 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.
•
Continuous abstinence must begin at least 30 days prior to initiation of study therapy.
•
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 participant chooses to forego complete abstinence.
•
Periodic abstinence (including, but not limited to, calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from failure rates when contraceptive methods are 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. For information specific to this study regarding permissibility of hormonal 
contraception, refer to Sections 6.1 INCLUSION CRITERIA and 7.9.1 PROHIBITED AND/OR RESTRICTED 
TREATMENTS of the protocol.
c IUSs are acceptable methods of contraception in the absence of definitive drug interaction studies or when 
hormone exposures from intrauterine devices do not alter contraception effectiveness. For information specific to 
this study regarding permissibility of hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 
7.9.1 PROHIBITED AND/OR RESTRICTED TREATMENTS of the protocol.
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Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of >1% per year when used consistently and correctly. *
•
Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mechanism of action. (This method of contraception cannot be used by WOCBP participants in studies 
where hormonal contraception is prohibited).
Unacceptable Methods of Contraception*
•
Periodic abstinence (calendar, symptothemral, 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.
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 considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are nonmeasurable.
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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.
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 
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suggested. As previously noted, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study.
1.4.2.4
Ultrasound
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
2.1
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) that are representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
should be representative of all involved organs, and should lend themselves to reproducible
repeated measurements.
A sum of the diameters for all target lesions will be calculated and reported as the baseline sum
diameters. For non-nodal lesions, the longest axis should be included in the baseline sum 
diameters. If lymph nodes are to be included in the sum, then as noted below, only the short axis 
is added into the baseline sum diameters. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease.
2.1.1
Lymph Nodes
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. Pathological nodes that are defined as 
measurable, and may be identified as target lesions, must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum
diameters. Nodes that have a short axis < 10 mm are considered nonpathological and should not 
be recorded or followed.
2.2
Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
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’).
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3
TUMOR RESPONSE EVALUATION
3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must also have reduction in the short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions,
taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: The appearance of 1 or more new lesions is also considered 
progression.)
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD.
3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
Lymph Nodes
Lymph nodes merit special mention since they are normal anatomical structures that may be visible 
by imaging even if not involved by tumor. Pathological nodes that are defined as measurable and 
may be identified as target lesions must meet the criterion of a short axis of ≥15 mm by CT scan. 
Only the short axis of these nodes will contribute to the baseline sum. Nodes that have a short axis 
< 10 mm are considered non-pathological and should not be recorded or followed.
3.1.1.2
Target Lesions That Become ‘Too Small to Measure’
All lesions (nodal and nonnodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation. If the radiologist is able to provide an actual measurement,
even if it is below 5 mm it should be recorded.
However, when such a lesion becomes difficult to assign an exact measurement to then:
•
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.
•
If the lesion or lymph node is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned =. This default value is derived from the 5-mm 
CT-slice thickness (but should not be changed with varying CT-slice thickness).
3.1.1.3
Target Lesions That Split or Coalesce on Treatment
•
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should 
be added together to calculate the target lesion sum.
•
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’.
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3.2
Evaluation of Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the timepoints specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must also be 
nonpathological in size (< 10 mm short axis).
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) above the normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: The 
appearance of 1 or more new lesions is also considered progression.)
3.2.1
Special Notes on Assessment of Non-Target Lesions
The concept of progression of non-target disease requires additional explanation.
3.2.1.1
When the Subject Also Has Measurable Disease
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in the presence of 
SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 
•
A modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. 
3.2.1.2
When the Subject Has Only Non-Measurable Disease
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. 
•
A modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. 
•
Because worsening in non-target disease cannot be easily quantified as the lesions are 
nonmeasurable, a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for target disease: that is, an increase in tumor burden representing an additional 
73% increase in ‘volume’ (which is equivalent to a 20% increase in diameter in a measurable 
lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’ or an increase 
in lymphangitic disease from localized to widespread or may be described in protocols as 
‘sufficient to require a change in therapy’. 
•
If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD 
at that point.
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3.2.1.3
Tumor Markers
Tumor markers alone cannot be used to assess objective tumor responses. If markers are initially 
above the upper normal limit, however, they must normalize in order for a subject to be considered 
as having attained a CR.
3.3
New Lesions
The appearance of new malignant lesions denotes PD. The finding of a new lesion should be 
unequivocal: that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (eg, some ‘new’ bone 
lesions may be simply healing or a flare of pre-existing lesions). This distinction is particularly 
important when the subject’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate PD. An example of this is the subject who has visceral 
disease at baseline and while on study has a CT or MRI brain scan that reveals metastases. The 
subject’s brain metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then PD should be declared using the date of the initial scan.
3.3.1
FDG-PET Evaluation
While [18F] fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of the qualitative assessment of FDG-PET scanning 
to complement CT scanning in assessment of PD (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: 
•
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD based 
on a new lesion. 
•
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
−
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
−
If the positive FDG-PET at follow-up is not confirmed as a new site of disease by CT, 
additional follow-up CT scans are needed to determine if there is truly PD occurring at that 
site (if so, the date of PD will be the date of the initial positive FDG-PET scan).
−
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.
4
RESPONSE CRITERIA
4.1
Timepoint Response
A response assessment should occur at each timepoint specified in the protocol. 
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For subjects who have measurable disease at baseline Table 4.1-1 provides a summary of the 
overall response status calculation at each timepoint.
Table 4.1-1:
Timepoint Response: Subjects with Target (+/– Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
NonCR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
NonPD or not all evaluated
No
PR
SD
NonPD or not all evaluated
No
SD
Not all evaluated
NonPD
No
NE
PD
Any
Yes or No
PD
Any 
PD
Yes or No
PD
Any
Any 
Yes
PD
Abbreviation: NE =not evaluable
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the subject is not evaluable 
at that timepoint. If only a subset of lesion measurements are made at an assessment, the subject
is also considered NE at that timepoint, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned timepoint 
response.
4.1.1
Confirmation Scans
•
Verification of Response: Confirmation of PR and CR is required at least 4 weeks following 
initial assessment to ensure responses identified are not the result of measurement error.
4.2
Best Overall Response: All Timepoints
The best overall response is determined once all the data for the subject are known. It is the best 
response recorded from the start of the study treatment until the date of objectively documented 
PD based on RECIST v1.1, taking into account any requirement for confirmation or the date of 
subsequent anti-cancer therapy, whichever occurs first in the study. The subject’s best overall 
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response assignment will depend on the findings of both target and non-target disease and will also 
take into consideration the appearance of new lesions. 
The best overall response is defined as the best response across all timepoints with subsequent 
confirmation. CR or PR may be claimed only if the criteria for each are met at a subsequent 
timepoint as specified in the protocol (generally 4 weeks later).
In this circumstance, the best overall response can be interpreted as specified in Table 4.2-1. When 
SD is believed to be best response, it must meet the protocol specified minimum time from 
baseline. Measurements must have met the SD criteria at least once after study entry at a minimum 
interval (in general, not less than 6 to 8 weeks) that is defined in the study protocol.
Table 4.2-1:
Best Overall Response When Confirmation of CR and PR Is 
Required
Overall Response
Overall Response
Best Overall Response
First Timepoint
Subsequent Timepoint
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise NE
NE
NE
NE
a If a CR is truly met at the first timepoint, then any disease seen at a subsequent timepoint, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since the disease must have reappeared after CR). 
The best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may 
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be claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not 
CR at the first timepoint. Under these circumstances, the original CR should be changed to PR and the best response 
is PR.
4.3
Duration of Response
4.3.1
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
4.3.2
Duration of Stable Disease
SD is measured from the start of the treatment (in randomized trials, from date of randomization) 
until the criteria for progression are met, taking as reference the smallest sum on study (if the 
baseline sum is the smallest, this is the reference for calculation of PD).
CR (Complete Remission)
The designation of CR requires all of the following:
1) Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms, if present before therapy.
a) Typically FDG-avid lymphoma: in patients without a pre-treatment PET scan or if the 
pre-treatment PET scan was positive, a post-treatment residual mass of any size is 
permitted as long as it is PET negative.
b) Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pre-treatment 
PET scan, or if a pre-treatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed on CT scan to normal size (≤1.5 cm in their greatest transverse 
diameter for nodes > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 
1.5 cm in their long axis and > 1.0 cm in their short axis before treatment must have 
decreased to ≤1.0 cm in their short axis after treatment.
2) The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should disappear. 
However, determination of splenic involvement is not always reliable because a spleen 
considered normal in size may still contain lymphoma, whereas an enlarged spleen may reflect 
variations in anatomy, blood volume, the use of hematopoietic growth factors, or causes other 
than lymphoma.
3) If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared 
. The 
 sample on which this determination is made 
must be adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample that is negative by 
immunohistochemistry, but demonstrates a small population of clonal lymphocytes by flow 
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cytometry, will be considered a CR until data become available demonstrating a clear 
difference in patient outcome.
PR (Partial Remission)
The designation of PR requires all of the following:
1) At least a 50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the 
largest dominant nodes or nodal masses. These nodes or nodal masses should be selected 
according to all of the following: they should be clearly measurable in at least 2 perpendicular 
dimensions; if possible, they should be from disparate regions of the body; and they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
2) No increase should be observed in the size of other nodes, liver, or spleen.
3) Splenic and hepatic nodules must regress by ≥50% in their SPD or, for single nodules, in the 
greatest transverse diameter.
4) With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable, and no measurable disease should be present.
5) Bone marrow assessment is irrelevant for determination of a PR, if the sample was positive 
before treatment. However, if positive, the cell type should be specified (eg, large-cell 
lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria but 
have persistent morphologic bone marrow involvement will be considered partial responders. 
When the bone marrow was involved before therapy and a clinical CR was achieved but with 
no bone marrow assessment after treatment, patients should be considered partial responders.
6) No new sites of disease should be observed.
7) FDG:
a) Typically FDG-avid lymphoma: for patients without a pre-treatment PET scan or if the 
pre-treatment PET scan was positive, the post-treatment PET scan should be positive in at 
least 1 previously involved site.
b) Variably FDG-avid lymphomas/FDG
avidity unknown: for patients without a 
pre-treatment PET scan, or if a pre-treatment PET scan was negative, CT criteria should 
be used. In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only 
indicated with 1 or at most 2 residual masses that have regressed by > 50% on CT; those 
with more than 2 residual lesions are unlikely to be PET negative and should be considered 
partial responders.
SD (Stable Disease)
1) The designation of SD requires all of the following: A patient is considered to have SD when 
he or she fails to attain the criteria needed for a CR or PR but does not fulfill those for PD (see 
Relapsed Disease [after CR]/PD [after PR, SD]).
2) Typically FDG-avid lymphomas: the PET should be positive at prior sites of disease with no 
new areas of involvement on the post-treatment CT or PET scan.
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3) Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pre-treatment 
PET scan or if the pre-treatment PET was negative, there must be no change in the size of the 
previous lesions on the post-treatment CT scan.
PD: Relapsed Disease (after CR)/PD (after PR, SD)
Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of the short 
axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if its 
short axis is > 1.0. Lymph nodes ≤1.0 × ≤1.0 cm will not be considered abnormal for relapse or 
progressive disease.
1) Appearance of any new lesion > 1.5 cm in any axis during or at the end of therapy, even if 
other lesions are decreasing in size. Increased FDG uptake in a previously unaffected site 
should only be considered relapsed or PD after confirmation with other modalities. In patients 
with no prior history of pulmonary lymphoma, new lung nodules identified by CT are mostly 
benign. Thus, a therapeutic decision should not be made solely on the basis of the PET scan 
without histologic confirmation.
2) At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single 
involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be considered 
PD, a lymph node with a diameter of the short axis of < 1.0 cm must increase by ≥50% and to 
a size of 1.5 × 1.5 cm or > 1.5 cm in the long axis.
3) At least a 50% increase in the longest diameter of any single previously identified node > 1 cm 
in its short axis.
4) Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was 
PET positive before therapy, unless the lesion is too small to be detected with current PET 
systems (< 1.5 cm in its long axis by CT).
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these assessments, the spleen is considered nodal disease. Disease that is only assessable by 
physical examination (eg, pleural effusions, bone lesions) will be recorded as present or absent 
only, unless, while an abnormality is still noted by imaging studies or physical examination, it is 
found to be histologically negative.
In clinical trials where PET is unavailable to the vast majority of participants, or where PET is not 
deemed necessary or appropriate for use (eg, a trial in patients with mucosa-associated lymphoid 
tissue lymphoma), response should be assessed as above, but only using CT scans. However, 
residual masses should not be assigned CRu status but should be considered a PR.
Reference: Cheson BD, Pfisner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 
2007;25:579-86.
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APPENDIX 6
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS
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APPENDIX 7
NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION
Heart failure is usually classified according to the severity of the patient’s symptoms. The table 
below describes the most commonly used classification system, the New York Heart Association 
(NYHA) functional classification. It places patients in 1 of 4 categories based on how much they 
are limited during physical activity.
Class
Patient Symptoms
I
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of 
breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, or dyspnea 
(shortness of breath).
III
Marked limitation of physical activity. Comfortable at rest. Less 
than ordinary activity causes fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort. 
Symptoms of heart failure at rest. If any physical activity is 
undertaken, discomfort increases.
Class
Objective Assessment
A
No objective evidence of cardiovascular disease. No symptoms 
and no limitation in ordinary physical activity.
B
Objective evidence of minimal cardiovascular disease. Mild 
symptoms and slight limitation during ordinary activity. 
Comfortable at rest.
C
Objective evidence of moderately severe cardiovascular disease. 
Marked limitation in activity due to symptoms, even during 
less-than-ordinary activity. Comfortable only at rest.
D
Objective evidence of severe cardiovascular disease. Severe 
limitations. Experiences symptoms even while at rest.
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APPENDIX 8
COUNTRY SPECIFIC REQUIREMENTS
Argentina, Czech Republic, France, Germany, Italy, Spain, and Any Other Countries Where 
Exclusion of HIV Positive Participants Is Locally Mandated
Country-specific language
Section 9.1.4 Clinical Safety Laboratory 
Assessments, Table 9.1.4-1: Clinical Laboratory 
Assessments
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion Criteria, Exclusion
criterion: 3), e), vii)
“Known human immunodeficiency virus (HIV) positive with an 
acquired immunodeficiency syndrome (AIDS) defining 
opportunistic infection within the last year, or a current CD4 count 
< 350 cells/uL. Participants with HIV are eligible if: they have 
received antiretroviral therapy (ART) for at least 4 weeks prior to 
treatment assignment as clinical indicated while enrolled on study; 
they continue on ART as clinically indicated while enrolled on 
study; CD4 counts and viral load are monitored per standard of 
care by a local health care provider” to be replaced with “Positive
test for HIV.”
Argentina Only:
“Positive human immunodeficiency virus (HIV) with an acquired 
immunodeficiency syndrome (AIDS) defining opportunistic 
infection within the last year, or a current CD4 count <350 
cells/uL. Participants with HIV are eligible if: they have received 
antiretroviral therapy (ART) for at least 4 weeks prior to treatment 
assignment as clinically indicated while enrolled on study; they 
continue on ART as clinically indicated while enrolled on study; 
CD4 counts and viral load are monitored per standard of care by a 
local health care provider”
Norway contraception requirements:
Country-specific language
Additional pregnancy testing information to 
Table 2-5
Pregnancy testing will continue beyond the 100 day follow-up visit 
until the end of the protocol-specified contraception requirement 
(ie, 5 months).
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APPENDIX 9
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 10
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 4.0
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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6HS
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APPENDIX 11
STATISTICAL METHODOLOGY
STATISTICAL DETAILS FOR BAYESIAN LOGISTIC REGRESSION MODEL (BLRM 
AND BLRM-COPULA) 
1
MODEL SETUP FOR BMS-986218 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 for dose recommendation during the 
monotherapy dose escalation phase. 
The BLRM will be fitted on the dose-limiting toxicity (DLT) data during the first 8 weeks of 
treatment accumulated throughout the dose escalation to model the dose-toxicity relationship of 
BMS-986218 in the monotherapy dose escalation phase. 
The dose-toxicity relationships for BMS-986218 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-986218 (please refer to the meaning of 
ߙଵand ߚଵin Section 1.2.1 for detailed implementation).
1.2
Prior Specification for BMS-986218 Monotherapy
The Bayesian approach requires the specification of prior distributions for model parameters,
which include parameters (ߙଵ, ߚଵ) for BMS-986218. A mixture prior will be used for parameters 
(ߙଵ, ߚଵ) for BMS-986218. There are two bivariate normal components in generating this mixture 
prior:
•
Meta-analytic predictive (MAP) component: Obtained based on the clinical safety and 
exposure profiles of ipilimumab using the MAP approach, because BMS-986218 is the 
nonfucosylated form of ipilimumab.
•
Weakly informative prior for BMS-986218 component: Reflecting the potential higher toxicity 
of BMS-986218 than ipilimumab and allowing for considerable prior uncertainty.
Derivation of prior distribution of these parameters is provided in the following subsections.
1.2.1
Meta-analytic Predictive Component 
The MAP component provides a prediction of the dose-toxicity curve for BMS-986218 based on 
prior data from ipilimumab. This dose-toxicity curve combines a weakly informative prior for 
ipilimumab with toxicities from a range of doses observed in a set of ipilimumab studies and adds 
an extra layer of variability to account for heterogeneity among ipilimumab studies. Note that this 
weakly informative prior is for ipilimumab and is different from the weakly informative prior for 
BMS-986218 described in Section 1.2.
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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 BMS-986218, (log(ߙଵ),log(ߚଵ)).
•
Weakly informative prior for ipilimumab is as follows: 
−
The median toxicity rate at the ipilimumab reference dose (10 mg/kg every 3 weeks) was 
assumed to be 30%, that is, mean (log(α1)) = logit(0.30) = -0.847.
−
A doubling in dose was assumed to double the odds of DLT, that is, mean (log(β1)) = 0.
−
The standard deviation of log(α1) was set to 2, and the standard deviation of log(β1) was 
set to 1, which allows for considerable prior uncertainty for the dose-toxicity profile.
−
The correlation between log(α1) and log(β1) was assumed to be 0 (assuming independence 
of log(α1) and log(β1)).
•
Dose-toxicity data for ipilimumab are as follows:
−
Phase 3 study of ipilimumab administered at 3 mg/kg versus 10 mg/kg (Study CA184169, 
N=360 per arm)
−
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).
Based on the exposure-response analysis, BMS-986218 appeared to be 10-fold more potent than 
ipilimumab, and therefore, toxicity of BMS-986218 at 0.3 mg/kg that was converted to 20 mg flat 
dose for the study was assumed to be similar to that of 3 mg/kg of ipilimumab. Similarly, toxicity 
of BMS-986218 at 70 mg and 2 mg was mapped to that of ipilimumab 10 mg/kg and 0.3 mg/kg, 
respectively. The data are summarized in Table 1.
Table 1:
Data from Phase 2 and 3 Ipilimumab Studies at BMS in 
Participants with Previously Treated or Untreated Advanced 
Melanoma
Dose of BMS-986218 (mg)
Dose of Ipilimumab (mg/kg*)
Toxicity (percentage [number of 
participants/total participants])a
2
0.3
10% (7/72)
7
20
3
18% (119/675)
70
10
32% (242/760)
200
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a % of participants with treatment-related Grade 3-4 AEs
In addition, heterogeneity between the historical study and the current study was incorporated 
using a MAP by defining between-trial standard deviations τ1 and τ2 for log(α_1) and log(β_1), 
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.
1.2.2
Weakly Informative Prior for BMS-986218 Component
1) The median DLT rate at the reference dose (BMS-986218 at 150 mg every 4 weeks [Q4W]) 
was assumed to be 30%, that is, mean (log(ߙଵ)) = logit(0.3) = log(0.3/(1-0.3)) = -0.847.
2) A doubling in dose was assumed to double the odds of DLT, that is, mean (log(ߚଵ)) = 0.
3) The standard deviation 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 results 
in sd (log(ߙଵ)) = 9.19/6 = 1.53.
4) The standard deviation of log(ߚଵ) was set to 2, which allows for considerably large prior 
uncertainty for the dose-toxicity relationship.
5) The correlation between log(ߙଵ) and log(ߚଵ) was set to 0.
6) log(ߙଵ) and log(ߚଵ) follow a bivariate normal distribution.
1.2.3
Mixture Prior
To obtain the mixture prior, 50% weight is assigned to the MAP component (described in 
Section 1.2.1), and 50% weight is assigned to the weakly informative component (described in 
Section 1.2.2) to balance the previous experience with ipilimumab and potential unknown toxicity 
profile of BMS-986218.
The mixture prior will be fitted into EAST® v6.3.1 Dose Escalation Module by Cytel for the 
Monotherapy Escalation (Part 1A) as stated in model setup section.
The mixture prior with both MAP and weakly informative components for the BLRM parameters 
of BMS-986218 is generated using R v3.3.2, the R2WinBUGS package v2.1-21, and 
WinBUGS v14 and is summarized in Table 2.
Table 2:
Prior Distribution for Model Parameters of BMS-986218
Parameter
Means
Standard 
Deviations
Correlation
MAP component
(-0.39, -0.62)
(0.305, 0.231)
0.463
Weakly informative prior for BMS-986218 component
(-0.847, 0)
(1.53, 2)
0
Mixture priors for BMS-986218: (log(ߙଵ), log(ߚଵ))
(-0.619, -0.304)
(1.123, 1.464)
-0.036
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2
MODEL SETUP FOR BMS-986218 AND NIVOLUMAB COMBINATION
2.1
Methodology Description for Combination Therapy
Toxicity profiles of both BMS-986218 monotherapy and nivolumab monotherapy will be 
incorporated to develop the combination model framework. A copula-type model will 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 both BMS-986218 (Part 1A) and nivolumab studies in advanced solid tumors, ie, 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 effects, 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 (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:
݌௜௝ൌ1 െ݁ݔ݌ሺെ൤ሼെ݈݋݃ሺ1 െ݌௜ሻሽ
ଵఊభ
ൗ
൅൛െ݈݋݃൫1 െݍ௝൯ൟ
ଵఊభ
ൗ൨
ఊభ
.
One dose for nivolumab (480 mg) and 7 doses for BMS-986218 (7, 20, 40, 70, 100, 150, and 200 
mg) will be used in the BMS-986218 and nivolumab combination arms for simulation purposes. 
The joint toxicity probability surface will be simplified into a 2-dimensional dose-toxicity curve 
for each of the different dose combinations that can be evaluated for the purpose of safety. 
Posteriors for the corresponding 5 parameters (2 logistic regression parameters [ߙଵ, ߚଵ] for BMS-
986218 and 2 logistic regression parameters [ߙଶ, ߚଶ] for nivolumab, 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.
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2.2
Prior Specification for Combination Therapy
2.2.1
Marginal Prior for BMS-986218
Posterior information on log(α1) and log(β1) from the monotherapy part of the study will be used 
as marginal BMS-986218 prior for combination with nivolumab. 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 posterior prior of BMS-986218 
using DLT from monotherapy part of the study and prior of BMS-986218 as described in Section 
1.2.3 (Table 2) is used for illustration purposes as
−
log(α1): mean -1.421 and standard deviation 0.637
−
log(β1): mean -1.041 and standard deviation 0.832
−
Correlation: 0.624
2.2.2
Marginal Prior Derivation for Nivolumab Parameters (log(α2), log(β2))
Similar to BMS-986218 monotherapy, the logistic model for nivolumab is as follows:
݈݋݃݅ݐ൫ݍ௝൯ൌ݈݋݃ሺߙଶሻ൅ߚଶ݈݋݃ሺ݀ଶ௝
݀ଶ
∗
൘
ሻ, 
where ݍ௝is the probability of toxicity at dose level ݀ଶ௝. Note that the ߙଶܽ݊݀ߚଶparameters 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 
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. In addition, dose proportionality of nivolumab exposures 
supports nivolumab 240 mg Q2W being comparable to 480 mg Q4W.
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.
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•
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 (Table 3) were used to generate the posterior for 
nivolumab, which is then used as the MAP prior for this study (Table 4).
Table 3:
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.
Table 4:
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
2.2.3
Prior for Interaction Parameters for Joint Toxicity of BMS-986218 and 
Nivolumab 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-986218 and nivolumab. Although 
no pharmacokinetic (PK) drug-drug interaction is expected, the possibility of a significant positive 
interaction between BMS-986218 and nivolumab 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:
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•
γଵfollows a gamma distribution with a mean centered at 1.1, which means the combination of 
2 agents is likely to have only a small synergistic effect.
•
The standard deviation of γ1 is 0.5, such that there is a 52% prior probability that γ1 is 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 48% prior probability that γଵis less than 1.
3
DOSE-ESCALATION PROCESS AND SIMULATION IN MONOTHERAPY
3.1
Dose-escalation Process
Dose escalation recommendations for BMS-986218 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
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 for 
the next cohort are the ones fulfilling the overdose criterion that there is no greater than 35% 
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 
the 
totality 
of 
available 
data 
including 
PK/pharmacodynamics from all treated participants.
Stopping Rules:
The following are the general stopping rules of BLRM during monotherapy dose escalation:
•
If all of 108 DLT-evaluable participants are treated.
•
If all of the current prespecified doses are considered intolerable according to the prespecified 
cutoff (ie, EWOC criteria), then the model will recommend stopping the current dose level, 
and a new intermediate dose level lower than the current lowest dose level will need to be 
identified.
•
The maximum number of 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. 
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•
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% to < 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 no greater than 35%); 
(3) Minimum number of participants (ie, 6), were treated at this dose level.
Final MTD/RP2D:
The final recommended MTD/RP2D will be based on the recommendation from the BLRM and 
overall clinical assessment of all available safety, PK/pharmacodynamic, and efficacy data. Lower 
doses of BMS-986218 may be tested if none of the planned doses are found to be tolerable as 
monotherapy or in combination with nivolumab. Such decisions will be made after discussion and 
agreement between the investigators and the BMS Medical Monitor.
3.2
Simulation Parameters
Simulation study was done for monotherapy dose escalation using various hypothetical scenarios. 
Ten thousand trial simulations were used for each scenario. All simulations were run using EAST 
6.4.1® software BLRM module for BMS-986218 monotherapy. The number of participants 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: ≤ 35% 
•
Target probability of toxicity: 0.33, the upper boundary of the targeted toxicity interval
•
Probability of achieving the target toxicity: > 50%
•
Maximum number of participants treated: 108
•
Prior specification on model parameters (based on mixture prior in Table 2 from Section 1.2.3): 
−
log(α2): mean -0.619 and standard deviation 1.123
−
log(β2): mean -0.304 and standard deviation 1.464
−
Correlation: -0.036
•
Posterior sampling method: Metropolis Hastings
•
Minimum number of participants treated at a given dose level in order to declare MTD: 6
•
Maximum number of participants at a dose:12
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The provisional dose levels for BMS-986218 monotherapy are 2, 4, 7, 20, 40, 70, 100, 150 and 
200 mg, with 150 mg as the reference dose.
3.3
Operating Characteristics of BLRM for Monotherapy
Three scenarios were investigated by selecting (1) dose-DLT relationship derived by the prior, (2) 
dose-DLT curve flatter than the 1 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 
v6.4.1 BLRM with no dose skipping option.
For scenario (1), the % DLT by prior was derived using the model solving for the probability, p୧
at the ith dose as follows:
logitሺp୧ሻൌlogሺαଵሻ൅βଵlogሺdଵ୧dଵ
∗
൘ሻ
The model can be re-written as follows:
p୧ൌ
݁ݔ݌ሺlogሺαଵሻ൅βଵlogሺdଵ୧dଵ
∗
൘ሻ
1 ൅݁ݔ݌ሺlogሺαଵሻ൅βଵlogሺdଵ୧dଵ
∗
൘ሻ
Using the estimates in Section 3.2, the prior probability of DLTs at doses of 2, 4, 7, 20, 40, 70, 
100, 150, and 200 mg is 0.02, 0.04, 0.05, 0.11, 0.17, 0.23, 0.29, 0.35, and 0.40. 
The simulation results are shown in Table 5 below.
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Table 5:
Simulation Results of BLRM for Monotherapy
Scenario
BMS-986218
Dose
2
4
7
20
40
70
100
150
200
MTD not 
Selected 
(%)
Fitted 
Median 
MTD
Avg 
Toxicity 
Observed 
(%)
Avg
# Pts
By prior
% DLT
2
4
5
11
17a
23a
29a
35
40
% MTD
0.1
0.2
1
8.6
23.7
31.1
26.7
6.9
1.4
0.3
125.4
15.0
25.8
# Pts
3.1
3.1
3.2
3.7
4.4
5
5.8
5.1
5.1
# DLTs
0.1
0.1
0.2
0.4
0.8
1.1
1.7
1.8
2.1
Flatter than 
the one by 
the prior
% DLT
7
8
10
12
16a
17a
21a
23a
25a
% MTD
1.1
1.3
4.5
12.1
18.1
19.1
20.4
11.3
9.3
2.9
147.9
15.8
26.1
# Pts
3.4
3.3
3.5
3.9
4.3
4.6
5.4
5.5
7.2
# DLTs
0.2
0.3
0.4
0.5
0.7
0.8
1.1
1.3
1.8
Narrow 
safety 
window
% DLT
2
4
6
8
9
16a
18a
32a
80
% MTD
0.1
0.2
0.9
4
9.9
23.1
42.9
18.5
0.2
0.3
156.5
13.3
28.6
# Pts
3.1
3.1
3.2
3.5
3.8
4.5
6.3
5.5
3.5
# DLTs
0.1
0.1
0.2
0.3
0.3
0.7
1.1
1.8
2.8
All low
% DLT
2
4
6
8
14
16a
18a
20a
25a
% MTD
0.1
0.2
0.9
5.7
14.4
19.8
26.1
19.2
13.3
0.4
165.8
12.6
28.7
# Pts
3.1
3.2
3.2
3.5
4.1
4.4
5.5
6
7.4
# DLTs
0.1
0.1
0.2
0.3
0.6
0.7
1
1.2
1.8
All high
% DLT
55
60
65
70
75
80
82
84
86
% MTD
3.6
0.8
0.3
0
0
0
0
0
0
95.4
0.5
64.2
5.1
# Pts
3.9
3.7
3.8
3.4
3
0
0
0
0
# DLTs
2.1
2.2
2.5
2.7
3
NA
NA
NA
NA
a
Doses with true target toxicity within the target toxicity interval (16%, 33%).
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Note: % DLT, true DLT rate; % MTD, proportion of the dose selected as the MTD; # Pts, average number of patients given the dose was tried; # DLTs, average 
number of DLTs given the dose was tried; Fitted MTD: fitted MTD at 33% as the target toxicity rate; % toxicity observed, average proportion of DLTs.
Abbreviation: Avg = average; NA = not applicable; Pts = participants.
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The average sample size was no more than 29 participants. Most scenarios have a fitted median 
MTD that is close to the reference dose, and the 100 mg dose was chosen as the MTD most 
frequently in all scenarios, except the all high and by prior scenarios. The results for the all high 
scenarios show how the EWOC principle limits the risk of exposing participants from a toxic dose 
level by not selecting an MTD in 95.4% of the simulations. The model performs well in the by 
prior, flat, narrow safety window and all low scenarios by correctly identifying the MTD within 
the target toxicity interval, (16%, 33%) at least 82%, 78%, 85%, and 78% of the time, respectively.
Overall, the scenarios illustrated above demonstrate that the model performs satisfactorily in the 
hypothetical scenarios investigated by correctly identifying the MTD while limiting participants 
from receiving excessive/unacceptable toxic dose levels.
4
DOSE-ESCALATION PROCESS AND SIMULATION IN COMBINATION 
THERAPY
4.1
Dose-escalation Process
Similar to the dose escalation process for BMS-986218 monotherapy (Section 3.1), the 
dose-escalation recommendations for BMS-986218 and nivolumab combination therapy 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
While the Bayesian model will use DLT information of all available data from the DLT period 
only, clinical assessment will take into consideration the totality of available data including PK/PD 
from all treated participants.
Following the principle of EWOC, after gaining information of each cohort of participants, the 
candidate doses are the ones fulfilling the overdose criterion that there is less than 35% chance of 
excessive toxicity. Only the candidate doses will be considered for the next dose decision by 
Investigators and BMS study personnel based on a synthesis of all relevant data available from all 
dose levels evaluated in the ongoing study.
A combination with a lower, intermediate, or higher dose level of BMS-986218 may be considered 
and tested if the model recommends it. Such decisions will be made after discussion and agreement 
between the investigators and the BMS Medical Monitor.
Stopping Rules:
The following are the general stopping rules of BLRM during combination therapy dose 
escalation:
•
If all of 84 DLT-evaluable participants are treated.
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•
If all of the current prespecified doses are considered intolerable according to the prespecified 
cutoff (ie, EWOC criteria), then the model will recommend stopping the current dose level, 
and a new intermediate dose level lower than the current lowest dose level will need to be 
identified.
•
The maximum number of 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 participants 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% to < 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 no greater than 35%). 
3) Minimum number of participants (ie, 6), were treated at this dose level.
Final recommended MTD for combination therapy:
The final recommended MTD for combination therapy will be based on the recommendation from 
the BLRM and overall clinical assessment of all available safety, PK/pharmacodynamic, and 
efficacy data. Lower doses of BMS-986218 may be tested if none of the planned doses are found 
to be tolerable as monotherapy or in combination with nivolumab. Such decisions will be made 
after discussion and agreement between the Investigators and the BMS Medical Monitor.
4.2
Simulation Parameters
A simulation study was done for combination dose escalation using various hypothetical scenarios.
For each scenario, 1000 trial simulations were used. All simulations were run using in 
house-developed code via Rv3.1.2 and R2OpenBugs v3.2 software. The number of participants to 
be treated in each cohort in a specific dose level, the stopping rules used to identify the model 
recommeneded MTD, and other simulation parameters are defined as:
•
Fixed cohort size: 3
•
Probability of overdosing: ≤35% 
•
Target probability of toxicity: 0.33, the upper boundary of the targeted toxicity interval
•
Probability of achieving the target toxicity: > 50%
•
Maximum number of participants treated: 84
•
Prior specification on model parameters are as follows :
−
BMS-986218 (based on marginal prior from Section 2.2.1): 
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♦log(α2): mean -1.421 and standard deviation 0.637
♦log(β2): mean -1.041 and standard deviation 0.832
♦Correlation: 0.624
−
Nivolumab (based on marginal prior in Table 4 from Section 2.2.2): 
♦log(α2): mean -1.856 and standard deviation 0.404
♦log(β2): mean -2.131 and standard deviation 0.546
♦Correlation: -0.009
−
Interaction parameter (from Section 2.2.3)
♦γଵ: mean 1.1 and standard deviation 0.5
•
Posterior sampling method: Metropolis Hastings
•
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-986218 in combination with nivolumab are 7, 20, 40, 70, 
100, 150, and 200 mg, with 150 mg as the reference dose.
4.3
Operating Characteristics of BLRM-Copula for Combination Therapy
To demonstrate the performance of the model, the following 5 scenarios are examined below:
•
Scenario 1 - Additive: General dose-DLT relationship derived by the prior with the assumption 
that higher doses will have higher DLT rates.
•
Scenario 2 - Synergistic Effect: Toxicity rates 25% higher than the additive Scenario 1 along 
with increased dose levels, with the highest dose toxicity level above 33%. 
•
Scenario 3 - Strong Synergistic Effect: Toxicity rates 50% higher than the additive Scenario 1 
along with increased dose levels, with the highest dose toxicity level above 33%. 
•
Scenario 4 - Sub-additive or Cancellation Effect: All dose levels with toxicities 25% lower 
than the additive Scenario 1.
•
Scenario 5 - Strong Sub-additive or Cancellation Effect: All dose levels with toxicities 50% 
lower than the additive Scenario 1.
•
For Scenario 1, the % DLT was derived using the BLRM-Copula model with the assumption 
that m = 1, n =1 and γ=1 (Additive model)
݌௜௝ൌ1 െ݁ݔ݌ሺെ൤ሼെ݈݋݃ሺ1 െ݌௜
௠ሻሽ
ଵఊ
ൗ൅൛െ݈݋݃ሺ1 െݍ௝
௡ሻൟ
ଵఊ
ൗ൨
ఊ
ሻ
•
where p୧and q୧at the ith dose are computed using the model for the marginal probability,
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p୧ൌ
݁ݔ݌ሺlogሺαଵሻ൅βଵlogሺdଵ୧dଵ
∗
൘ሻ
1 ൅݁ݔ݌ሺlogሺαଵሻ൅βଵlogሺdଵ୧dଵ
∗
൘ሻ
q୧ൌ
݁ݔ݌ሺlogሺαଶሻ൅βଶlogሺdଶ୧dଶ
∗
൘ሻ
1 ൅݁ݔ݌ሺlogሺαଶሻ൅βଶlogሺdଶ୧dଶ
∗
൘ሻ
•
Using the prior in Section 4.2 as estimates, the marginal probabilities for BMS-986218 (p୧) 
and nivolumab (q୧) are 0.08, 0.11, 0.13, 0.16, 0.17, 0.19, 0.21 for BMS-986218 and 0.14 for 
nivolumab, and therefore prior probability of DLTs (݌௜௝) are 0.20, 0.23, 0.25, 0.27, 0.28, 0.30
and 0.32 for BMS-986218 in combination with nivolumab at dose 7, 20, 40, 70, 100, 150, and 
200 mg, with 150 mg as the reference dose.
The simulation results are shown in Table 6 below. The model seems to work as expected.
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Table 6:
Simulation Results of BLRM-Copula for BMS-986218 in 
Combination With Nivolumab
Scenario
BMS-
986218 
Dose
7
20
40
70
100
150
200
MTD not 
Selected 
(%)
Fitted 
Median 
MTD 
Avg 
Toxicity 
Observed 
(%)
Avg 
# Pts
Additive
% DLT
20a
23a
25a
27a
28a
30a
32a
% MTD
32.1
18.7
24.4
17.1
3.5
0.2
0.1
3.9
206.8
26.8
13.4
# Pts
4.5
3.7
3.2
1.6
0.4
0.0
0.0
# DLTs
0.9
0.8
0.8
0.5
0.1
0.0
0.0
Synergistic 
(25% more 
tox than 
additive)
% DLT
25a
28a
31a
33
35
37
40
% MTD
43.0
22.8
17.1
8.0
1.2
0.0
0.0
7.9
151.3
32.4
12.0
# Pts
4.8
3.6
2.5
0.9
0.2
0.0
0.0
# DLTs
1.2
1.0
0.7
0.3
0.1
0.0
0.0
Strong 
Synergertic 
(50% more 
tox than 
additive)
% DLT
30a
34
37
40
42
45
48
% MTD
54.4
18.3
10.0
3.2
0.4
0.0
0.0
13.7
110.3
37.8
10.8
# Pts
5.2
3.2
1.8
0.5
0.1
0.0
0.0
# DLTs
1.6
1.1
0.6
0.2
0.0
0.0
0.0
Sub additive 
(25% less tox 
than additive)
% DLT
15
17a
19a
20a
21a
22a
24a
% MTD
17.3
15.4
24.2
27.4
13.6
0.4
0.3
1.4
330.4
20.4
15.5
# Pts
4.0
3.8
3.8
2.7
1.1
0.1
0.0
# DLTs
0.6
0.6
0.7
0.6
0.2
0.0
0.0
Strong sub 
additive 
(50% less tox 
than additive)
% DLT
10
11
12
13
14
15
16a
% MTD
6.9
6.2
17.2
30.8
33.9
1.6
3.1
0.3
664.2
13.6
18.0
# Pts
3.4
3.5
4.1
3.8
2.6
0.4
0.2
# DLTs
0.3
0.4
0.5
0.5
0.4
0.1
0.0
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a Doses with true target toxicity within the target toxicity interval (16%, 33%).
Note: % DLT, true DLT rate; % MTD, proportion of the dose selected as the MTD; # Pts, average number of patients given the dose was tried; # DLTs, average 
number of DLTs given the dose was tried; Fitted MTD: fitted MTD at 33% as the target toxicity rate; % toxicity observed, average proportion of DLTs
Abbreviation: Avg = average; NA = not applicable; Pts = participants.
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5
INTERIM MONITORING EXAMPLE TO ILLUSTRATE PROVISION OF 
DOSE RECOMMENDATIONS DURING DOSE-ESCALATION IN 
MONOTHERAPY
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 2 mg, 7 mg, 20 mg, 70 mg, and 200 mg in 
the BMS-986218 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; these 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 3 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 a decision making:
•
Dose-DLT profile for the doses ranging between 0 mg and 200 mg (Figure 1).
•
Stacking histograms displaying predictive probabilities on DLT rates classified into 3 different 
categories (Underdosing, Target dosing and Overdosing) (Figure 2).
•
Box plots summarizing the Markov Chain Monte Carlo samples of predicted DLT rates for the 
5 prespecified dose levels (Figure 3).
Figure 1: 
Updated Dose-DLT Profile After Incorporating Prior Information 
and All Previous and Current DLT Information 
Abbreviations: L = lower DLT boundary; U = upper DLT boundary.
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Interpretation and Use of Figure 1:
Figure 1 is a snapshot of an updated dose-DLT profile with DLT information available at dose 
level 2 mg for monotherapy. The dose-DLT profile is captured with a continuous dose spectrum 
ranging from 0 to 200 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 new DLT information becomes available from the study. 
In Figure 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 
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 
(0.16 and 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 13 mg-dose could be a potential intermediate dose level corresponding to the 
lower prespecified DLT rate boundary of 0.16, and the 205 mg dose 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 for monotherapy, a case not shown on the current Figure 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 (2 mg) by 
using the DLT-rate boundaries.
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Figure 2:
Updated Stacking Histogram After Incorporating Prior Information 
and All Previous and Current DLT Information to Classify Predicted 
DLT Rates into 3 Categories (Underdosing, Target Dosing, and 
Overdosing)
Interpretation and Use of Figure 2:
Figure 2 is a snapshot of stacking histogram with DLT information available at dose level 2 mg. 
This figure will be updated each time new DLT information becomes available. 
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-986218 in 
combination with nivolumab). 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%). However, there will be no dose skipping during the 
dose-escalation monotherapy phase of the study.
As illustrated in Figure 2, the distribution of predicted DLT rates will be characterized into 
possibilities falling into 3 different categories. First, dose levels of 70 and 200 mg for BMS-986218 
are excluded according to the higher-than-cutoff (0.3 for combination therapy) overdosing 
probabilities (0.344 for 70 mg and 0.482 for 200 mg). Among the remainder of tolerable dose 
levels, the BLRM recommends the dose that maximizes the probability of being within the target 
dosing interval. Therefore, the model’s recommendation would be to escalate to 20 mg, which is 
associated with the highest target dosing probability of 0.352 compared with that of 2 mg (0.214) 
and 7 mg (0.289).
Similarly (although not shown on Figure 2), according to the rules specified above, the model 
could possibly recommend to de-escalate to a lower dose level than the current treated dose level, 
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extend the current dose level, or even recommend to stop and identify a new dose level lower than 
2 mg, the lowest pre-specified dose level. Please refer to the description of Figure 1 for details on 
how to specify the new dose levels.
Figure 3:
Updated Box Plot After Incorporating Prior Information and All 
Previous and Current DLT Information
Interpretation and Use of Figure 3:
Figure 3 is a snapshot with DLT information available at dose level 2 mg. 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 there 
is new DLT information available. 
This plot supplements the information provided in Figure 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.
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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 12
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 baseline 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 13
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 06, 22-Dec-2020
This study has been revised to update the contraception language for women of child-bearing 
potential (WOCBP) participants and male participants, and their WOCBP partners. In addition,
the protocol was revised to incorporate feedback from Investigators
 around 
pregnancy testing and contraception requirements, respond to the Coronavirus Disease 2019 
(COVID-19) pandemic, and to align with nivolumab program standards.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & Title
Description of Change
Brief Rationale
Title page
Updated medical monitoring contact 
information and added clinical 
scientist contact information.
Administrative update. 
Medical Monitor has changed 
from 
 to 
 and 
 has 
been added as Clinical 
Scientist.
Synopsis, Table 1-1 Section 2, Schedule 
of Activities, Table 2-1, Table 2-2, 
Table 2-3, Table 2-4, and Table 2-5
Section 3.3, Benefit-Risk Assessment
Section 4, Objectives and Endpoints, 
Table 4-1 
Section 6.2, Exclusion Criteria 3(g) and 
3(h)
Section 6.4.1, Retesting During Screening 
Section 7.6.3, Dose Delays Due to 
Toxicity
Section 7.6.3.1, Criteria to Resume 
Treatment
Section 7.9.1, Prohibited and/or 
Restricted Treatments
Section 9.2.1, Time Period and Frequency 
for Collecting AE and SAE Information
Section 9.2.3, Follow-up of AEs and 
SAEs
Changes were made throughout the 
protocol to 
 add the risks associated with 
SARS-CoV-2 infection and study 
participation; and clarify the collection 
and following of adverse events (AEs) 
and serious adverse events (SAEs).
For consistency with BMS 
standards, in the face of the 
rapidly evolving COVID-19 
pandemic.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & Title
Description of Change
Brief Rationale
Synopsis, Number of Participants
Section 5.2, Number of Participants
Section 7.4, Method of Treatment 
Assignment
Added language to continue 
enrollment in selected arms in Part 2A 
and Part 2B.
To allow flexibility to better 
assess an initial efficacy 
signal.
Section 6.1, Inclusion Criteria
The following contraception 
requirement updates were made:
•
Updated wording in criterion 4c
•
Criterion 4e is no longer 
applicable
•
The first sentence in criterion 4f is 
no longer applicable (the second 
sentence pertaining to WOCBP is 
still applicable)
•
Removed text related to male 
contraception in the last 
paragraph and added a statement 
regarding transmission of study 
drug to a developing fetus
•
Added criterion 4g
These changes were made to: 
•
Provide clarification and 
additional details 
regarding inclusion and 
contraception 
requirements for both 
WOCBP and for women 
who are not of 
childbearing potential
•
Remove contraceptive 
requirements for male 
participants based on 
current safety information
Section 6.2, Exclusion Criteria 
•
Revised eligibility for participants 
with human immunodeficiency 
virus (HIV) infection
•
Added criterion 3i to exclude 
participants with leptomeningeal 
metastases
Aligned with current 
nivolumab program standards.
Section 8.1, Discontinuation from Study 
Treatment
Revised text on reporting pregnancy.
Aligned with BMS standards.
Section 9.2.5, Pregnancy
Added a statement about the 
benefit/risk ratio of continuation of 
study treatment for pregnant 
participants.
Aligned with BMS standards.
Section 9.5, Pharmacokinetic and 
Immunogenicity Assessments, Table 9.5-
2, Table 9.5-3, Table 9.5-4, Table 9.5-5
Added text on serum sample 
bioanalytical assay and updated table 
footnote text on end of infusion 
pharmacokinetic (PK) collection.
To clarify end of infusion 
(EOI) sample collection.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & Title
Description of Change
Brief Rationale
Section 10.1.3, The Randomized BMS-
986218 Monotherapy Cohort Expansion 
in Cutaneous Melanoma (Part 2A)
Section 10.1.4, The BMS-986218 Cohort 
Expansion Monotherapy (Part 2B)
Clarified sample size considerations 
for the expansion.
Updated information 
Section 10.3.1, Efficacy Analyses, Table 
10.3.1-1
Clarified efficacy analysis for the 
expansion.
To align with current BMS 
standards.
Appendix 4, Women of Childbearing 
Potential Definitions and Methods of 
Contraception
Revised Appendix 4.
To align with current BMS 
standards and remove male 
contraception.
Appendix 8, Country Specific 
Requirements
•
Updated country-specific HIV 
language. 
•
Added Norway-specific 
additional pregnancy testing 
language to Table 2-5.
Revised Appendix 8 to align 
with current BMS standards 
.
Appendix 10, Management Algorithms 
for Studies Under CTCAE Version 4.0
Updated Appendix 10.
To align with current BMS 
standards.
All
Minor formatting and typographical 
corrections.
Minor, therefore have not been 
summarized.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Overall Rationale for Revised Protocol 05, 14-Aug-2019
The primary reasons for the changes outlined below are to specify the doses and schedules for 
expansions Part 2A and Part 2B and to include a subgroup of additional participants with advanced 
stage cutaneous melanoma in Part 1A.
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
All
Removed reference to Q3W dosing for 
BMS-986218.
Q3W schedule is not being studied in the 
expansion Part 2A.
Synopsis
Synopsis was updated.
Synopsis was updated to reflect the 
changes in the body of the protocol as 
summarized below.
2.0 Schedule of Activities
Table 2-3
Corrected symptom directed physical 
examination.
To correct and clarify directions 
provided in the Schedule of Activities.
2.0 Schedule of Activities
Table 2-4
Added note to Vital Signs.
To correct and clarify directions 
provided in the Schedule of Activities.
3.2.1 BMS 986218
Updated text with information from 
current IB.
To refer the reader to the IB.
3.2.2 Nivolumab  
Updated text with information from 
current IB.
To refer the reader to the IB.
3.2.3 Ipilimumab  
Updated text with information from 
current IB.
To refer the reader to the IB.
5.1 Overall Design
Revised text to reflect updated dosing 
regimen.
To specify dose in the expansion and 
provide additional details in Part 1.
5.1 Overall Design
Figure 5.1-1
Updated study schematic and associated 
footnotes.
To specify dose in the expansion and 
provide additional details in Part 1
To add subgroup of participants with 
cutaneous melanoma.
5.1 Overall Design
Figure 5.1-2
Removed reference to Q3W dosing for 
BMS-986218.
Q3W schedule is not being studied in the 
expansion Part 2A.
5.1.2 Treatment Period
Revised text to remove Q3W dosing for 
BMS-986218.
Added text detailing dosing instructions 
for participants receiving BMS-986218 
with nivolumab or ipilimumab.
To specify dose in the expansion and 
provide additional details in Part 1.
To clarify dosing procedures.
5.1.2.1 The BMS-986218 
Monotherapy Escalation 
(Part 1A)
Revised text to include 100 and 150 mg 
doses of BMS-986218.
Updated number of participants.
Added text to provide for up to 20 
additional evaluable participants with
advanced stage cutaneous melanoma.
Additional intermediate doses and 
participants added to study safety and 
tolerability.
To assess additional clinical safety, PK 
and pharmacodynamic evaluation of 
participants with a single tumor type 
(advanced stage cutaneous melanoma).
Protocol Amendment No.: 07
Date: 29-Jul-2021
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1.0
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
5.1.2.2 The Safety 
Evaluation of Combination 
Doses of BMS-986218 with 
Nivolumab (Part 1B)
Updated number of participants.
Additional participants added to reflect 
planned number of dose levels under 
study.
5.1.2.4 The Randomized 
BMS 986218 Monotherapy 
Cohort Expansion in 
Cutaneous Melanoma (Part 
2A), the BMS-986218 
Cohort Expansion 
Monotherapy (Part 2B), and 
the BMS-986218 Cohort 
Expansion Combination 
Therapy (Part 2C) Cohort 
Expansions
Deleted text related to the Sentinel 
Participant rule. 
Revised text to reflect changes in dosing 
for Part 2.
The Sentinel participant rule is not 
required in expansion (Part 2A and Part 
2B) as the doses have cleared safety in 
escalation (Part 1A).
Doses and schedule to be studied are 
specified.
5.2 Number of Participants
Updated number of participants.
Additional participants added to reflect 
planned number of dose levels under 
study.
5.4.1 Rationale for the 
BMS-986218 Monotherapy 
Escalation (Part 1A) and the 
Safety Evaluation of 
Combination Doses of 
BMS-986218 with 
Nivolumab (Part 1B) Design
Revised text to replace MTD/RP2D with 
specific doses.
Doses and schedule to be studied are 
specified.
5.5.2 Rationale for Dose 
Selection and Dosing 
Schedule
Table 5.5.2-1
Revised table to remove references to 
MTD/RP2D, and to replace Q2W and 
Q3W dosing of BMS-986218 with Q4W 
dosing.
Doses and schedule to be studied are 
specified.
6.1 Inclusion Criteria
Deleted Inclusion Criterion 4e stating 
women must not be breastfeeding (note 
this criterion is included as Exclusion 
criterion 3f).
Added Inclusion Criterion 2.c.iv.1 
providing for the addition of subgroup for 
participants with advanced stage 
cutaneous melanoma under certain 
conditions.
Added Inclusion Criterion 2.c.vi, 
describing conditions under which 
participants with advanced stage 
cutaneous melanoma may be enrolled.
Removed Inclusion Criterion 2.J.i.1.a to 
remove option of replacement of 
participants with TMB < 10 mutations per 
To meet current protocol model 
document standards.
To include evaluation of participants 
with advanced stage cutaneous 
melanoma.
To clarify treatment of participants with 
cutaneous melanoma.
Analysis of TMB data is not part of 
primary objectives and therefore it is not 
driving the sample size.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
megabase and PD L1 < 1% for purposes 
of statistical analyses.
6.2 Exclusion Criteria
Revised Exclusion Criterion 5a stating 
incarcerated individuals may participate 
in the study in countries where local 
regulations permit under strict conditions.
To meet current protocol model 
document standards.
7.1 Treatments 
Administered
Table 7.1-1
Updated Packaging/Appearance.
To reflect current drug supply 
characteristics.
7.3 Schedule of Dose for 
Each Investigational 
Product
Table 7.3-1
Updated dosing for BMS-986218, added 
detail regarding infusion times.
Doses and schedule to be studied are 
specified.
7.4 Method of Treatment 
Assignment
Revised to remove references to 
MTD/RP2D, and to update dosing for 
BMS-986218.
Doses and schedule to be studied are 
specified.
7.6.2 Management 
Algorithms for Immuno-
oncology Agents
Replaced Cardiac with Myocarditis in list 
of treatment algorithms.
To provide current treatment-related 
adverse event management algorithms.
8.1 Discontinuation from 
Study Treatment
Updated text with regards to incarcerated 
individuals who may participate in the 
study in countries where local regulations 
permit under strict conditions.
To meet current protocol model 
document standards.
9.5 Pharmacokinetic and 
Immunogenicity 
Assessments
Table 9.5-4
Revised table to remove PK sample 
collections for BMS-986218 Q3W.
Q3W dosing schedule is not being 
studied in the Part 2A and Part 2B 
expansion.
10.1.1 Monotherapy Dose 
Escalation (Part 1A)
Updated number of participants.
Additional participants added to reflect 
dose levels under study.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
Added text describing analysis of
pharmacodynamic changes in participants 
in the cutaneous melanoma tumor
subgroup.
To describe evaluation of participants 
with advanced stage cutaneous
melanoma.
10.1.3 The Randomized 
BMS 986218 Monotherapy 
Cohort Expansion in 
Cutaneous Melanoma (Part 
2A)
Revised to remove references to 
MTD/RP2D, and to update dosing for 
BMS-986218.
Doses and schedule to be studied are 
specified.
10.1.4 The BMS-986218 
Cohort Expansion   
Monotherapy (Part 2B)
Revised to remove references to 
MTD/RP2D, and to update dosing for 
BMS-986218.
Deleted paragraph referring to the Gehan 
design as a guide for the derivation of 
sample size in the Part 2B monotherapy 
expansion cohorts.
Doses and schedule to be studied are 
specified.
Use of the Gehan design is no longer 
applicable. The derivation of sample size 
is provided in subsequent text.
Appendix 2 Study 
governance considerations
Replaced with current version of the 
Appendix.
To meet current standards.
Appendix 3 Adverse events 
and serious adverse events: 
definitions and procedures 
for recording, evaluating, 
follow-up, and reporting
Replaced with current version of the 
Appendix.
To meet current standards.
Appendix 4 Women of 
childbearing potential 
definitions and methods of 
contraception
Revised text to match most current
version of the Appendix.
To meet current standards.
Appendix 10 Management 
algorithms for immuno-
oncology agents
Replaced with current version of the 
Appendix, including algorithm for 
myocarditis.
To meet current standards.
All
Minor formatting and typographical 
corrections.
Minor, therefore have not been 
summarized.
Protocol Amendment No.: 07
Date: 29-Jul-2021
266
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930111276
8.0
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1.0
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Overall Rationale for Revised Protocol 04, 25-Dec-2018
The primary reasons for the changes outlined below are to:
1) Update pharmacokinetic (PK) and immunogenicity assessments sampling schedules to add 
and/or clarify blood and anti-drug antibody (ADA) samples.
Clarify relevant systemic exposure of study drugs for male participant contraceptive guidance.
Summary of key changes for Revised Protocol 04
Section Number 
& Title
Description of Change
Brief Rationale
Section 9.5 
Pharmacokinetic 
and 
Immunogenicity 
Assessments
Section 9.5 was modified as follows:
• Table 9.5-2, Table 9.5-3, and Table 9.5-5 were 
updated to include additional ADA samples.
• Table 9.5-4 was updated to include separate 
columns for BMS-986218 and ipilimumab 
blood samples and ADA samples.
PK and ADA sampling schedules were 
updated to add and/or clarify blood and 
ADA sample collections.
Appendix 4 
Women of 
Childbearing 
Potential 
Definitions and 
Methods of 
Contraception
Relevant systemic exposure was updated in the 
third bullet of Contraception Guidance for Male 
Participants with Partner(s) of Childbearing 
Potential to until 165 and 215 days after the end 
of treatment for monotherapy and combination 
therapy, respectively.
Relevant systemic exposure was updated 
to ensure consistency throughout 
guidance on contraceptive methods for 
male participants with partner(s) of 
childbearing potential.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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8.0
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1.0
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Overall Rationale for Revised Protocol 03, 24-Oct-2018
The primary reason for these changes are to update the study design as follows: 
•
Part 1A: Inclusion of alternative every-2-weeks (Q2W) dosing schedule to study BMS-986218 
in the context of rapid T-regulatory cell (Treg) depletion and recovery.
•
Part 1B: Inclusion of Bayesian Logistic Regression Model (BLRM) using the escalation with 
overdose control (EWOC) principle, and a starting dose 1 at dose level below the current 
safety-cleared monotherapy cohort (to allow initiation of this study part prior to declaring the 
RP2D and evaluation of different doses in combination in select tumor types).
•
Part 2A: Inclusion of several dose levels and/or schedules to study BMS-986218 monotherapy 
and ipilimumab monotherapy in a randomized setting in participants with cutaneous melanoma
•
Part 2B: Inclusion of several dose levels and/or schedules to study BMS-986218 monotherapy 
in a randomized setting in participants with non-small cell lung cancer (NSCLC). 
Other key changes include 
clarification of expectations and timing of scheduled activities, updates to eligibility criteria, 
 to the study. Additional 
amendments, including to sections of the Synopsis, have been made to align the protocol with 
respect to these changes.
Summary of key changes for Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
Title Page
Updated Study Director/Medical Monitor and 
contact information.
Incorporated contact information 
updates per Administrative Letter 02 
and Administrative Letter 03.
Title Page; 
1: Synopsis
Short Title added.
Short Title added for clarity and 
alignment with Short Title provided 
on ClinicalTrials.gov.
1: Synopsis
Added “Data Monitoring Committee” (DMC) 
sub-section at the end of the Synopsis section. 
Clarified that a DMC is not used for 
this study and provided BMS process 
to ensure safety monitoring.
2: Schedule of 
Activities
The following modifications were made for 
Section 2 tables:
• Moved footnotes, as appropriate, to 
corresponding rows in Notes columns.
• Updated notes throughout tables for clarity 
(eg, defined collection windows, added details 
for tumor assessments).
• Updated table titles to align with study design 
updates described below.
These changes were made to improve 
table readability, clarify expectations 
and timing of scheduled activities, and 
align the schedule of activities with 
the study design and sampling 
schedule updates described below.
Protocol Amendment No.: 07
Date: 29-Jul-2021
268
8.0
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930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
3.1: Study 
Rationale; 
3.2.1: 
BMS-986218
3.3: Benefit/Risk 
Assessment
The following modifications were made:
• Updated descriptions of clinical experience with 
BMS-986218 and nivolumab in combination 
with ipilimumab.
These changes were made to:
• Align the description of clinical 
experience with study treatments 
with currently available data.
4: Objectives and 
Endpoints
Added Prostate Cancer Working Group (PCWG 3) 
criteria to efficacy assessment endpoints and 
secondary 
to objectives and endpoints.
Updated objectives and endpoints to 
clarify that PCWG 3 criteria is used in 
some cases for efficacy assessments 
.
5.1 Overall 
Design
The following modifications were made:
• Part 1A
o Added alternative Q2W dosing for 
BMS-986218 to further characterize safety 
and PK in participants with selected tumor 
types that may be more likely to have higher 
T-regulatory cell (Treg) levels at baseline.
• Part 1B
o Updated design from a 2-arm randomized 
design to a BLRM design employing the 
EWOC principle.
• Part 2A
o Updated participant population from RCC, 
urothelial carcinoma, and advanced-stage 
pancreatic ductal adenocarcinoma to 
cutaneous melanoma.
o Added language describing the 3 dose levels 
and/or schedules of BMS-986218 that may 
explored in addition to ipilimumab.
These changes were made to:
• Incorporate additional dose levels or 
schedules that may be explored, 
including Q2W dosing in Part 1A 
and/or Part 2, which may be the 
more relevant dosing frequency to 
achieve the pharmacodynamic goals 
of the program, given that Tregs are 
depleted within the first few days of 
BMS-986218 dosing and recover 
rapidly during the second week, as 
observed in preclinical models. 
The decision on which dose levels 
or schedules (eg, Q2W, Q3W) will 
be evaluated in Part 2 will be made 
prior to initiating Part 2A and 
Part 2B of the study. The rationale 
for evaluating multiple dose levels 
or schedules is to optimize the 
benefit-risk ratio for the participant. 
• Update the Safety Evaluation of 
Combination Doses of BMS-986218 
with Nivolumab to a BLRM with 
EWOC principle study design.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
5.1 Overall 
Design (cont)
• Part 2B
o Updated population to focus on participants 
with NSCLC in a randomized setting.
o Added language clarifying prior 
immunotherapy requirements.
o Added language describing the 3 dose levels 
and/or schedules of BMS-986218 that may 
be explored.
• Part 2C
o Replaced description of study design with the 
statement “A future amendment will include 
2 to 3 indications to evaluate this combination 
in a Phase 2 randomized setting.”
• Update and clarify participant 
population and treatments to be 
explored in the expansion parts of 
the study. Tumor indications and 
prior therapies revised based on 
mechanism of action of 
BMS-986218 and study now 
includes tumor types that are likely 
to have enriched Tregs in tumor 
microenvironment. 
The number of lines of treatment 
was revised to take into account that 
patients who have progression of 
disease on 2 lines of treatment have 
poor prognosis and may not have 
significant benefit from additional 
lines of treatment.
• Update and clarify that further 
details on the study design of 
Part 2C will be provided in a future 
amendment.
5.1: Overall 
Design;
5.1.2: Treatment 
Period; 
5.1.3: Follow-up 
Period
Updated duration of treatment to be a maximum of 
2 calendar years for BMS-986218 Q4W ±
nivolumab Q4W or BMS-986218 Q2W, and a 
maximum of 4 doses for ipilimumab and 
BMS-986218 Q3W within text and Figure 5.1-2.
Aligned the maximum duration of 
BMS-986218 Q3W and ipilimumab 
Q3W with the current standard of care 
for ipilimumab.
5.1.2: Treatment 
Period (including 
subsections 
5.1.2.1, 5.1.2.2, 
5.1.2.3, and 
5.1.2.4)
The following modifications were made:
• Added language to clarify every-12-weeks 
(Q12W) tumor assessments in Part 2A.
• Updated description of participant populations 
for each study part, as needed to align with 
changes to study design noted above.
• Added language providing dose level and 
schedule details for alternative Q2W dosing 
schedule for Part 1A, Part 2A, and Part 2B, and 
alternative Q3W dosing schedule for Part 2A 
and Part 2B.
• Aligned Part 1B with change to design from a 
2-arm randomized design to a BLRM design 
employing the EWOC principle.
• Added description of sentinel participant rule for 
Part 1B, Part 2A, Part 2B, and Part 2C.
There changes were made to:
• Clarify timing and expectations for 
treatment period and tumor 
assessments.
• Update the description of the 
BMS-986218 monotherapy and 
expansion parts of the study to align 
with the changes made to the 
Overall Design.
5.1.3.2: Response 
Follow-up Period
Added window of ± 1 week for every-8-weeks 
(Q8W) tumor assessments.
Clarified expectations and timing for 
follow-up tumor assessments.
Protocol Amendment No.: 07
Date: 29-Jul-2021
270
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930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
5.1.4: Data 
Monitoring 
Committee and 
Other External 
Committees
Updated rationale for no DMC and language 
describing BMS multi-layered process to ensure 
safety monitoring during the study.
Clarified BMS process to ensure 
safety monitoring.
5.2: Number of 
Participants
Updated participant numbers per changes to 
Overall Study Design noted above.
Aligned planned number of 
participants with updated study design 
outlined above.
5.4.5: Rationale 
for Two Years 
Fixed Duration of 
Treatment with 
Checkpoint 
Blockade
Updated text describing the justification for 2-year 
fixed duration of treatment with checkpoint 
blockade per recently reported data.
Aligned justification of 2-year fixed 
duration of checkpoint blockade per 
currently available information.
5.4.6: Rationale 
for Treatment 
Beyond 
Progression
Removed last paragraph describing scenarios in 
which treatment beyond progression may be 
appropriate.
Removed text not related to this 
section (ie, rationale) for clarity.
5.5.2: Rationale 
for Dose Selection 
and Dosing 
Schedule
Updated Tumor Types and Dose columns in 
Table 5.5.2-1 to reflect changes to study design for 
each study part, as described above.
Aligned dosing schedule with updated 
study design outlined above.
5.5.2.1: 
BMS-986218
Added paragraph describing rationale for 
alternative Q2W and Q3W dosing schedules that 
may be explored to characterize the safety and PK 
of BMS-986218.
Provided rationale for inclusion of 
alternative Q2W and Q3W dosing 
schedules for BMS-986218 in updated 
study design.
5.5.2.2 
Nivolumab
Updated text to align description of BMS-986218 
and nivolumab doses and permitted dose 
reductions with updated study design for Part 1B.
Aligned BMS-986218 and nivolumab 
doses with updated study design 
outlined above.
Protocol Amendment No.: 07
Date: 29-Jul-2021
271
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
6.1: Inclusion 
Criteria
The following modifications were made:
• 2) c) i) no longer applicable; replaced with
2) c) iii) revised to limit permission of all solid 
tumor histologies to the Q4W dosing schedule in 
Part 1A.
• 2) c) iv): added criterion on permitted tumor 
histologies for Q2W dosing schedule in Part 1A.
• 2) c) ii) no longer applicable; replaced with 
2) c) v) revised to received, and then progressed, 
relapsed or intolerant to at least 2 standard 
treatment regimens with proven survival benefit, 
and clarified prior therapy criteria for 
hormone-sensitive and prostate cancers.
• 2) d) i) no longer applicable; replaced with 
2) h) i) to clarify included histologies.
• 2) d) ii) and 2) e) i) no longer applicable; 
replaced with 2) h) ii) and 2) i) i) to clarify 
scenarios for prior systemic therapy.
• 2) f) i) (1), (2), (3) no longer applicable; replaced 
with 2) j) i) (1) and (2) to update and clarify 
permitted tumor histologies for Part 2B.
• 2) g) and accompanying subbullets no longer 
applicable.
• 3) f): added criterion on expectations for 
toxicities related to prior systemic therapy.
Updated and clarified eligibility 
criteria in alignment with updated 
study design outlined above. 
Tumor indications and prior therapies 
revised based on mechanism of action 
of BMS-986218 and study now 
includes tumor types that are likely to 
have enriched Tregs in tumor 
microenvironment.
The number of lines of treatment was 
revised to take into account that 
patients who have progression of 
disease on 2 lines of treatment have 
poor prognosis and may not have 
significant benefit from additional 
lines of treatment.
6.2: Exclusion 
Criteria
The following modifications were made:
• 2) e): added criterion on expectations for prior 
radiation therapy.
• 2 f): added criterion on expectations for 
LHRH/GnRH agonist therapy in male 
participants.
• 2) g): added criterion on expectations for 
botanical preparations prior to study treatment, 
including use of marijuana and its derivatives.
• 3) e) ix) no longer applicable; replaced with
3) e) xii) clarifying expectations for prior 
vaccinations.
Updated and clarified eligibility 
criteria in alignment with updated 
study design outlined above.
6.4: Screen 
Failures
Added phrase “as applicable” to Consolidated 
Standards of Reporting Trials (CONSORT) 
statement.
Clarified requirements for screen 
failure information.
7.1: Treatments 
Administered
Added new subsections, Section 7.1.1 
BMS-986218, Section 7.1.2 Nivolumab, and 
Section 7.1.3 Ipilimumab to provide additional 
details for administration of each study drug.
Provided additional details on 
administration of BMS-986218, 
nivolumab, and ipilimumab.
7.3: Schedule of 
Dose for Each 
Updated Table 7.3-1 for consistency with study 
design updates.
Aligned the selection and timing of 
doses for all study parts with updated 
study design outlined above.
Protocol Amendment No.: 07
Date: 29-Jul-2021
272
8.0
Approved
930111276
8.0
v
Approved
1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
Investigational 
Product
7.4: Method of 
Treatment 
Assignment
Removed paragraphs describing randomization of 
Part 1B and updated/added text describing 
randomization of Part 2A and Part 2B.
Aligned treatment assignment 
methods with updates to study design 
outlined above.
7.5: Blinding
Added new section related to blinding.
Clarified expectations for access to 
treatment and/or randomization 
assignments prior to database lock.
7.6.1.1: 
Gastrointestinal 
Dose-limiting 
Toxicity; 7.6.1.5: 
Other Dose-
Limiting 
Toxicities; 
Added “regardless of duration” to bullet for Grade 
≥3 diarrhea or colitis, and updated list of Grade 3 
or 4 events not considered to be a DLT to add that 
a confirmatory laboratory test is required for 
conclusions related to electrolyte abnormalities 
and to remove diarrhea.
Updated expectations for 
treatment-related events considered to 
be dose-limiting toxicities (DLTs).
7.6.3: Dose 
Delays Due to 
Toxicity
Added “due to any cause” to first sentence.
Clarified expectations for events 
considered reasons for withholding all 
study treatments.
7.6.4: Exceptions 
to Permanent 
Discontinuation 
Criteria
Updated list of drug-related AEs meeting DLT 
criteria not requiring permanent discontinuation to:
• Update first bullet to remove diarrhea and update 
duration from 3 days to 48 hours either 
spontaneously or with medical intervention.
• Remove Grade 4 increase in amylase or lipase 
that is not associated with clinical or 
radiographic evidence of pancreatitis.
Updated expectations for events 
requiring permanent discontinuation.
7.9.1: Prohibited 
and/or Restricted 
Treatments
Added botanical preparations, marijuana and its 
derivatives, and live/attenuated vaccines to list of 
prohibited and/or restricted treatments.
Updated list of restricted and/or 
prohibited treatments to include 
botanical preparations, marijuana, and 
live/attenuated vaccines.
7.9.4: Palliative 
Radiation
Added new section describing scenarios in which 
palliative radiation for disease-related symptoms is 
permitted for participants on the study. 
Provided details on scenarios in which 
palliative radiation for disease-related 
symptoms is permitted for participants 
on the study.
7.9.5: Surgery
Added new section describing scenarios in which 
study treatment should be held for participants 
undergoing surgery during the study.
Provided details on expectations for 
holding study treatment for 
participants who undergo surgery 
during the study.
7.10: Treatment 
After the End of 
the Study
Updated section to note that BMS will not 
continue to provide BMS-supplied study treatment 
to participants/Investigators unless BMS chooses 
to extend the study.
Clarified expectations for treatment 
after the end of the study.
8.1: 
Discontinuation 
from Study 
Treatment
Added Grade 4 amylase or lipase elevation as a 
reason for discontinuation.
Updated reasons for discontinuation 
from study treatment to include 
Grade 4 amylase or lipase elevation.
8.1: 
Discontinuation 
from Study 
Updated language to clarify that, in the case of 
pregnancy, study treatment will be permanently 
continued in an appropriate manner, and removed 
Clarified expectations and scenarios 
for reporting and discontinuation of 
study treatment in the case of 
pregnancy.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
Treatment;
9.2.5: Pregnancy
text related to scenarios for continuing study 
treatment in the context of pregnancy.
8.1.1: Treatment 
Beyond 
Progression
Added text “prior to treatment beyond 
progression” to last paragraph. 
Clarified that all decisions to continue 
treatment beyond initial progression 
must be discussed with the BMS 
Medical Monitor or designee prior to 
treatment beyond progression.
9.3: Efficacy 
Assessments; 
9.3.1: Imaging 
Assessment for 
the Study
Added text describing the timing of efficacy 
assessments and imaging modalities for imaging 
assessments in the context of each study part.
Clarified timing and expectations of 
efficacy/imaging assessments across 
study parts and in alignment with 
changes made to the Overall Design.
9.4: Overdose
Updated text describing overdose event and 
monitoring actions in the event of an overdose.
Clarified the definition and monitoring 
expectations for overdose.
9.5: 
Pharmacokinetics 
and 
Immunogenicity 
Assessments
The following modifications were made:
• Table 9.5-2 and Table 9.5-5
o Updated footnote b to include reference to 
Table 7.3-1 for information on infusion 
duration.
o Added footnote c providing time windows 
for sample collections for C1D8, C1D15, 
C1D22, C3D8, C3D15, and C3D22 in 
Table 9.5-2 and Table 9.5-4.
• Added new Table 9.5-3 Table 9.5-4 for Q2W 
and Q3W dosing schedules, respectively.
These changes were made to:
• Clarify timing details for 
end-of-infusion samples.
• Clarify time windows for PK and 
immunogenicity sample collections 
for C1D8, C1D15, and C1D22 
timepoints.
• Align PK and immunogenicity 
sampling schedules with alternative 
Q2W and Q3W dosing schedules
added to the study design.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
10.1: Sample Size 
Determination 
(including 
subsections)
Updated description of study design, planned 
number of participants, and/or target populations 
across study parts per updates made to the study 
design.
Aligned description of sample size 
determination with updated study 
design outlined above.
11: References
Updated references as needed per literature 
supporting newly added text and current versions 
of Investigator Brochures.
Provided references to the most 
current versions of Investigator 
Brochures for nivolumab and 
ipilimumab.
Appendix 2: 
Study Governance 
Considerations
Modified Good Clinical Practice section in 
Appendix 2 to:
• Add bullet to clarify that the study will also be 
conducted in accordance with ethical principles 
derived from international guidelines, including 
the Declaration of Helsinki and Council for 
International Organizations of Medical Sciences 
International Ethical Guidelines Good Clinical 
Practice.
• Align with revised definition of serious breach to 
Regulation No 536/2014 of the European 
Parliament and of the Council.
Modified text to align with statement 
in the informed consent form and 
TransCelerate Common Protocol 
Template.
Appendix 3: 
Adverse Events 
and Serious 
Adverse Events 
Definitions and 
Procedures for 
Recording, 
Evaluating, and 
Follow-up and 
Reporting
Added new sections for Events Meeting the AE 
Definition, Events Not Meeting the AE Definition, 
and Definition of Serious Adverse Event (SAE).
Modified the following sections: SAEs (text 
related to pregnancy and drug-induced liver 
injury); Evaluating AEs and SAEs (updated and 
rearranged bulleted information); and Reporting of 
SAEs to Sponsor or Designee (updated and 
rearranged bulleted information related to 
pregnancy and paper report forms).
Modifications made to information 
related to AEs and SAEs to align with 
the TransCelerate Common Protocol 
Template, regulatory definition EMA 
GVP Module VI (EMA/873138/2011) 
and ICH E2A, and clarify the 
instructions for reporting pregnancy.
Appendix 10: 
Management 
Algorithms for 
Immuno-oncology 
Agents
In Hepatic Adverse Event Management algorithm, 
footnote stating that immuno-oncology therapy 
may be delayed rather than discontinued if 
AST/ALT ≤8 × ULN or T.bili ≤5 × ULN was 
removed.
Language was modified to align 
protocol with current study treatment 
Investigator Brochures and program 
safety parameters.
Appendix 11: 
Statistical 
Methodology
Updated statistical methodology to incorporate 
changes to study design.
Updated statistical methods to align 
with updated study design outlined 
above.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes for Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
All
Minor formatting and typographical corrections.
Corrections for clarity and consistency 
within the document were minor, and 
therefore have not been summarized.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Overall Rationale for the Revised Protocol 02, 14-Feb-2018
The primary reasons for these changes are to expand enrollment in Part 1A to include up to 60 
participants, extend the treatment period to 2 calendar years, modify eligibility criteria for 
participants with advanced PDAC, permit the use of concomitant palliative hormonal therapy, 
remove the option of re-treatment following progression, 
 Additional amendments have been made to align the protocol with respect to these 
changes.
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: On Treatment - Schedule 
of Activities for the BMS-986218 
Monotherapy Escalation (Part 1A), the 
Safety Evaluation of Combination 
Doses of BMS-986218 with 
Nivolumab (Part 1B), the Randomized 
BMS-986218 Monotherapy Cohort 
Expansion in Melanoma (Part 2A; 
BMS-986218 arm only), the 
BMS-986218 Cohort Expansion 
Monotherapy (Part 2B), and the 
BMS-986218 Cohort Expansion -
Combination Therapy (Part 2C); 
Table 2-3: On Treatment - Schedule 
of Activities for the Randomized 
BMS-986218 Monotherapy Cohort 
Expansion in Melanoma (Part 2A), 
Ipilimumab Monotherapy Only
On-treatment schedule of activities was 
modified as follows for all study parts:
• Added text to column headers for each 
cycle specifying a visit window of 
± 2 days.
• Added footnotes detailing that, beyond 
cycle 3, 
electrocardiograms 
(ECGs) 
must be performed every 3 cycles up to 
end of treatment (EOT).
• Updated 
CT/MRI 
tumor 
imaging 
assessment from being performed from 
baseline/screening to first dose.
Clarified the visit window 
for each on-treatment 
activity and the frequency 
and timing of performing 
EGCs beyond cycle 3. 
Modified tumor imaging 
assessments to be 
performed from first dose.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-1: Screening Schedule of 
Activities for All Study Parts; Table 
2-2: On Treatment - Schedule of 
Activities for the BMS-986218 
Monotherapy Escalation (Part 1A), the 
Safety Evaluation of Combination 
Doses of BMS-986218 with 
Nivolumab (Part 1B), the Randomized 
BMS-986218 Monotherapy Cohort 
Expansion in Melanoma (Part 2A; 
BMS-986218 arm only), the 
BMS-986218 Cohort Expansion 
Monotherapy (Part 2B), and the 
BMS-986218 Cohort Expansion -
Combination Therapy (Part 2C); 
Table 2-3: On Treatment - Schedule 
of Activities for the Randomized 
BMS-986218 Monotherapy Cohort 
Expansion in Melanoma (Part 2A), 
Ipilimumab Monotherapy Only; 
Section 5.1.2.4: The Randomized 
BMS 986218 Monotherapy Cohort 
Expansion in Melanoma (Part 2A), the 
BMS-986218 Cohort Expansion 
Monotherapy (Part 2B), and the BMS-
986218 Cohort Expansion 
Combination Therapy (Part 2C) 
Cohort Expansions; Section 5.1.2.5: 
Treatment Beyond Progression; 
Section 6.1: Inclusion Criteria; 
Section 8.1: Discontinuation from 
Study Treatment; Section 8.1.1: 
Treatment Beyond Progression; Table 
10.3.1-1
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.
Table 2-4: Follow-up Procedural 
Outline for All Study Parts 
(CA022001); Section 5.1.3.2: 
Response Follow-up Period
Text and footnotes related to 
tumor/response assessments were 
modified as follows:
• Updated language to specify:
Modified tumor/response 
assessment schedule; 
clarified submission and 
review of scans.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
o Continuation of tumor assessments 
following 
EOT/study 
treatment 
discontinuation every 8 weeks (Q8W) 
until 
subsequent 
tumor-directed 
therapy.
o Participants who remain free of 
subsequent therapy will continue to 
receive tumor assessment scans for the 
first 48 weeks after discontinuation of 
study treatment/EOT visit and then 
Q12W (± 2 weeks) for a total duration 
of 2 years.
• Added that assessment scans will be 
submitted for blinded independent 
central review (BICR).
Table 2-4: Follow-up Procedural 
Outline for All Study Parts 
(CA022001); Section 5.1.3.2: 
Response Follow-up Period; Section 
5.1.3.3: Survival Follow-up Period 
Added “(± 2 weeks)” next to Q12W 
follow-up intervals.
Clarified follow-up 
window permitted for 
response and survival 
follow-up schedules.
Table 2-5: Re-treatment Screening 
Procedural Outline (CA022001); 
Figure 5.1-2: Study Period and 
Participant Flow for BMS-986218, 
Ipilimumab, and Nivolumab; Section 
5.1.3.4: Re-treatment During Follow-
up Periods; Section 5.4: Scientific 
Rationale for Study Design; Table 
9.5-4: PK and Anti-Drug Antibody 
Sampling Schedule for BMS-986218 
Q4W Monotherapy and Ipilimumab 
Q3W Monotherapy During Re-
treatment; Table 9.5-5: PK and Anti-
Drug Antibody Sampling Schedule for 
BMS-986218 Q4W in Combination 
with Nivolumab Q4W During Re-
treatment; 
Removed all language related to 
re-treatment for patients with disease 
progression during response follow-up.
Modified response follow-
up to exclude option for 
re-treatment for 
participants with disease 
progression.
Section 3.3: Benefit/Risk Assessment; 
Section 5.5.1.1: BMS-986218 
Rationale for Starting Dose in 
Humans; Section 5.5.2.2: Nivolumab; 
Section 7.5.2: Management
Algorithms for Immuno-oncology 
Agents
Replaced “immune-related adverse events 
(AEs)” to “immune-mediated AEs.”
Modified description of 
AEs that may reflect 
activation of the immune 
system. 
Table 4-1: Objectives and Endpoints; 
Table 10.3.1-1: Efficacy - Statistical 
Analyses
Added 24- and 48-week analyses for 
progression-free survival rate (PFSR) by 
RECIST v1.1.
Modified PFSR study 
endpoint to include 
analyses at 24 weeks and 
Protocol Amendment No.: 07
Date: 29-Jul-2021
279
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8.0
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1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
48 weeks, in addition to at 
36 weeks.
Section 5.1: Overall Design
Updated duration of study from 
approximately 3 years to approximately 5 
years.
Modified study duration.
Figure 5.1-1: Study Design 
Schematic; Section 5.1.2.1: The 
BMS-986218 Monotherapy Escalation 
(Part 1A); Section 5.2: Number of 
Participants; Section 10.1.1: 
Monotherapy Dose Escalation (Part 
1A)
Text related to the number of participants 
in Part 1A (BMS-986218 monotherapy 
escalation) was modified as follows:
• Planned enrollment for Part 1A was 
updated from approximately 30 to up to 
60 participants.
• Rationale for the number of participants 
to be included in Part 1A was added.
Modified number of 
participants to be included 
in Part 1A to fulfill the 
expected number of 
participants needed for 
Bayesian Logistic 
Regression Model (BLRM) 
and allow for further 
evaluation of safety, 
pharmacokinetic (PK), or 
pharmacodynamic 
parameters.
Figure 5.1-1: Study Design 
Schematic; Section 6.1: Inclusion 
Criteria
The inclusion criteria for Part 2B 
(BMS-986218 Cohort Expansion 
Monotherapy) were modified to remove 
tumor infiltration requirements for 
patients with advanced pancreatic ductal 
adenocarcinoma (PDAC). 
Modified the eligibility 
criteria to include patients 
with advanced PDAC in 
Part 2B, regardless of 
tumor infiltration status.
Figure 5.1-1: Study Design 
Schematic; Figure 5.1-2: Study Period 
and Participant Flow for BMS-
986218, Ipilimumab, and Nivolumab; 
Section 5.1.2: Treatment Period; 
Section 5.1.3.1: Safety Follow-up 
Period; Section 5.1.3.4: Re-treatment 
During Follow-up Periods; Section 
5.4: Scientific Rationale for Study 
Design
Text and footnotes related to treatment 
period were updated to extend the 
duration of treatment to up to 2 calendar 
years for all study parts.
Modified treatment period 
to allow all participants to 
receive study treatment for 
a maximum of 2 calendar 
years.
Section 5.1.2.5: Treatment with 
Additional Cycles Beyond 36 Weeks
This section was removed.
In accordance with the 
additional revised protocol 
02 modification extending 
the treatment period to a 
maximum of 2 calendar 
years, this section is no 
longer applicable.
Section 5.1.3.3: Survival Follow-up 
Period
The survival follow-up period following 
the first dose of study treatment was 
updated from 2 years to 4 years.
Modified the survival 
follow-up period following 
the first dose of study 
treatment in accordance 
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
with the additional revised 
protocol 02 update 
extending the treatment 
period to a maximum of 2 
calendar years. 
Section 5.4.5: Rationale for Two 
Years Fixed Duration of Treatment 
with Checkpoint Blockade
This section has replaced Section 5.4.5: 
Rationale for Treatment Duration in the 
previous amendment of this protocol.
Modified the rationale 
provided for treatment 
duration to reflect the 
additional revised protocol 
02 update extending the 
treatment period to a 
maximum of 2 calendar 
years.
Section 6.2: Exclusion Criteria
The exclusion criteria were modified to:
• Remove the list of permitted prior 
anticancer treatments within the 2) 
Prohibited Treatments subsection.
• Add reference to new Appendix 8 
(Country Specific Requirements) for 
HIV testing within the 3) Medical 
History 
and 
Concurrent 
Diseases 
subsection.
• Removed text around prisoners or 
involuntarily incarcerated participants 
being permitted to continue as a
participant” 
within 
the 
5) 
Other 
Exclusion Criteria subsection
Clarified which therapies 
are prohibited within the 
eligibility criteria and 
country-specific 
requirements for HIV 
testing. Change to text for 
prisoners/involuntarily 
incarcerated participants
was made because the 
statement referring to 
“continue as participant” 
was not applicable to the 
eligibility criteria.
Section 7.4: Method of Treatment 
Assignment
Text added describing scenarios in which 
participant replacement is not permitted 
after study discontinuation in Part 1B and 
Part 2A.
Clarified when participant 
replacement is not 
permitted.
Section 7.5.1: Dose-limiting 
Toxicities
Added scenarios in which participants 
withdrawn from the study during the dose 
limiting toxicity (DLT) period may be
considered DLT-evaluable.
Clarified which 
participants may be 
considered DLT-evaluable.
Section 7.8.1: Prohibited and/or 
Restricted Treatments; Section 7.8.3: 
Permitted Therapy
Added permitted use of palliative 
hormonal therapy.
Modified permitted therapy 
to include palliative 
hormonal therapy when 
indicated.
Section 8.1: Discontinuation from 
Study Treatment
Modified text in this section to:
• Remove 
bullet 
regarding 
separate 
discontinuation criteria for nivolumab 
and BMS-986218.
• Add a note to bullet describing 
discontinuation for participants who 
become imprisoned or involuntarily 
Clarified that participants 
receiving combination 
therapy must discontinue 
both therapies if they meet 
discontinuation criteria and 
that there may be specific 
circumstances that permit 
study treatment 
continuation.
Protocol Amendment No.: 07
Date: 29-Jul-2021
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Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
incarcerated to clarify scenarios in 
which continuation is permitted.
Section 8.1.1.1: Discontinuation Due 
to Further Progression (Confirmed 
Progression)
Added scenarios in which participants 
who have progressed should continue to 
receive treatment and monitoring or 
should discontinue the study.
Clarified when participants 
should remain on the trial 
or permanently discontinue 
the study following 
progression. 
Section 9.2.1: Time Period and 
Frequency for Collecting AE and SAE 
Information
Added further direction on when 
information on AEs and serious AEs 
(SAEs) must be collected.
Clarified the time period 
for collecting AE and SAE 
information.
Section 9.2.2: Method of Detecting 
AEs and SAEs
Added text related to avoiding bias when 
collecting AEs and SAEs.
Clarified expectation for 
collecting AEs/SAEs and 
inquiry guidance based on 
program/protocol.
Section 9.3.1: Imaging Assessment for 
the Study
Added language describing the timing 
and frequency of tumor assessments for 
participants at the time of EOT or study 
treatment discontinuation and participants 
who are allowed to be treated beyond 
initial disease progression.
Clarified tumor assessment 
schedules for participants 
at EOT or study treatment 
discontinuation and 
participants treated beyond 
progression.
Section 9.5: Pharmacokinetic and 
Immunogenicity Assessments; Table 
9.5-2: Pharmacokinetic and Anti-Drug 
Antibody Sampling Schedule for 
BMS-986218 Q4W Monotherapy in 
Dose Escalation and Dose Expansion 
and Ipilimumab Q3W Monotherapy in 
Dose Expansion (Parts 1A, 2A, and 
2B); Table 9.5-3: Pharmacokinetic 
and Anti-Drug Antibody Sampling 
Schedule for BMS-986218 Q4W in 
Combination with Nivolumab Q4W in 
Dose Escalation and Dose Expansion 
(Parts 1B and 2C)
Modified PK assessment text and tables 
to:
• Update sample collection types and 
frequency between C5D1 and EOT.
• Remove collection of dose delay 
samples.
Modified PK assessments 
to collect predose BMS-
986218 and nivolumab 
blood samples every fourth 
cycle after C5 until EOT 
and exclude collection of 
dose delay samples.
Protocol Amendment No.: 07
Date: 29-Jul-2021
282
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930111276
8.0
v
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1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 10.3: Statistical Analyses
Added statement that a description of the 
participant population will be included in 
the statistical output reported, including 
subgroup of age, gender, and race.
Statement added to meet 
compliance requirements.
Appendix 2: Study Governance 
Considerations
Added bullet to clarify that the study will 
also be conducted in accordance with 
ethical principles derived from 
international guidelines including the 
Declaration of Helsinki and Council for 
International Organizations of Medical 
Sciences International Ethical Guidelines 
Good Clinical Practice.
Modified text to align with 
statement in the ICF and 
TransCelerate Common 
Protocol Template.
Appendix 8: Country Specific 
Requirements
Added new appendix for country specific 
requirements related to HIV testing.
Appendix added to support 
country specific 
requirements for HIV 
testing within the 3) 
Medical History and 
Concurrent Diseases 
subsection.
Appendix 12: 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.
Protocol Amendment No.: 07
Date: 29-Jul-2021
283
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8.0
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1.0
v

Clinical Protocol
CA022001
BMS-986218
anti-CTLA4-NF mAb
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
All
Minor formatting and typographical 
corrections.
Made corrections for 
clarity and consistency 
within the document.
Protocol Amendment No.: 07
Date: 29-Jul-2021
284
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930111276
8.0
v
Approved
1.0
v