A Phase 1/2 Study of Nivolumab (BMS-936558) in Combination With Ipilimumab (BMS-734016) in Chinese Participants With Previously Treated Metastatic or Recurrent Solid Tumors
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 1/2 Study of Nivolumab (BMS-936558) in Combination with Ipilimumab 
(BMS-734016) in Chinese Participants with Previously Treated Metastatic or Recurrent 
Solid Tumors 
NCT Number: NCT03195478 
Document Date (Date in which document was last revised): 22-Aug-2022 

Page:
1
Protocol Number:
CA209672
IND Number:
N/A
Ex-US
Non-IND
EUDRACT Number
N/A
Date:
25-Apr-2016
Revised Date:
22-Aug-2022
CLINICAL PROTOCOL CA209672
A Phase 1/2 Study of Nivolumab (BMS-936558) in Combination with Ipilimumab 
(BMS-734016) in Chinese Participants with Previously Treated Metastatic or Recurrent Solid 
Tumors
Protocol Amendment Number: 07
Incorporates Administrative Letter 07
Clinical Trial Physician - Medical Monitor
Clinical Scientist
Bristol-Myers Squibb Company
1717 West Nanjing Road
Shanghai 200040, P.R. China
Bristol-Myers Squibb Company
3401 Princeton Pike, Lawrenceville, NJ 08648
Telephone (office): 
Telephone (office):
Fax: 
Email: 
Email: 
24-hr Emergency Telephone Number
USA:
International: 
Bristol-Myers Squibb Research and Development
1717 West Nanjing Road
Shanghai 200040, P.R. China
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BMS-936558
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Protocol Amendment No.: 07
Date: 22-Aug-2022
2
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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Protocol Amendment No.: 07
Date: 22-Aug-2022
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 07
22-Aug-2022
Due to significant landscape change and shrinkage of eligible patient 
pool, Bristol-Myers Squibb made a decision to close the CA209672 Part 2 
Study to enrollment in Dec-2021. Based on current timelines, projections 
show that the study will not be able to meet its scientific objectives in this 
rapidly evolving therapeutic landscape. Enrollment closure of the study is 
unrelated to safety. The protocol has been revised to modify or reduce the 
assessments and data collection to minimize the burden on study 
participants and site staff. 
Key changes in Protocol Amendment 07 include the removal of 
pharmacokinetic and immunogenicity sampling, as well as the tumor 
assessments and safety follow-up beyond 100 days post study drug
discontinuation.
Administrative 
Letter 07
25-Feb-2022
The purpose of this letter is to change the contact information for the 
Medical Monitor.
Protocol 
Amendment 06
02-Jul-2021

Updated study language for post-study access to therapy (criteria of 
study termination and disposition for those subjects still in study 
when the study terminates) and program level language for 
nivolumab and ipilimumab including language associated with 
SARS-CoV-2 infection

Added a section about outcome research analyses

Replaced older versions of appendices (management algorithms and 
WOCBP) with newer versions

Reported personnel changes

Incorporated Administrative Letter 06
Administrative 
Letter 06
02-Jul-2020

Corrected inconsistencies in SAE collection period in Table 5.1-1, 
Table 5.1-2, and appendix 4.
Revised Protocol 
05
09-Jan-2020

Removal of sample collection as a control for MSI/MRR status 
confirmation
Administrative 
Letter 05
20-May-2019

Change in Study Director/Medical Monitor
Revised Protocol 
04
08-Apr-2019

Incorporates Administrative Letter 01, 02, 03 and 04

Added Part 2, Arm D, expansion cohort for recurrent or metastatic 
MSI-H/dMMR colorectal cancer subjects

Corrected inconsistencies, typographical and formatting errors, and 
updated all abbreviations throughout
Administrative 
Letter 04
11-Dec-2018

Corrected inconsistencies in SAE collection period throughout the 
protocol
Administrative 
Letter 03
14-Mar-2018

Provided rationale for modifying MSI testing requirement in the 
administrative letter 02.
Administrative 
Letter 02
25-Jan-2018

Clarified MSI testing requirement in CRC subjects in revised 
protocol version 03.
Administrative 
Letter 01
22-Nov-2017
Corrected inconsistencies in Appendix 3 of the Chinese translation of 
revised protocol version 03
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Protocol Amendment No.: 07
Date: 22-Aug-2022
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Document
Date of Issue
Summary of Change
Revised Protocol 
03
26-Oct-2017

Incorporates Amendment 03
Amendment 03
26-Oct-2017

Removed RCC and NPC tumor types from and to add CRC 
MSI-H/dMMR to Arm B

Added of neutralizing antibody analysis as part of immunogenicity 
analysis

Appendix 3 updated
Corrected inconsistencies, typographical and formatting errors, and 
make small language clarifications 
Revised Protocol
02
20-Apr-2017

Incorporates Amendment 02
Amendment 02
20-Apr-2017

Defines 2 years or 24 months of treatment duration

Removal of tumor sample collection at screening and biomarker 
analysis of tumor sample

Incorporates nivolumab program updates
To make any typographical edits, format updates and clarifications 
identified within and throughout the protocol
Revised Protocol
01
20-Dec-2016

Incorporates Amendment 01
Amendment 01
20-Dec-2016

Assessment of anti-tumor activity of nivolumab and ipilimumab
changed to exploratory objective from secondary objective

Clarification to safety monitoring during the study.

Clarification to eligibility criteria for GC subjects.

Incorporates revised duration of contraception

Removal of less effective method of contraception and addition of 
progestogen only hormonal contraception

Updates to adverse event management algorithm in Appendix 3
To make any typographical edits, format updates and clarifications 
identified within and throughout the protocol
Original Protocol
25-Apr-2016
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07:
Due to significant landscape change and shrinkage of eligible patient pool, Bristol-Myers Squibb
(BMS) made a decision to close the CA209672 Part 2 Study to enrollment in Dec-2021. Based on 
current timelines, projections show that the study will not be able to meet its scientific objectives 
in this rapidly evolving therapeutic landscape. Enrollment closure of the study is unrelated to safety. 
The protocol has been revised to modify or reduce the assessments and data collection to minimize 
the burden on study participants and site staff. 
Key changes in Protocol Amendment 07 include the removal of pharmacokinetic (PK) and 
immunogenicity sampling, as well as the tumor assessments and safety follow-up beyond 100 days 
post study drug discontinuation.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Updated medical monitor information
Administrative update
Synopsis
Section 1.3.2: Secondary 
Objectives
Section 1.3.3: Exploratory 
Objectives
Section 8.3.2.2: Part 2
Section 8.3.3.2: Part 2
Changed overall survival evaluation from 
secondary objective to exploratory 
objective
Due to early closure of the trial
Synopsis
Section 1.3.3: Exploratory 
Objectives
Section 5.1: Flow 
Chart/Time and Events 
Schedule
Section 5.5: 
Pharmacokinetic and 
Immunogenicity 
Assessments
Section 5.5.2: 
Pharmacokinetic Sample 
Analyses
Section 5.9.1: 
Immunogenicity 
Assessment
Section 8.3.3.2: Part 2

Added language about the changes 
made to PK and immunogenicity 
sampling and assessments  

Removed selected serum sample 
analysis
To reduce collection of samples due 
to early closure of the trial 
Synopsis
Section 1.3.3: Exploratory 
Objectives
Section 5.1: Flow 
Chart/Time and Events 
Schedule
Removed the investigator-assessed second 
disease progression or death during next 
line of treatment (PFS2) for Part 2
PFS2 evaluation was removed due to 
limited number of participants
enrolled in Part 2 up to study closure
Protocol Amendment No.: 07
Date: 22-Aug-2022
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Section 8.3.3.2: Part 2
Section 8.4.2.2: Part 2
Synopsis
Section 1.3.3: Exploratory 
Objectives
Section 8.3.3.2: Part 2
Section 8.4.5: Biomarker 
Analyses
Removed exploratory objectives for 
concordance rate of microsatellite 
instability/mismatch repair deficient
(MSI/MMR) for Part 2
Removed due to limited number of 
patients enrolled in Part 2 up to study 
closure
Synopsis
Section 3.1.1: Overall 
Design and Schematic
Section 3.1.5: Follow-Up
Section 5.1: Flow 
Chart/Time and Events 
Schedule
Table 5.1-1: Screening 
Procedural Outline 
(CA209672)
Section 5.1.1: Retest 
During Screening or 
Lean-in Period
Removed survival follow-up
Survival follow-up was removed due 
to early closure of the trial
Synopsis
Section 3.1.1: Overall 
Design and Schematic
Section 3.3: Study 
Population
Section 8.1.2: Part 2
Added language about study enrollment 
status and Part 2 enrollment closure
To clarify early study closure and 
align with rest of changes
Synopsis
Section 8.4.2.2: Part 2
Revised analysis methods for efficacy 
endpoints
To simplify efficacy analysis due to 
limited number of participants
enrolled up to study closure
Section 1.1.1: Rationale to 
Support Dose/Schedule of 
Nivolumab Combined with
Ipilimumab
Updated clinical data for nivolumab and 
ipilimumab based on the 
CHECKMATE-142 trial
To reflect clinical data updates from
the study CHECKMATE-142
Section 1.5: Overall 
Risk/Benefit Assessment
Added text about the global coronavirus 
disease 2019 (COVID-19) pandemic being 
identified as a potential risk to clinical trial 
participants, mitigation, and reporting of 
adverse events and serious adverse events
To update the COVID-19-related
benefit/risk and mitigation for 
protection of study participants in the 
context of the COVID-19 pandemic
Section 3.1.3.2: Screening
Section 8.4.7.1: European 
Organization for Research 
and Treatment of Cancer 
Corrected the descriptions about 
randomization
To clarify that this is not a 
randomized study
Protocol Amendment No.: 07
Date: 22-Aug-2022
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Quality of Life 
Questionnaire (QLQ-C30)
Section 3.1.5: Follow-Up
Section 3.6: Post Study 
Drug Follow up
Section 5.1: Flow 
Chart/Time and Events 
Schedule
Changed language about safety monitoring 
and tumor assessments
To describe the modifications made 
to assessments as a result of early 
enrollment termination  
Section 3.1.6: Treatment 
beyond Progression
Deleted Section 3.1.6
To remove duplicate information 
already contained in Section 4.5.7
Section 3.4.1: Prohibited 
and/or Restricted 
Treatments
Added COVID-19 vaccine guidance
To state that the efficacy and safety 
of COVID-19 vaccination in
participants who are receiving
nivolumab and/or ipilimumab are 
unknown
Section 4.5.7: Treatment 
Beyond Disease 
Progression
Added language about maximum treatment 
duration of 2 years
Added for clarity
Section 8.2: Populations 
for Analyses
Removed outcomes research subjects 
(Part 2 only) from populations for analyses
To describe the modifications made 
to statistical analyses as a result of 
early enrollment termination
Section 8.4.3: Safety 
Analyses
Added vital signs, physical examination 
abnormality findings, and ECG readings to 
safety analyses for Part 2
To add additional details for Part 2 
safety analyses 
Section 8.4.4: 
Pharmacokinetic Analyses
Removed summary statistics for PK 
analyses for part 2
To describe the modifications made 
to statistical analyses as a result of 
early enrollment termination
Section 8.4.5: Biomarker 
Analyses
Added text stating that baseline MSI/MMR 
will be listed
To describe the modifications made 
to statistical analyses as a result of 
early enrollment termination
Section 9.5: Data 
Protection, Data Privacy, 
and Data Security
Added description of BMS policies 
regarding data protection, data privacy, 
and data security
To ensure the privacy, protection, 
and confidentiality of collected 
personal data
Throughout Document

Changed “RECIST v1.1” to “RECIST 
1.1” where applicable

Changed “subject” to “participant” 
where applicable

Changed “MMR/MSI” to 
“MSI/MMR” where applicable

Corrected minor and typographical 
and formatting errors

To ensure alignment and 
consistency regarding 
terminology throughout the 
document

To correct formatting and 
typographical errors
Protocol Amendment No.: 07
Date: 22-Aug-2022
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SYNOPSIS
Clinical Protocol CA209672
Protocol Title: A Phase 1/2 Study of Nivolumab (BMS-936558) in Combination with Ipilimumab (BMS-734016) 
in Chinese Participants with Previously Treated Metastatic or Recurrent Solid Tumors
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Participants will receive
Part 1:
Arm A--nivolumab 3 mg/kg IV Q2W plus ipilimumab 1 mg/kg IV Q6W.
Arm B--nivolumab 3 mg/kg IV plus ipilimumab 1 mg/kg IV Q3W × 4, followed by nivolumab 240 mg IV Q2W
Arm C--nivolumab 1 mg/kg IV plus ipilimumab 3 mg/kg IV Q3W × 4, followed by nivolumab 240 mg IV Q2W
Part 2:
Arm D--nivolumab 3 mg/kg IV plus ipilimumab 1 mg/kg IV Q3W × 4, followed by nivolumab 240 mg IV Q2W
Study Phase: 1/2
Research Hypothesis:
Part 1: There is no formal primary research hypothesis for Arms A, B, and C to be statistically tested.
Part 2: Treatment with nivolumab combined with ipilimumab will have clinical activity in participants with recurrent 
or metastatic microsatellite instability-high (MSI-H)/DNA mismatch repair deficient (dMMR) colorectal cancer
(CRC).
Objectives:
Primary Objectives:
Part 1: To establish the safety, tolerability and dose-limiting toxicities (DLTs) of nivolumab plus ipilimumab in 
Chinese participants with advanced or recurrent solid tumor.
Part 2: To evaluate the blinded independent central review (BICR)-assessed objective response rate (ORR) of 
nivolumab in combination with ipilimumab in Chinese participants with recurrent or metastatic MSI-H/dMMR CRC
Secondary Objectives:
Part 1:

To characterize the pharmacokinetics of nivolumab and ipilimumab in Chinese participants when administered 
in combination.

To assess the immunogenicity of nivolumab and ipilimumab in Chinese participants when administered in 
combination.
Part 2:

To evaluate the investigator-assessed ORR of nivolumab in combination with ipilimumab in Chinese participants 
with recurrent or metastatic MSI-H/dMMR CRC. 

To evaluate the investigator- and BICR-assessed disease control rate (DCR) of nivolumab in combination with 
ipilimumab in Chinese participants with recurrent or metastatic MSI-H/dMMR CRC. 

To evaluate Investigator-assessed and BICR-assessed progression-free survival (PFS) in Chinese participants 
with recurrent or metastatic MSI-H/dMMR CRC who received nivolumab in combination with ipilimumab.

To evaluate Investigator-assessed and BICR-assessed duration of response (DOR) in Chinese participants with 
recurrent or metastatic MSI-H/dMMR CRC who received nivolumab in combination with ipilimumab.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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Exploratory Objectives:
Part 1:

To assess preliminary anti-tumor activity of nivolumab and ipilimumab in Chinese participants when 
administered in combination.
Part 2:
Per Protocol Amendment 07, collection of pharmacokinetic (PK) and immunogenicity data is not applicable. PK
sample analyses and immunogenicity assessments will be based on samples collected before the implementation of 
Protocol Amendment 07. No analyses of concordance rate between results from central and local testing, and 
investigator-assessed second disease progression or death during next line of treatment are planned due to the limited 
number of participants enrolled.

To determine the safety and tolerability (defined as toxicity rates [worst Common Terminology Criteria (CTC) 
Grade per participant]) of AEs and specific laboratory tests of nivolumab in combination with ipilimumab in 
Chinese participants with recurrent or metastatic MSI-H/dMMR CRC.

To characterize the PK of nivolumab and ipilimumab when administered in combination, and to explore exposure-
response relationships.

To characterize the immunogenicity of nivolumab and ipilimumab when administered in combination.

To evaluate health-related quality of life using a validated instrument in the European Organisation for Research 
and Treatment of Care (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30).

To evaluate patient-reported general health status as assessed by the EuroQol 5 Dimensions questionnaire (EQ-
5D-3L).

To evaluate overall survival (OS) in Chinese participants with recurrent or metastatic MSI-H/dMMR CRC who 
received nivolumab in combination with ipilimumab.
Study Design: This is an open-label, multi-dose, 2-part Phase 1/2 study of nivolumab in combination with ipilimumab 
in Chinese participants with previously treated metastatic or recurrent solid tumors. 
As of 20-Dec-2021, the study was closed to new enrollment for Part 2, and a total of 36 participants (9 participants
each in Arms A, B, C, and D) were enrolled. The study will consist of 3 periods: screening period, treatment period 
(until disease progression, intolerable toxicities, withdrawal of consent, completion of maximum treatment duration
specified in protocol Section 3.1.1, the study ends, or other reasons specified in the protocol, whichever occurs first); 
and a follow-up period (up to 100 days for Arms A, B, C, and D). The response assessment must be completed from 
date of first dosing every 6 weeks for the first 24 weeks, and then every 12 week thereafter until disease progression 
or unacceptable toxicities for Part 1, or until initiation of subsequent anti-cancer treatment for Part 2. Every effort 
should be made to schedule visits within the timeframe stated in the protocol. For Part 2 only, images will be submitted 
to a central imaging vendor for BICR during the study. 
For Part 1, a safety evaluation is planned after a total of 9 participants completed the first 6 weeks of treatment and 
associated evaluation in a given arm. However, tolerability beyond 6 weeks may also be taken into consideration. 
Participants who do not complete the DLT observation period for reasons other than DLTs will be replaced. The 
following tables shows the guidance for safety monitoring based on observed toxicity outcome.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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Number of participants treated 
and followed up for at least 6 
weeks after start of study 
treatment
Number of 
participants with 
DLTs
Next Step
9
2
Tolerable
9
3
To be discussed between sponsor and 
Investigators to review benefit/risk ratio
Study Design Schematic
Part 1
Part 2
* If a participant with following tumor types is enrolled, he/she can only be treated using one specific dosing schedule, 
e.g. NSCLC, SCCHN or mesothelioma patient is to be treated in Arm A only. SCLC patients is to be treated in 
Arm C only.
**Participants may be treated beyond progression under protocol-defined circumstances. Treatment continues until 
progression, unacceptable toxicity, withdrawal of consent, completion of maximum treatment duration of 
24 months EXCEPT in participants with late response (during second year of treatment) who may receive treatment 
for up to an additional 12 months after onset of response, the study ends, or other reasons specified in the protocol, 
whichever occurs first.
Study Population:
Key inclusion criteria:

Mainland Chinese participants (at least 18 years of age).

ECOG 0-1

Have progression or refractory disease

Arm A: solid tumor including but not limited to NSCLC, NPC;
Advanced or recurrent 
solid tumor* previously 
treated:
-Arm A:  including but not 
limited to NSCLC, NPC
- Arm B:  including but 
not limited to CRC 
(MSI-H/dMMR)
- Arm C:  including but 
not limited to SCLC, GC 
and melanoma
Follow-up 
Visit 1 and 
Visit 2
Nivolumab 240 mg 
flat dose Q2W until 
disease 
progression** or 
unacceptable toxicity
Until disease 
progression** or 
unacceptable toxicity
Arm A:  Nivo 3 mg/kg 
Q2W + ipi 1 mg/kg Q6W
Arm B:  Nivo 3 mg/kg
+ ipi 1 mg/kg Q3W x 4
Arm C: Nivo 1 mg/kg
+ ipi 3 mg/kg Q3W x 4
Advanced or recurrent 
solid tumor previously 
treated:
- Arm D:  recurrent or 
metastatic CRC 
(MSI-H/dMMR)
Follow-up 
Visit 1 and 
Visit 2
Nivolumab 240 mg 
flat dose Q2W until 
disease 
progression** or 
unacceptable toxicity
Arm D:  Nivo 3 mg/kg
+ ipi 1 mg/kg Q3W x 4
Protocol Amendment No.: 07
Date: 22-Aug-2022
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
Arm B: solid tumor including but not limited to CRC MSI-H/dMMR;

Arm C: solid tumor including but not limited to SCLC, GC and melanoma.

Arm D: histologically confirmed recurrent or metastatic MSI-H/dMMR CRC;

If a participant with following tumor types is enrolled, he/she can only be treated using one specific dosing 
schedule, e.g. NSCLC, SCCHN or mesothelioma patient is to be treated in Arm A only. SCLC patient is to 
be treated in Arm C only.

For Part 1, failing at least 1 line of systemic therapy for advanced disease; OR, well documented refusal of 
participants to receive chemo or biological therapy.

For Part 2, additional criteria must be met for inclusion:

Participants must have shown progression during, after, or have been intolerant to 1 line treatment(s) for 
metastatic disease, which must include at least a fluoropyrimidine, and oxaliplatin or irinotecan (participants 
who receive oxaliplatin in an adjuvant setting should have progressed during or within 6 months of 
completion of adjuvant therapy in order for oxaliplatin to count as a prior therapy needed for entry)

Participants willing to comply to provide tumor tissue (archival or fresh biopsy specimen), including possible 
pre-treatment biopsy

Women of childbearing potential (WOCBP) must not be nursing or pregnant and must be using an acceptable 
method of contraception. WOCBP must have a negative pregnancy test within 24 hours prior to dosing with study 
drug.
Study Drug: includes both investigational [medicinal] products (IP/IMP) and non-investigational [medicinal] 
products (Non-IP/Non-IMP) as listed:
Study Drug for CA209672
Medication 
Potency 
IP/Non-IP 
Nivolumab (BMS-936558-01) 
Solution for Injection
100 mg (10 mg/mL)
IP
Ipilimumab Solution for Injection
50 mg (5 mg/mL), 200 mg 
(5-mg/mL)
IP
Maximum treatment duration: treatment with nivolumab or nivolumab with ipilimumab will be given for up to 
24 months in the absence of disease progression or inacceptable toxicity EXCEPT in participant with late response 
(during second year of treatment) who may receive treatment for up to an additional 12 months after onset of response.
Study Assessments:

Safety Outcome Measures:  Safety assessments will be based on medical review of adverse event reports and the 
results of vital sign measurements, ECOG status, ECGs, physical examinations, and clinical laboratory tests. The 
incidence of observed adverse events will be tabulated and reviewed for potential significance and clinical 
importance. Toxicity will be evaluated by the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.0.

Dose-Limiting Toxicity: DLTs are defined in protocol Section 4.5.1 and will be determined based on the 
incidence, intensity, and duration of adverse event (AE) that are related to study drug, and that occur within 42
days (6 weeks, through completion of cycle 1) of initiation of study drug;

Not applicable per Protocol Amendment 07: Pharmacokinetic Evaluation: Serial blood samples for 
pharmacokinetic assessments will be collected from all participants at specified time points.

Not applicable per Protocol Amendment 07: Immunogenicity Evaluations: Blood samples to evaluate 
development of positive anti-drug antibody (ADA) response will be collected at specified time points for all 
participants.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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
Efficacy Assessment: Computed tomography/magnetic resonance imaging (CT/MRI) for chest, abdomen, pelvis, 
and brain will be performed at screening and at specified time points in Table 5.1-2, Table 5.1-3, and 5.1-4. 
Measurement of tumor burden must be reviewed and documented before initiating further treatment with 
nivolumab. Tumor response status will be assessed with RECIST 1.1.
Statistical Considerations:
Sample Size:
Part 1: With 9 participants in each arm, if 0, 1, 2, or 3 participants experienced DLTs, the upper limit of the one-sided 
exact 90% confidence interval (CI) for the true DLT rate will be less than 23%, 37%, 49%, and 60% respectively. The 
calculations are based on the Clopper-Pearson method for the exact confidence intervals.
Part 2: With an estimated discrepancy rate of 25% between local and repeating testing in central lab for MSI/MMR
status, it is expected that approximately 33 patients with MSI-H/dMMR mCRC determined by local testing will be 
treated on study. A sample size of 33 will allow the lower bound of one-sided 95% CI excluding 35% when the 
observed ORR is 50% in the nivolumab/ipilimumab combination arm. The 35% ORR is expected for local diagnosed 
MSI-H/dMMR mCRC patients treated with PD-1 inhibitor monotherapy. This sample size will also provide at least 
90% power to demonstrate statistical difference with historical ORR of 5% for TKI monotherapy in a similar setting 
at a two-sided alpha of 0.05.
Due to challenges with enrollment, the enrollment for Part 2 was closed after 9 participants were treated, out of the 33 
participants planned. 
Endpoints:
Primary endpoints:
Part 1:

Frequency of adverse events occurring up to 100 days after the last dose of study drug

Frequency of serious adverse events occurring up to 100 days after the last dose of study drug

Frequency of adverse events leading to discontinuation occurring up to 100 days after the last dose of study drug

Frequency of adverse events leading to death occurring up to 100 days after the last dose of study drug

Frequency of participants with clinical laboratory abnormalities by worst toxicity grade by NCI CTCAE version 
4.0 (as assessed at the planned times listed in Table 5.1-1, Table 5.1-2, Table 5.1-3, Table 5.1-4, Table 5.1-5, 
Table 5.1-6 and Table 5.1-7). 
Part 2:

BICR-assessed ORR: Defined as the number of participants with a best overall response (BOR) of confirmed 
complete response (CR) or partial response (PR), according to RECIST 1.1 criteria
Secondary endpoints:
Part 1:

Pharmacokinetics: PK parameters including Cmax, Cmin, Ceoinf, Tmax, AUC(0-T), and AUC(TAU) of 
nivolumab and ipilimumab derived from serum concentration versus time data.

Immunogenicity: The frequency of baseline ADA positive participants and ADA positive participants.
Part 2:

Investigator-assessed ORR: defined as the BOR of confirmed CR or PR, according to RECIST 1.1 criteria.

Investigator- and BICR-assessed DCR defined as number of participants with a BOR of confirmed CR, PR, or 
SD lasting at least 12 weeks divided by the number of treated participants.
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Date: 22-Aug-2022
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nivolumab

Investigator-assessed and BICR-assessed progression-free survival (PFS), defined as the time from the first 
dosing date to the date of first objectively documented disease progression per RECIST 1.1 (ie, radiologic) or 
death due to any cause, whichever occurs first.
Exploratory endpoints:
Part 1:

ORR is defined as the proportion of all treated participants whose BOR is either a CR or PR by investigator using 
Response Evaluation Criteria in Solid Tumor (RECIST 1.1);

The PFS Rate (PFSR) is defined as the proportion of treated participants remaining progression free and surviving 
at time T (eg, 24 weeks) since the first dosing date. The proportion will be calculated by the K-M estimate which 
takes into account censored data.

Overall Survival (OS) for Arm B participants, defined as the time from the date of the first dose to the date of 
death due to any cause. A participant who has not died will be censored at last known date alive.
Part 2:

To determine the safety and tolerability [defined as toxicity rates (worst CTC grade per participant) of adverse 
events and specific laboratory tests] of nivolumab in combination with ipilimumab in participants with recurrent 
or metastatic MSI-H/dMMR CRC.

To characterize the PK of nivolumab and ipilimumab when combined, and to explore exposure-response 
relationships.

To characterize the immunogenicity of nivolumab and ipilimumab when combined.

To evaluate health-related quality of life using a validated instrument in the European Organisation for Research 
and Treatment of Care General Cancer Module (QLQ-C30).

To evaluate patient reported general health status as assessed by the five item EQ-5D-3L.

To evaluate OS, defined as the time from first dosing date to the date of death due to any cause. A participant 
who has not died will be censored at last known date alive.
Analyses:
Safety analysis
Part 1:

All recorded AEs will be coded according to the most current version of MedDRA and listed by arm and overall. 
AEs will be summarized for each arm and overall by system organ class and preferred term using the worst grade 
within each category within a participant. Toxicity changes from baseline in clinical laboratory test results will 
be summarized by dose level and tumor type and overall using the worst on treatment CTC grade values. Vital 
signs, ECGs and clinical laboratory test results will be listed and summarized by arm and overall.
Part 2:

Safety analyses will be performed in all treated participants. Descriptive statistics of safety will be presented using 
NCI CTCAE version 4.0. On-study AEs will be tabulated using worst grade per NCI CTCAE v4.0 criteria by 
system organ class and MedDRA preferred term. On-study lab parameters including hematology, chemistry, liver 
function, thyroid function, and renal function will be summarized using worst grade per NCI CTCAE v4.0 criteria.
Protocol Amendment No.: 07
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Efficacy analysis
Part 1:

Listing of tumor measurements will be provided by participant and study day in each arm. Individual participant’s 
best overall response (BOR) will be listed based on RECIST 1.1. To describe the anti-tumor activity of nivolumab 
plus ipilimumab, ORR will be calculated. ORR and corresponding 2-sided exact 95% exact confidence interval 
by Clopper and Pearson will be provided by treatment arm and dose level. In addition, PFS rate, the probability 
of a participant remaining progression free or surviving to 24 weeks, will be estimated by Kaplan-Meier 
methodology, by treatment arm. The corresponding 90% confidence interval will be derived based on Greenwood 
formula.
Part 2:

The BICR-assessed ORR will be summarized. A response rate estimate and corresponding two-sided 95% exact 
CI using the Clopper and Pearson method will be provided. BICR-assessed ORR will be further characterized by 
the rate of CR and PR. 

ORR based on investigators’ assessment will be summarized and further characterized by rate of CR and PR
similarly as above.

BICR-assessed and Investigator-assessed DCR will be summarized and corresponding two-sided exact 95% CI 
using the Clopper-Pearson method will be provided.

BICR-assessed and Investigator-assessed DOR will be listed for participants who achieve confirmed PR or CR.

PFS and OS will be listed.
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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 ................ 
 
SYNOPSIS .................................................................................................................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
1.1 Study Rationale ................................................................................................. 
 
1.1.1 Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab .................................................................................................. 
 
1.1.2 Rationale for Nivolumab Flat Dose in Nivolumab Monotherapy Portion
..................................................................................................................... 
 
1.1.3 Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab .... 
 
1.1.4 Rationale for Restricting Specific Tumor Types to Specific Arm ............ 
 
1.1.5 Rationale for Two-Year Duration of Treatment ...................................... 
 
1.2 Research Hypothesis ......................................................................................... 
 
1.3 Objectives(s) ..................................................................................................... 
 
1.3.1 Primary Objectives .................................................................................. 
 
1.3.2 Secondary Objectives ............................................................................... 
 
1.3.3 Exploratory Objectives ............................................................................ 
 
1.4 Product Development Background ................................................................... 
 
1.4.1 Pharmacology .......................................................................................... 
 
1.4.2 Toxicity ..................................................................................................... 
 
1.4.3 Preclinical Metabolism and Pharmacokinetics ....................................... 
 
1.4.4 Clinical Pharmacology and Safety .......................................................... 
 
1.4.4.1 Pharmacokinetics of Nivolumab ..................................................... 
 
1.4.4.2 Pharmacokinetics of Ipilimumab .................................................... 
 
1.4.4.3 Pharmacokinetics of Nivolumab with Ipilimumab .......................... 
 
1.4.4.4 Safety Summary of Nivolumab in Combination with Ipilimumab ... 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
 
2.1 Good Clinical Practice ...................................................................................... 
 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
 
2.3 Informed Consent.............................................................................................. 
 
3 INVESTIGATIONAL PLAN .................................................................................... 
 
3.1 Study Design and Duration ............................................................................... 
 
3.1.1 Overall Design and Schematic ................................................................. 
 
3.1.2 Part 1 - Safety Monitoring ....................................................................... 
 
3.1.3 Part 2 ....................................................................................................... 
 
3.1.3.1 Mismatch Repair/Microsatellite Instability Testing ....................... 
 
3.1.3.2 Screening ......................................................................................... 
 
3.1.3.3 Review of Safety .............................................................................. 
 
3.1.4 Intra-Subject Dose Reductions ................................................................ 
 
3.1.5 Follow-Up ................................................................................................ 
 
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3.2 Post Study Access to Therapy .......................................................................... 
 
3.3 Study Population ............................................................................................... 
 
3.3.1 Inclusion Criteria ..................................................................................... 
 
3.3.2 Exclusion Criteria .................................................................................... 
 
3.3.3 Women of Childbearing Potential ........................................................... 
 
3.4 Concomitant Treatments ................................................................................... 
 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
 
3.4.2 Other Restrictions and Precautions ......................................................... 
 
3.5 Discontinuation of Participants following any Treatment with Study Drug .... 
 
3.6 Post Study Drug Follow up ............................................................................... 
 
3.6.1 Withdrawal of Consent ............................................................................ 
 
3.6.2 Lost to Follow-Up .................................................................................... 
 
4 STUDY DRUG .......................................................................................................... 
 
4.1 Investigational Product ..................................................................................... 
 
4.2 Non-investigational Product ............................................................................. 
 
4.3 Storage and Dispensing..................................................................................... 
 
4.4 Method of Assigning Participant Identification ................................................ 
 
4.5 Selection and Timing of Dose for Each Participant .......................................... 
 
4.5.1 Dose Limiting Toxicities .......................................................................... 
 
4.5.2 Dose Adjustment ...................................................................................... 
 
4.5.3 Dose Delay Criteria ................................................................................. 
 
4.5.4 Dose Reduction ........................................................................................ 
 
4.5.5 Criteria to Resume Treatment .................................................................. 
 
4.5.6 Treatment Discontinuation Criteria ........................................................ 
 
4.5.7 Treatment Beyond Disease Progression .................................................. 
 
4.5.8 Management Algorithms for Immuno-Oncology Agents ......................... 
 
4.5.9 Treatment of Nivolumab or Ipilimumab Infusion Reactions .................... 
 
4.6 Blinding/Unblinding ......................................................................................... 
 
4.7 Treatment Compliance ...................................................................................... 
 
4.8 Destruction of Study Drug ................................................................................ 
 
4.9 Return of Study Drug ........................................................................................ 
 
4.10 Retained Samples for Bioavailability/Bioequivalence ................................... 
 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
 
5.2 Study Materials ................................................................................................. 
 
5.3 Safety Assessments ........................................................................................... 
 
5.3.1 Laboratory Test Assessments ................................................................... 
 
5.4 Efficacy Assessments ........................................................................................ 
 
5.4.1 Imaging and Clinical Assessment ............................................................ 
 
5.4.2 Imaging Assessment by BICR for Part 2 .................................................. 
 
5.4.3 Methods of Measurement ......................................................................... 
 
5.5 Pharmacokinetic and Immunogenicity Assessments ........................................ 
 
5.5.1 Pharmacokinetic and Immunogenicity Collection & Processing ............ 
 
5.5.2 Pharmacokinetic Sample Analyses .......................................................... 
 
5.5.3 Labeling and Shipping of Biological Samples ......................................... 
 
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5.6 Biomarker Assessments .................................................................................... 
 
5.6.1 Part 1 ....................................................................................................... 
 
5.6.2 Part 2 ....................................................................................................... 
 
5.7 Exploratory Biomarker Assessments ................................................................ 
 
5.8 Outcomes Research Assessments ..................................................................... 
 
5.8.1 Part 1 ....................................................................................................... 
 
5.8.2 Part 2 ....................................................................................................... 
 
5.9 Other Assessments ............................................................................................ 
 
5.9.1 Immunogenicity Assessment ..................................................................... 
 
5.10 Additional Research Collection ...................................................................... 
 
6 ADVERSE EVENTS ................................................................................................. 
 
6.1 Serious Adverse Events .................................................................................... 
 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
 
6.2 Nonserious Adverse Events .............................................................................. 
 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
 
6.3 Laboratory Test Result Abnormalities .............................................................. 
 
6.3.1 Clinical Safety Laboratory Assessments .................................................. 
 
6.4 Pregnancy .......................................................................................................... 
 
6.5 Overdose ........................................................................................................... 
 
6.6 Potential Drug Induced Liver Injury ................................................................. 
 
6.7 Other Safety Considerations ............................................................................. 
 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
 
8 STATISTICAL CONSIDERATIONS....................................................................... 
 
8.1 Sample Size Determination ............................................................................... 
 
8.1.1 Part 1 ....................................................................................................... 
 
8.1.2 Part 2 ....................................................................................................... 
 
8.2 Populations for Analyses .................................................................................. 
 
8.3 Endpoints .......................................................................................................... 
 
8.3.1 Primary Endpoint(s) ................................................................................ 
 
8.3.1.1 Part 1 .............................................................................................. 
 
8.3.1.2 Part 2 .............................................................................................. 
 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.3.2.1 Part 1 .............................................................................................. 
 
8.3.2.2 Part 2 .............................................................................................. 
 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
 
8.3.3.1 Part 1 .............................................................................................. 
 
8.3.3.2 Part 2 .............................................................................................. 
 
8.4 Analyses ............................................................................................................ 
 
8.4.1 Demographics and Baseline Characteristics........................................... 
 
8.4.2 Efficacy Analyses ..................................................................................... 
 
8.4.2.1 Part 1 .............................................................................................. 
 
8.4.2.2 Part 2 .............................................................................................. 
 
8.4.3 Safety Analyses......................................................................................... 
 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.5 Biomarker Analyses ................................................................................. 
 
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8.4.6 Exploratory Biomarker Analyses ............................................................. 
 
8.4.7 Outcomes Research Analyses .................................................................. 
 
8.4.7.1 European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire (QLQ-C30) ............................................ 
 
8.4.7.2 EQ-5D-3L ....................................................................................... 
 
8.4.8 Other Analyses ......................................................................................... 
 
8.5 Interim Analyses ............................................................................................... 
 
9 STUDY MANAGEMENT ........................................................................................ 
 
9.1 Compliance ....................................................................................................... 
 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
 
9.1.2 Monitoring ............................................................................................... 
 
9.1.2.1 Source Documentation .................................................................... 
 
9.1.3 Investigational Site Training.................................................................... 
 
9.2 Records ............................................................................................................. 
 
9.2.1 Records Retention .................................................................................... 
 
9.2.2 Study Drug Records ................................................................................. 
 
9.2.3 Case Report Forms .................................................................................. 
 
9.3 Clinical Study Report and Publications ............................................................ 
 
9.4 Dissemination of Clinical Study Data............................................................... 
 
9.5 Data Protection, Data Privacy, and Data Security ............................................ 
 
10 GLOSSARY OF TERMS ........................................................................................ 
 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
12 REFERENCES ........................................................................................................ 
 
APPENDIX 1 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
 
APPENDIX 2 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 3 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 4.0 ......................................................................................................... 
 
APPENDIX 4 MSI STATUS TESTING ...................................................................... 
 
APPENDIX 5 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 6 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
 
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BMS-936558
nivolumab
1
INTRODUCTION AND STUDY RATIONALE
Cancer is now the leading cause of death in China, causing about one fourth of all death in China. 
Patients with metastatic or refractory solid tumors have very poor prognosis. Despite advances in 
multimodal therapy, improvement in overall survival has been limited. Thus, these patients 
represent a large population who have unmet medical needs and it is necessary to test compounds 
that have novel mechanisms of action in clinical studies.
Immune checkpoint blockade is a rapidly advancing therapeutic approach in the field of immuno-
oncology (IO) and treatment with investigational agents targeting this mechanism has induced 
regressions in several types of cancer. Programmed death 1 (PD-1) receptor and cytotoxic 
T-lymphocyte–associated antigen 4 (CTLA-4) are two important cellular targets that play 
complementary roles in regulating adaptive immunity. Whereas PD-1 contributes to T-cell 
exhaustion in peripheral tissues, CTLA-4 inhibits at earlier points in T-cell activation. In 
preclinical models, combined blockade of PD-1 and CTLA-4 achieved more pronounced 
antitumor activity than blockade of either pathway alone, leading to the clinical development of 
immune checkpoint inhibitors both as monotherapy and as combination therapy in various tumor 
types.1
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal 
antibody (mAb); immunoglobulin G4 [IgG4]-S228P) that targets the PD-1 cluster of 
differentiation (CD) 279 cell surface membrane receptor. PD-1 is a negative regulatory molecule 
expressed by activated T- and B- lymphocytes. Binding of PD-1 to its ligands, programmed 
death-ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. 
Inhibition of the interaction between PD-1 and its ligands promotes immune responses and 
antigen-specific T-cell responses to both foreign antigens as well as self-antigens. Nivolumab is 
expressed in Chinese hamster ovary cells and is produced using standard mammalian cell 
cultivation and chromatographic purification technologies. The clinical study product is a sterile 
solution for parenteral administration.
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 (Jun-2015), and Japan 
(Jul-2014).2,3,4,5,6,7
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma 
(RCC), classical Hodgkin lymphoma (cHL), small-cell lung cancer (SCLC), gastric cancer, 
squamous cell carcinoma of the head and neck (SCCHN), urothelial cancer, hepatocellular 
carcinoma (HCC), and colorectal carcinoma (CRC).2,3,4,5,6,7 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 United States Package 
Insert (USPI) and Summary of Product Characteristics (SmPC).
Protocol Amendment No.: 07
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BMS-936558
nivolumab
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4) is a fully human monoclonal IgG1 kappa 
specific for human CTLA-4 (CD152), which is expressed on a subset of activated T-cells. CTLA-4 
is 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 T-regulatory cell 
function, which may contribute to a general increase in T-cell responsiveness, including the anti-
tumor response.
Multiple clinical studies have evaluated nivolumab combined with ipilimumab at different doses 
and schedules. Based on Phase 3 data showing improved survival over standard of care therapies, 
nivolumab combined with ipilimumab has been approved in multiple countries for the treatment 
of patients with unresectable or metastatic melanoma, intermediate or poor risk, previously 
untreated advanced RCC, and microsatellite instability-high or mismatch repair deficient (MSI-
H/dMMR) colorectal cancer. Details of the clinical activity in these various malignancies are 
provided in the USPI and SmPC.
CA209672 is an open-label, multi-dose, 2-part, Phase 1/2 study of nivolumab in combination with 
ipilimumab in Chinese participants with previously treated advanced or recurrent solid tumors.
1.1
Study Rationale
1.1.1
Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab
The combination of nivolumab and ipilimumab has been investigated in multiple studies and in 
several tumor types, and has demonstrated improved anti-tumor activity and overall survival 
benefits. In a Phase 1b multiple ascending dose study in subjects with advanced melanoma
(CA209004), antitumor activity was observed in 5 different combination cohorts: nivolumab 
0.3 mg/kg and ipilimumab 3 mg/kg (Cohort 1, n = 14), nivolumab 1 mg/kg and ipilimumab 
3 mg/kg (Cohort 2, n = 17), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (Cohort 2a, n = 16), 
nivolumab 3 mg/kg and ipilimumab 3 mg/kg (Cohort 3, n = 6), and nivolumab 1 mg/kg and 
ipilimumab 3 mg/kg (Cohort 8, n = 41). From this study, it has been found that the 3 mg/kg 
nivolumab and 3 mg/kg ipilimumab combination regimen exceeded the maximum tolerated dose
(MTD). Even though the drug-related discontinuation rates in combination cohorts were 
approximately 26 - 27%, the objective response rate (ORR) in these cohorts were still higher 
compared to nivolumab monotherapy (42% - 44% versus 36%).
Additional studies have demonstrated the potential for IO combinations to improve antitumor 
responses across the nivolumab program.8 An ORR of 62 - 65% has been observed in advanced 
melanoma (CA209067 and CA209069, N = 407) with a combination regimen of nivolumab 
1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (Q3W) × 4. In RCC patients (CA209016), both 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (n = 21) and nivolumab 1 mg/kg plus ipilimumab 3 
mg/kg (n = 23) showed antitumor activity with an ORR of 38%-40%. Both nivolumab 3 mg/kg 
plus ipilimumab 1 mg/kg (n = 54) and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (n = 61) 
showed antitumor activity with an ORR of 19%, and 23%, respectively, in patients with SCLC 
Protocol Amendment No.: 07
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Clinical Protocol
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nivolumab
whose disease progressed after 1 prior regimen (CA209032). In NSCLC patients (CA209012), 
both combination regimens resulted in high discontinuation rates (up to 39%); therefore, multiple 
alternative schedules were evaluated. Nivolumab 3 mg/kg combined with more extended 
ipilimumab dosing (1 mg/kg, every 6 weeks [Q6W] or every 12 weeks [Q12W]) was well 
tolerated, with similarly low discontinuation rates as monotherapy (10%, 5% respectively vs 10%) 
and promising response rates of 31-39% (48% in PD-L1+). Nivolumab in combination with 
ipilimumab has demonstrated remarkable benefit for several solid tumor types, including 
previously treated MSI-H/dMMR metastatic CRC (mCRC).9 CA209142 is a Phase 2, open-label, 
multi-center trial of nivolumab monotherapy and nivolumab in combination with other agents in 
subjects whose colorectal tumors have defects in the deoxyribonucleic acid (DNA) mismatch 
repair system (MSI-H/dMMR) or in subjects whose colorectal tumors have proficient mismatch 
repair (pMMR/non-MSI-H). 10 ,11 Preliminary evidence from the nivolumab plus ipilimumab 
cohort (n = 119) in study CA209142 demonstrated additional clinical improvement of this 
combination in MSI-H mCRC patients over the cohort of subjects treated with nivolumab 
monotherapy (n = 74) beyond second-line (2L) of treatment. At data cutoff of September 2021, 
the median follow-up in the nivolumab plus ipilimumab combination therapy cohort was 64.0
months (range 60.0 to 75.8 months). The objective response rate (ORR) per investigator was 
achieved in 65% (95% confidence interval [CI]: 55, 73) of subjects, including 17% of subjects 
who demonstrated complete response (CR). This was numerically higher than the ORR observed 
in the cohort of 74 subjects who received nivolumab monotherapy (39%, 95% CI: 28, 51) in the 
same study with median follow-up of 70.0 months. 12 Thus, nivolumab plus ipilimumab 
combination therapy provided a numerically higher ORR, including CR, and disease control rate 
(DCR) relative to nivolumab monotherapy during a similar follow-up period. The improved ORR 
with nivolumab plus ipilimumab combination therapy was translated to the numerically improved 
progression-free survival (PFS) and OS rates over nivolumab monotherapy. In the combination 
cohort, Grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of patients and were 
manageable.13
Based on these data, the following three dose arms will be evaluated in CA209672:

Arm A - nivolumab 3 mg/kg every 2 weeks (Q2W) + ipilimumab 1 mg/kg Q6W; for 
participants with solid tumor including but not limited to NSCLC, nasopharyngeal carcinoma 
(NPC);

Arm B - nivolumab 3 mg/kg + ipilimumab 1 mg/kg, Q3W × 4, followed by nivolumab 240 mg 
Q2W; for participants with solid tumor including but not limited to metastatic CRC (mCRC)
DNA mismatch repair deficient (dMMR)/MSI-H;

Arm C - nivolumab 1 mg/kg + ipilimumab 3 mg/kg, Q3W × 4, followed by nivolumab 240 mg 
Q2W; for participants with solid tumor including but not limited to SCLC, gastric cancer (GC),
and melanoma.

Arm D - nivolumab 3 mg/kg + ipilimumab 1 mg/kg, Q3W × 4, followed by nivolumab 240 mg 
Q2W; for participants with recurrent or metastatic MSI-H/dMMR CRC.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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1.1.2
Rationale for Nivolumab Flat Dose in Nivolumab Monotherapy Portion
The nivolumab dose of 240 mg Q2W was selected based on clinical data and modeling and 
simulation approaches using population pharmacokinetics (PPK) and exposure-response analyses 
of data from studies in multiple tumor types (melanoma, NSCLC, and RCC) where body weight 
normalized dosing (mg/kg) has been used. 
Nivolumab pharmacokinetics (PK) has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, RCC, cHL, SCCHN, CRC, and urothelial carcinoma and has been safely 
administered at doses up to 10 mg/kg Q2W. Nivolumab monotherapy was originally approved as 
a body-weight based dose of 3 mg/kg Q2W, and was updated to 240 mg Q2W or 480 mg every 4 
weeks (Q4W) in multiple indications (Nivolumab USPI). Nivolumab 360 mg Q3W is also under 
evaluation in monotherapy and in combination therapy studies. Less frequent 360 mg Q3W and 
480 mg Q4W dosing regimens can reduce the burden to patients of frequent, lengthy IV treatments 
and allow combination of nivolumab with other agents using alternative dosing regimens. 
The benefit-risk profiles of nivolumab 240 mg Q2W, 360 mg Q3W, and 480 mg Q4W are 
predicted to be comparable to 3 mg/kg Q2W. This assessment is based on a comprehensive 
characterization of nivolumab PK, safety, efficacy, and exposure-response relationships across 
indications. Population PK (PPK) analyses have shown that the PK of nivolumab is linear with 
proportional exposures over a dose range of 0.1 to 10 mg/kg; no clinically meaningful differences 
in PK across ethnicities and tumor types were observed. Using the PPK model, the exposures 
following administration of several dosing regimens of nivolumab administered as a flat dose were 
simulated, including 240 mg Q2W, 360 mg Q3W, and 480 mg Q4W. The simulated average serum 
concentration at steady state following administration of nivolumab 360 mg Q3W and 480 mg 
Q4W are predicted to be similar to those following administration of nivolumab 240 mg Q2W and 
nivolumab 3 mg/kg Q2W administered to patients over a wide body weight range (34-180 kg) 
across tumor types. 
Extensive exposure-response (E-R) analyses of multiple PK measures (maximum serum 
concentration at Day 1, average serum concentration at Day 28 [Cavg28], and trough serum 
concentration at Day 28) and efficacy and safety endpoints indicated that the efficacy of the flat-
dose 480 mg IV regimen are similar to that of 3 mg/kg Q2W IV regimen. In E-R efficacy analyses 
for OS and ORR conducted in melanoma, RCC, and NSCLC using Cavg28 as the exposure 
measure, probabilities of achieving a response and survival probabilities at 1 year and 2 years for 
IV 480 mg Q4W were similar to that of IV 3 mg/kg Q2W. In E-R safety analyses, it was 
demonstrated that the exposure margins for safety are maintained following nivolumab 480 mg 
Q4W, and the predicted risks of discontinuations due to AEs or death, AE Grade 3+, and immune-
mediated AEs (IMAEs) Grade 2+ are similar following nivolumab 480 mg Q4W relative to 
nivolumab 3 mg/kg Q2W across tumor types. In addition, nivolumab exposures with 240 mg Q2W, 
360 mg Q3W, and 480 mg Q4W flat-dose IV regimens across tumor types are maintained well 
below the corresponding exposures observed with the well-tolerated 10 mg/kg IV nivolumab Q2W 
dose regimen.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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1.1.3
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab
Long infusion times place a burden on patients and treatment centers. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of 30 minutes duration in 
subjects will diminish the burden, provided that there is no change in safety profile. Previous 
clinical studies of nivolumab and ipilimumab monotherapies and the combination of nivolumab 
and ipilimumab have used a 60-minute infusion duration for nivolumab and a 90-minute infusion 
duration for ipilimumab (1 - 3 mg/kg dosing for both). However, both nivolumab and ipilimumab 
have been administered at up to 10 mg/kg with the same infusion duration (60 minutes).
Nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg safely 
over a long treatment duration. In subjects with advanced/metastatic clear cell RCC (CA209010), 
a dose association was observed for infusion-site reactions and hypersensitivity reactions (1.7% at 
0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1/2 and were 
manageable. An infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided 
at 10 mg/kg) is not expected to present any safety concerns compared to the prior experience at 
10 mg/kg nivolumab dose infused over a 60-minute duration.
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In subjects with 
advanced Stage III or Stage IV melanoma (CA184022), where ipilimumab was administered up 
to a dose of 10 mg/kg, on-study drug related hypersensitivity events (Grade 1/2) were reported in 
1 (1.4%) subject in the 0.3-mg/kg and in 2 (2.8%) subjects in the 10-mg/kg group. There were no 
drug-related hypersensitivity events reported in the 3 mg/kg group. Across the 3 treatment groups, 
no Grade 3/4 drug-related hypersensitivity events were reported and there were no reports of 
infusion reactions. Ipilimumab 10 mg/kg monotherapy has also been safely administered as a 
90-minute infusion in a large Phase 3 study in prostate cancer (CA184043) and as adjuvant therapy 
for stage III melanoma (CA184029), with infusion reactions occurring in subjects. Administering 
1 mg/kg of ipilimumab represents one-tenth of the 10-mg/kg dose.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across clinical studies of nivolumab, ipilimumab and nivolumab/ipilimumab combinations. 
Furthermore, a 30-minute break after the first infusion for the combination cohort will ensure the 
appropriate safety monitoring before the start of the second infusion. Overall, a change in safety 
profile is not anticipated with 30-minute infusion of nivolumab, ipilimumab or combination.
1.1.4
Rationale for Restricting Specific Tumor Types to Specific Arm
If a participant with following tumor types is enrolled, he/she can only be treated using one specific 
dosing schedule.
A NSCLC participant is to be treated in Arm A only due to reasons described in Section 1.1.1 and 
Section 1.4.4.3.
A SCLC participant is to be treated in Arm C only. In Phase 1/2 Study CA209032, subjects with 
advanced SCLC progressing after 1 prior platinum-containing regimen received 3 mg/kg Q2W 
nivolumab (n=98), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg [n=3], 1 mg/kg plus 
3 mg/kg [n=61], or 3mg/kg plus 1 mg/kg [n=54]) every 3 weeks for 4 cycles, followed by 
Protocol Amendment No.: 07
Date: 22-Aug-2022
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nivolumab 3 mg/kg every 2 weeks. ORR were 10%, 23% and 19% for nivolumab-3, 
nivolumab-1/ipilimumab-3, and nivolumab-3/ipilimumab-1, respectively. 13%, 30%, and 19% 
experienced Grade 3 or 4 treatment-related AEs, and 4%, 11%, and 7% discontinued due to 
treatment-related 
AEs
for 
nivolumab-3, 
nivolumab-1/ipilimumab-3, 
and 
nivolumab-3/ipilimumab-1, respectively. The study cohorts were not randomized and the study 
was not powered for formal comparisons across cohorts; however, cohorts were well balanced by 
baseline characteristics, and data suggest that the nivolumab-1/ipilimumab-3 regimen has higher 
efficacy than nivolumab-3/ipilimumab-1 or nivolumab-3. The combination regimen of nivolumab 
1 mg/kg with ipilimumab 3 mg/kg every 3 weeks is currently being evaluated in a Phase 3 study 
CheckMate 451 and a Phase 1/2 study CheckMate 032.
If a squamous cell cancer of the head and neck (SCCHN) or mesothelioma participant is to be 
enrolled, he/she can be treated in Arm A only. The two tumor types are believed to respond to 
nivolumab similarly to NSCLC.
1.1.5
Rationale for Two-Year Duration of Treatment
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumor types in the nivolumab and ipilimumab development program 
indicated that most of the responses occur early, with a median time to response of 2-4 
months,14,15,16,17,18 and emerging data suggests that benefit can be maintained in the absence of 
continued treatment. A retrospective pooled analysis of 2 melanoma studies suggested the majority 
of patients who discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in 
the absence of further treatment.19 Furthermore, a limited duration of ipilimumab, including only 
4 induction doses, resulted in long term survival in patients with metastatic melanoma, with a 
sustained plateau in survival starting around 2 years after the start of treatment.20
Accumulating data suggested that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 patients with NSCLC), specified a maximum treatment duration of 2 years. Among 
16 patients with non-small cell lung cancer (NSCLC) who discontinued nivolumab after 
completing 2 years of treatment, 12 patients were alive > 5 years and remained progression-free 
without any subsequent therapy. In the CA209003 NSCLC cohort, the overall survival (OS) curve 
began to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.21 These 
survival outcomes were similar to phase 3 studies in previously treated NSCLC, in which 
nivolumab treatment was continued until progression or unacceptable toxicity (2 year OS rates of 
23% and 29%, and 3 year OS rates of 16% to 18% for squamous and non-squamous NSCLC 
respectively).22
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.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
PFS compared to those who were randomized to stop treatment, with median PFS (post-
randomization) not reached vs 10.3 months, respectively; hazard ration (HR) = 0.42 (95% CI, 
0.25 to 0.71). With a median follow up of 14.9 months post randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (ie, 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.
Collectively, these data suggest that there is minimal, if any benefit, derived from continuing IO 
treatment beyond 2 years in advanced tumors. Even though immunotherapy is well tolerated, 
patients will be at risk for additional toxicity with longer-term treatment. 
Recent analysis of the data from CA209-142 study in patients with MSI-H mCRC tumors suggests 
that minority of the patients experience relatively late objective response to nivolumab 
monotherapy (up to Month 23) or nivolumab plus ipilimumab combination (up to Month 14).23
It’s not known yet if treatment discontinuation after 2 years in participants with late partial 
response impacts on duration of response. Therefore, to minimize the potential risk of disease 
recurrence as a result of premature treatment discontinuation, all patients who achieved objective 
response within second year of treatment, will continue to receive study therapy for additional 
12 months. Thus, the proposed approach for treatment duration will not only mitigate the potential 
risk of disease recurrence in patients with late partial response, but also ensures that patients with 
objective response to be followed for at least 12 months from the onset of response.
For these reasons, in study CA209672, treatment with nivolumab or nivolumab with ipilimumab 
will be given for up to 24 months in the absence of disease progression or inacceptable toxicity, 
EXCEPT in participants with late response (during second year of treatment). In participants with 
late response study treatment will continue for up to an additional 12 months after onset of 
response, in absence of disease progression, unacceptable toxicity, withdrawal of consent. Above 
defined maximum treatment duration of 2 years includes treatment beyond progression.
1.2
Research Hypothesis
Part 1: There is no formal primary research hypothesis for Arms A, B, and C to be statistically 
tested.
Part 2: Treatment with nivolumab combined with ipilimumab will have clinical activity in 
participants with recurrent or metastatic MSI-H/dMMR CRC.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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nivolumab
1.3
Objectives(s)
1.3.1
Primary Objectives
The primary objective for Part 1 is to establish the safety, tolerability, and dose-limiting-toxicities 
(DLTs) of nivolumab plus ipilimumab in Chinese participants with advanced or recurrent solid 
tumor.
The primary objective for Part 2 is to evaluate the blinded independent central review 
(BICR)-assessed ORR of nivolumab in combination with ipilimumab in Chinese participants with 
recurrent or metastatic MSI-H/dMMR CRC.
1.3.2
Secondary Objectives
The secondary objectives of Part 1 are:

To characterize the pharmacokinetics of nivolumab and ipilimumab in Chinese participants 
when administered in combination.

To assess the immunogenicity of nivolumab and ipilimumab in Chinese participants when 
administered in combination.
The secondary objectives of Part 2 are:

To evaluate the Investigator-assessed ORR of nivolumab in combination with ipilimumab in 
Chinese participants with recurrent or metastatic MSI-H/dMMR CRC.

To evaluate the Investigator-assessed and BICR-assessed disease control rate (DCR) of 
nivolumab in combination with ipilimumab in Chinese participants with recurrent or metastatic 
MSI-H/dMMR CRC. 

To evaluate Investigator-assessed and BICR-assessed progression-free survival (PFS) in 
Chinese participants with recurrent or metastatic MSI-H/dMMR CRC.

To evaluate Investigator-assessed and BICR-assessed duration of response (DoR) in Chinese 
participants with recurrent or metastatic MSI-H/dMMR CRC.
1.3.3
Exploratory Objectives
The exploratory objective for Part 1 is:

To assess preliminary anti-tumor activity of nivolumab and ipilimumab in Chinese participants 
when administered in combination.
The exploratory objectives for Part 2 are:
Per Protocol Amendment 07, collection of PK and immunogenicity data is not applicable. PK 
sample analyses and immunogenicity assessments will be based on samples collected before the 
implementation of protocol amendment 07. No analyses of concordance rate between results from
central and local testing and the investigator-assessed second disease progression or death during 
next line of treatment are planned due to the limited number of participants enrolled.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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BMS-936558
nivolumab

To determine the safety and tolerability (defined as toxicity rates [worst Common Terminology 
Criteria (CTC) Grade per participant]) of AEs and specific laboratory tests of nivolumab in 
combination with ipilimumab in Chinese participants with recurrent or metastatic 
MSI-H/dMMR CRC.

To characterize the PK of nivolumab and ipilimumab when administered in combination, and 
to explore exposure-response relationships.

To characterize the immunogenicity of nivolumab and ipilimumab when administered in 
combination.

To evaluate health-related quality of life using a validated instrument in the European 
Organisation for Research and Treatment of Care (EORTC) Quality of Life Questionnaire 
Core-30 (QLQ-C30).

To evaluate subject-reported general health status as assessed by the EQ-5D-3L questionnaire.

To evaluate overall survival (OS) in Chinese participants with recurrent or metastatic 
MSI-H/dMMR CRC who received nivolumab in combination with ipilimumab.
1.4
Product Development Background
1.4.1
Pharmacology
Detailed information can be found in the current version of the BMS-936558 Investigator’s 
Brochure (IB) and BMS-734016 IB.8,24
1.4.2
Toxicity
Detailed information can be found in the current version of the BMS-936558 IB and BMS-734016 
IB.8, 24
1.4.3
Preclinical Metabolism and Pharmacokinetics
Detailed information can be found in the current version of the BMS-936558 IB and BMS-734016 
IB.8, 24
1.4.4
Clinical Pharmacology and Safety
1.4.4.1
Pharmacokinetics of Nivolumab
The PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg 
administered as a single dose or as multiple doses of nivolumab as a 60-minute intravenous 
infusion every 2 or 3 weeks. Nivolumab clearance (CL) decreases over time, with a mean maximal 
reduction (% coefficient of variation [CV%]) from baseline values of 24.5% (47.6%) resulting in 
a geometric mean steady-state clearance (CLss) of 8.2 mL/h (CV% = 53.9%) in patients with 
metastatic tumors; the decrease in CLss is not considered clinically relevant. Nivolumab clearance 
does not decrease over time in patients with completely resected melanoma, as the geometric mean 
population clearance is 24% lower in this patient population compared with patients with 
metastatic melanoma at steady state. The geometric mean volume of distribution at steady state 
(Vss) is 6.8 L (CV% = 27.3%), and geometric mean elimination half-life is 25 days (77.5%). 
Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg 
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every 2 weeks, and systemic accumulation was 3.7-fold. The exposure to nivolumab increases 
dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The 
predicted exposure (average concentration and maximum observed concentration [Cmax]) of 
nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion. 
Full details on the clinical pharmacology aspects of nivolumab can be found in the IB.8
1.4.4.2
Pharmacokinetics of Ipilimumab
The PPK of ipilimumab was studied with 785 subjects and demonstrated that the PK of ipilimumab 
is linear and exposures are dose proportional across the tested dose range of 0.3 to 10 mg/kg, and 
the model parameters are time invariant. Upon repeated dosing of ipilimumab administered every 
three weeks, minimal systemic accumulation was observed by an accumulation index of 1.5-fold 
or less and ipilimumab steady-state concentrations were achieved by the third dose. The 
ipilimumab clearance of 16.8 mL/h from PPK analysis is consistent with that determined by 
non-compartmental PK analysis. The terminal half-life (T-HALF) and Vss of ipilimumab 
calculated from the model were 15.4 days and 7.47 L, which are consistent with that determined 
by non-compartmental analysis. Volume of central (Vc) and peripheral compartment were found 
to be 4.35 L and 3.28 L, respectively, suggesting that ipilimumab first distributes into plasma 
volume and subsequently into extracellular fluid space. Clearance of ipilimumab and Vc were 
found to increase with increasing body weight. Nevertheless, there was no significant increase in 
exposure with increase in body weight when dosed on a mg/kg basis, supporting dosing of 
ipilimumab based on a weight normalized regimen.
Full details on the clinical pharmacology aspects of ipilimumab can be found in the IB.24
1.4.4.3
Pharmacokinetics of Nivolumab with Ipilimumab
When nivolumab 1 mg/kg was administered in combination with ipilimumab 3 mg/kg, the CL of 
nivolumab was increased by 29%, and the CL of ipilimumab was unchanged compared to 
nivolumab administered alone. When nivolumab 3 mg/kg was administered in combination with 
ipilimumab 1 mg/kg, the CL of nivolumab and ipilimumab were unchanged. When nivolumab was 
administered in combination with ipilimumab, the presence of anti-nivolumab antibodies 
increased the CL of nivolumab by 20% and the CL of ipilimumab was unchanged in presence of 
anti-ipilimumab antibodies.
Specific Populations: The population PK analysis suggested that the following factors had no 
clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 
160 kg), gender, race, baseline lactate dehydrogenase (LDH), PD-L1 expression, solid tumor type, 
tumor size, renal impairment, and mild hepatic impairment. 
Renal Impairment: The effect of renal impairment on the clearance of nivolumab was evaluated 
by a population PK analysis in patients with mild (estimated glomerular filtration rate [eGFR] 60 
to 89 mL/min/1.73 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), or severe (eGFR 15 to 29 
mL/min/1.73 m2) renal impairment. No clinically important differences in the clearance of 
nivolumab were found between patients with renal impairment and patients with normal renal 
function.
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Date: 22-Aug-2022
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Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was 
evaluated by population PK analyses in patients with HCC and in patients with other tumors with 
mild hepatic impairment (total bilirubin [TB] less than or equal to the upper limit of normal (ULN)
and aspartate aminotransferase (AST) greater than ULN or TB greater than 1 to 1.5 times ULN 
and any AST) and in HCC patients with moderate hepatic impairment (TB > 1.5 to 3 times ULN 
and any AST). No clinically important differences in the clearance of nivolumab were found 
between patients with mild/moderate hepatic impairment.
Full details on the clinical pharmacology aspects of nivolumab can be found in the Investigator 
Brochure8 and product label.
1.4.4.4
Safety Summary of Nivolumab in Combination with Ipilimumab
The combination of nivolumab and ipilimumab has been studied in a number of clinical studies 
across multiple tumor types. The combination of nivolumab and ipilimumab was initially 
evaluated in CA209004 (MDX1106-04), a Phase 1b multiple ascending dose study in subjects 
with treatment-naive and previously treated advanced melanoma. Results showed promising 
activity with higher, but tolerable toxicity than ipilimumab alone. 
Extensive details on the safety profile of nivolumab are available in the Investigator Brochure
(IB),8 and will not be repeated here. Additional details on the safety profile of nivolumab, including 
results from other clinical studies, are also available in the nivolumab IB. The safety profile of 
nivolumab in combination with ipilimumab therapy is generally consistent with the safety profiles 
observed with either agent alone and, in some cases, both frequency and severity of AEs were 
greater than that observed with either agent alone. The safety profile of nivolumab + ipilimumab 
combination therapy is also consistent with the mechanisms of action of nivolumab and 
ipilimumab. A dose of 3 mg/kg nivolumab/3 mg/kg ipilimumab exceeded the MTD, and both 1 
mg/kg nivolumab/3 mg/kg ipilimumab and 3 mg/kg nivolumab/1 mg/kg ipilimumab were 
identified as the MTD. For nivolumab monotherapy and combination therapy, most AEs were low 
grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. Most high-grade 
events were manageable with use of corticosteroids or hormone replacement therapy 
(endocrinopathies) as instructed in established management guidelines.
Safety of Nivolumab and Ipilimumab Combination in Melanoma
This section presents the safety data observed in the melanoma clinical studies (CA209069, 
CA209067, CA209066, CA209037) conducted with nivolumab monotherapy and nivolumab in 
combination with ipilimumab.
Safety data for nivolumab monotherapy was pooled and presented from the nivolumab 
treatment groups in CA209067 (N = 313), CA209066 (N = 200), and CA209037 (N = 268). 
Safety data for nivolumab + ipilimumab combination therapy was pooled and presented from 
the nivolumab + ipilimumab treatment groups in CA209067 (N = 313) and CA209069 
(N = 94). 
Key safety findings:25
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
One (0.1%) death in the pooled monotherapy group and 2 (0.5%) deaths in the pooled 
combination therapy group within 100 days of the last dose were reported by the investigators 
due to study drug toxicity. After database lock, a third death occurred in the pooled 
combination therapy group.

Overall, AEs were manageable, primarily Grade 1/2 and considered not related to study drug. 
The types of AEs (all grades, all causality) were similar between the treatment groups; 
however, the frequency and severity of AEs was generally higher in the pooled combination 
therapy group than in the pooled monotherapy group. 

The most frequently reported drug-related AEs (15% of subjects) in the pooled 
monotherapy group were fatigue (29.2%), pruritus (18.4%), diarrhea (17.2%), and rash 
(16.9%).

The most frequently reported drug-related AEs (15% of subjects) in the pooled 
combination therapy group were diarrhea (43.0%), fatigue (35.4%), pruritus (33.4%), 
rash (31.0%), nausea (24.8%), pyrexia (18.7%), alanine aminotransferase (ALT) 
increased (18.2%), aspartate aminotransferase (AST) increased (16.7%), and decreased 
appetite (16.2%).

The overall frequency of serious adverse events (SAEs) occurring up to 30 days after last 
dose (regardless of causality) was lower in the pooled monotherapy group (40.5%) than in 
the pooled combination therapy group (67.6%).

Select AEs are AEs of special clinical interest that include preferred terms (PTs) describing 
specific events rather than events belonging to broader categories. These analyses included 
relevant events occurring within 30 days of the last dose and regardless of causality.

The most frequently reported (10% of subjects) drug-related select AEs (all grades) 
in the pooled monotherapy group were select AEs for skin (38.4%), gastrointestinal 
(GI) (17.7%), and endocrine (10.8%) categories. 

The most frequently reported (10% of subjects) drug-related select AEs (all grades) 
in the pooled combination therapy group were select AEs for skin (61.9%), GI (46.4%), 
endocrine (29.7%), and hepatic (29.0%) categories.

No Grade 5 select AEs were reported in either group.

Immune-mediated AEs were manageable using the recommended treatment guidelines 
for early work-up and intervention.

Most Grade 3/4 select AEs resolved, except for events belonging to the endocrine select 
AE categories.

For nivolumab-treated subjects in the primary studies CA209067, CA209069, and 
CA209004 Cohort 8, the safety profile in the subgroups (age, gender, race, and region) was 
consistent with the overall safety profile.

Early safety signals were identified through the dose-escalation Cohorts 1-3 in CA209004.

Hematology laboratory results, liver function, renal function, and thyroid function 
remained stable in the majority of subjects; however, there was a higher frequency of liver 
(alkaline phosphatase [ALP], ALT, AST, and total bilirubin) and thyroid test abnormalities 
reported in the pooled combination therapy group compared with the pooled monotherapy 
group.
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One (0.1%) subject in the pooled monotherapy group and 18 (4.6%) subjects in the pooled 
combination therapy group were persistent positive (anti-drug antibody [ADA]-positive sample at 
2 or more consecutive time points, where the first and last ADA-positive samples are at least 
16 weeks apart) or positive for neutralizing antibodies. There was no evidence of an altered safety 
profile with ADA development.
Safety of Nivolumab and Ipilimumab Combination in Lung Cancer
Study CA209012 is a multi-arm, Phase 1 safety study of nivolumab in combination with 
gemcitabine/cisplatin, pemetrexed/cisplatin, carboplatin/paclitaxel, bevacizumab maintenance, 
erlotinib, ipilimumab or as monotherapy in subjects with stage IIIB/IV NSCLC.
In CA209012, the combination of nivolumab and ipilimumab has been studied as first-line therapy 
for subjects with previously untreated stage IV or recurrent NSCLC at several different doses and 
schedules. The original cohorts (Arms G, H, I, and J) resulted in significant toxicity, with 39% of 
patients discontinuing treatment due to a treatment-related AE. 

nivolumab 1 mg/kg + ipilimumab 3 mg/kg, Q3W × 4, followed by nivolumab 3 mg/kg Q2W
(Arms G and H, n = 24);

nivolumab 3 mg/kg + ipilimumab 1 mg/kg, Q3W × 4, followed by nivolumab 3 mg/kg Q2W
(Arms I and J, n = 25).
In order to improve the safety of the nivolumab and ipilimumab combination in chemotherapy
naive NSCLC, an additional 117 subjects have been treated in the newer 3 cohorts, and the safety 
profile appears much improved. Only 8% of subjects have discontinued treatment due to a 
treatment related AE, a rate similar to what has been observed with nivolumab monotherapy; 31% 
have experienced Grade 3/4 treatment-related AEs. The regimen of nivolumab 3 mg/kg every 2 
weeks with ipilimumab 1 mg/kg every 6 weeks is currently being evaluated in a Phase 3 study, 
CheckMate 227. This regimen provides the highest dose density for nivolumab when combined 
with ipilimumab.
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Table 1.4.4.4-1:
First-Line Nivolumab + Ipilimumab Safety Summary
Treatment-Related AEs, 
%
Treatment-Related AEs 
leading to discontinuation, %
Nivo 1 Q2W + Ipi 1 Q6W (n=40)
Any Grade
73
8
Grade 3-4
35
8
Nivo 3 Q2W + Ipi 1 Q12W (n=38)
Any Grade
74
5
Grade 3-4
29
3
Nivo 3 Q2W + Ipi 1 Q6W (n=39)
Any Grade
69
10
Grade 3-4
28
10
Abbreviations: AEs = adverse events; Ipi = ipilimumab; Q2W = every 2 weeks; Q6W = every 6 weeks; Q12W = every 
12 weeks.
Patients with advanced SCLC progressing after 1 prior platinum-containing regimen were 
treated with nivolumab monotherapy or nivolumab and ipilimumab combination in Phase 1/2 
study CA209032. Most toxicities in the nivolumab-3 (n=98) and nivolumab-3/ipilimumab-1
(n=54) cohorts were mild to moderate, with only 4 (4%) and 4 (7%) subjects discontinuing due to 
toxicity, respectively. A higher rate of treatment-related Grade 3 or 4 AEs was seen in the 
nivolumab-1/ipilimumab-3 cohort (n = 61; 30% vs 13% for nivolumab-3), with 7 (11%) subjects 
discontinuing due to toxicity. This regimen was used effectively and safely in a Phase 3 trial in 
subjects with melanoma, suggesting that this schedule is feasible in subjects with SCLC. In all 
cohorts, fewer treatment-related toxicities were reported when compared with trials of topotecan 
or amrubicin.
Safety of Nivolumab and Ipilimumab Combination in MSI-H/dMMR Metastatic Colon 
Cancer
Study CA209142 is a multi-arm, Phase 2, clinical trial of nivolumab or nivolumab combinations, 
in recurrent and metastatic MSI-H and non-MSI-H colon cancer.
In the nivolumab + ipilimumab (N+I) cohort, 119 pre-treated MSI-H/dMMR CRC subjects were 
treated with nivolumab in combination with ipilimumab, as well as a subset of 82 subjects who 
had received prior 5-fluoropyrimidine, oxaliplatin, and irinotecan (5FU-Oxa-Iri): nivolumab 
administered intravenously (IV) over 60 minutes at 3 mg/kg combined with ipilimumab 
administered IV over 90 minutes at 1 mg/kg every 3 weeks for four doses followed by nivolumab 
administered IV over 60 minutes at 3 mg/kg every 2 weeks until progression.
The overall safety profile of nivolumab in combination with ipilimumab was acceptable in subjects 
with recurrent or metastatic MSI-H/dMMR CRC who had progression during or after, or have 
been intolerant to ≥ 1 line of treatment(s) for their metastatic disease. No new safety concerns with 
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combination treatment were identified. As of DBL of 19-Feb-2019 (hereafter, the Feb-2019 DBL) 
with a clinical data cutoff date of 07-Jan-2019, and a minimum follow-up of 27.5 months for 
subjects treated with nivolumab + ipilimumab in CA209142, 33 deaths were reported, all of which 
were due to disease progression and there were no deaths attributed to study drug toxicity. The 
frequencies of drug-related SAEs were 22.7% for any-grade and 20.2% for Grade 3-4, the 
frequencies of drug-related AEs leading to discontinuation were 13.4% for any-grade and 10.1% 
for Grade 3-4. Drug-related AEs of any grade occurred in 95 of 119 evaluable patients (79.8%). 
Grade 3/4 AEs were reported in 31.9% of subjects. The most common drug-related AEs occurring 
in ≥ 15% of subjects were diarrhea (25.2%), pruritus (20.2%), fatigue (18.5%), hypothyroidism 
(17.6%), AST increased (16%), pyrexia (15.1%), and rash (15.1%). A similar safety profile was 
observed between the all-combination treated subjects and the subset of subjects treated with prior 
5FU-Oxa-Iri.
Most select AEs and immune-mediated AEs were Grade 1/2. The majority of select AEs and 
immune-mediated AEs resolved and were manageable using the recommended treatment 
guidelines for early work-up and intervention.
Abnormalities in hematology laboratory results, liver tests, kidney function tests, and electrolytes 
in nivolumab combined with ipilimumab treated subjects were primarily Grade 1 or 2.
With 27.5 months of minimum safety follow-up for MSI-H/dMMR mCRC subjects treated with 
nivolumab + ipilimumab combination followed by nivolumab monotherapy in CA209142, the 
overall safety profile of the nivolumab + ipilimumab combination regimen was acceptable based 
on the Feb-2019 DBL and continues to support a positive benefit-risk profile for the nivolumab + 
ipilimumab combination regimen.
1.5
Overall Risk/Benefit Assessment
The combination of nivolumab and ipilimumab has the potential for increased benefit compared 
to both ipilimumab monotherapy and nivolumab monotherapy. In Study CA209004, 53% of the 
subjects with advanced melanoma treated at the dose level of nivolumab 1 mg/kg combined with 
ipilimumab 3 mg/kg had an objective response, the majority of which had deep tumor reduction 
of 80% or more. This deep response compares favorably to results with 3 mg/kg ipilimumab 
monotherapy or nivolumab monotherapy and is the basis for an ongoing randomized Phase 3 study 
in advanced melanoma (CA209067), in which the ORR were 57.6% in the nivolumab
+ ipilimumab group, 43.7% in the nivolumab group, and 19.0% in the ipilimumab group; median 
PFS was 11.5 months with nivolumab plus ipilimumab, as compared with 2.9 months with 
ipilimumab, and 6.9 months with nivolumab. Studies investigating the efficacy and safety of 
nivolumab in combination with ipilimumab are ongoing in various tumor types.
The combination of nivolumab and ipilimumab has the potential for increased frequencies of AEs
compared to ipilimumab monotherapy or nivolumab monotherapy. The most common (reported 
at > 10% incidence) treatment-related AEs are fatigue, rash, pruritus, diarrhea, lipase increased, 
pyrexia, ALT increase, AST increased, amylase increased, and vitiligo. This class of AEs are 
expected for the combination of nivolumab and ipilimumab based on the known AE profile of 
each drug alone. In addition, many of the Grade 3/4 AEs were laboratory in nature (ie, liver 
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function tests [LFTs], lipase, amylase), were without clinical sequalae and have been manageable 
and reversible following intervention dose delays or with systemic steroid treatment. However, 
these AEs have the potential to be fatal if not detected early and managed per the established 
algorithm and fatal AEs have been reported for both ipilimumab and nivolumab monotherapy. As 
of June 2013, one subject died because of a study treatment-related AE (toxic epidermal necrolysis 
[TEN]) in the nivolumab + ipilimumab development program. Fatal TEN has previously been 
reported for ipilimumab monotherapy.
Across multiple tumors, 3 mg/kg nivolumab as well as 3 mg/kg ipilimumab monotherapy have 
demonstrated a tolerable AE profile in hundreds, respectively thousands of subjects that appears 
to be independent of tumor type. The combination of 1 mg/kg nivolumab + 3 mg/kg ipilimumab 
has demonstrated an acceptable AE profile in melanoma in Phase 3 CA209067 study. Both 
1 mg/kg nivolumab/3 mg/kg ipilimumab and 3 mg/kg nivolumab/1 mg/kg ipilimumab were 
identified as the MTD in Phase 1b CA209004 study. Less frequent dosing of ipilimumab at 
1 mg/kg Q6W when given with nivolumab 3 mg/kg Q2W was found to have a similar 
discontinuation rate to that observed in nivolumab monotherapy (11% vs 10%) in preliminary data 
from CA209012. These 3 combination dosing regimens are currently being studied in various 
tumor types. 
Nevertheless, these safety data were established in a population mainly of Caucasians. Therefore, 
it is possible that Chinese participants may experience unanticipated AEs. This protocol has been 
designed to minimize overall risk to participants. Adverse events will be reviewed expeditiously 
by the medical monitor and discussed with the study investigators. Also, there are detailed 
management guidelines for AEs listed in the protocol. To assure an ongoing safety assessment for 
participants enrolled in CA209672, clinical safety monitoring during the study will be performed 
on regular basis.
The global coronavirus disease 2019 (COVID-19) pandemic has been identified as a potential risk 
to clinical trial participants in general and may particularly affect individuals with CRC on IO
therapy. It is not known whether taking nivolumab plus ipilimumab increases the risk of severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or the duration or severity of 
COVID-19. Therefore, this study has been designed with study visits that allow for close 
monitoring of participants’ safety throughout the clinical trial (Section 5.1), 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. Meanwhile, in order to facilitate enhanced reporting of COVID-19 events that 
occur during the study, all AEs and SAEs reported after the time of consent that are related to 
SARS-CoV-2 infection or COVID-19 will be reported (Section 6).
In conclusion, the overall risk-benefit assessment for Study CA209672 does justify the conduct of 
the trial.
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the study or 
the protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the participants of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
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 participants. The investigator 
or BMS should also provide the IRB/IEC with a copy of the IB or product labeling information to 
be provided to participants and any updates. 
The investigator or BMS 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.
2.3
Informed Consent
Investigators must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
In situations where consent cannot be given to 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. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form(s) which will include all elements required by ICH, GCP, and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
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Investigators must:

Provide a copy of the consent form(s) 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(s) and any other information to be provided to the 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 participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participants' signed 
ICF.
The consent form(s) must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Participants unable to give their written consent (eg, stroke or participants with or severe dementia) 
may only be enrolled in the study with the consent of a legally acceptable representative. The 
participant must also be informed about the nature of the study to the extent compatible with his 
or her understanding, and should this participant become capable, he or she should personally sign 
and date the consent form as soon as possible. The explicit wish of a participant who is unable to 
give his or her written consent, but who is capable of forming an opinion and assessing information 
to refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
The rights, safety, and well-being of the study participants are the most important considerations 
and should prevail over interests of science and society.
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3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
3.1.1
Overall Design and Schematic
This is an open-label, multi-dose, 2-part, Phase 1/2 study of nivolumab in combination with 
ipilimumab in Chinese participants with previously treated metastatic or recurrent solid tumors.
As of 20-Dec-2021, the study was closed to new enrollment for Part 2, and a total of 36 participants
(9 participants each in Arms A, B, C, and D) were treated in the 3 nivolumab/ipilimumab 
combination dosing regimens as described below and in Table 3.1.1-1. For all arms, treatment was
not randomized.
In Part 1, 9 participants were treated in each of the three arms:

Arm A: Nivolumab administered IV over 30 minutes at 3 mg/kg every 2 weeks combined 
with ipilimumab administered IV over 30 minutes at 1 mg/kg every 6 weeks 

Arm B: Nivolumab administered IV over 30 minutes at 3 mg/kg combined with ipilimumab 
administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab 
administered IV over 30 minutes at 240 mg every 2 weeks

Arm C: Nivolumab administered IV over 30 minutes at 1 mg/kg combined with ipilimumab 
administered IV over 30 minutes at 3 mg/kg every 3 weeks for 4 doses followed by nivolumab 
administered IV over 30 minutes at 240 mg every 2 weeks
In Part 2, a total of 9 participants with recurrent or metastatic MSI-H/dMMR CRC determined by 
local testing were treated in the following treatment arm:

Arm D:  Nivolumab administered IV over 30 minutes at 3 mg/kg combined with ipilimumab 
administered IV over 30 minutes at 1 mg/kg every 3 weeks for four doses followed by 
nivolumab administered IV over 30 minutes at 240 mg every 2 weeks.
Table 3.1.1-1:
Nivolumab and Ipilimumab Dose Levels
Dosing Arm
Nivolumab (mg/kg, frequency)
Ipilimumab (mg/kg, frequency)
A
3 mg/kg, Q2W
1 mg/kg, Q6W
B
3 mg/kg, Q3W × 4
240 mg, Q2W thereafter
1 mg/kg, Q3W × 4
C
1 mg/kg, Q3W × 4
240 mg, Q2W thereafter
3 mg/kg, Q3W × 4
D
3 mg/kg, Q3W × 4
240 mg, Q2W thereafter
1 mg/kg, Q3W × 4
Abbreviations: AEs = adverse events; Ipi = ipilimumab; Q2W = every 2 weeks; Q3W = every 3 weeks; Q6W = every 
6 weeks.
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Treatment continues until progression, unacceptable toxicity, withdrawal of consent, completion 
of maximum treatment duration, the study ends, or other reasons specified in the protocol, 
whichever occurs first. Treatment beyond initial Investigator-assessed Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1-defined progression is permitted if the participant has 
investigator assessed clinical benefit and is tolerating nivolumab, as specified in Section 4.5.7.
Maximum treatment duration will be 24 months from the first dose of study treatment EXCEPT 
in participants with late response (during second year of treatment) who may receive for up to an 
additional 12 months after onset of response, in absence of disease progression, unacceptable
toxicity and withdrawal of consent. Above defined maximum treatment duration includes 
treatment beyond progression.
The study will consist of 3 periods: screening period; treatment period (until disease progression, 
intolerable toxicities, withdrawal of consent, completion of maximum treatment duration, the 
study ends, or other reasons specified in the protocol, whichever occurs first); and a follow-up 
period (up to 100 days for Arms A, B, C, and D). For Part 1, tumor assessment must be completed 
every 6 weeks for the first 24 weeks from date of first dosing, and then every 12 weeks thereafter 
until disease progression (including treatment beyond progression) or unacceptable toxicities. For 
Part 2, tumor assessment must be completed every 6 weeks from date of first dosing for the first 
24 weeks, and then every 12 weeks thereafter (including treatment beyond progression) until 
initiation of subsequent anticancer treatment. See Section 5.4 for details of imaging assessment 
requirement.
Every effort should be made to schedule visits within the timeframe stated in the protocol. 
Participants will undergo screening evaluations to determine eligibility prior to administration of 
study drug. For Part 1 only, for the purpose of PK sample collection, participants will be admitted 
to the clinical facility prior to dosing (Day -1) only on Cycle 1/Day 1 and Cycle 3/Day 1 for Arm 
A, and Cycle 1/Day 1 and Cycle 2/Day 22 for Arms B and C, and will remain in the clinical facility 
until 24 hours after study drug administration.
For Part 2 only, images will be submitted to a central imaging vendor for BICR during the study. 
Prior to scanning first participant sites should be qualified and understand the image acquisition 
guidelines and submission process as outlined in the CA209-672 Imaging Manual provided by the 
central imaging vendor. 
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The study design schematic is presented in Figure 3.1.1-1. 
Figure 3.1.1-1:
Study Design Schematic
Part 1
Part 2
* If a participant with following tumor types is enrolled, he/she can only be treated using one specific dosing schedule, 
eg, NSCLC, SCCHN, or mesothelioma participant is to be treated in Arm A only. SCLC participant is to be treated 
in Arm C only.
**Participants may be treated beyond progression under protocol-defined circumstances. Treatment continues until 
progression, unacceptable toxicity, withdrawal of consent, completion of maximum treatment duration of 2 years
EXCEPT in participants with late response (during second year of treatment) who may receive treatment for up to 
an additional 12 months after onset of response, the study ends, or other reasons specified in the protocol, whichever 
occurs first.
3.1.2
Part 1 - Safety Monitoring
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical 
laboratory evaluations will be performed at selected times throughout the dosing interval. 
Participants will be closely monitored for adverse events throughout the study. Blood samples will 
be collected before and after study drug administration for PK analysis. 
Less than 350 mL of blood will be drawn from each participant during the study.
In part 1, safety evaluation is planned after a total of 9 participants completed the first 6 weeks of 
treatment and associated evaluation in a given arm. However, tolerability beyond 6 weeks may 
Advanced or recurrent 
solid tumor* previously 
treated:
-Arm A:  including but not 
limited to NSCLC, NPC
- Arm B:  including but 
not limited to CRC (MSI-
H/dMMR)
- Arm C:  including but 
not limited to SCLC, GC 
and melanoma
Follow-up 
Visit 1 and 
Visit 2
Nivolumab 240 mg 
flat dose Q2W until 
disease 
progression** or 
unacceptable toxicity
Until disease 
progression** or 
unacceptable toxicity
Arm A:  Nivo 3 mg/kg 
Q2W + ipi 1 mg/kg Q6W
Arm B:  Nivo 3 mg/kg
+ ipi 1 mg/kg Q3W × 4
Arm C: Nivo 1 mg/kg
+ ipi 3 mg/kg Q3W × 4
Advanced or recurrent 
solid tumor previously 
treated:
- Arm D:  recurrent or 
metastatic CRC (MSI-
H/dMMR)
Follow-up 
Visit 1 and 
Visit 2
Nivolumab 240 mg 
flat dose Q2W until 
disease progression** 
or unacceptable 
toxicity
Arm D:  Nivo 3 mg/kg
+ ipi 1 mg/kg Q3W × 4
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also be taken into consideration. Participants who do not complete the DLT observation period for 
reasons other than DLTs will be replaced.
The participants’ safety will be monitored on an ongoing basis. Adverse events will be reviewed 
expeditiously by medical monitor and discussed with the study investigators. The sponsor and the 
study investigators will make an assessment on the tolerability of each combination regimen. 
Existing clinical safety database from earlier studies may be referred to. The criteria for tolerability
Table 3.1.2-1 are based on dose limiting toxicities (listed in Section 4.5.1) and include:

If no more than two out of the nine participants in a given treatment arm permanently 
discontinue study medication prior to Week 6 due to treatment related adverse events, then this 
dose arm will be deemed as tolerable.

If at least three out of the nine participants in a treatment arm permanently discontinue study 
medication prior to Week 6 due to treatment-related AEs, then the safety, tolerability, and 
efficacy of that treatment arm will be reviewed and discussed by the sponsor and investigators 
for benefit/risk ratio. 
Table 3.1.2-1:
Guidance for Safety Monitoring Based on Observed Toxicity 
Outcomes
Number of participants treated and 
followed up for at least 6 weeks after 
start of study treatment
Number of participants 
with DLTs
Next Step
9
2
Tolerable
9
3
To be discussed between sponsor and 
investigators to review benefit/risk ratio
The duration of the study is anticipated to be approximately 2 years. The end of the trial will occur 
on the day of the last visit of the last participant.
3.1.3
Part 2
3.1.3.1
Mismatch Repair/Microsatellite Instability Testing
MSI testing
Microsatellite instability - high is most frequently determined by polymerase chain reaction (PCR). 
MSI-H in tumors refers to changes in two or more of the five microsatellite markers in tumor tissue 
identified by National Cancer Institute (NCI)-recommended panels. The original Bethesda 
guidelines (1997) proposed a panel of five microsatellite markers for the uniform analysis of MSI 
in hereditary non-polyposis colorectal cancer (HNPCC). This panel, which is referred to as the 
Bethesda panel, included two mononucleotide (BAT-25 and BAT-26) and three dinucleotide 
(D5S346, D2S123, and D17S250) repeats.26 Individual testing sites may utilize a slightly different 
panel of markers incorporating alternative mononucleotide and/or dinucleotide markers. 
Regardless of the panel of markers, samples with instability in ≥ 30% or more of these markers 
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are defined as MSI-H, whereas those with < 30% unstable markers are designated as MSI-Low 
(MSI-L). Samples with no detectable alterations are MSS.
MMR testing
DNA mismatch repair deficiency determined by immunohistochemistry (IHC) refers to the loss of 
expression of one or more of the mismatch repair proteins (MLH1, MSH2, MSH6, or PMS2). Loss 
of expression is restricted to tumor cells, with preserved expression in immune infiltrate, and 
normal adjacent tissue. Loss of MLH1 expression is usually accompanied by loss of PMS2, and 
loss of MSH2 is usually accompanied by the loss of MSH6 expression.
In Part 2, participants with MSI-H/dMMR status determined prior to screening by local testing as 
part of the standard of care assessment can be eligible to the study. Please refer to Appendix 4 
regarding MSI/MMR testing panel descriptions and classification of MSI/MMR status to ensure 
historical MSI/MMR status determination is aligned with the protocol requirements prior to 
enrollment.
3.1.3.2
Screening
A complete schedule of activities for screening can be found in Table 5.1-1.
Before Protocol Amendment 07, enrollment had stopped.

Begins by establishing the participant’s initial eligibility and signing of the informed consent 
form (ICF).

Inclusion/Exclusion criteria are assessed during the screening period and must be confirmed 
prior to first dose

All medical history relevant to the disease under study should be collected.

Tumor tissue obtained from primary or metastatic site of disease. 

Sufficient tumor tissue obtained before start of study treatment in the primary or metastatic 
sites (block or minimum of 10 slides, obtained from core biopsy, punch biopsy, excisional 
biopsy, or surgical specimen) will be submitted to the central laboratory.

For participants where a fresh biopsy is not feasible, archival tumor material are required.

An additional source of tumor tissue must be available if the tissue obtained adhering to 
the above guidelines cannot be tested due to poor quality or insufficient quantity.

Central lab must confirm receipt of evaluable tumor tissue prior to vial assignment for 
MSI/MMR testing (see Section 5.6.2).

Prior to screening, medical record documentation of MSI/MMR testing results must be
available. Related pathology reports must be available. Reports must contain MSI/MMR status 
results, and specific results per markers tested for MSI/MMR are also required if available.

Collect RAS and BRAF mutation status, if available. Tests for these alterations are expected 
to be already performed for Arm D participants.

Eligibility and baseline assessments should be performed within required timeframe according 
to Table 5.1-1. The screening phase either ends with confirmation of full eligibility and 
treatment assignment for the participant or with the confirmation that the participant is a screen 
failure.
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3.1.3.3
Review of Safety
The participants’ safety will be monitored on an ongoing basis as described fully in Section 6. In 
addition, a BMS medical safety team (MST) routinely reviews safety signals across the entire 
nivolumab program including combination studies with ipilimumab.
3.1.4
Intra-Subject Dose Reductions
Intra-subject dose reduction is not permitted for any reason. Dose delays for the management of 
study treatment-related AEs are described in Section 4.5.3.
3.1.5
Follow-Up
Follow-up begins when the decision to discontinue a participant from study therapy is made (no 
further treatment with study therapy).
Participants will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline, or are deemed irreversible up to follow-up visit 2 (FU2) or 100 days of study drug 
discontinuation, whichever occurs later. All AEs occurring within 100 days after last dose will be 
documented.
Tumor assessments for Arm D will continue until FU2 or 100 days after last dose, whichever is 
later.
Refer to Table 5.1-5, Table 5.1-6, and Table 5.1-7 for additional follow-up assessments.
3.2
Post Study Access to Therapy
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be
eligible to receive BMS supplied study treatment for the maximum treatment duration of 2 years
specified in protocol Section 3.1.1. Study treatment will be provided via an extension of the study, 
a rollover study requiring approval by responsible health authority and ethics committee, or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to BMS supplied study treatment if any of the following occur: a) the study is terminated due to 
safety concerns; b) the development of nivolumab and/or ipilimumab is terminated for other 
reasons, including but not limited to lack of efficacy and/or not meeting the study objectives; c) the 
participant can obtain medication from a government sponsored or private health program. In all 
cases BMS will follow local regulations.
3.3
Study Population
For entry into the study, the following criteria MUST be met prior to dosing on Day 1. No 
exceptions will be granted. As of 20-Dec-2021, enrollment into this study Part 2 was closed.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
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before the performance of any protocol related procedures that are not part of normal 
participant care.
b) Participants must be willing and able to comply with scheduled visits (including overnight 
stays), treatment schedule, laboratory tests and other requirements of the study.
2) Target Population
a) Chinese participants with advanced or recurrent solid tumors
i)
histologically confirmed
(1) All CRC participants must be histologically confirmed metastatic or recurrent, with 
historically documented MSI-H or dMMR status by local testing (please refer to 
Appendix 4 for definition of MSI-H/dMMR and panel to be used by local testing).
ii) must have failed at least one prior systemic chemotherapy for advanced disease, OR, 
well documented refusal of participants to receive chemo or biological therapy
(1) SCLC participant must have failed at least one prior systemic therapy for advanced 
disease including one platinum based regimen.
iii) must have at least 1 measurable lesion per Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) (Appendix 1).
(1) GC participants must have at least one measurable lesion or evaluable disease by 
computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 
criteria.
(2) Participants with lesions in a previously irradiated field as the sole site of 
measurable disease will be permitted to enroll provided the lesion(s) have 
demonstrated clear progression and can be measured accurately.
b) Eastern Cooperative Oncology Group Performance Status of 0 or 1 (Appendix 2).
c) Life expectancy 3 months.
d) Not applicable per Protocol Amendment 04.
e) Not applicable per Protocol Amendment 04.
f)
Not applicable per Protocol Amendment 04.
g) Not applicable per Protocol Amendment 04.
h) Not applicable per Protocol Amendment 04.
i)
Not applicable per Protocol Amendment 04.
ii) Not applicable per Protocol Amendment 04.
iii) Not applicable per Protocol Amendment 04.
iv) Not applicable per Protocol Amendment 04.
v) Not applicable per Protocol Amendment 04. 
vi) Not applicable per Protocol Amendment 04.
vii)Not applicable per Protocol Amendment 04.
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viii)
Not applicable per Protocol Amendment 04.
i)
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been treated). If re-
enrolled, the participant must be re-consented. Obtain agreement from the Medical Monitor 
prior to re-enrolling a participant.
Additional Criteria for Participants Enrolled in Part 2
j)
Participants must have shown progression during, after, or have been intolerant to 1 line 
treatment(s) for metastatic disease, which must include at least a fluoropyrimidine, and 
oxaliplatin or irinotecan (participants who receive oxaliplatin in an adjuvant setting should 
have progressed during or within 6 months of completion of adjuvant therapy in order for 
oxaliplatin to count as a prior therapy needed for entry).
k) Participant willing to comply to provide tumor tissue (archival or fresh biopsy specimen) 
(see Section 5.6.2 for additional details regarding the requirements for tumor tissue).
3) Age and Reproductive Status
Investigators shall counsel women of child-bearing potential (WOCBP) on the importance of 
pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal 
toxicity occurring due to transmission of study drug to a developing fetus. 
a) Female Participants
i)
Females ages 18 years, or age of majority, or older at time of consent
ii) Women who are not of childbearing potential are exempt from contraceptive
requirements
iii) Women participants must have documented proof that they are not of childbearing
potential.
iv) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 
IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the 
start of study treatment. An extension up to 72 hours prior to the start of study treatment 
is permissible in situations where results cannot be obtained within the standard 24-
hour window.
v) Additional requirements for pregnancy testing during and after study intervention are
located in Section 5, Schedule of Assessments.
vi) The investigator is responsible for review of medical history, menstrual history, and
recent sexual activity to decrease the risk for inclusion of a woman with an early
undetected pregnancy
vii)WOCBP must agree to follow instructions for method(s) of contraception defined in
Appendix 5 and as described below and included in the ICF.
viii)
WOCBP are permitted to use hormonal contraception methods (as described in
Appendix 5)
ix) A female participant is eligible to participate if she is not pregnant or breastfeeding,
and at least one of the following conditions applies:
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(1) Is not a WOCBP
OR
(2) Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of < 1% per year), with low user dependency, as described in Appendix 5 during 
the intervention period and for at least 5 months and agrees not to donate eggs (ova, 
oocytes) for the purpose of reproduction for the same time period
b) Male Participants
i)
Males, ages 18 years, or age of majority, or older at time of consent
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Participants with untreated symptomatic central nervous system (CNS) metastases are 
excluded. Participants are eligible if CNS metastases are adequately treated and 
participants are neurologically returned to baseline (except for residual signs or symptoms 
related to the CNS treatment) for at least 2 weeks prior to enrollment. In addition, 
participants must be either off corticosteroids, or on a stable or decreasing dose of 10 mg 
daily prednisone (or equivalent). Imaging performed within 28 days prior to treatment 
assignment must document radiographic stability of CNS lesions and be performed after 
completion of any CNS directed therapy.
b) Participants with leptomeningeal metastases.
2. Medical History and Concurrent Diseases
a) Participants with previous malignancies or concurrent malignancies (present during 
screening) requiring treatment (except non-melanoma skin cancers, and the following in 
situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) 
are excluded unless a complete remission was achieved at least 2 years prior to study start
AND no additional therapy is required or anticipated to be required during the study period.
b) Participants with active, known or suspected autoimmune disease. Participants with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis 
only requiring hormone replacement are permitted to enroll.
c) Not applicable per Protocol Amendment 04.
d) Active Tuberculosis (TB) infection based on chest X-ray, sputum tests, and clinical 
examination. Participants with a history of active TB infection within the last 1 year are 
excluded, even if it was treated. Participants with a history of active TB infection greater 
than 1 year ago are excluded unless there is documentation of adequate prior anti-TB 
treatment.
e) Not applicable per Protocol Amendment 04.
f)
Not applicable per Protocol Amendment 04.
g) Not applicable per Protocol Amendment 04.
h) Not applicable per Protocol Amendment 04.
i)
Not applicable per Protocol Amendment 04.
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j)
Not applicable per Protocol Amendment 04.
k) Any other sound medical, psychiatric and/or social reason as determined by the 
investigator.
l)
Participants with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity.
m) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 days 
of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
n) Not applicable per Protocol Amendment 04. 
o) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue (which 
can be Grade 2) must have been resolved to ≤Grade 1, or returned to baseline, or stabilized 
before administration of study drug. Participants with toxicities attributed to prior anti-
cancer therapy which are not expected to resolve to Grade 1 and result in long lasting 
sequelae, such as neuropathy after platinum based therapy, are permitted to enroll.
p) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the participant to receive protocol therapy, or interfere with the interpretation 
of study result.
q) Women who are of childbearing potential or breastfeeding
3. Physical and Laboratory Test Findings
a) Not applicable per Protocol Amendment 04.
b) Not applicable per Protocol Amendment 04.
c) Not applicable per Protocol Amendment 04. 
d) WBC < 2000/μL
e) Neutrophils < 1500/μL
f)
Platelets < 100 × 103/μL
g) Hemoglobin < 9.0 g/dL 
h) Serum creatinine > 1.5× ULN, unless creatinine clearance ≥ 40 mL/min (measured or 
calculated using the Cockroft-Gault formula):
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
i)
AST: > 3.0× ULN
j)
ALT: > 3.0× ULN
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k) Bilirubin > 1.5× ULN (except participants with Gilbert Syndrome who must have total 
bilirubin < 3.0× ULN)
l)
Any positive test result for hepatitis B virus (HBV) indicating presence of virus, eg,
Hepatitis B surface antigen (Australia antigen) positive.
Any positive test result for hepatitis C virus (HCV) indicating presence of active viral 
replication (detectable HCV-ribonucleic acid [RNA]). Note: Participants with positive 
HCV antibody and an undetectable HCV-RNA are eligible to enroll.
m) Positive blood screen for human immunodeficiency virus (HIV)-1, or -2 antibody.
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
5. Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and BMS approval is required).
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Inability to comply with restrictions and prohibited activities/treatments as listed in 
Section 3.4
6. Prior /Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint 
pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory 
antitumor agents
b) Treatment with any chemotherapy, curative intent radiation therapy, biologics for cancer, 
or investigational therapy must have been completed at least 28 days before first 
administration of study treatment. Prior focal palliative radiotherapy must have been 
completed at least 2 weeks before study drug administration. Participants with prior 
cytotoxic or investigational products < 4 weeks prior to treatment might be eligible after 
discussion between investigator and sponsor, if toxicities from the prior treatment have 
been resolved to ≤Grade 1 (NCI Common Terminology Criteria for Adverse Events 
[CTCAE] version 4.0) or returned to baseline.
c) Participants who have received a live / attenuated vaccine within 30 days of first treatment
d) Prior major surgery requiring general anesthesia must be completed at least 2 weeks before 
study drug administration. Surgery requiring regional/epidural anesthesia must be 
completed at least 72 hours before study drug administration and participants must be 
recovered. Cutaneous biopsies with only local anesthesia should be completed at least 
1 hour prior to study drug administration.
e) Any use of immunosuppressive systemic medications, such as steroids (dose > 10 mg/day 
prednisone or equivalent) within 2 weeks of study drug administration.
f)
Any use of traditional medicinal herbal preparations within 2 weeks of study drug 
administration.
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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.
3.3.3
Women of Childbearing Potential
See Appendix 5. 
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications and treatments are prohibited during the study (unless utilized to treat 
a drug-related adverse event):

Immunosuppressive agents

Immunosuppressive doses of systemic corticosteroids. Participants are permitted the use of 
topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption). Adrenal replacement steroid doses > 10 mg daily prednisone are 
permitted. 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) is permitted.

Any concurrent systemic anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents for treatment of CRC)

Any non-palliative radiation therapy. Radiation therapy administered with palliative intent (ie,
for pain, bleeding, spinal cord compression, brain metastasis, new or impending pathologic 
fracture, superior vena-cava syndrome, or obstruction) is permitted. 

Any complementary medications (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such medications are permitted if they are used as 
supportive care.

Any live / attenuated vaccine (eg, varicella; zoster; yellow fever; rotavirus; oral polio; and 
measles, mumps, rubella) during treatment and until 100 days post last dose.
−
COVID-19 vaccines that are NOT live are allowed and should be handled in the same
manner as other vaccines. Administration may occur during the study, including during 
the administration of the BMS study treatment and after the last administration of the BMS 
study treatment. Non-live COVID-19 vaccination is considered a simple concomitant 
medication within the study. However, the efficacy and safety of non-live vaccines 
(including non-live COVID-19 vaccines) in participants receiving nivolumab and/or
ipilimumab are unknown.
3.4.2
Other Restrictions and Precautions
Participants are permitted the use of topical, ocular, intra-articular, intranasal and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids (ie, prednisone 10 mg/day) are permitted. A brief course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
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type hypersensitivity reaction caused by a contact allergen) or for management of study drug-
induced adverse events are permitted.
Surgical Resection following Initial Response
Investigators may choose to resect solitary lesions in participants with residual disease and render 
the participant free of macroscopic disease. Participants enrolled in this study may have lesions 
surgically resected only following consultation with the medical monitor and following the Week 
24 tumor imaging assessments. If additional tumor shrinkage is noted compared to the tumor 
imaging assessments at Week 18, it is highly encouraged that surgical resection be delayed until 
subsequent scans fail to demonstrate further shrinkage. Participants with a confirmed partial 
response (PR) who go on to have surgical resection of remaining disease will be considered a PR. 
Participants with stable disease (SD) who go on to have surgical resection of remaining disease 
will be considered a SD. Participants may continue treatment after surgery. Tumor tissue of any 
resected solitary lesion should be submitted to BMS (see Section 5.6.2). Detailed instructions of 
the obtaining, processing, labeling, handling, storage, and shipment of these specimens will be 
provided in a separate procedure manual at the time of study initiation.
3.5
Discontinuation of Participants following any Treatment with Study 
Drug
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Participant’s request to stop study treatment and/or participation in the study

Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant

Pregnancy*

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

Inability to comply with protocol

Documented disease progression (or documentation of further progression for participants
receiving treatment beyond progression; see Section 4.5.7). Participants without documented 
disease progression can discontinue study treatment if they have investigator assessed clinical 
deterioration that is unstable to perform further tumor assessment, and it should be well 
documented). 

Any AE meeting discontinuation criteria (see Section 4.5.6).
* In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur
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All participants who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5. 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 drug 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.
3.6
Post Study Drug Follow up
Participants who discontinue study treatment must continue to be followed for safety up to 
100 days following drug discontinuation. 
3.6.1
Withdrawal of Consent
Participants who request to discontinue study drug will remain in the study and must continue to 
be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by the participant to provide this information. Participants should notify the 
investigator of the decision to withdraw consent from future follow-up in writing, whenever 
possible. The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study drug 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.
3.6.2
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 as noted above. Lost to 
follow-up is defined by the inability to reach the participant after a minimum of three documented 
phone calls, faxes, texts, or emails as well as lack of response by participant to one registered mail 
letter. All attempts should be documented in the participant’s medical records. If it is determined 
that the participant has died, the site will use permissible local methods to obtain the date and cause 
of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the participant’s informed consent, then the investigator may use a sponsor-
retained third-party representative to assist site staff with obtaining participant’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all attempts, 
the participant remains lost to follow-up, then the last known alive date as determined by the 
investigator should be reported and documented in the participant’s medical records.
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4
STUDY DRUG
Study drug includes both investigational [medicinal] product (IP/IMP) and non-investigational 
[medicinal] product (Non-IP/Non-IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial.

Study required premedication,

Other drugs administered as part of the study that are critical to claims of efficacy (eg, 
background therapy, rescue medications)

Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
Product description and storage information is described in Table 4-1.
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Table 4-1:
Study Drugs for CA209672 - Treatment Period
Product Description 
Class and Dosage Form
Potency
Primary Packaging 
(Volume)/Label Type
Secondary Packaging 
(Qty)/Label Type
Packaging/Appearance
Storage Conditions
(per label)
Nivolumab (BMS-
936558-01) Solution for 
Injection
100 mg (10 mg/mL)
10 mL vial/
Open-label
5 vials per carton/
Open-label
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
Store at 2 to 8C. Protect 
from light and freezing
Ipilimumab Solution for 
Injection
200 mg (5 mg/mL)
50 mg (5 mg/mL)
40 mL vial
10 mL vial/
Open-label
4 vials per carton
1 vial per carton /
Open-label
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
Store at 2 to 8C. Protect 
from light and freezing
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4.1
Investigational Product
An investigational product, 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.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug 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 drug arise, the study drug should not be dispensed
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
For nivolumab and ipilimumab, please refer to the current version of the IBs and/or pharmacy 
reference sheets for complete storage, handling, dispensing, and infusion information.
Nivolumab is to be administered as an approximately 30-minute IV infusion. At the end of the 
infusion, flush the line with a sufficient quantity of normal saline or dextrose solution. Ipilimumab 
is to be administered as an approximately 30-minute IV infusion. At the end of the infusion, flush 
the line with a sufficient quantity of normal saline or 5% dextrose solution. When both study drugs 
are to be administered on the same day, separate infusion bags and filters must be used for each 
infusion. Nivolumab is to be administered first. The nivolumab infusion must be promptly 
followed by a saline flush to clear the line of nivolumab before starting the infusion. The second 
infusion will always be ipilimumab and will start at least 30 minutes after completion of the 
nivolumab infusion, filters changed, and patient observed to ensure no infusion reaction has 
occurred. Begin study treatment within 3 calendar days of treatment assignment.
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4.4
Method of Assigning Participant Identification
CA209672 is an open-label, non-randomized, parallel-arm study. During the screening visit, the 
investigative site will call into the enrollment option of the Interactive Voice Response System 
(IVRS) designated by BMS for assignment of a 5-digit participant number that will be unique.
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 
. The patient identification number (PID) 
will ultimately be comprised of the site number and participant number. Those enrolled 
participants meeting inclusion and exclusion criteria will be eligible to be dosed. Specific 
instructions and procedures for using IVRS will be provided to the investigational site in a separate 
document/ manual.
4.5
Selection and Timing of Dose for Each Participant
4.5.1
Dose Limiting Toxicities
Dose limiting toxicities are defined as any of the items listed below which occur during the first 
6 weeks.

Any Grade 2 drug-related uveitis or eye pain that does not respond to topical therapy and does 
not improve to Grade 1 severity within the re-treatment period OR requires systemic treatment

Any Grade 2 drug-related pneumonitis or interstitial lung disease that does not resolve to dose 
delay and systemic steroids. 

Any Grade 3 non-skin drug-related adverse event regardless of duration with the exception of 
laboratory abnormalities

Any Grade 4 drug-related adverse event including laboratory abnormalities except Grade 4 
leukopenia or neutropenia lasting < 7 days

Any of the following drug-related hepatic function laboratory abnormalities:

Grade 3 drug-related AST, ALT or Total bilirubin

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN

Grade 3 thrombocytopenia associated with bleeding
4.5.2
Dose Adjustment
Dosing calculations should be based on the body weight assessed at baseline. 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. All doses should be rounded to the nearest milligram. There will be no 
other dose modifications allowed. 
4.5.3
Dose Delay Criteria
Study treatment should be delayed for the following:

Any Grade 2 non-skin, drug-related AE, except for fatigue

Grade 2 drug-related creatinine, AST, ALT, and/or Total Bilirubin Abnormalities, with the 
following exceptions: 
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−If a participant has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥ 3 toxicity
−See Section 4.5.6 for discontinuation criteria for drug-related ALT, AST and/or Total 
Bilirubin Abnormalities 

Any Grade 3 skin drug-related AE

Any Grade 3 drug-related laboratory abnormality with the following exceptions:
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require a dose delay

Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Dosing of nivolumab and ipilimumab should be delayed for any adverse event, laboratory
abnormality, or intercurrent illness which, in the judgment of the investigator, warrants delaying 
the dose of study medication. Study therapy should also be delayed in cases of confirmed or 
suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection regardless of 
the severity.
Participants receiving nivolumab in combination with ipilimumab who have drug-related toxicities 
that meet the criteria for dose delay should have both drugs (nivolumab and ipilimumab) delayed 
until treatment resumption criteria are met.
Participants who require delay of nivolumab and/or ipilimumab should be re-evaluated weekly or 
more frequently if clinically indicated and resume nivolumab and/or ipilimumab dosing when 
retreatment criteria are met. 
Dose delay criteria apply for all drug-related adverse events regardless of whether the event is 
attributed to nivolumab or ipilimumab or both.
Doses of nivolumab or ipilimumab may be interrupted, delayed, or discontinued depending on 
how well the participant tolerates the treatment. Dosing visits are not skipped, only delayed.
Rescheduling
Participants who require delay of treatment should be re-evaluated weekly or more frequently if 
clinically indicated and resume dosing when re-treatment criteria are met. Continue tumor 
assessments per protocol even if dosing is delayed.
Arm A:

Nivolumab may be delayed until the next planned ipilimumab dose if the next ipilimumab dose 
is scheduled within the next 12 days. This will permit periodic ipilimumab dosing to be 
synchronized with nivolumab dosing.

Ipilimumab should be dosed at the specified interval regardless of any delays in intervening 
nivolumab doses. However, in order to maintain periodic synchronized dosing of ipilimumab 
and nivolumab, the dosing days of nivolumab and ipilimumab may be adjusted within the 
permitted 2 day window, as long as consecutive nivolumab doses are given at least 12 days 
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apart. Ipilimumab may be delayed beyond the 2-day window if needed to synchronize with the 
next nivolumab dose.

If an ipilimumab dose is delayed beyond 6 weeks from the prior ipilimumab dose, then 
subsequent ipilimumab doses should be rescheduled to maintain the 6-week interval between 
consecutive ipilimumab doses.

A dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 4.5.5.
Arm B, C and D: Participants may be dosed no less than 12 days and 19 days from the previous 
treatment during Q2W (nivolumab) and Q3W (nivolumab combined with ipilimumab) dosing, 
respectively.
4.5.4
Dose Reduction
There will be no dose reductions for nivolumab or ipilimumab.
4.5.5
Criteria to Resume Treatment
Participants may resume study treatment when the drug-related AE(s) resolve(s) to Grade 1 or 
baseline, with the following exceptions:

Participants may resume treatment in the presence of Grade 2 fatigue.

Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.

For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete. Participants with baseline Grade 1 AST/ALT or total bilirubin elevations 
who require dose delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin 
may resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin. 

Participants with isolated AST/ALT elevations or combined with total bilirubin elevations 
meeting discontinuation parameters (Section 4.5.6) should have treatment permanently 
discontinued, except situations outlined in the Section 4.5.6.

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor.

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor. If 
participant experienced Grade 3 adrenal insufficiency study treatment should not be resumed 
regardless of control with hormone replacement.
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following conditions are met:
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
At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive test result (eg, reverse transcription polymerase chain reaction or viral antigen)

Resolution of acute symptoms (including at least 24 hours has passed since last fever without 
fever reducing medications)

Evaluation by the investigator with confirmation that there are no sequelae that would place 
the participant at a higher risk of receiving investigational treatment.
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 treatment in a participant with a dosing delay lasting > 8 weeks, the Medical 
Monitor (or designee) must be consulted. Continue tumor assessments per protocol even if dosing 
is delayed. Continue periodic study visits to assess safety and laboratory studies every 8 weeks or 
more frequently if clinically indicated during such dosing delays.
When criteria to resume treatment are met, resume both nivolumab and ipilimumab on the same 
day unless the investigator determines that 1 of the agents must be discontinued due to toxicity 
attributed to that agent alone.
4.5.6
Treatment Discontinuation Criteria
Treatment should be permanently discontinued for any of the following:

Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment

Any Grade 3 non-skin, drug-related AE lasting > 7 days, with the following exceptions for 
drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion 
reactions, endocrinopathies, diarrhea, colitis, neurologic toxicity and laboratory abnormalities:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, myocarditis, 
neurologic toxicity, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation. Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation. Grade 3 adrenal 
insufficiency requires discontinuation regardless of control with hormone replacement. 
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:

Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation.

Grade ≥ 3 drug-related AST, ALT or Total Bilirubin requires discontinuation*

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN*

*In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug(s), a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
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
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events, which do not require discontinuation:

Grade 4 neutropenia 7 days

Grade 4 lymphopenia or leukopenia 

Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis. The BMS Medical Monitor should be consulted for 
Grade 4 amylase or lipase abnormalities

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset

Grade 4 drug-related endocrinopathy adverse events such as 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

Dosing delays lasting > 6 weeks for Q2W dosing (nivolumab monotherapy) or > 8 weeks for 
Q3W dosing (nivolumab combined with ipilimumab) from the previous dose requires 
discontinuation. The following exceptions apply:

Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 

Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. 

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the BMS 
medical monitor must be consulted. Tumor assessments should continue as per protocol even if 
dosing is delayed. Periodic study visits to assess safety and laboratory studies should also continue 
every 6 weeks or more frequently if clinically indicated during such dosing delays.
The assessment for discontinuation of ipilimumab should be made separately from the assessment 
made for discontinuation of nivolumab. Although there is an overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued. 
If a participant meets the criteria for discontinuation of ipilimumab but not nivolumab, treatment 
with nivolumab may not resume until the AE/SAE has fully resolved and the participant has 
discontinued steroids, if they were required for treatment of the AE/SAE. The relationship to 
ipilimumab should be well documented in the source documents. Nivolumab should be resumed 
at the dose according to the treatment schedule (Table 5.1-2, Table 5.1-3 and Table 5.1-4).
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Participants receiving nivolumab plus ipilimumab treatment arm, who meet criteria for treatment 
discontinuation and an investigator is unable to determine whether the event is related to both or 
one study drug, the participant should discontinue both nivolumab and ipilimumab and be taken 
off the treatment phase of the study.
4.5.7
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of progressive disease (PD).27
Participants treated with nivolumab or nivolumab plus ipilimumab combination will be permitted 
to continue treatment beyond initial RECIST 1.1-defined PD, assessed by the investigator up to a 
maximum of 24 months from date of first dose as long as they meet the following criteria: The 24-
month maximum treatment duration of the study includes time spent in treatment beyond 
progression.

Investigator-assessed clinical benefit

Tolerance of study treatment

Stable performance status

Participant provides written informed consent prior to receiving additional nivolumab 
treatment. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply.
Radiographic assessment/scan(s) in accordance with the Section 5.1 Flow Chart/Time and Events 
Schedule for the duration of the treatment beyond progression and should be submitted to the 
central imaging vendor for Part 2 only. Balance the assessment of clinical benefit with clinical 
judgment as to whether the participant is clinically deteriorating and unlikely to receive any benefit 
from continued treatment with nivolumab.
If the investigator feels 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 Time and Events Schedule on Table 5.1-2 to Table 5.1-7.
For the participants who continue nivolumab study therapy beyond progression, further 
progression is defined as an additional 10% increase in tumor burden with a minimum 5 mm 
absolute increase from time of initial PD. This includes an increase in the sum of diameters of all 
target lesions and/or the diameters of new measurable lesions compared to the time of initial PD. 
Upon documentation of further progression, permanently discontinue nivolumab treatment unless 
the clinical judgement of the investigator is that continuing treatment is in the patient’s best 
interest. New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes which must have a short axis of 
at least 15 mm). Any new lesion considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
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inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
4.5.8
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology agents are associated with AEs that can differ in severity and duration than AEs 
caused by other therapeutic classes. Nivolumab and ipilimumab are considered IO agents in this 
protocol. Early recognition and management of AEs associated with immuno-oncology agents 
may mitigate severe toxicity. Management algorithms have been developed to assist investigators 
in assessing and managing the following groups of AEs:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathy

Skin

Neurological
The above algorithms are found in both the nivolumab and ipilimumab IBs,8 as well as in 
Appendix 3.
4.5.9
Treatment of Nivolumab or Ipilimumab Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an SAE 
if criteria are met. Infusion reactions should be graded according to NCI CTCAE (Version 4.0) 
guidelines.
Treatment recommendations 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 
additional nivolumab or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
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anti-inflammatory 
drugs, 
narcotics, 
corticosteroids, 
bronchodilators, 
IV 
fluids]; 
prophylactic medications indicated for 24 hours)

Stop the nivolumab or ipilimumab 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 nivolumab or ipilimumab will be administered at 
that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 
participant until resolution of symptoms. The amount of study drug infused must be recorded 
on the electronic case report form (eCRF).

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 nivolumab or ipilimumab infusions. If 
necessary, corticosteroids (up to 25 mg of SoluCortef 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 
impairment, pulmonary infiltrates]; Grade 4: Life threatening; pressor or ventilatory 
support indicated)

Immediately discontinue infusion of nivolumab or ipilimumab. 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. Nivolumab or 
ipilimumab will be permanently discontinued. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. Remain at bedside and monitor participant until 
recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
4.6
Blinding/Unblinding
This is an open-label study. Treatment assignments will be released to the bioanalytical laboratory 
in order to minimize unnecessary analysis of samples.
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4.7
Treatment Compliance
Study drug will be administered in the clinical facility. Treatment compliance will be monitored 
by drug accountability as well as the participant’s medical record and eCRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS study monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are 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 standard operating procedures (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.
If conditions for destruction cannot be met the responsible BMS study monitor will make 
arrangements for return of study drug.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible study monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, 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. 
4.10
Retained Samples for Bioavailability/Bioequivalence
Not applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Study assessments and procedures are presented in Table 5.1-1, Table 5.1-2, Table 5.1-3, Table 
5.1-4, Table 5.1-5, Table 5.1-6, and Table 5.1-7.
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Table 5.1-1:
Screening Procedural Outline (CA209672)
This study is not actively enrolling participants.
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
x
A participant is considered enrolled only when a protocol specific informed consent is signed. Study 
allows for re-enrollment of a participant that has discontinued the study as a pre-treatment failure. If re-
enrolled, the participant must be re-consented and assigned a new participant number from IRT.
Inclusion/Exclusion Criteria
x
Must be confirmed prior to treatment assignment. See Section 3.3.
Medical History
x
Include any toxicities or allergy related to previous treatments.
Diagnosis confirmation and stage
x
Tumor-specific therapy information
x
MSI Status (CRC Participants Only)
x
For CRC participants in Arms B and D, sites should record historically documented MSI/MMR testing 
results on the CRF.
Pathology reports containing MSI/MMR testing results must be available. Reports must contain
MSI/MMR status results, and specific results per markers tested for MSI/MMR are also required if 
available.
Tumor Tissue Sample
x
For Part 2 only, sufficient evaluable tumor tissue obtained before start of study treatment in the metastatic 
setting or from an unresectable site (block or minimum of 10 slides, obtained from core biopsy, punch 
biopsy, excisional biopsy or surgical specimen). 
For participants where a fresh biopsy is not feasible, archival tumor material must be available.
Central laboratory must confirm receipt of evaluable tumor tissue prior to vial assignment (Section 5.6.2). 
RAS Mutation Status
x
For Part 2 only, if available, record result.
BRAF Mutation Status
x
For Part 2 only, if available, record result.
History of Lynch Syndrome
For Part 2 only, if available, record result.
Safety Assessments
Physical Examination (PE)
x
To be collected within 14 days prior to date of first dosing.
Physical Measurements
x
Includes height, weight; should be recorded within 14 days prior to date of first dosing.
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Table 5.1-1:
Screening Procedural Outline (CA209672)
This study is not actively enrolling participants.
Procedure
Screening
Visit
Notes
ECOG Performance Status
x
See Appendix 2; should be recorded within 14 days prior to date of first dosing.
Vital Signs and Oxygen Saturation
x
Includes body temperature, respiratory rate, and seated or supine blood pressure and heart rate, O2 
saturation by pulse oximetry at rest. Blood pressure and heart rate should be measured after the participant
has been resting quietly for at least 5 minutes.
Vital signs should be obtained at screening and within 72 hours prior to date of first dosing.
Electrocardiogram (ECGs)
x
ECGs should be recorded after the participant has been supine for at least 5 minutes; should be recorded 
within 14 days prior to date of first dosing.
Monitor for Serious Adverse Events
x
All SAEs that occur during the screening period and within 100 days of discontinuation of dosing must be
collected.
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection collected from time of consent.
Concomitant Medication Collection
x
All medications taken within 14 days prior to date of first dosing will be recorded.
Laboratory Tests
x
CBC w/differential; Full Chemistry Panel: LDH, AST, ALT, ALP, T.Bili, (Direct Bili if T.Bili > ULN), 
BUN (or serum urea level), creatinine, Ca+, Mg+, Na+, K+, Cl-, glucose, albumin, T.Protein. 
Lab tests should be completed within 14 days prior to date of first dosing.
Serology (HCV, HBV, HIV)
x
Includes hepatitis C antibody or HCV RNA, hepatitis B surface antigen, and HIV-1 and -2 antibody. If
anti-HCV test is positive, then HCV RNA is mandatory. 
Viral testing to be performed within 28 days prior to date of first dosing.
Serology test result must be available and reviewed prior to dosing on Day 1.
Pregnancy Test
x
All WOCBP must have a negative urine or serum β-HCG pregnancy test minimum sensitivity 25 IU/L or 
equivalent units of HCG within 24 hours before the first infusion; FSH > 40 mIU/mL is required to 
confirm menopause. See Appendix 5.
Baseline Tumor Assessment 
x
Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all known sites of disease should 
be performed within 28 days prior to date of first dosing. See Section 5.4. 
CT/MRI (brain)
x
MRI of the brain without and with contrast is required if participant is symptomatic or has a history of 
brain metastasis, and has not had brain imaging within 28 days prior to date of first dosing. CT of the 
Brain (without and with contrast) can be performed if MRI is contraindicated. See Section 5.4.
Protocol Amendment No.: 07
Date: 22-Aug-2022
65
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209672)
This study is not actively enrolling participants.
Procedure
Screening
Visit
Notes
Other Imaging (eg, Bone Scan)
x
As clinically indicated per local standards. Performed within 28 days prior to date of first dosing. See 
Section 5.4
Protocol Amendment No.: 07
Date: 22-Aug-2022
66
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Procedural Outline (CA209672) - Part 1, Arm A: nivolumab 3 mg/kg Q2W + 
ipilimumab 1 mg/kg Q6W combination
Procedure
Cycle 1 and beyond
(1 cycle = 6 weeks)
Notes
Day 1a
Day 15a
Day 29a
Day 42a
Admission to Clinical Facility
x
For the purpose of PK sample collection, participants will be admitted to the 
clinical facility prior to dosing (Day -1) on Cycle 1/Day 1 and Cycle 3/ Day 
1, and will remain in the clinical facility until 24 hrs after study drug 
administration.
Safety Assessments
Targeted PE
X
x
x
Targeted examination must include at a minimum the following body 
systems:

Cardiovascular

Gastrointestinal

Pulmonary

Neurological exam for participants with brain metastases
Obtain prior to each dose. 
Physical Measurements 
X
x
X
Weight only. Dose adjustments are required to be made if there has been a > 
10% percent weight change (increase or decrease) from the previous dose. 
Obtain prior to each dose. 
Vital Signs and Oxygen 
Saturation
X
x
X
Includes body temperature, respiratory rate, and seated or supine blood 
pressure and heart rate, O2 saturation by pulse oximetry at rest. Blood 
pressure and heart rate should be measured after the participant has been 
resting quietly for at least 5 minutes.
Vital signs should be taken as per institutional standard of care at visits and 
prior to, during, and after the infusion with nivolumab. 
ECOG Performance Status
X
x
X
Obtain prior to each dose. 
See Appendix 2
Protocol Amendment No.: 07
Date: 22-Aug-2022
67
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Procedural Outline (CA209672) - Part 1, Arm A: nivolumab 3 mg/kg Q2W + 
ipilimumab 1 mg/kg Q6W combination
Procedure
Cycle 1 and beyond
(1 cycle = 6 weeks)
Notes
Day 1a
Day 15a
Day 29a
Day 42a
Electrocardiogram (ECGs)
X
ECGs should be recorded after the participant has been supine for at least 5 
minutes. 
AE Assessment (including SAE 
Assessment) 
X
Should occur at every visit throughout the study.
See Sections 6.1 and 6.2.
All AEs (SAEs or non-serious AEs), including those associated with SARS-
CoV-2 infection, must be collected continuously during the treatment 
period.
Review of Concomitant 
Medications
X
x
X
Should occur at every visit throughout the study.
Laboratory Tests
Laboratory Tests
X
x
X
Include CBC w/differential and platelets; Full Chemistry Panel: LDH, AST, 
ALT, ALP, T.Bili (Direct Bili if T.Bili > ULN), BUN (or serum urea level), 
creatinine, Ca+, Mg+, Na+, K+, Cl-, amylase, lipase, glucose, albumin, 
T.Protein
To be done within 72 hours prior to dosing and results must be reviewed 
prior to dosing. Screening labs are acceptable if performed within the 
previous 72 hours and results are available.
Thyroid function testing 
X
TSH, (free T3, Free T4 if TSH not within normal limits).
To be done within 72 hours prior to dosing and results must be reviewed 
prior to dosing.
Pregnancy Test
X
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG) to be done at screening visit and within 24 hours prior to first 
dose and then every 4 weeks (± 1 week) regardless of dosing schedule. 
Protocol Amendment No.: 07
Date: 22-Aug-2022
68
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Procedural Outline (CA209672) - Part 1, Arm A: nivolumab 3 mg/kg Q2W + 
ipilimumab 1 mg/kg Q6W combination
Procedure
Cycle 1 and beyond
(1 cycle = 6 weeks)
Notes
Day 1a
Day 15a
Day 29a
Day 42a
Efficacy Assessments
Tumor assessments 
X
The scans must be performed every 6 weeks (between Days 35 and 42 of the 
cycle) from date of first dosing for the first 24 weeks, and then every 12 
weeks (between Days 35 and 42 of the cycle) thereafter until disease 
progression (including treatment beyond progression) or unacceptable 
toxicity. This schedule should be followed even if treatment delay occurs. 
All PR or CR evaluations must be confirmed by a second scan performed ³
4 weeks later. See Section 5.4 for further details.
CT/MRI (brain)
See Notes
Participants with a history of brain metastasis should have surveillance MRI 
per standard of care (approximately every 12 weeks, or sooner if clinically 
indicated). 
CT of the Brain (without and with contrast) can be performed if MRI is 
contraindicated. 
See Section 5.4.
Other Imaging (eg, Bone Scan)
See Notes
As clinically indicated per local standards. See Section 5.4 for further 
details.
Pharmacokinetic (PK) 
Assessments
Blood PK Sampling
X
Refer to Table 5.5.1-1 for specific PK sampling time points. See Section 5.5.
Immunogenicity (ADA) 
Assessments
Blood ADA Sample
X
Refer to Table 5.5.1-1 for specific ADA sampling time points. See 
Section 5.5.
Protocol Amendment No.: 07
Date: 22-Aug-2022
69
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Procedural Outline (CA209672) - Part 1, Arm A: nivolumab 3 mg/kg Q2W + 
ipilimumab 1 mg/kg Q6W combination
Procedure
Cycle 1 and beyond
(1 cycle = 6 weeks)
Notes
Day 1a
Day 15a
Day 29a
Day 42a
Clinical Drug Supplies
Nivolumab Administration
x
x
X
Those supplied by BMS or sourced by the investigator.
Ipilimumab Administration
x
Those supplied by BMS or sourced by the investigator.
a To be done ± 2 days of scheduled visit. Every effort should be made to schedule visits within the timeframe stated in the protocol. In the case that the visits 
cannot be within the timeframe stated in protocol then the treatment period study procedures can be performed ± 2 days of the scheduled visit.
Protocol Amendment No.: 07
Date: 22-Aug-2022
70
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Procedural Outline (CA209672) - Part 1, Arms B and C – Arm B: nivolumab 3 mg/kg + 
ipilimumab 1 mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W, Arm C: nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W
Procedure
Cycles 1 to 2 
Q3W (1 cycle = 6 wks) 
Cycle 3+
Q2W (1 cycle = 6 wks)
Notes
Day  
1a
Day 
22a
Day 
42a
Day  
1a
Day 
15a
Day 
29a
Day 
42a
Admission to Clinical Facility
x
x
For the purpose of PK sample collection, participants will be 
admitted to the clinical facility prior to dosing (Day -1) on Cycle 
1/Day 1 and Cycle 2/ Day 22, and will remain in the clinical 
facility until 24 hrs after study drug administration.
Safety Assessments
Targeted Physical Examination
x
x
x
x
x
Targeted examination must include at a minimum the following 
body systems:

Cardiovascular

Gastrointestinal

Pulmonary

Neurological exam for participants with brain metastases
Obtain prior to each dose.
Physical Measurements 
x
x
x
x
x
Weight only. Dose adjustments are required to be made in cycles 
1 and 2 if there has been a > 10% percent weight change 
(increase or decrease) from the previous dose. 
Obtain prior to each dose.
Vital Signs and Oxygen Saturation
x
x
x
x
x
Includes body temperature, respiratory rate, and seated or supine 
blood pressure and heart rate, O2 saturation by pulse oximetry at 
rest. Blood pressure and heart rate should be measured after the 
participant has been resting quietly for at least 5 minutes.
Vital signs should be taken as per institutional standard of care at 
visits and prior to, during, and after the infusion with nivolumab. 
ECOG Performance Status
x
x
x
x
x
Obtain prior to each dose. 
Protocol Amendment No.: 07
Date: 22-Aug-2022
71
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Procedural Outline (CA209672) - Part 1, Arms B and C – Arm B: nivolumab 3 mg/kg + 
ipilimumab 1 mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W, Arm C: nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W
Procedure
Cycles 1 to 2 
Q3W (1 cycle = 6 wks) 
Cycle 3+
Q2W (1 cycle = 6 wks)
Notes
Day  
1a
Day 
22a
Day 
42a
Day  
1a
Day 
15a
Day 
29a
Day 
42a
See Appendix 2
Electrocardiograms (ECGs)
x
x
ECGs should be recorded after the participant has been supine 
for at least 5 minutes.
AE Assessment (including SAE 
Assessment)
x
Should occur at every visit throughout the study.
All AEs (SAEs or non-serious AEs), including those associated 
with SARS-CoV-2 infection, must be collected continuously 
during the treatment period.
Review of Concomitant 
Medications
x
Should occur at every visit throughout the study.
Laboratory Tests
Laboratory Tests
x
x
x
x
x
Within 72 hours prior to dosing. Include CBC w/differential and 
platelets; Full Chemistry Panel: LDH, AST, ALT, ALP, T.Bili, 
(Direct Bili if T.Bili > ULN) , BUN (serum urea level), 
creatinine, Ca+, Mg+, Na+, K+, Cl-, amylase, lipase, glucose, 
albumin, T.Protein
To be done within 72 hours prior to dosing and results must be 
reviewed prior to dosing. Screening labs are acceptable if 
performed within the previous 72 hours and results are available.
Thyroid function testing 
x
x
TSH, (free T3, Free T4 if TSH not within normal limits).
To be done within 72 hours prior to dosing and results must be 
reviewed prior to dosing.
Pregnancy Test
x
x
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) to be done at screening visit and within 
Protocol Amendment No.: 07
Date: 22-Aug-2022
72
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Procedural Outline (CA209672) - Part 1, Arms B and C – Arm B: nivolumab 3 mg/kg + 
ipilimumab 1 mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W, Arm C: nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W
Procedure
Cycles 1 to 2 
Q3W (1 cycle = 6 wks) 
Cycle 3+
Q2W (1 cycle = 6 wks)
Notes
Day  
1a
Day 
22a
Day 
42a
Day  
1a
Day 
15a
Day 
29a
Day 
42a
24 hours prior to first dose and then every 4 weeks (± 1 week) 
regardless of dosing schedule. 
Efficacy Assessments
Tumor assessments 
x
x
The scans must be performed every 6 weeks (between Days 35 
and 42 of the cycle) from date of first dosing for the first 24 
weeks, and then every 12 weeks (between Days 35 and 42 of the 
cycle) thereafter until disease progression (including treatment 
beyond progression) or unacceptable toxicity. This schedule 
should be followed even if treatment delay occurs. 
All PR or CR evaluations must be confirmed by a second scan 
performed ³ 4 weeks later. 
See Section 5.4 for further details. 
CT/MRI (brain)
See Notes
Participants with a history of brain metastasis should have 
surveillance MRI per standard of care (approximately every 12 
weeks, or sooner if clinically indicated). 
CT of the Brain (without and with contrast) can be performed if 
MRI is contraindicated. 
See Section 5.4
Other Imaging (eg, Bone Scan)
See Notes
As clinically indicated per local standards. See Section 5.4 for 
further details.
Pharmacokinetic (PK) Assessments
Blood PK Sampling
x
Refer to Table 5.5.1-2 for specific PK sampling time points. See 
Section 5.5.
Protocol Amendment No.: 07
Date: 22-Aug-2022
73
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Procedural Outline (CA209672) - Part 1, Arms B and C – Arm B: nivolumab 3 mg/kg + 
ipilimumab 1 mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W, Arm C: nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W
Procedure
Cycles 1 to 2 
Q3W (1 cycle = 6 wks) 
Cycle 3+
Q2W (1 cycle = 6 wks)
Notes
Day  
1a
Day 
22a
Day 
42a
Day  
1a
Day 
15a
Day 
29a
Day 
42a
Immunogenicity (ADA) 
Assessments
Blood ADA Sample
x (See note)
Refer to Table 5.5.1-2 for specific ADA sampling time points. 
See Section 5.5.
Clinical Drug Supplies
Nivolumab Administration
x
x
x
x
x
Those supplied by BMS or sourced by the investigator.
Arm B: nivo 3 mg/kg Q3W × 4 followed by 240 mg Q2W
Arm C: nivo 1 mg/kg Q3W × 4 followed by 240 mg Q2W
Ipilimumab Administration
x
x
Those supplied by BMS or sourced by the investigator.
Arm B: ipi 1 mg/kg Q3W × 4
Arm C:ipi 3 mg/kg Q3W × 4
a To be done ± 2 days of scheduled visit. Every effort should be made to schedule visits within the timeframe stated in the protocol. In the case that the visits 
cannot be within the timeframe stated in protocol then the treatment period study procedures can be performed ± 2 days of the scheduled visit.
Protocol Amendment No.: 07
Date: 22-Aug-2022
74
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-4:
On-Treatment Procedural Outline (CA209672) - Part 2, Arm D: nivolumab 3 mg/kg + ipilimumab 1 
mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W
Procedure
Cycles 1 to 2
Q3W (1 cycle = 6 wks) 
Cycle 3+
Q2W (1 cycle = 6 wks)
Notes
Day
1a
Day 
22a
Day 
42a
Day 
1a
Day 
15a
Day 
29a
Day 
42a
Safety Assessments
Targeted Physical Examination
x
x
x
x
x
Targeted examination must include at a minimum the following 
body systems: 

Cardiovascular 

Gastrointestinal 

Pulmonary 

Neurological exam for participants with brain metastases 
Obtain prior to each dose.
Physical Measurements 
x
x
x
x
x
Weight only. Dose adjustments are required to be made in cycles 1 
and 2 if there has been a > 10% percent weight change (increase or 
decrease) from the previous dose. 
Obtain prior to each dose.
Vital Signs
x
x
x
x
x
Includes body temperature, respiratory rate, and seated or 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.
Vital signs should be taken as per institutional standard of care at 
visits and prior to, during, and after the infusion with nivolumab. 
ECOG Performance Status
x
x
x
x
x
See note in screening procedures.
AE Assessment (including SAE 
Assessment)
x
Should occur at every visit throughout the study.
All AEs (SAEs or non-serious AEs), including those associated 
with SARS-CoV-2 infection, must be collected continuously 
during the treatment period.
Protocol Amendment No.: 07
Date: 22-Aug-2022
75
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-4:
On-Treatment Procedural Outline (CA209672) - Part 2, Arm D: nivolumab 3 mg/kg + ipilimumab 1 
mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W
Procedure
Cycles 1 to 2
Q3W (1 cycle = 6 wks) 
Cycle 3+
Q2W (1 cycle = 6 wks)
Notes
Day
1a
Day 
22a
Day 
42a
Day 
1a
Day 
15a
Day 
29a
Day 
42a
Review of Concomitant 
Medications
x
Should occur at every visit throughout the study.
Laboratory Tests
Laboratory Tests
x
x
x
x
x
Within 72 hours prior to dosing. Include CBC w/differential and 
platelets; Full Chemistry Panel:  LDH, AST, ALT, ALP, T.Bili, 
(Direct Bili if T.Bili > ULN), BUN (or serum urea level), 
creatinine, Ca+, Mg+, Na+, K+, Cl-, amylase, lipase, glucose, 
albumin, T.Protein
To be done within 72 hours prior to dosing and results must be 
reviewed prior to dosing. Screening labs are acceptable if 
performed within the previous 72 hours and results are available.
Thyroid function testing
x
x
TSH, (free T3, Free T4 if TSH not within normal limits).
To be done within 72 hours prior to dosing and results must be 
reviewed prior to dosing.
Pregnancy Test
x
x
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) to be done at screening visit and within 
24 hours prior to first dose and then every 4 weeks (± 1 week) 
regardless of dosing schedule. 
Efficacy Assessments
Tumor assessmentsb
x
x
The scans must be performed every 6 weeks (between Days 35 and 
42 of the cycle) from date of first dosing for the first 24 weeks, and 
then every 12 weeks (between Days 35 and 42 of the cycle) 
thereafter (including treatment beyond progression) until initiation 
of subsequent anti-cancer treatment. This schedule should be 
followed even if treatment delay occurs.
Protocol Amendment No.: 07
Date: 22-Aug-2022
76
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-4:
On-Treatment Procedural Outline (CA209672) - Part 2, Arm D: nivolumab 3 mg/kg + ipilimumab 1 
mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W
Procedure
Cycles 1 to 2
Q3W (1 cycle = 6 wks) 
Cycle 3+
Q2W (1 cycle = 6 wks)
Notes
Day
1a
Day 
22a
Day 
42a
Day 
1a
Day 
15a
Day 
29a
Day 
42a
All PR or CR evaluations must be confirmed by a second scan 
performed ³ 4 weeks later.
All imaging scans should be submitted to a third party for BICR 
assessment until initiation of subsequent anti-cancer treatment. 
See Section 5.4 for further details.
CT/MRI (brain)
See Notes
Participants with a history of brain metastasis should have 
surveillance MRI per standard of care (approximately every 12 
weeks, or sooner if clinically indicated). 
CT of the Brain (without and with contrast) can be performed if 
MRI is contraindicated. 
See Section 5.4
Other Imaging (eg, Bone Scan)
See Notes
As clinically indicated per local standards. See Section 5.4 for 
further details.
Pharmacokinetic (PK) Assessmentsb
Blood PK Sampling
x
Refer to Table 5.5.1-3 for specific PK sampling time points. See 
Section 5.5.
Immunogenicity (ADA) Assessmentsb
Blood ADA Sampling
x
Refer to Table 5.5.1-3 for specific ADA sampling time points. See 
Section 5.5.
Outcomes Research Assessments
QLQ-C30 Questionnaire
x
x
Assessed prior to dosing every 6 weeks. 
Questionnaires to be administered at the start of the clinic visit 
before the participant sees the physician and before any study-
Protocol Amendment No.: 07
Date: 22-Aug-2022
77
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-4:
On-Treatment Procedural Outline (CA209672) - Part 2, Arm D: nivolumab 3 mg/kg + ipilimumab 1 
mg/kg Q3W × 4, followed by nivolumab 240 mg Q2W
Procedure
Cycles 1 to 2
Q3W (1 cycle = 6 wks) 
Cycle 3+
Q2W (1 cycle = 6 wks)
Notes
Day
1a
Day 
22a
Day 
42a
Day 
1a
Day 
15a
Day 
29a
Day 
42a
related procedures are done (with the exception of procedures 
completed 72 hours prior to visit). If a dose is delayed, the 
administration of the participant-reported outcome measures 
scheduled for that same time point should also be delayed to 
coincide with when that time point’s dosing actually occurs. 
EQ-5D-3L Questionnaire
x
x
Assessed prior to dosing every 6 weeks. 
Questionnaires to be administered at the start of the clinic visit 
before the participant sees the physician and before any study-
related procedures are done (with the exception of procedures 
completed 72 hours prior to visit). If a dose is delayed, the 
administration of the participant-reported outcome measures 
scheduled for that same time point should also be delayed to 
coincide with when that time point’s dosing actually occurs. 
Clinical Drug Supplies
Nivolumab Administration
x
x
x
x
x
Those supplied by BMS or sourced by the investigator.
Ipilimumab Administration
x
x
Those supplied by BMS or sourced by the investigator.
a To be done ± 2 days of scheduled visit. Every effort should be made to schedule visits within the timeframe stated in the protocol. In the case that the visits 
cannot be within the timeframe stated in protocol then the treatment period study procedures can be performed ± 2 days of the scheduled visit.
b As of Protocol Amendment 07: Assessments necessary for monitoring safety will continue per protocol until the follow-up visit 2 or 100 days after study drug 
discontinuation, whichever occurs later. Collection of PK and immunogenicity data is not applicable. Analyses of PK and immunogenicity will be based on the 
samples analyzed before implementation of protocol amendment 07.
Protocol Amendment No.: 07
Date: 22-Aug-2022
78
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-5:
Follow-Up Period (CA209672) –Part 1, Arm A and C
Procedure
Follow-Up
Visit 1a
Last Visit + 30
days (±7 days)
Follow-Up
Visit 2
Previous Follow-
up Visit + 70 Days 
(± 7 days)
Notes
Safety Assessments
Targeted Physical Examination, 
Measurements, Vital Signs, Oxygen
Saturation and Performance Status 
x
x
To assess for potential late emergent study drug related issues. Weight, 
BP, HR, temperature, oxygen saturation and ECOG status.
Targeted physical examination to be performed only as clinically 
indicated. 
Adverse Events Assessment 
(Including SAE) 
x
x
All AEs to be collected for 100 days after last dose of nivolumab 
treatment. 
Participants will be followed for all SAEs, non-serious AEs of special 
interest, and all 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, or for suspected cases, until SARS-CoV-2 infections is ruled 
out.
Review of Concomitant Medications
x
x
ECG
x
As clinically indicated or for study drug related toxicities. 
Laboratory Tests
See Notes
On site/local laboratory testing. 
To be performed at FU1. To be repeated at FU2 if study drug related 
toxicity persists. 
CBC w/differential; Full Chemistry Panel: LDH, AST, ALT, ALP, T.Bili, 
(Direct Bili if T.Bili > ULN), BUN (or serum urea level), creatinine, Ca+, 
Mg+, Na+, K+, Cl-, glucose, albumin, T.Protein
Thyroid function 
See Notes
On site/local laboratory testing. 
To be performed at FU1. To be repeated at FU2 if study drug related 
toxicity persists. 
TSH, (free T3, Free T4 if TSH not within normal limits)
Protocol Amendment No.: 07
Date: 22-Aug-2022
79
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.1-5:
Follow-Up Period (CA209672) –Part 1, Arm A and C
Procedure
Follow-Up
Visit 1a
Last Visit + 30
days (±7 days)
Follow-Up
Visit 2
Previous Follow-
up Visit + 70 Days 
(± 7 days)
Notes
Pregnancy Test
x
x
Serum or urine
Pharmacokinetic (PK) Assessmentsb
Blood PK Sampling
Refer to Table 5.5.1-2 for specific PK sampling time points.
Immunogenicity (ADA) Assessmentsb
Blood ADA Sample
Refer to Table 5.5.1-1 for specific ADA sampling time points. See Section 5.5.
a When a participant discontinues study drug treatment, all remaining visits of that treatment cycle should be completed (without infusion and with only a single 
pharmacokinetic sample taken at applicable visits), and the participant should enter the Follow-up Period (Follow-up 1 and then Follow-up 2). When a participant
is withdrawn from the study (during the Treatment or Follow-up Period), all evaluations associated with that study visit should be performed and the date and 
reason for study discontinuation should be documented on the CRF. Follow-up visit #1 (FU1) occurs approximately 30 days after the last dose (± 7 days) or 
coincides with the date of discontinuation (± 7 days) if date of discontinuation is greater than 30 days after last dose. Follow-Up Visit #2 (FU2) occurs approximately 
70 days (7 days) after FU1. Both Follow Up visits should be conducted in person.
b As of Protocol Amendment 07: Assessments necessary for monitoring safety will continue per protocol until FU2 or 100 days after study drug discontinuation, 
whichever occurs later. Collection of PK and immunogenicity data is not applicable. Analyses of PK and immunogenicity will be based on the samples analyzed 
before implementation of protocol amendment 07.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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BMS-936558
nivolumab
Table 5.1-6:
Follow-Up Period (CA209672) –Part 1, Arm B
Procedure
Follow-Up
Visit 1a
Last Visit + 30 
days (±7 days)
Follow-Up
Visit 2
Previous Follow-up 
Visit + 70 Days 
(± 7 days)
Notes
Safety Assessmentsb
Targeted Physical Examination, 
Measurements, Vital Signs, Oxygen 
Saturation and Performance Status 
x
x
To assess for potential late emergent study drug related issues. 
Weight, BP, HR, temperature, oxygen saturation and ECOG status.
Targeted physical examination to be performed only as clinically 
indicated. 
Adverse Events Assessment (Including 
SAE) 
x
x
All AEs to be collected for 100 days after last dose of nivolumab 
treatment.
Review of Concomitant Medications
x
x
ECG
x
As clinically indicated or for study drug related toxicities.
Laboratory Tests
See Notes
On site/local laboratory testing. 
To be performed at FU1. To be repeated at FU2 if study drug 
related toxicity persists. 
CBC w/differential; Full Chemistry Panel: LDH, AST, ALT, ALP, 
T.Bili, (Direct Bili if T.Bili > ULN), BUN (or serum urea level), 
creatinine, Ca+, Mg+, Na+, K+, Cl-, glucose, albumin, T.Protein
Thyroid function
See Notes
On site/local laboratory testing. 
To be performed at FU1. To be repeated at FU2 if study drug 
related toxicity persists. 
TSH, (free T3, Free T4 if TSH not within normal limits)
Pregnancy Test
x
x
Serum or urine 
Protocol Amendment No.: 07
Date: 22-Aug-2022
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BMS-936558
nivolumab
Table 5.1-6:
Follow-Up Period (CA209672) –Part 1, Arm B
Procedure
Follow-Up
Visit 1a
Last Visit + 30 
days (±7 days)
Follow-Up
Visit 2
Previous Follow-up 
Visit + 70 Days 
(± 7 days)
Notes
Participant Status
Survival Status and Subsequent Therapy 
Information 
x
x
May be accomplished by visit, phone contact, or email.
Pharmacokinetic (PK) Assessmentsb
Blood PK Sampling
Refer to Table 5.5.1-2 for specific PK 
sampling time points.
Immunogenicity (ADA) Assessmentsb
Blood ADA Sample
Refer to Table 5.5.1-1 for specific ADA 
sampling time points. See Section 5.5.
a When a participant discontinues study drug treatment, all remaining visits of that treatment cycle should be completed (without infusion and with only a single 
pharmacokinetic sample taken at applicable visits), and the participant should enter the Follow-up Period (Follow-up 1 and then Follow-up 2). When a participant
is withdrawn from the study (during the Treatment or Follow-up Period), all evaluations associated with that study visit should be performed and the date and 
reason for study discontinuation should be documented on the CRF. Follow-up visit #1 (FU1) occurs approximately 30 days after the last dose (± 7 days) or 
coincides with the date of discontinuation (± 7 days) if date of discontinuation is greater than 30 days after last dose. Follow-Up Visit #2 (FU2) occurs approximately 
70 days (7 days) after FU1. Both Follow Up visits should be conducted in person.
b As of Protocol Amendment 07: Assessments necessary for monitoring safety will continue per protocol until FU2 or 100 days after study drug discontinuation, 
whichever occurs later. Collection of PK and immunogenicity data is not applicable. Analyses of PK and immunogenicity will be based on the samples analyzed 
before implementation of protocol amendment 07.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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BMS-936558
nivolumab
Table 5.1-7:
Follow-Up Period (CA209672) –Part 2, Arm D
Procedure
Follow-Up
Visit 1a
Last Visit + 
30 days (±7 
days)
Follow-Up
Visit 2
Previous 
Follow-up Visit 
+ 70 Days 
(± 7 days)
Notes
Safety Assessmentsb
Targeted Physical Examination, 
Measurements, Vital Signs, and 
Performance Status 
x
x
To assess for potential late emergent study drug related issues. Weight, BP, 
HR, temperature, and ECOG status.
Targeted physical examination to be performed only as clinically indicated. 
Adverse Events Assessment 
(Including SAE) 
x
x
All AEs to be collected for 100 days after last dose of nivolumab treatment. 
For participants assigned to treatment and never treated with study drug, SAEs 
should be collected for 30 days from the date of treatment assignment.
Review of Concomitant Medications
x
x
ECG
x
As clinically indicated or for study drug related toxicities.
Laboratory Tests
See Notes
On site/local laboratory testing. 
To be performed at FU1. To be repeated at FU2 if study drug related toxicity 
persists. 
CBC w/differential; Full Chemistry Panel: LDH, AST, ALT, ALP, T.Bili, 
(Direct Bili if T.Bili > ULN), BUN (or serum urea level), creatinine, Ca+, 
Mg+, Na+, K+, Cl-, glucose, albumin, T.Protein
Thyroid function
See Notes
On site/local laboratory testing. 
To be performed at FU1. To be repeated at FU2 if study drug related toxicity 
persists. 
TSH, (free T3, Free T4 if TSH not within normal limits)
Pregnancy Test
x
x
Serum or urine
Protocol Amendment No.: 07
Date: 22-Aug-2022
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BMS-936558
nivolumab
Table 5.1-7:
Follow-Up Period (CA209672) –Part 2, Arm D
Procedure
Follow-Up
Visit 1a
Last Visit + 
30 days (±7 
days)
Follow-Up
Visit 2
Previous 
Follow-up Visit 
+ 70 Days 
(± 7 days)
Notes
Efficacy Assessments
Tumor assessmentsb
Participants who enter the follow-up period will continue to have tumor imaging assessments by investigators and 
BICR as per on-treatment schedule: every 6 weeks from date of first dosing for the first 24 weeks, and then every 12 
weeks thereafter until initiation of subsequent anti-cancer treatment or until 100 days post study drug discontinuation. 
See Section 5.4 for details on methodology. 
Brain Imaging 
Participants with a history of brain metastasis or symptoms should have surveillance MRI per standard of care 
(approximately every 12 weeks) or sooner if clinically indicated. See Section 5.4 for further details. No brain 
imaging beyond 100 days post study drug discontinuation is necessary.
Other Imaging (eg., Bone Scan) 
As clinically indicated per local standards. See Section 5.4 for further details. No other imaging beyond 100 days 
post study drug discontinuation is necessary.
Outcomes Research Assessments
QLQ-C30 Questionnaire
x
x
No collection beyond 100 days post study drug discontinuation is necessary.
EQ-5D-3L Questionnaire
x
x
Can be collected either during a clinic visit or by telephone. No collection 
beyond 100 days post study drug discontinuation is necessary.
Participant Status
Survival Status and Subsequent 
Therapy Information 
x
x
May be accomplished by visit, phone contact, or email. No collection beyond 
100 days post study drug discontinuation is necessary.
a When a participant discontinues study drug treatment, all remaining visits of that treatment cycle should be completed (without infusion and with only a single 
pharmacokinetic sample taken at applicable visits), and the participant should enter the Follow-up Period (Follow-up 1 and then Follow-up 2). When a participant
is withdrawn from the study (during the Treatment or Follow-up Period), all evaluations associated with that study visit should be performed and the date and 
reason for study discontinuation should be documented on the CRF. Follow-Up Visit #1 (FU1) occurs approximately 30 days (7 days) after last dose or coinciding 
Protocol Amendment No.: 07
Date: 22-Aug-2022
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BMS-936558
nivolumab
with the date of discontinuation (7 days) if date of discontinuation is greater than 35 days after last dose. Follow-Up Visit #2 (FU2) occurs approximately 70 
days (7 days) after FU1. Both Follow Up visits should be conducted in person.
b
As of Protocol Amendment 07: Assessments necessary for monitoring safety and tumor assessments will continue per protocol until FU2 or 100 days after 
study drug discontinuation, whichever occurs later. 
Protocol Amendment No.: 07
Date: 22-Aug-2022
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BMS-936558
nivolumab
5.1.1
Retesting During Screening or Lead-in Period
This study is not actively enrolling participants.
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to dosing) and 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 5.1-1, Screening Procedural 
Outline, may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the medical monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
5.2
Study Materials
The following materials will be provided at study start:

NCI CTCAE version 4.0

Nivolumab/ipilimumab IBs

Laboratory manuals for collection and handling of blood (including PK, biomarker, and 
immunogenicity) and tissue specimens

Site manual for operation of IVRS

Enrollment worksheets

Serious Adverse Event (or eSAE) CRF pages

Pregnancy Surveillance Forms
The site will provide all materials required for accurate source documentation of study activities 
and for housing the participants during the study. The site will source marketed product from a 
single commercial lot.
BMS will provide a BMS-approved protocol and any amendments or administrative letters (if 
required). Case report forms (electronic) will be provided by BMS. The central laboratory will 
provide labels and tubes for the collection of blood samples for PK analysis.
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. Baseline 
signs and symptoms are those that are assessed within 2 weeks prior to dosing. The baseline 
physical examination should include weight, height, BP, HR, and temperature. These should be 
performed within 28 days of treatment. Concomitant medications will be collected from within 
2 weeks prior to treatment assignment through the study treatment period.
Testing for asymptomatic SARS-CoV-2 infection, for example 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 
Protocol Amendment No.: 07
Date: 22-Aug-2022
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Clinical Protocol
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BMS-936558
nivolumab
have asymptomatic SARS-CoV-2 infection during the screening period. In such cases, participants 
may be eligible for the study after recovery from infection or completion of quarantine period in 
case of asymptomatic infection/potential exposure.
Toxicity assessments will be continuous during the treatment phase until 100 days (equal to 
approximately 5 half-lives of nivolumab) after the last dose of nivolumab. 
Adverse events and laboratory values will be graded according to the NCI CTCAE version 4.0.
Vital signs should be taken as per institutional standard of care at visits and prior to, during, and 
after the infusion with nivolumab. The start and stop time of the study drug infusion should be 
documented. If there are any new or worsening clinically significant changes since the last exam, 
report these changes on the appropriate AE or SAE page.
Perform additional measures, including non-study required laboratory tests, 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 
drug-related toxicities resolve, return to baseline, or are deemed irreversible.
Evaluate participant immediately to rule out cardiac or pulmonary toxicity if participant shows 
cardiac or pulmonary-related signs (hypoxia, abnormal heart rate, or changes from baseline) or 
symptoms (eg, dyspnea, cough, chest pain, fatigue, palpitations).
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.1
Laboratory Test Assessments
A central/local laboratory will perform the analyses and will provide reference ranges for these 
tests.
Results of clinical laboratory tests performed on Day -1 visit must be available prior to dosing.
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
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 (see Section 6.3).
Please refer to Table 5.1-1, Table 5.1-2, Table 5.1-3, Table 5.1-4, Table 5.1-5, Table 5.1-6, and 
Table 5.1-7 for required laboratory tests and schedule.
5.4
Efficacy Assessments
5.4.1
Imaging and Clinical Assessment
Change in tumor measurements and tumor response will be assessed by investigators (Part 1) or 
by both BICR and investigators (Part 2) using the RECIST 1.1 criteria (Appendix 1).
Protocol Amendment No.: 07
Date: 22-Aug-2022
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Study evaluations will take place in accordance with Table 5.1-1, Table 5.1-2, Table 5.1-3, Table 
5.1-4, Table 5.1-5, Table 5.1-6, and Table 5.1-7.
Baseline assessments should be performed within 28 days before date of first dosing. Chest, 
abdomen, pelvis and any clinically indicated sites determined by the investigator should be 
assessed at baseline. Subsequent assessments should utilize the same imaging modality. For Part 
1, tumor response should be evaluated every 6 weeks from date of first dosing for the first 24 weeks
(between days 35 and 42 of the cycle), and then every 12 weeks (between days 35 and 42 of the 
cycle) thereafter until disease progression (including treatment beyond progression) or 
unacceptable toxicities. For Part 2, tumor response should be evaluated every 6 weeks (between 
days 35 and 42 of the cycle) from date of first dosing for the first 24 weeks and then every 12 weeks
(between days 35 and 42 of the cycle) thereafter until initiation of subsequent anti-cancer treatment.
Tumor assessments for all participants should continue as per protocol even if dosing is delayed 
or discontinued. Changes in tumor measurements and tumor responses will be assessed by the 
same investigator per study design using RECIST 1.1 criteria. Investigators will also report the 
number and size of new lesions that appear while on study. The time point of tumor assessments 
will be reported on the eCRF based on the investigator’s assessment using RECIST 1.1 criteria 
(See Appendix 1). Assessments of PR and CR must be confirmed at least 4 weeks (28 days) after 
initial response. A Best Overall Response of SD requires a minimum of 35 days on study from 
date of first dosing to the date of the first imaging assessment.
Tumor assessments at other time points may be performed if clinically indicated, and should be 
submitted to the central imaging vendor as soon as possible for Part 2. Unscheduled CT/MRI 
should be submitted to central imaging vendor. X-Ray and bone scans that clearly demonstrate 
interval progression of disease, most commonly as unequivocal lesions that are unmistakably new 
since the prior CT/MRI, should be submitted to central imaging vendor. Otherwise, radiographs 
do not need to be submitted centrally.
5.4.2
Imaging Assessment by BICR for Part 2
For Part 2, images will be submitted to a central imaging vendor for blinded independent central 
review (BICR) at any time during the study. Sites should be qualified prior to scanning the first 
study participant and understand the image acquisition guidelines and submission process as 
outlined in the CA209-672 Imaging Manual to be provided by the vendor. 
Sites should submit all scans to a BICR, preferably within 7 days of scan acquisition, throughout 
the duration of the study. BICR will review scans, and remain blinded to treatment arm and 
investigator assessment of submitted scans. 
Participants should undergo tumor assessments by both investigators and BICR continuously 
according to the protocol-specified (Section 5.1) schedule, or sooner if clinically indicated. Scans 
should be submitted to BICR until initiation of subsequent anti-cancer therapy. Collect any 
additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled timepoints and/or at an outside institution) for RECIST 1.1 tumor 
assessment and submit to the BICR.
Protocol Amendment No.: 07
Date: 22-Aug-2022
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All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment. 
5.4.3
Methods of Measurement
CT with contrast of the chest, abdomen, pelvis, and any clinically indicated sites are to be 
performed for tumor assessments at the time points outlined in Table 5.1-1, Table 5.1-2, Table 5.1-
3, Table 5.1-4, Table 5.1-5, Table 5.1-6 and Table 5.1-7. 
CT scans should be acquired with 5 mm slices with no intervening gap (contiguous). Should a 
participant have a contraindication for CT IV contrast, a non-contrast CT of the chest and a contrast 
enhanced MRI of the abdomen and pelvis may be obtained. MRI’s should be acquired with slice 
thickness of 5 mm and < 2 mm gap (preferably no gap/contiguous). Every attempt should be 
made to image each participant using an identical acquisition protocol on the same scanner for all 
imaging time points.
MRI brain scans during on-study treatment and follow up periods are required only if there is a 
prior history of lesions present at Screening, or as clinically indicated for new signs and symptoms 
that suggest CNS involvement.
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the investigator as per standard 
medical/clinical judgment.
5.5
Pharmacokinetic and Immunogenicity Assessments
Collection of PK and immunogenicity data is not applicable per Protocol Amendment 07. Analyses 
will be based on the samples analyzed before implementation of protocol amendment 07. The
following information refers to the original study design and is not applicable per Protocol 
Amendment 07.
5.5.1
Pharmacokinetic and Immunogenicity Collection & Processing
Table 5.5.1-1 (Part 1, Arm A), Table 5.5.1-2 (Part 1, Arms B and C), and Table 5.5.1-3 (Part 2, 
Arm D) list the sampling schedule to be followed to assess the PK and immunogenicity of 
nivolumab and ipilimumab. Blood samples should be drawn from a site other than the infusion site 
(ie, contralateral arm) on days of infusion. All predose samples should be collected just prior to 
the start of infusion administration, and end-of-infusion (EOI) samples should be collected as close 
to EOI as possible (preferably within 2 minutes prior to EOI) from the contralateral arm (ie, the 
arm not for the 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 and ADA 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, an additional 
predose sample should not be collected. If the infusion was interrupted, the reason for interruption 
should also be documented on the CRF. Blood samples will be processed to collect serum. The 
serum samples will be analyzed for nivolumab and ipilimumab by validated methods. Further 
Protocol Amendment No.: 07
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details of blood collection, labeling, processing, storage and shipping will be provided to the site 
in the procedure manual.
Table 5.5.1-1:
Pharmacokinetics and Immunogenicity Sampling Schedule for 
Nivolumab and Ipilimumab (Part 1, Arm A)
CYCLE
(1 CYCLE = 6 
WEEKS)
Study Day 
of Sample 
Collectiona
Event
Time 
(Relative To 
Start of 
Infusion of 
Nivolumab)
Hour: Min
PK
Blood 
Sample 
for nivob
PK
Blood 
Sample 
for ipib
ADA 
Blood 
Sample 
for nivob
ADA 
Blood 
Sample 
for ipib
Cycle 1 Week 1
1
Predosec
00:00
X
X
X
X
EOI of ipid
01:30
X
X
08:00
X
X
2
24:00
X
X
3
48:00
X
X
5
96:00
X
X
Cycle 1 Week 2
8
168:00
X
X
Cycle 1 Week 3
15
predosec
00:00
X
X
X
X
Cycle 2 Week 3
15
predosec
00:00
X
X
X
X
Cycle 3 Week 1
1
predosec
00:00
X
X
EOI of ipid
01:30
X
X
08:00
X
X
2
24:00
X
X
3
48:00
X
X
5
96:00
X
X
Cycle 3 Week 2
8
168:00
X
X
Cycle 3 Week 3
15
predosec
00:00
X
X
Cycle 4 Week 3
15
predosec
00:00
X
X
X
X
Day 15 of every 
3rd cycle after 
cycle 4 week 3 
until 
discontinuation 
of Study 
Treatment  
15
predosec
00:00
X
X
X
X
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Date: 22-Aug-2022
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Clinical Protocol
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BMS-936558
nivolumab
Table 5.5.1-1:
Pharmacokinetics and Immunogenicity Sampling Schedule for 
Nivolumab and Ipilimumab (Part 1, Arm A)
CYCLE
(1 CYCLE = 6 
WEEKS)
Study Day 
of Sample 
Collectiona
Event
Time 
(Relative To 
Start of 
Infusion of 
Nivolumab)
Hour: Min
PK
Blood 
Sample 
for nivob
PK
Blood 
Sample 
for ipib
ADA 
Blood 
Sample 
for nivob
ADA 
Blood 
Sample 
for ipib
Follow-Up 
Visits 1 & 2
(EXCEPT for 
participants that 
WITHDRAW 
CONSENT)
X
X
X
X
a If a participant permanently discontinues both nivolumab and ipilimumab study drug treatment during the sampling 
period, they will move to sampling at follow-up visits.
b If ipilimumab is discontinued and nivolumab continues, then nivolumab PK and ADA samples are continued to be 
collected, and ipilimumab PK and ADA should be collected only for the next 2 predose time points corresponding 
to nivolumab collection.
c Predose samples should be collected on the day of dosing just prior to the start of the infusion (preferably within 
30 minutes). For combination dosing, predose samples for both nivolumab and ipilimumab should be collected 
prior to the start of nivo infusion. 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, an additional predose sample should not be collected.
d EOI: End of Infusion. This sample should be collected immediately prior to stopping the infusion. For combination 
dosing, both nivo and ipi EOI samples should be collected immediately prior to stopping the ipilimumab infusion 
(preferably within 2 minutes prior to the end of ipi infusion). In the event of a delay in ipi infusion administration 
beyond 30 min, the EOI samples should be collected immediately prior to the actual END of the infusion. 
Ipilimumab infusion should be started no less than 30 min after stopping the nivolumab infusion.
Table 5.5.1-2:
Pharmacokinetics and Immunogenicity Sampling Schedule for 
Nivolumab and Ipilimumab (Part 1, Arms B and C)
CYCLE
(1 CYCLE =6 
WEEKS)
Study Day 
of Sample 
Collectiona
Event
Time 
(Relative To 
Start of 
Infusion of 
Nivolumab)
Hour: Min
PK
Blood 
Sample 
for nivo 
PK
Blood 
Sample 
for ipi
ADA 
Blood 
Sample 
for nivo
ADA Blood 
Sample for 
ipi
Cycle 1 Week 1
1
Predoseb
00:00
X
X
X
X
EOI of ipic
01:30
X
X
08:00
X
X
2
24:00
X
X
3
48:00
X
X
5
96:00
X
X
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Date: 22-Aug-2022
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Clinical Protocol
CA209672
BMS-936558
nivolumab
Table 5.5.1-2:
Pharmacokinetics and Immunogenicity Sampling Schedule for 
Nivolumab and Ipilimumab (Part 1, Arms B and C)
CYCLE
(1 CYCLE =6 
WEEKS)
Study Day 
of Sample 
Collectiona
Event
Time 
(Relative To 
Start of 
Infusion of 
Nivolumab)
Hour: Min
PK
Blood 
Sample 
for nivo 
PK
Blood 
Sample 
for ipi
ADA 
Blood 
Sample 
for nivo
ADA Blood 
Sample for 
ipi
Cycle 1 Week 2
8
168:00
X
X
Cycle 1 Week 3
15
336:00
X
X
Cycle 1 Week 4
22
predoseb
00:00
X
X
Cycle 2 Week 1
1
predoseb
00:00
X
X
X
X
Cycle 2 Week 4
22
predoseb
00:00
X
X
EOI of ipic
01:30
X
X
08:00
X
X
23
24:00
X
X
24
48:00
X
X
26
96:00
X
X
Cycle 2 Week 5
29
168:00
X
X
Cycle 2 Week 6
36
336:00
X
X
Cycle 3 Week 1
1
predoseb
00:00
X
X
X
X
Cycle 5 Week 1d
1
predoseb
00:00
X
X
Day 1 of every 
3rd cycle (18 
weeks) after C5 
until 
discontinuation 
of Study 
Treatmentd
1
predoseb
00:00
X
X
Follow-Up Visits
1 & 2 (EXCEPT 
for participants 
who 
WITHDRAW 
CONSENT)d
X
X
a If a participant permanently discontinues study drug treatment during the sampling period, they will move to 
sampling at follow-up visits.
b Predose samples should be collected on the day of dosing just prior to the start of the infusion (preferably within 
30 minutes). For combination dosing, predose samples for both nivo and ipi should be collected prior to the start of 
nivo infusion. If it is known that a dose is going to be delayed, then the predose sample should be collected just 
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prior to the delayed dose. However, if a predose sample is collected but the dose is subsequently delayed, an 
additional predose sample should not be collected
c EOI: End of Infusion. This sample should be taken immediately prior to stopping the infusion. For combination 
dosing, both nivo and ipi EOI samples should be collected immediately prior to stopping the ipilimumab infusion 
(preferably within 2 minutes prior to the end of ipi infusion). In the event of a delay in ipi infusion administration 
beyond 30 min, the EOI samples should be collected immediately prior to the actual END of the infusion. 
Ipilimumab infusion should be started no less than 30 min after stopping the nivolumab infusion.
d Only nivolumab PK and ADA blood samples will be collected from Cycle 5 and beyond. Samples are not required 
to be collected for follow-up visits.
Table 5.5.1-3:
Pharmacokinetics and Immunogenicity Sampling Schedule for 
Nivolumab and Ipilimumab (Part 2, Arm D)
CYCLE
(1 CYCLE = 6 
WEEKS)
Study Day 
of Sample 
Collection
Event
Time
(Relative to 
Start of 
Infusion of 
Nivolumab)
Hour: Min
PK
Blood 
Sample 
for Nivo 
PK
Blood 
Sample
for Ipi
ADA 
Blood 
Sample 
for Nivo
ADA Blood 
Sample for 
Ipi
Cycle 1 Week 1
1
Predosea
00:00
X
X
X
X
Cycle 1 Week 4
22
Predosea
00:00
X
X
Cycle 2 Week 1
1
Predosea
00:00
X
X
X
X
Cycle 3 Week 1
1
Predosea
00:00
X
X
X
X
Cycle 5 Week 1
1
Predosea
00:00
X
X
X
X
Week 1 Day 1 of 
every 4th cycle 
(24 weeks) after 
C5 until 
discontinuation 
of study 
treatment
1
Predosea
00:00
X
X
Note: Samples are not required to be collected for Arm D per Protocol Amendment 07.
a Predose samples should be collected on the day of dosing just prior to the start of the infusion (preferably within 
30 minutes). For combination dosing, predose samples for both nivo and ipi should be collected prior to the start of 
nivo infusion. 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, an 
additional predose sample should not be collected.
5.5.2
Pharmacokinetic Sample Analyses
The serum samples will be analyzed for nivolumab and ipilimumab by validated methods.
5.5.3
Labeling and Shipping of Biological Samples
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
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5.6
Biomarker Assessments
5.6.1
Part 1
Arms A, B, and C: Not applicable.
5.6.2
Part 2
Tumor biopsy specimens will be obtained from consenting participants prior to treatment with 
nivolumab combined with ipilimumab to confirm MSI/MMR status in central lab. 
Fresh biopsies is preferred for biomarker analysis if accessible and deemed safe by the investigator. 
The fresh biopsies submitted to central lab must be the same tissue sample as was used for local 
MSI/MMR testing.
If fresh biopsy cannot be obtained, archived tumor tissue (a block or 10 slides) prior to therapy is 
acceptable only if the archived tissue is the same tissue that was used for local MSI/MMR testing. 
Central lab must confirm receipt of evaluable tumor tissue prior to vial assignment. 
NOTE: Exceptions to above requirements need to be discussed with the medical monitor and will
be handled in a case-by-case basis. An additional source of tumor tissue must be available if the 
tissue obtained adhering to the above guidelines can’t be tested due to poor quality or quantity. 
5.7
Exploratory Biomarker Assessments
Not applicable.
5.8
Outcomes Research Assessments
5.8.1
Part 1
Not applicable.
5.8.2
Part 2
Outcomes research data including health-related quality of life and participant-reported symptom 
burden provide a more complete understanding of the impact of treatment by incorporating the 
patients’ perspective. These data offer insights into the patient experience that may not be captured 
through physician reporting. The EQ-5D (EQ-5D-3L) will be collected in order to assess the 
impact of nivolumab on generic health-related quality of life, and the data will be used for 
populating health economic models, most notably, cost effectiveness analysis. The QLQ-C30 will 
be collected in order to assess cancer-specific, health-related quality of life. The combination of 
the generic scale for general health status and economic evaluation and the cancer specific scale 
will provide a robust outcomes research package.
The QLQ-C30 is a 30-item instrument comprising six functional scales (physical functioning, 
cognitive functioning, emotional functioning, role functioning, social functioning, and global 
quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties). Except for the overall health status 
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and global quality of life items, responses for all items are 4-point categorical scales ranging from 
1 (Not at all) to 4 (Very much). The overall health status/quality of life responses are 7-point Likert 
scales. It has gone through appropriate psychometric testing and is available in over 81 languages.
General health status will be measured using the EQ-5D. The EQ-5D is a standardized instrument 
for use as a measure of self-reported general health status. The EQ-5D comprises five dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety) and a visual analog scale 
(VAS). The utility data generated from the EQ-5D is recommended for and commonly used in 
cost effectiveness analysis. If exceptional circumstances preclude the continued administration of 
measures using planned modalities, then alternate administration methods may be required, after 
consultation with the Sponsor or the Sponsor’s representative.
Please refer to procedural tables found in Section 5.1 for information regarding the timing of 
outcomes research assessments using the EQ-5D-3L and QLQ-C30.
5.9
Other Assessments
5.9.1
Immunogenicity Assessment
Collection of immunogenicity data is not applicable per Protocol Amendment 07. Analyses will 
be based on the samples analyzed before implementation of protocol amendment 07. The 
following information refers to the original study design and is not applicable per Protocol 
Amendment 07.
Blood samples for immunogenicity analysis will be collected from all participants at time points 
specified in Table 5.5.1-1, Table 5.5.1-2, and Table 5.5.1-3. Serum will be analyzed by validated 
immunogenicity assays. All on-treatment immunogenicity sampling time points are intended to 
align with days on which study drug is administered, if dosing occurs on a different day, the 
sampling should be adjusted accordingly. Samples may be analyzed for neutralizing antibodies by 
a validated method. The corresponding serum samples designated for either PK, immunogenicity,
or biomarker assessments may also be used for any of those analyses, if required (eg, insufficient 
sample volume to complete testing, follow up on suspected immunogenicity related AE, etc.).
Detailed instructions for the immunogenicity blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
5.10
Additional Research Collection
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of study drug, whether or not considered related to the 
study drug.
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Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form. Every adverse event must be assessed by the 
investigator with regard to whether it is considered immune-mediated. For events which are 
potentially immune-mediated, additional information will be collected on the participant’s case 
report form.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term “reasonable causal relationship” means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
BMS will be reporting AEs to regulatory authorities and ethics committees according to local 
applicable laws including European Directive 2001/20/EC and Code of Federal Regulations 21 
CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug-induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
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Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential DILI are not always serious by regulatory 
definition, these events must be handled as SAEs. (See Section 6.1.1 for reporting pregnancies.)
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 (eg, 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the IB represent the Reference Safety Information to determine 
expectedness of SAEs for expedited reporting. 

Following the participant’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be associated 
with protocol-specified procedures. All SAEs must be collected that occur during the screening 
period and within 100
days of discontinuation of dosing. However, any SAE occurring after 
the start of a new treatment that is suspected to be related to study treatment by the investigator 
will be reported.

For participants assigned to treatment and never treated with study drug, SAEs should be 
collected for 30 days from the date of treatment assignment.

The investigator must report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure (eg, a follow-up skin biopsy).

Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF module.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours.
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
The investigator will submit any updated SAE data to the sponsor or designee within 24 hours 
of updated information being available.
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS or 
designee within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning. 
In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
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 drug 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.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as an SAE.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of non-serious AE (with the exception of non-serious AEs related to SARS-CoV-2 
infection) information should begin at initiation of study treatment and continue during the 
treatment period and for a minimum of 100 days following discontinuation of study treatment. . 
Non-serious AE information should also be collected from the start of a placebo lead-in period or 
other observational period intended to establish a baseline status for the participants. All AEs 
(SAEs and non-serious AEs) associated with confirmed or suspected SARS-CoV-2 infection must 
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be collected from the date of the participant’s written consent until 100 days following 
discontinuation of dosing.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest and AEs (SAEs 
and non-serious AEs) associated with confirmed or suspected SARS-CoV-2 infection will be 
followed until resolution, until the condition stabilizes, until the event is otherwise explained, until 
the event is deemed irreversible, or until the participant is lost to follow-up (as defined in 
Section 3.6.2), or for suspected cases, until SARS-CoV-2 infection is ruled out. 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.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (electronic) as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.3.1
Clinical Safety Laboratory Assessments
Hematology - CBC
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin (Direct Bili if T.Bili > ULN)
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN) or serum UREA
Glucose
Albumin
Total protein
Sodium
Potassium
Chloride
Calcium
Magnesium
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Amylase, Lipase - on treatment
TSH, with reflexive fT3 and fT4 if TSH is 
abnormal - on treatment 
Serology
Hepatitis B/C, (HBV sAG, HCV antibody or HCV RNA), - screening only
HIV1/2 antibody-screening only
Other Analyses
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG).
Follicle stimulating hormone (FSH) screening - only required to confirm menopause in women 
< age 55) 
Abbreviations: CBC = complete blood count; HBVsAG = hepatitis B surface antigen; HCG = human chorionic 
gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IU = international unit; L = liter; RNA 
= ribonucleic acid; fT3 = free triiodothyronine; fT4 = free thyroxine; TSH = thyroid-stimulating hormone; ULN = 
upper limit normal; WOCBP = women of childbearing potential.
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of study exposure, including during 
at least 5 half-lives 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 the BMS designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24 hours 
of awareness of the pregnancy.
The investigator must immediately notify the BMS medical monitor or designee of this event and 
complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours of 
awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome, and where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
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6.6
Potential Drug Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential DILI is defined as: 
1. Aminotransaminases (AT) (ALT or AST) elevation > 3 times ULN
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, or any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
For part 2, a BICR will be used for determination of BICR-assessed ORR and other efficacy 
endpoints. Details of BICR responsibilities and procedures will be specified in the BICR charter. 
Images will be submitted to an imaging third-party vendor for central review. Sites will be trained 
prior to enrolling the first study patient. Imaging acquisition guidelines and submission process 
will be outlined in the Study Imaging Manual to be provided by the vendors. Refer to Section 5.4
Imaging Assessment for the Study for further details. 
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
8.1.1
Part 1
With 9 participants in each arm, if 0, 1, 2, or 3 participants experienced DLTs, the upper limit of 
the one-sided exact 90% CI for the true DLT rate will be less than 23%, 37%, 49%, and 60% 
respectively. The calculations are based on the Clopper-Pearson method for the exact confidence 
intervals.
8.1.2
Part 2
With an estimated discrepancy rate of 25% between local and repeating testing in central lab for 
MSI/MMR status, it is expected that approximately 33 participants with MSI-H/dMMR mCRC 
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determined by local testing will be treated in the study. A sample size of 33 will allow the lower 
bound of one-sided 95% CI excluding 35% when the observed ORR is 50% in the 
nivolumab/ipilimumab combination arm. The 35% ORR is expected for local diagnosed 
MSI-H/dMMR mCRC patients treated with PD-1 inhibitor monotherapy. This sample size will 
also provide at least 90% power to demonstrate statistical difference with historical ORR of 5% 
for TKI monotherapy in a similar setting at a two-sided alpha of 0.05.
Based on the estimated discrepancy rate between local and central MSI/MMR testing, of 33 treated
participants, approximately 25 participants will have their MSI-H/dMMR status confirmed by 
repeating central lab testing. During the study, the discrepancy rate will be monitored in an ongoing 
basis, and study accrual may continue beyond 33 if the discrepancy rate exceeds 25%.
Due to challenges with enrollment, the enrollment for Part 2 was closed after 9 participants were 
treated, out of the 33 participants planned. 
8.2
Populations for Analyses
The following participant populations will be used in the study:

All enrolled participants: All participants who signed an ICF and were registered into the 
IVRS;

All treated participants: All participants who received at least one dose of study medication;

Pharmacokinetic Population: All participants who received any study drug and have available 
concentration time data;

Immunogenicity Population: All participants who received any study drug and have at least 
one post treatment immunogenicity measurement;

Biomarker Population: All MSI-H/dMMR CRC centrally confirmed participants who received 
any study drug unless otherwise stated
8.3
Endpoints
8.3.1
Primary Endpoint(s)
8.3.1.1
Part 1
The primary objective of Part 1 is to characterize the safety and tolerability of nivolumab plus 
ipilimumab in Chinese participants. The primary objective will be measured by:

Number and percent of all treated participants that experience AEs occurring up to 100 days 
after the last dose of study drug (time frame - on a continuous basis up to 100 days after the 
last dose of study drug)

Number and percent of all treated participants that experience SAEs occurring up to 100 days 
after the last dose of study drug (time frame - on a continuous basis up to 100 days after the 
last dose of study drug)

Number and percent of all treated participants that experience AEs leading to discontinuation 
occurring up to 100 days after the last dose of study drug (time frame - on a continuous basis 
up to 100 days after the last dose of study drug)
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
Number and percent of all treated participants that experience AEs leading to death occurring 
up to 100 days after the last dose of study drug (time frame - on a continuous basis up to 100
days after the last dose of study drug)

Number and percent of participants with clinical laboratory abnormalities by worst toxicity 
grade by NCI CTCAE version 4.0 (as assessed at the planned times listed in Table 5.1-1, Table 
5.1-2, Table 5.1-3, Table 5.1-4, Table 5.1-5, Table 5.1-6 and Table 5.1-7) (time frame - on a 
continuous basis up to 100 days after the last dose of study drug)
8.3.1.2
Part 2
The primary objective of Part 2 will be measured by the primary endpoint of BICR-assessed ORR. 
It is defined as the number of participants with a BOR of confirmed CR or PR, according to 
RECIST 1.1 criteria, divided by the number of treated participants. The final analysis of the 
primary endpoint will occur at least 6 months after the last participant’s first dose of study therapy. 
The BOR is defined as the best response designation recorded between the date of first dose and 
the date of initial objectively documented progression per RECIST 1.1 or the date of subsequent 
therapy, whichever occurs first. For participants without documented progression or subsequent 
therapy, all available response designations will contribute to the BOR determination. For
purposes of analysis, if a participant receives one dose and discontinues the study without 
assessment or receives subsequent therapy prior to assessment, this participant will be counted in 
the denominator (as non-respondent). 
The BICR-assessed ORR will be further characterized by rate of CR and PR.
8.3.2
Secondary Endpoint(s)
8.3.2.1
Part 1
Pharmacokinetics
The Part 1 secondary objective of characterizing the PK of nivolumab and ipilimumab in Chinese 
participants will be measured by PK parameters derived from serum concentration versus time 
data by non-compartmental analysis method. Details of PK sample collection are provided in 
Section 5.5. All individual PK parameters will be listed and summarized for each analyte, 
including any exclusions and reasons for exclusion from summaries. The PK parameters to be 
assessed for nivolumab and ipilimumab, if data permits, include

Cmax - Maximum observed serum concentration 

Tmax - Time of maximum observed serum concentration

AUC(0-T) - Area under the plasma concentration-time curve from time zero to the last time of 
the last quantifiable concentration.

AUC(TAU) - Area under the concentration-time curve in one dosing interval 

Ceoinf - Serum concentration achieved at the end of study drug infusion

Ctrough - Trough observed serum concentration at the end of dosing interval

Ctau - Concentration at the end of dosing interval
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
CLT - Total body clearance

Css-avg - Average concentration over a dosing interval (AUC(TAU)/tau)

AI - Accumulation index; ratio of an exposure measure at steady-state to that after the first 
dose (exposure measure includes AUC (TAU), Cmax, or Ctau).

T-HALFeff - Effective elimination half-life that explains the degree of accumulation observed 
for a specific exposure measure (exposure measure includes AUC(TAU), Cmax, or Ctau)
The serum concentration may also be pooled with other datasets for population PK analysis, which 
will be presented in a separate report.
Immunogenicity
The Part 1 secondary objective relating to immunogenicity will be measured by the ADA status 
both at the sample level and at the participant level, and Nab if data permits. At the sample level a 
sample is characterized as baseline ADA-positive and ADA- persistent positive or ADA-negative 
to each study drug. At the participant level, relevant ADA endpoints include proportion of 
participants with a baseline ADA-positive sample, and proportion of ADA- persistent positive 
participants for each study drug. Time points for collection are specified in Table 5.5.1-1 and Table 
5.5.1-2. Additional details will be presented in the statistical analysis plan.
8.3.2.2
Part 2
The secondary endpoint for Part 2 will be measured by:

Investigator-assessed ORR, defined as the proportion of all treated participants whose BOR is 
either confirmed complete response (CR) or confirmed partial response (PR). 

Investigator-assessed and BICR-assessed disease control rate (DCR), defined as the proportion 
of participants whose BOR is confirmed CR or confirmed PR or stable disease (SD) for at least 
12 weeks.

Investigator-assessed and BICR-assessed duration of response (DOR), defined as the time 
between the date of first confirmed response to the date of the first documented tumor 
progression (per RECIST 1.1), or death due to any cause, whichever occurs first

Investigator-assessed and BICR-assessed progression-free survival (PFS), defined as the time 
from the first dosing date to the date of first objectively documented disease progression per 
RECIST 1.1 (ie, radiologic) or death due to any cause, whichever occurs first.
8.3.3
Exploratory Endpoint(s)
8.3.3.1
Part 1
The Part 1 exploratory objective of assessing the anti-tumor response of nivolumab will be 
measured by the following endpoints at participant level:

BOR by investigators using Response Evaluation Criteria in Solid Tumor RECIST 1.1
The following endpoints will be summarized by arm and/or across arm:
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
ORR is defined as the proportion of all treated participants whose BOR is either a CR or PR 
by investigators using RECIST 1.1
1. PFS Rate (PFSR) at 6 months, as defined as the proportion of treated participants remaining 
progression free and surviving at 6 months since the first dosing date. The proportion will be 
calculated by the Kaplan-Meier estimate which takes into account censored data. 
2. Overall Survival (OS) for Arm B participants, defined as the time from the first dosing date to 
the date of death due to any cause. A participant who has not died will be censored at last 
known date alive.
8.3.3.2
Part 2
Part 2 exploratory objectives include the following:

Safety and tolerability of nivolumab in combination with ipilimumab in participants with 
recurrent or metastatic MSI-H/dMMR CRC, as measured by the incidence of AEs and 
specific laboratory abnormalities (worst grade). Toxicities will be graded using the NCI 
CTCAE version 4.0.

PK, which will be measured using serum concentration-time data. 

OS is defined as the time from first dosing date to the date of death due to any cause. A 
participant who has not died will be censored at last known date alive.
Other exploratory endpoints for immunogenicity and outcomes research are discussed in detail in 
Section 5.5 and Section 5.8, respectively.
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender, race, and other categorical demographic variables will be 
tabulated by arm. Summary statistics for age, body weight, height, body mass index (BMI), and 
other categorical demographic variables will be tabulated by arm.
8.4.2
Efficacy Analyses
8.4.2.1
Part 1
Individual participant’s BOR will be listed by arm and/or across arm based on RECIST 1.1. BOR 
outcomes will be tabulated by arm and/or across arms for all treated participants. 
ORR will be calculated and corresponding two-sided 95% exact CIs using Clopper-Pearson 
method will be provided by arm and/or across arms for all treated participants.
PFS will be calculated by the Kaplan-Meier estimate for all treated participants.
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8.4.2.2
Part 2
Primary Endpoint Methods
The BICR-assessed ORR will be summarized. A response-rate estimate and corresponding 
two-sided exact 95% CI using the Clopper-Pearson method will be provided. BICR-assessed ORR 
will be further characterized by the rate of CR and PR.
Secondary and Exploratory Endpoint Methods
ORR based on Investigators’ assessment will be summarized and further characterized by rate of 
CR and PR as above.
BICR-assessed and Investigator-assessed DCR will be summarized and corresponding two-sided 
exact 95% CI using the Clopper-Pearson method will be provided.
BICR-assessed and Investigator-assessed DOR will be listed for participants who achieve 
confirmed PR or CR.
PFS and OS will be listed. 
8.4.3
Safety Analyses
Part 1
All recorded AEs will be listed and tabulated by system organ class, preferred term and treatment. 
Vital signs and clinical laboratory test results will be listed and summarized by treatment. Any 
significant physical examination findings, and clinical laboratory results will be listed. ECG 
readings will be evaluated by the investigator and abnormalities, if present, will be listed.
Part 2
Safety analyses will be performed in all treated participants. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.0. On-study AEs will be tabulated using worst grade per 
NCI CTCAE v4.0 criteria by system organ class and Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term. On-study lab parameters including hematology, chemistry, liver 
function, thyroid function, and renal function will be summarized using worst grade per NCI 
CTCAE v4.0 criteria. Vital signs, physical examination abnormality findings, and ECG readings 
will be listed.
8.4.4
Pharmacokinetic Analyses
Part 1
Summary statistics will be tabulated for PK parameters of nivolumab and ipilimumab as specified 
in Section 8.3.2.1 by treatment, dose, and cycle as appropriate. Geometric means and coefficients 
of variation will be presented for Cmax, Ceoinf, AUC(0-T), AUC(TAU), Ctrough, Ctau, CLT, and 
AI. Median, minimum, and maximum will be presented for Tmax. Means and %CV will be 
provided for the remaining PK parameters. To assess attainment of steady state, plots of geometric 
mean Ctrough versus time will be provided. Pharmacokinetic concentrations of nivolumab and 
ipilimumab from all participants will be listed and summary statistics will be tabulated by 
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treatment (arm), cycle, study day and nominal time, and may be used in combination with other 
studies for exposure-response or population PK modeling, which will be part of a separate report.
Part 2
Pharmacokinetic concentrations of nivolumab and ipilimumab from all participants will be listed, 
and may be used in combination with other studies for exposure-response or population PK 
modeling, which will be part of a separate report.
8.4.5
Biomarker Analyses
Biomarker analyses are not applicable for Part 1 Arms A, B and C.
For Part 2 Arm D, baseline MSI/MMR status, both central and local testing, will be listed.
8.4.6
Exploratory Biomarker Analyses
Not applicable. 
8.4.7
Outcomes Research Analyses
8.4.7.1
European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire (QLQ-C30)
The analysis of European Organization for Research and Treatment of Cancer quality of life 
questionnaire (EORTC QLQ-C30) will be performed in all treated participants. The questionnaire 
completion rate, defined as the proportion of questionnaires actually received out of the expected 
number, will be calculated and summarized at each assessment point.
All scales and single items are scored on a categorical scale and linearly transformed to 0 to 100 
scales with higher scores for a functional scale representing higher levels of functioning, higher 
scores for the global health status/quality of life representing higher levels of global health 
status/quality of life, and higher scores for a symptom scale representing higher level of symptoms. 
Baseline, each post baseline assessment, and change from baseline in EORTC QLQ-C30 global 
health status/quality of life composite scale data and the remaining EORTC QLQ-C30 scale data 
will be summarized by time point using descriptive statistics for each cohort (N, mean with SD
and 95% CI, median, first and third quartiles, minimum, maximum). In addition, the percentage 
of participants demonstrating a clinically meaningful deterioration (defined as a 10-point change 
from baseline) will be presented for each scale at each assessment time point. Percentages will be 
based on number of participants assessed at assessment time point.
8.4.7.2
EQ-5D-3L
The analysis of EQ-5D-3L will be performed in all treated participants. Participant’s overall health 
state on a visual analog scale (EQ-VAS) and utility index scores (based on UK weighting 
algorithm), at each assessment time point will be summarized using descriptive statistics (N, mean, 
with SD and 95% CI, median, first and third quartiles, minimum, maximum). The proportion of 
participants reporting no, moderate, or extreme problems will be presented for each of the 5 EQ-
5D-3L dimensions at each assessment time point. Percentages will be based on number 
participants assessed at assessment time point.
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The questionnaire completion rate, defined as the proportion of questionnaires actually received 
out of the expected number, will be calculated and summarized at each assessment point.
A by-participant listing of EQ-5D-3L with the problem levels for each of the 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), health state (5 
dimensions digits combined in a 5-digit number), utility index and EQ-VAS will be provided.
8.4.8
Other Analyses
Immunogenicity Analyses
Data from the assessment of immunogenicity markers will be listed by participant. Number and 
frequency of ADA response classifications will be summarized by arm, as appropriate. The details 
of the ADA response classifications will be provided in the study statistical analysis plan.
8.5
Interim Analyses
Part 1
Administrative interim analyses may be performed at several times prior to completion of the study 
in order to facilitate program decisions and to support presentations or publications.
Part 2
The final analysis of the primary endpoint ORR will occur at least 6 months after the last 
participant’s first dose of study therapy. 
In addition, other interim analyses may be conducted to seek initial efficacy signal or for external 
data disclosure for this cohort.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
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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 
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 participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 
In addition, the study may be evaluated by BMS 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 BMS.
9.1.2.1
Source Documentation
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
AE 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. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
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9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study and BMS will notify the investigator 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, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include the following investigational 
product. 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

retained samples for bioavailability/bioequivalence, if applicable 

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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9.2.3
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 BMS 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 
or 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 BMS. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a sub-investigator and who is delegated this task on the 
Delegation of Authority Form. 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 BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the signatory investigator will be selected as appropriate based on the following 
criteria:

Participant recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation and 
must adhere to BMS’s publication requirements as set forth in the approved clinical trial agreement 
(CTA). All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to BMS at the earliest practicable time for review, but at any 
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event not less than 30 days before submission or presentation unless otherwise set forth in the 
CTA. BMS shall have the right to delete any confidential or proprietary information contained in 
any proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application.
9.4
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.
9.5
Data Protection, Data Privacy, and Data Security
BMS collects and processes personal data of study participants, patients, health care providers, 
and researchers for biopharmaceutical research and development to advance innovative, high-
quality medicines that address the medical needs of patients. BMS ensures the privacy, protection, 
and confidentiality of such personal data to comply with applicable laws. To achieve these goals, 
BMS has internal policies that indicate measures and controls for processing personal data. BMS 
adheres to these standards to ensure that collection and processing of personal data are limited and 
proportionate to the purpose for which BMS collects such personal data. This purpose is clearly 
and unambiguously notified to the individual at the time of collection of personal data. In the true 
spirit of science, BMS is dedicated to sharing clinical trial information and data with participants, 
medical/research communities, the media, policy makers, and the general public. This is done in a 
manner that safeguards participant privacy and informed consent while respecting the integrity of 
national regulatory systems. Clinical trial data, health-related research, and pharmacovigilance 
activities on key-coded health data transferred by BMS across national borders is done in 
compliance with the relevant data protection laws in the country and GCP requirements.
BMS protects Personal Information with adequate and appropriate security controls as indicated 
under the data protection laws. To align with the recommended security standards, BMS has 
adopted internal security standards and policies to protect personal data at every stage of 
its processing.
To supplement these standards, BMS enters into Clinical Trial Agreements (CTAgs) with 
confidentiality obligations to ensure proper handling and protection of personal data by third 
parties accessing and handling personal data.
BMS takes unauthorized access and disclosure of Personal Information very seriously. BMS has 
adopted the security standards that include National Institute of Standards and Technology 
Cybersecurity Framework for studies in the US. BMS aligns with these standards to continuously 
assess and improve its ability to protect, detect, and respond to cyber attacks and other 
unauthorized attempts to access personal data. These standards also aid in mitigating possible 
adverse effects. Furthermore, BMS Information Technology has defined 6 principles to protect our 
digital resources and information: 
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1.
Responsibilities of IT Personnel
2. Securing the BMS Digital Infrastructure
3. Identity and Access Management
4. External Partner Connections
5. Cyber Threat Detection and Response
6. Internal Cyber Incident Investigation
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
This also means that abstinence is the preferred and usual lifestyle of the 
participant. This does not mean periodic abstinence (eg, calendar, 
ovulation, symptothermal, profession of abstinence for entry into a 
clinical trial, post-ovulation methods) and withdrawal, which are not 
acceptable methods of contraception. Women must continue to have 
pregnancy tests. Acceptable alternate methods of highly or less effective 
contraception must be discussed in the event that the participant chooses 
to forego complete abstinence.
Additional Research
Those scientific activities which cannot be reasonably anticipated at the 
time of trial design, for which we would like to collect and/or retain 
samples from study participants. Examples of additional research include, 
but are not limited to, new assay development and validation, companion 
diagnostic development, new hypotheses in the interaction of drug and 
the human body, and exploration of emerging science in the 
understanding of disease.
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11
LIST OF ABBREVIATIONS
Term
Definition
ADA
anti-drug antibody
AE
adverse event
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
BICR
blinded independent central review
BMI
body mass index
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
Cavg28
average serum concentration at Day 28
CBC
complete blood count
CD
cluster of differentiation
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
cHL
classical Hodgkin lymphoma
CI
confidence interval
CL
clearance
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Term
Definition
CLss
clearance at steady state
CLT
total body clearance
Cmax
maximum observed concentration
CNS
Central nervous system
COVID-19
coronavirus disease 2019
CR
complete response
CRC
Colorectal cancer
CrCl
creatinine clearance
CRF
Case Report Form, paper or electronic
CRR
complete response rate
CT
computed tomography
CTA
clinical trial agreement
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte–associated antigen 4
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
CV%
% coefficient of variation
DBL
data base lock
DCR
disease control rate
DILI
drug-induced liver injury
DLTs
dose-limiting-toxicities
dMMR
DNA mismatch repair deficient
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eGFR
estimated glomerular filtration rate
EMRs/EHRs
electronic medical/health records
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Term
Definition
EOI
end-of-infusion
EORTC
European Organisation for Research and Treatment of Care
EQ-5D-3L
EuroQol 5 Dimensions questionnaire
E-R
exposure-response
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer quality of 
life questionnaire
FSH
follicle stimulating hormone
FU2
follow-up visit 2
GC
gastric cancer
GCP
Good Clinical Practice
GI
gastrointestinal
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCG
human chorionic gonadotrophin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HNPCC
hereditary non-polyposis colorectal cancer
HR
heart rate
HRT
hormone replacement therapy
HuMAb
human monoclonal antibody
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonisation 
IgG
immunoglobulin G
IHC
immunohistochemistry
IMAE
immune mediated adverse events
IO
immuno-oncology
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IRT
Interactive Response Technology
IUDs
intrauterine devices
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Term
Definition
IV
intravenous
IVRS
Interactive Voice Response System
LDH
lactate dehydrogenase
LFTs
liver function tests
mAb
monoclonal antibody
mCRC
metastatic CRC
MedDRA
Medical Dictionary for Regulatory Activities
MMR
mismatch repair deficient
MRI
magnetic resonance imaging
MSI-H
microsatellite instability high
MSI-L
MSI-Low
MST
medical safety team
MTD
maximum tolerated dose
NCI
National Cancer Institute
NPC
nasopharyngeal cancer
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed death 1
PD-L1
programmed death–ligands 1
PD-L2
programmed death–ligands 2
PFS
progression-free survival
PID
patient identification number
PK
pharmacokinetics
PPK
population PK
PR
partial response
PTs
preferred terms
Q2W
every 2 weeks
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Term
Definition
Q3W
every 3 weeks
Q4W
every 4 weeks
QLQ-C30
Quality of Life Questionnaire Core-30
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RTPCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCCHN
Squamous Cell Cancer of the Head and Neck
SCLC
small cell lung cancer
SD
stable disease
SOP
Standard Operating Procedures
SmPC
Summary of Product Characteristics
TB
tuberculosis
TEN
toxic epidermal necrolysis
T-HALFeff_AUC
Effective elimination half-life that explains the degree of AUC 
accumulation observed
Tmax
time of maximum observed concentration
ULN
upper limit of normal
USPI
United States Package Insert
VAS
visual analog scale
Vc
Volume of central
Vss
volume of distribution at steady state
WBC
white blood cell
WOCBP
women of childbearing potential
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12
REFERENCES
1
Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands 
infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. 
PNAS 2010; 107: 4275-80.
2
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-
Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015; 373(2):123-35.
3
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015; 373(17):1627-39.
4
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced 
Renal-Cell Carcinoma. N Engl J Med. 2015; 373(19):1803-13.
5
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without 
BRAF mutation. N Engl J Med. 2015; 372(4):320-30.
6
Hodi FS, O'Day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in Patients with 
Metastatic Melanoma; N Engl J Med. 2010 Aug 19;363(8):711-23.
7
Robert C, Thomas L, Bondarenko et al. NEJM, 2011, Ipilimumab plus Dacarbazine for 
Previously Untreated Metastatic Melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26.
8
Investigator Brochure, Anti-PD-1 Human Monoclonal Antibody, BMS-936558, Version 
No.16, 23-Jun-2017. BMS Document Control No.930038243.
9
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N 
Engl J Med 2015;372:2509–20.
10 Overman MJ, Lonardi S et al. Nivolumab (nivo) + low-dose ipilimumab (ipi) in previously 
treated patients (pts) with microsatellite instability-high/mismatch repair-deficient (msi-
h/dmmr) metastatic colorectal cancer (mcrc): long-term follow-up. J Clin Oncol. 2019; 37(4) 
suppl: 635.
11 Overman MJ, Bergamo F, et al. Nivolumab in patients with DNA mismatch repair-
deficient/microsatellite instability-high (dmmr/msi-h) metastatic colorectal cancer (mcrc): 
long-term survival according to prior line of treatment from CheckMate-142. J Clin Oncol
2018;36 (4) suppl: 554.
12 Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA 
mismatch repair deficient/microsatellite instability-high colorectal cancer (CheckMate 142): an 
open-label, multicentre, phase 2 study [published erratum appears in Lancet Oncol 
2017;18:1182-91].
13 Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus 
ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic 
colorectal cancer. J Clin Oncol 2018;36:773-9.
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14 Heinemann V, von Weikersthal LF, Decker T. et al. FOLFIRI plus cetuximab versus FOLFIRI
plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer 
(FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75.
15 Robert C, Long GV, Schachter J, et al. Long-term outcomes in patients with ipilimumab-naive 
advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab 
treatment; Journal of Clinical Oncology. 2017; 35(15 suppl):9504-9504.
16 Nivolumab (BMS-936558): Study CA209-142 Ad Hoc efficacy report. Bristol-Myers Squibb
Company. 2017. Document Control No. 930111779.
17 Guinney J. The consensus molecular subtypes of colorectal cancer. Nature Medicine.
2015;21:1350-1356.
18 Carbone DP, Reck M, Paz-Ares L, et al. First-Line Nivolumab in Stage IV or Recurrent Non-
Small-Cell Lung Cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426.
19 Yarchoan M, Hopkins A, Jaffee E. Tumor Mutational Burden and Response Rate to PD-1 
Inhibition. N Engl J Med 377;25 nejm.org December 21, 2017: P 2500-2501.
20 Wirta EV, Seppala T, Friman M, et al. Immunoscore in mismatch repair-proficient and -
deficient colon cancer. J Pathol Clin Res. 2017 Jul 19; 3(3):203-213.
21 Weber R, Fleming V, Hu X, et al. Myeloid-derived suppressor cells hinder the anti-cancer 
activity of immune checkpoint inhibitors. Front Immunol. 2018;9:1310.
22 Karakasheva TA, Dominguez GA, Hashimoto A, et al. CD38+ M-MDSC expansion 
characterizes a subset of advanced colorectal cancer patients. JCI Insight. 2018 Mar 
22;3(6):pii:97022.
23 Nivolumab (BMS-936558): Study CA209-142 Ad Hoc efficacy report. Bristol-Myers Squibb
Company. 2017. Document Control No. 93011177.
24 Bristol-Myers Squibb Investigator Brochure: Ipilimumab, BMS-734016, MDX010. Version 
17; 10-Mar-2014. BMS Document Control No. 930017531 11.0.
25 Nivolumab (BMS-936558) Module 2.7.2 Summary of Clinical Safety. Bristol-Myers Squibb 
Company; 2015. Document Control No. 930091270.
26 Umar A, Boland Cr, Terdiman JP, et al. Revised Bethesda Guidelines for Hereditary 
Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability. J Nat 
Cancer Inst 2004;96:261-68.
27 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20.
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APPENDIX 1
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ≥2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be 15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis 10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with 10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions

Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.

Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.

Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above.
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
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small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.

Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 

Non-CR/Non-PD: Persistence of one or more non-target lesion(s)

Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
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disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: 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
Abbreviations: 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
Abbreviations: CR = complete response, PD = progressive disease and NE = inevaluable.
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study). If the subject is not on-study for 
at least this amount of time, any tumor assessment indicating stable disease before this time period 
will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
Abbreviations: 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 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 2
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.
5
Dead
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5: 649 - 655, 1982.
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APPENDIX 3
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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APPENDIX 4
MSI STATUS TESTING
TESTING PANEL DESCRIPTIONS (PCR AND IHC)
Bethesda method and Promega MSI Multiplex System (PCR) Panel Description and Classification 
of MSI Status

Reference panel:

BAT25 (mononucleotide)

BAT26 (mononucleotide)

D5S346 (dinucleotide)

D2S123 (dinucleotide)

D17S250 (dinucleotide)

Alternative loci:

BAT40

BAT34C4

TGF-β-RII

ACTC (635/636)

NR-21 

NR-24

MONO-27 

Classification:

If 5 loci tested (reference panel):
MSI-H: 2 markers with instability
MSI-L: 1 marker with instability
MSS or MSI-L: 0 markers with instability

If > 5 loci tested (reference panel plus alternative loci):
MSI-H: 30-40% markers with instability
MSI-L: < 30-40% markers with instability
MSS or MSI-L: 0 marker with instability

In the case of 1 PCR amplification failure:
If 3 markers of 4MSI-H
If 1 marker of 4re-amplify
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IHC method Panel Description and Classification of MSI Status Panel 

hMSH2

hMLH1

hMSH6

hPMS2
Classification: 

MSI-H: 1 markers with instability

MSS: 0 marker with instability

MSI-L: not evaluable with this technique
Prioritization of Tumor Tissue Samples for MSI Testing
1) Fresh biopsy (Preferred)
a) For MSI status confirmation 
2) Archive tissue
a) For MSI status confirmation
If fresh biopsy cannot be obtained, archived tumor tissue prior to therapy is acceptable only if the 
archived tissue is the same tissue that was used for local MSI/MMR testing. 
Important Reminders:

Refer to Central Lab Flow Chart and protocol for specific sample requirements

Central lab must confirm receipt of evaluable tumor tissue prior to vial assignment.

Please contact BMS or The Central Lab if there are any questions
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APPENDIX 5
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 5 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 3.3.1 of the protocol. Only the contraception methods as described in 
Section 3.3.1 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 types 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.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
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.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (These methods of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol)b 

Oral (birth control pills)

Intravaginal (rings)

Transdermal 

Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy.

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 cannot be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol)b

Intrauterine device

Intrauterine hormone-releasing system (IUS) (This method of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol) b,c
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
Bilateral tubal occlusion

Vasectomized partner
Having a vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 

Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.

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 participants 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 in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient 
evidence that the 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 7.7.1 PROHIBITED AND/OR 
RESTRICTED TREATMENTS of the protocol.
c IUSs are acceptable methods of contraception in the absence of definitive drug interaction studies 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 3.3.1 INCLUSION CRITERIA and 
3.4.1 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).
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of > 1% per year when used consistently and correctly.
Unacceptable Methods of Contraception*

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus).

Spermicide only

LAM
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 Appendix 3．
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APPENDIX 6
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 06, 02-Jul-2021
The main purpose of this amendment is to:

update the study language for post-study access to therapy (criteria of study termination and 
disposition for those subjects still in study when the study terminates)

add a section about outcome research analyses

replace older versions of appendices (management algorithms and WOCBP) with newer 
versions

align the protocol with current program-level language for nivolumab and ipilimumab
including language associated with SARS-CoV-2 infection. 
In addition, personnel changes, and administrative letter 06 have been incorporated.
Summary of Key Changes for Protocol AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
Title page
Changed Medical Monitor (MM) 
from 
 
 (Clinical Trial Physician-MM) 
and added 
 Clinical 
Scientist
To report important personnel 
changes
Synopsis: Study 
Population; Section 
3.3.1, Inclusion 
Criteria
2. Target population j)
Previously written:
Subjects must have shown 
progression during, after, or have 
been intolerant to 1 line 
treatment(s) for metastatic disease, 
which must include a 
fluoropyrimidine, oxaliplatin, and 
irinotecan
Changed to:
Subjects must have shown 
progression during, after, or have 
been intolerant to 1 line 
treatment(s) for metastatic disease, 
which must include at least a 
fluoropyrimidine, and oxaliplatin or 
irinotecan
To clarify that the inclusion 
criteria is in line with the study 
purpose and it is for subjects 
with second-line+ (2L+) 
recurrent/metastatic CRC
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Summary of Key Changes for Protocol AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis: Study Drug 
for CA209672
Added information about the 
availability of Ipilimumab Solution 
for Injection, 50 mg (5 mg/mL)
Added nivolumab name next to 
BMS-936558-01
Added a new formulation dose 
option for Ipilimumab Solution 
and nivolumab name for 
completeness
Synopsis: Study 
Design Schematic; 
Figure 3.1.1-1: Study 
Design Schematic
Added text to the note indicating 
that maximum treatment duration is 
of 24 months EXCEPT in 
participants with late response 
(during second year of treatment) 
who may receive treatment for up 
to an additional 12 months after 
onset of response
To clarify that the maximum 
treatment duration is of 24 
months except for participants 
with late response
Section 1: 
Introduction and 
Study Rationale
Added most recent background 
information including mechanism 
of action and clinical activity for 
nivolumab and ipilimumab
To align with the current state 
of knowledge about nivolumab 
and ipilimumab
Section 1.1.1: 
Rationale to Support 
Dose/Schedule of 
Nivolumab Combined 
with Ipilimumab
Updated clinical data for nivolumab 
and ipilimumab based on the 
CHECKMATE-142 trial
To reflect clinical data updates 
from the study 
CHECKMATE-142
Section 1.1.2: 
Rationale for 
Nivolumab Flat Dose 
in Nivolumab 
Monotherapy Portion
Updated clinical data for nivolumab 
from studies in multiple tumor types 
and dosing schedules
To align with the current state 
of knowledge about nivolumab
Section 1.1.5: 
Rationale for Two-
Year Duration of 
Treatment
Revised the section based on data 
from on-going clinical trials for 
nivolumab and ipilimumab and 
retrospective pooled analysis
To align with the current state 
of knowledge about nivolumab 
and ipilimumab
Section 1.4.4.1: 
Pharmacokinetics of 
Nivolumab; Section 
1.4.4.3: 
Pharmacokinetics of 
Nivolumab with 
Ipilimumab
Added clinical pharmacology 
information for nivolumab alone 
and in combination with 
ipilimumab
Added new scientific 
information
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Summary of Key Changes for Protocol AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
Section 1.4.4.4: Safety 
Summary of 
Nivolumab in 
Combination with 
Ipilimumab
Updated safety data for nivolumab 
and ipilimumab based on 
CHECKMATE-142 trial
To reflect safety data updates 
from study CHECKMATE-
142
Section 3.1.3.2: 
Screening
Added the following text:

A complete schedule of 
activities for screening can 
be found in Table 5.1-1

Inclusion/Exclusion Criteria 
are assessed during the 
screening period and must 
be confirmed prior to 
randomization

All medical history relevant 
to the disease under study 
should be collected
Clarified the location of 
screening related schedule of 
activities and other criteria in 
the protocol.
Section 3.2: Post 
Study Access to 
Therapy
Revised description of provisions 
for accessing study treatments by 
subjects after the conclusion and in 
the event of termination of the 
clinical study
Changed to clarify post-study 
access provisions to therapy
Section 3.3.1: 
Inclusion Criteria 3. 
Age and Reproductive 
Status
Edited inclusion criteria 3 to align 
with the program level standards
To align with program level 
language for nivolumab
Section 3.3.2: 
Exclusion Criteria 1a, 
1b, 2a, 3g, 3h, 3i, 3j, 
3k, and 4a
Edited 1a, 1b, 2a, 3g, 3h, 3i, 3j, 3k, 
and 4a to align with the program 
level standards
To clarify and align with 
program level language for 
nivolumab
Section 3.4.1: 
Prohibited and/or 
Restricted Treatments
Modified or added the following
prohibited and/or restricted 
treatments:

Immunosuppressive agents 
including systemic 
corticosteroids

Any concurrent systemic 
antineoplastic therapy

Non-palliative radiation 
therapy
Clarified concomitant therapy 
restrictions
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Summary of Key Changes for Protocol AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale

Any complementary 
medications

Any live / attenuated 
vaccine
Section 3.6: Post 
Study Drug Follow up
Added text about potential 
collection of survival data on all 
treated participants outside of the 
protocol defined window (Table 
5.1-5)
To align with program level 
language
Table 4-1: Study 
Drugs for CA209672 -
Treatment Period
Added information about the 
availability of an Ipilimumab 
Solution for Injection as a 10 mL 
vial (50 mg [5 mg/mL], 1 vial per 
carton)
Added nivolumab name next to 
BMS-936558-01
Added a new formulation dose 
option for Ipilimumab Solution 
and nivolumab name for 
completeness
Section 4.3: Storage 
and Dispensing
Added a statement saying that 
patients dosed with nivolumab and 
ipilimumab should be observed to 
ensure that no infusion reaction has 
occurred and begin study treatment 
within 3 calendar days of treatment 
assignment
To ensure patient safety
Section 4.5.3: Dose 
Delay Criteria
Edited dose delay criteria to 
conform with current standards
To align with program level 
language for nivolumab
Section 4.5.5: Criteria 
to Resume Treatment
Added conditions to resume 
treatment for participants with 
SARS-CoV-2 infection (either 
confirmed or suspected) 
To mitigate risks to 
participants with known or 
suspected SARS-CoV-2
infection
Section 4.5.6: 
Treatment 
Discontinuation 
Criteria
Myocarditis was added to Grade 3 
drug related adverse events
To align with the text in the 
Investigator Brochure
Section 4.5.7: 
Treatment Beyond 
Disease Progression
Updated statement that the decision 
to continue treatment beyond initial 
investigator-assessed progression, 
defined per RECIST v1.1, should 
Clarified that treatment beyond 
progression is defined by 
RECIST v1.1 and needs to be 
agreed by the Investigator
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Summary of Key Changes for Protocol AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
be discussed with and agreed by the 
Investigator
Table 5.1-1: Screening 
Procedural Outline 
(CA209672) 
Added a note to Informed Consent 
row: “Study allows for re-
enrollment of a participant that has 
discontinued the study as a pre-
treatment failure. If re-enrolled, the 
participant must be re-consented 
and assigned a new participant 
number from IRT.”
Added a note to 
Inclusion/Exclusion Criteria, 
Screening visit: “Must be 
confirmed prior to 
randomization/treatment 
assignment”
To align with program level 
language for nivolumab
Table 5.1-1: Screening 
Procedural Outline 
(CA209672)
Added a note to Monitor for 
Serious Adverse Events row: “All 
SAEs that occur during the 
screening period and within 100 
days of discontinuation of dosing 
must be collected.”
To correct an inconsistency, 
communicated previously as a 
part of the administrative letter 
06
Table 5.1-1: Screening 
Procedural Outline 
(CA209672);
Table 5.1-2: On-
Treatment Procedural 
Outline (CA209672) -
Part 1, Arm A;
Table 5.1-3: On-
Treatment Procedural 
Outline (CA209672) 
Part 1, Arms B and C;
Table 5.1-4: On-
Treatment Procedural 
Outline (CA209672) -
Part 2, Arm D
Added text to the comment cell of 
SAE/AEs row: All AEs (SAEs or 
non-serious AEs) associated with 
SARS-CoV-2 infection collected 
from time of consent
To align with program level 
language for SARS-CoV-2 
infection
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Clinical Protocol
CA209672
BMS-936558
nivolumab
Summary of Key Changes for Protocol AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
Table 5.1-5: Follow-
Up Period 
(CA209672) –Part 1, 
Arm A and C
Added text to the comment cell of 
AEs row: “Participants will be 
followed for all SAEs, non-serious 
AEs of special interest, and all 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, or for suspected cases, 
until SARS-CoV-2 infections is 
ruled out.”
To align with program level 
language for SARS-CoV-2 
infection
Table 5.1-7: Follow-
up Period (CA209672) 
- Part 2, Arm D
Added a note to Adverse Events 
Assessment (including SAE) row: 
“For participants assigned to 
treatment and never treated with 
study drug, SAEs should be 
collected for 30 days from the date 
of treatment assignment.”
Clarified collection timelines 
for SAEs
Section 5.3: Safety 
Assessment
Added management of SARS-CoV-
2 infection during the screening 
period.
Added other measures to monitor 
and evaluate laboratory, cardiac, or 
pulmonary toxicities
To ensure patient safety
Section 5.4.2: Imaging 
Assessment by BICR 
for Part 2
Added a note saying: “Collect any 
additional imaging that may 
demonstrate tumor response or 
progression (including scans 
performed at unscheduled 
timepoints and/or at an outside 
institution) for RECIST 1.1 tumor 
assessment and submit to the 
BICR.”
Clarified additional imaging 
collection details
Section 5.8.2: Part 2 
of Outcomes Research 
Assessments
Added text, “If exceptional 
circumstances preclude the 
continued administration of 
measures using planned modalities, 
then alternate administration 
To align with 
recommendations from PRC 
reviewers
Protocol Amendment No.: 07
Date: 22-Aug-2022
151
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Summary of Key Changes for Protocol AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
methods may be required, after 
consultation with the Sponsor or the 
Sponsor’s representative.”
Section 5.10: 
Additional Research 
Collection
Added that: “Additional research is 
optional for all study participants, 
except where retention and/or 
collection is prohibited by local 
laws or regulations, ethics 
committees, or institutional 
requirements.”
Clarified Additional Research 
Collection details
Section 6: Adverse 
Events
Added description, assessment, and 
collection of immune-mediated 
adverse events (IMAEs)
Updated AEs with respect to 
IMAEs
Section 6.1.1: Serious 
Adverse Event 
Collection and 
Reporting
Added notes stating that: 

for 
participants 
assigned 
a 
treatment and never treated with 
study drug, collect SAEs for 30 
days from the date of treatment 
assignment 

the investigator will submit any 
updated SAE data to the sponsor 
or designee within 24 hours of 
updated 
information 
being 
available
Clarified SAE collection, 
submission, and reporting 
requirements for patients with 
or without study drugs
Section 6.2.1: 
Nonserious Adverse 
Event Collection and 
Reporting
Added details on the time period, 
frequency, and follow-up period for 
collecting AE and SAE information 
related to patients with or without 
SARS-CoV-2 infection
Clarified details regarding 
collecting AEs/non-serious 
SAE information for patients 
with or without SARS-CoV-2 
infection
Section 6.3.1: Clinical 
Safety Laboratory 
Assessments
Listed Hematology, Chemistry, 
Serology, and other clinical safety 
laboratory analyses
Clarified to specify collection 
of clinical safety laboratory 
assessments being carried out 
for this study
Section 8.4.7: 
Outcomes Research 
Analyses; Section 
8.4.7.1: European 
Organization for 
Research and 
Created a new section and 
subsections describing Outcome 
Research Analyses
To align with recommendation 
from PRC reviewer regarding 
PRO endpoint
Protocol Amendment No.: 07
Date: 22-Aug-2022
152
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Summary of Key Changes for Protocol AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
Treatment of Cancer 
Quality of Life 
Questionnaire (QLQ-
C30);
Section 8.4.7.2 EQ-
5D-3L
Section 9.1.2: 
Monitoring
Added text about monitoring plan
Clarified what 
monitoring/monitoring plan 
represent
Section 9.4: 
Dissemination of 
Clinical Study Data
Added a new section describing 
dissemination of clinical trial data 
and results
To conform with regulatory 
and BMS requirements
Appendix 3: 
Management 
Algorithms Studies 
Under CTCAE 
Version 4.0
Replaced the older version of 
appendix under CTCAE v4.0, 2018 
with a newer version of the 
appendix (v4.0, 2020)
To align with the current state 
of knowledge about 
management algorithms
Appendix 4: MSI 
Status Testing
Removed the following under 
“Important Reminders: “A normal 
control ACD whole blood sample is 
required as well as tumor tissue.”
To correct an inconsistency, 
communicated previously as a 
part of the administrative letter 
06
Appendix 4: MSI 
Status Testing
Adding alternative loci NR-21, NR-
24 and MONO-27 for MSI status 
testing applying from Promega 
panel
Changes made to “Prioritization of 
Tumor Tissue Samples for MSI 
Testing” to clarify that fresh biopsy 
is preferred over archived tissue
To expand the criteria for MSI 
status detection according to 
current clinical guideline 
recommendations
Appendix 5: Women 
of
Childbearing Potential 
Definitions and 
Methods of 
Contraception
Replaced the older appendix with a 
newer version of the appendix
To align with program level 
language for nivolumab
All
Minor formatting and 
typographical/editorial corrections
Minor, therefore have not been 
summarized
Protocol Amendment No.: 07
Date: 22-Aug-2022
153
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Overall Rationale for the Revised Protocol 05, 09-Jan-2020
Revised Protocol 05 will made a removal of blood sample collection as a control for MSI/MMR 
status confirmation as it is not necessary in the Biocartis PCR assay.
0BSUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.1 Flow 
Chart/Time and 
Events Schedule
Table 5.1-1
Removal of Blood sample 
collection in Screening as a control 
for MSI/MMR status confirmation
Blood sample as a control is 
not needed for the Biocartis 
assay for utilized the study
All Sections
Minor formatting and typographical 
corrections
Minor, therefore have not been 
summarized
Overall Rationale for the Revised Protocol 04, 08-Apr-2019
Colorectal cancer (CRC) DNA mismatch repair deficient (dMMR)/microsatellite instability - high 
(MSI-H) patients are not sensitive to chemotherapy, especially in second-line and above patients. 
Thus, there is significant unmet medical need for pre-treated CRC dMMR/MSI-H patients.
CA209142 study showed that total 84 pre-treated dMMR/MSI-H CRC subjects were treated with 
nivolumab (3 mg/kg) in combination with ipilimumab (1 mg/kg):

NIVO + IPI provided durable responses, sustained disease control, and encouraging survival 
data in pretreated patients with dMMR/MSI-H mCRC

Objective response rate (ORR) of 55%, with 79% of patients achieving disease control for 
≥ 12 weeks

88% of patients alive at 9 months

NIVO + IPI demonstrated a manageable safety profile; 29% of patients had grade 3/4 
treatment-related adverse events (TRAEs)
Revised Protocol 04 will add Part 2, Arm D cohort to evaluate efficacy of nivolumab in 
combination with ipilimumab in recurrent or metastatic dMMR/MSI-H CRC subjects.
Reference: Thierry Andre, et al. Combination of nivolumab (NIVO) + ipilimumab (IPI) in the treatment of patients 
(pts) with deficient DNA mismatch repair (dMMR)/high microsatellite instability (MSI-H) metastatic colorectal 
cancer (mCRC): CheckMate 142 Study, 2017 ASCO Poster 3531. ClinicalTrials.gov identifier NCT02060188)
Protocol Amendment No.: 07
Date: 22-Aug-2022
154
8.0
Approved
930101457
8.0
v
Approved
1.0
v

Clinical Protocol
CA209672
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
All Sections
Rationale, objectives, background, 
investigational plan, and all details 
have been added to account for the 
additional Arm D recurrent or 
metastatic dMMR/MSI-H CRC 
cohort.
To evaluate efficacy of 
nivolumab in combination with 
ipilimumab in recurrent or 
metastatic dMMR/MSI-H 
CRC subjects.
Section 3.3.1, 
Inclusion Criteria
Inclusion criteria 2) a) i) CRC 
subjects with historically 
documented MSI-H or dMMR 
status detected by local laboratory
Eligibility criteria
Section 3.3.3
Women of 
Childbearing Potential
Removed entire section and added 
Appendix 5 WOCBP
To align with the latest BMS 
standards.
Section 4.5
Selection and Timing 
of Dose for Each 
Subject
Entire section was updated to align 
with the updated BMS standards for 
Dose delay, Dose reduction and 
Criteria to Resume Treatment
To align with the latest BMS 
standards.
Section 7, Data 
Monitoring 
Committee and Other 
External Committees
A blinded independent central 
review (BICR) will be added to this 
study.
For determination of BICR-
assessed ORR
All Sections
Minor formatting and typographical 
corrections
Minor, therefore have not been 
summarized
Appendix 4
Added
Added to describe MSI status 
testing
Appendix 5
Added
Added to provide information 
on contraception requirements 
for WOCBP
Protocol Amendment No.: 07
Date: 22-Aug-2022
155
8.0
Approved
930101457
8.0
v
Approved
1.0
v